The History of Neuroscience in Autobiography

VOLUME 13

The History of Neuroscience in Autobiography

VOLUME 13

Edited by Thomas D. Albright
and Larry R. Squire

Society for Neuroscience

Society for Neuroscience

The Society for Neuroscience publishes works that advance
the understanding of the brain and nervous system.

Copyright © 2024 by the Society for Neuroscience

Published by the Society for Neuroscience
1121 14th Street, NW
Washington, DC 20005
www.sfn.org

All rights reserved. No part of this publication may be reproduced,
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without the prior permission of the Society for Neuroscience.

Library of Congress Control Number: 96070950

978-0-916110-12-3

Printed in the United States of America

Contents

Previous Contributors

Preface to Volume 1

Preface to Volume 13

Allan Irwin Basbaum

Joanne Berger-Sweeney

György Buzsáki

John H. Byrne

Patricia Smith Churchland

Robert Desimone

Charles Douglas Gilbert

Daniel Johnston

Mu-ming Poo

Joseph S. Takahashi

Shimon Ullman

Index

Previous Contributors

Volume 1

Denise Albe-Fessard

Julius Axelrod

Peter O. Bishop

Theodore H. Bullock

Irving T. Diamond

Robert Galambos

Viktor Hamburger

Sir Alan L. Hodgkin

David H. Hubel

Herbert H. Jasper

Sir Bernard Katz

Seymour S. Kety

Benjamin Libet

Louis Sokoloff

James M. Sprague

Curt von Euler

John Z. Young

Volume 2

Lloyd Beidler

Arvid Carlsson

Donald Griffin

Roger Guillemin

Ray W. Guillery

Masao Ito

Martin Larrabee

Jerry Lettvin

Paul MacLean

Brenda Milner

Karl Pribram

Eugene Roberts

Gunther Stent

Volume 3

Morris H. Aprison

Brian B. Boycott

Vernon B. Brooks

Pierre Buser

Hsiang-Tung Chang

Claudio A. Cuello

Robert W. Doty

Bernice Grafstein

Ainsley Iggo

Jennifer Lund

Edith and Patrick McGeer

Edward R. Perl

Donald B. Tower

Patrick D. Wall

Wally Welker

Volume 4

Per Andersen

Mary Bartlett Bunge

Jan Bures

Jean Pierre G. Changeux

William Maxwell (Max) Cowan

John E. Dowling

Oleh Hornykiewicz

Richard F. Thompson

Andrew F. Huxley

JacSue Kehoe

Edward A. Kravitz

James L. McGaugh

Randolf Menzel

Mircea Steriade

Volume 5

Samuel H. Barondes

Joseph E. Bogen

Alan Cowey

David R. Curtis

John S. Edwards

Mitchell Glickstein

Arnold Bernard Scheibel

Carlton C. Hunt

Gerald Westheimer

Lynn T. Landmesser

Rodolfo R. Llinás

Alan Peters

Martin Raff

Ennio De Renzi Wilfrid Rall

Mark R. Rosenzweig

Volume 6

Bernard W. Agranoff

Emilio Bizzi

Marian Cleeves Diamond

Charles G. Gross

Richard Held

Leslie L. Iversen

Masakazu Konishi

Lawrence Kruger

Susan E. Leeman

Vernon B. Mountcastle

Shigetada Nakanishi

Solomon H. Snyder

Nobuo Suga

Hans Thoenen

Volume 7

Floyd E. Bloom

Joaquín Fuster

Michael S. Gazzaniga

Bertil Hille

Ivan Izquierdo

Edward Jones

Krešimir Krnjevic´

Nicole M. Le Douarin

Terje Lømo

Michael M. Merzenich

John Wilson Moore

Robert Y. Moore

Michael I. Posner

Peter H. Schiller

Gordon M. Shepherd

Robert H. Wurtz

Volume 8

Huda Akil

Philippe Ascher

Giovanni Berlucchi

Lily Jan

Yuh-Nung Jan

Bruce Sherman McEwen

Frederick A. Miles

Peter M. Milner

Fernando Nottebohm

Tomaso A. Poggio

Marcus E. Raichle, Sr.

Pablo Rudomin

Anne Treisman

Stanley J. Watson, Jr.

Anne Buckingham Young

Volume 9

David H. Cohen

Yadin Dudai

Gerald D. Fischbach

Sten Grillner

Jon Howard Kaas

Eric Kandel

Nancy Kopell

Margaret Stratford Livingstone

Giacomo Rizzolatti

Trevor W. Robbins

Wolf Singer

David C. Van Essen

Volume 10

Ben A. Barres

Anders Björklund

Thomas J. Carew

Dennis W. Choi

Joseph T. Coyle

Kjell Fuxe

Michael E. Goldberg

Mary Elizabeth Hatten

Steven E. Hyman

Eve Marder

Roger A. Nicoll

S. Murray Sherman

Douglas G. Stuart

Volume 11

Barry J. Everitt

Tamás F. Freund

Uta Frith

Mary B. Kennedy

Eric I. Knudsen

Pierre J. Magistretti

Yasushi Miyashita

Dale Purves

Larry R. Squire

Michael Paul Stryker

Larry W. Swanson

Richard W. Tsien

Volume 12

Richard A. Andersen

Corey S. Goodman

Tomas Hokfelt

Darcy B. Kelley

George F. Koob

Stephen G. Lisberger

Gail Mandel

Kelsey Catherine Martin

Kevan A. C. Martin

Pasko Rakic

Joshua Richard Sanes

Wolfram Schultz

David L. Sparks

Nicholas C. Spitzer

Preface to Volume 1

Before the Alfred P. Sloan Foundation series of books began to appear in 1979, the scientific autobiography was a largely unfamiliar genre. One recalls Cajal’s extraordinary Recollections of My Life, translated in English in 1937 and the little gem of autobiography written by Charles Darwin for his grandchildren in 1876. One supposes that this form of scientific writing is scarce because busy scientists would rather continue to work on scientific problems than to indulge in a retrospective exercise using a writing style that is usually outside their scope of experience. Yet, regardless of the nature of one’s own investigative works, the scientific enterprise describes a community of activity and thought in which all scientists share. Indeed, an understanding of the scientific enterprise should in the end be accessible to anyone because it is essentially a human endeavor, full of intensity, purpose, and drama that are universal to human experience.

While writing a full autobiographical text is a formidable undertaking, preparing an autobiographical chapter, which could appear with others in a volume, is perhaps less daunting work and is a project that senior scientists might even find tempting. Indeed, a venture of this kind within the discipline of psychology began in 1930 and is now in eight volumes (A History of Psychology in Autobiography). So it was that during my term as president of the Society for Neuroscience in 1993 to 1994, I developed the idea of collecting autobiographies from senior neuroscientists, who at this period in the history of our discipline are in fact pioneers of neuroscience. Neuroscience is quintessentially interdisciplinary, and careers in neuroscience come from several different cultures, including biology, psychology, and medicine. Accounts of scientific lives in neuroscience hold the promise of being informative and interesting, and they could be a source of inspiration to students. Moreover, personal narratives provide for scientists and nonscientists alike an insight into the nature of scientific work that is simply not available in ordinary scientific writing.

This volume does have a forerunner in neuroscience. In 1975, MIT Press published The Neurosciences: Paths of Discovery, a collection of 30 chapters in commemoration of F. O. Schmitt’s 70th birthday, edited by F. Worden, J. Swazey, and G. Adelman. The contributing neuroscientists, all leaders of their discipline, described the paths of discovery that they had followed in carrying on their work. While writing in the style of the conventional review article, some authors did include a good amount of anecdote, opinion, and personal reflection. A second, similar volume, The Neurosciences: Paths of Discovery II, edited by F. Samson and G. Adelman, appeared in 1992.

In any case, neuroscience writing that is deliberately and primarily autobiographical has not been collected before. This project, The History of Neuroscience in Autobiography, is the first major publishing venture by the Society for Neuroscience after The Journal of Neuroscience. The book project was prepared with the active cooperation of the Committee on the History of Neuroscience, which serves as an editorial board for the project. The first chairperson of the committee was Edward (Ted) Jones; its members were Albert Aguayo, Ted Melnechuk, Gordon Shepherd, and Ken Tyler. This group compiled the names and carried out the deliberations that led to the first round of invitations. In 1995 Larry Swanson succeeded Ted Jones as chair of the committee, and as we go to press with Volume 1 the committee members are Albert Aguayo, Bernice Grafstein, Ted Melnechuk, Dale Purves, and Gordon Shepherd.

In the inaugural volume of the series, we are delighted to be able to present together 17 personal narratives by some of the true pioneers of modern neuroscience. The group includes four Nobel Laureates and 11 members or foreign associates of the National Academy of Sciences, USA. The contributors did their scientific work in the United States, Canada, England, Australia, France, and Sweden. It is difficult to imagine a finer group of scientists with which to inaugurate our autobiographical series. The autobiographical chapters that appear here are printed essentially as submitted by the authors, with only light technical editing. Accordingly, the chapters are the personal perspectives and viewpoints of the authors and do not reflect material or opinion from the Society for Neuroscience.

Preparation of this volume depended critically on the staff of the book’s publisher, the Society for Neuroscience. The correspondence, technical editing, cover design, printing, and marketing have all been coordinated by the Society’s central office, under the superb direction of Diane M. Sullenberger. I thank her and her assistants Stacie M. Lemick (publishing manager) and Danielle L. Culp (desktop publisher) for their dedicated and skillful work on this project, which was carried out in the midst of demands brought by the first in-house years of the Society’s Journal of Neuroscience. I also thank my dear friend Nancy Beang (executive director of the Society for Neuroscience) who from the beginning gave her full enthusiasm to this project.

Larry R. Squire
Del Mar, California
September 1996

Preface to Volume 13

In this 13th volume of The History of Neuroscience in Autobiography, we are pleased to present 11 personal narratives by leaders in our field of science.

This autobiographical series was founded three decades ago by Larry Squire during his tenure as president of the Society for Neuroscience. From the beginning, the Society leadership understood the importance of documenting the explosive modern growth of a field that brings innovation to medical practice and resonates with a public eager to understand the workings of the brain. Larry’s key insight was that the historical record need not simply reflect the timeline of discoveries; there is also value in recording the “activity and thought in which all scientists share,” for science itself “is essentially a human endeavor, full of intensity, purpose, and drama that are universal to human experience.”

Collectively, the chapters contained in this series provide a first-hand chronicle of a bold venture in biomedical research, as it has played out in the late 20th and early 21st centuries. Individually, they are treasures, for they are cast in the irresistible and uniquely human form of expression: the story. As such, they not only connect the dots along paths of scientific discovery but also convey the human elements behind those connections, the rich drama and comedy of interpersonal relationships, the sudden flashes of insight, the folly of hubris and the pain of missed opportunities, the beauty of new ideas, and the raw excitement of discovery. These stories are populated by imposing and quirky characters, magnified by the lenses of memory and attention. There are tales of brilliance, fantasy, risk, sacrifice, triumph, and camaraderie, but the theme that binds every one of the chapters in this series is success. Thus, these chapters not only entertain in the way that only good stories can but also offer appealing models and nuanced lessons for success in the human side of science for the next generation of vanguards in our field.

Tom Albright joined Larry as coeditor beginning with Volume 9. With the publication of Volume 13, the library of chapters now numbers 180. Many more great stories are in the making, of course, as the field of neuroscience bounds ahead, and we look forward to curating them in these pages.

Beginning with Volume 8 in the series, the Society for Neuroscience assumed full responsibility for this project. Volume 13 was prepared with the advice of the Society’s Publications Committee, which serves as editorial board for the project. With input from this committee, from the Council of the Society for Neuroscience, and many others, names were compiled for Volume 13. Production was overseen by Kelly Newton, who serves as the Society’s director of scientific publications.

Autobiographical chapters contained in Volume 13 are freely available from the Society website, along with the 169 chapters that appeared in the first 12 volumes of the series. From the Society homepage, chapters can be accessed using the “Publications/History of Neuroscience Autobiographical Chapters” or the “About/History of Neuroscience” menu tabs. They can also be accessed directly at https://www.sfn.org/about/history-of-neuroscience/autobiographical-chapters. Hardbound copies of Volume 13 are available for purchase (send inquiries to jn@sfn.org).

We hope readers will find Volume 13 as interesting and useful as the earlier volumes.

Thomas D. Albright and Larry R. Squire
Del Mar, California
June 2024

Allan Irwin Basbaum

BORN:

Montreal, Quebec, Canada

October 18, 1947

EDUCATION:

McGill University, Montreal, Quebec, BSc (1968)

University Pennsylvania, Philadelphia, PA, Psychology, PhD (1972)

University College London, London, UK, Postdoc (1972–1975)

University California–San Francisco, Postdoc (1975–1977)

APPOINTMENTS:

Assistant, Associate, Full Professor, UCSF, School of Medicine (1977–present)

Chair, Department of Anatomy, University California–San Francisco (1998–present)

National Advisory Council, NINDS, NIH (2019–2023)

Member, NIH Director’s HEAL Multi-Disciplinary Working Group (2019–present)

Cochair, Steering Comm., Intergovernmental Pain Research Coordinating Committee (2015–2018)

Editor-in-Chief, Pain (2003–2013)

Treasurer, International Association for the Study of Pain (1993–1999)

HONORS AND AWARDS (SELECTED):

Alfred P. Sloan Fellow (1979)

Jacob Javits Investigator Award (1985; 1992; 2007)

SFN Public/Special Lecturer (1986; 1997)

F.W. Kerr Memorial Prize: American Pain Society (1993)

Bristol-Myers Squibb Prize in Pain Research (1994)

John Bonica Distinguished Lecture and Prize (2002)

Fellow, American Academy of Arts and Sciences (2003)

Elected Member, National Academy Medicine (2005)

Elected Fellow, Royal Society, UK (2006)

Elected Fellow, British Academy Medical Science (2007)

Yngve Zotterman Prize, Stockholm Physiological Society (2007)

Elected Fellow, American Association for the Advancement of Science (2009)

Joseph Erlanger Lecture, American Physiological Society (2010)

Member (Chevalier) French Order of Merit (2011)

Founder’s Award, American Academy of Pain Medicine (2013)

NIH Director’s Lecture, (2016)

Reeve-Irvine Medal and Prize for Spinal Cord Injury and Pain Research (2017)

Thomas Willis Lecture, Oxford, UK (2017)

Elected Member, USA National Academy of Science (2019)

Fellow, American Society of Regional Anesthesia and Pain Medicine (2023)

Elected, Council Member of the Neuroscience Section of the AAAS (2024)

Mentor of the Year Award, NIH HEAL PURPOSE Initiative (2024)

Ralph W. Gerard Award, Society for Neuroscience (2024)

Allan Basbaum’s research takes a multidisciplinary approach to study peripheral (sensory neuron) and central nervous system (spinal cord) mechanisms that process pain and itch messages, including the neurochemical and neuroimmune mechanisms that generate and control chronic pain after tissue or nerve injury. Recently, using calcium imaging, his laboratory developed methods to monitor spinal cord neurons, long term in the awake, behaving animal. The laboratory also turned its attention to cortical mechanisms of pain processing, including the action of existing and novel general anesthetics. In collaboration with UCSF colleagues who use in silico screening, his laboratory discovered several novel analgesics with excellent therapeutic windows.

Allan Irwin Basbaum

The Origin of Serendipity

While on sabbatical in France in 1985, in the middle of a research study, I was commenting on a really interesting and unexpected finding of a technician in the Parisian laboratory of Jean-Marie Besson, a giant in the pain research field. As I grew up in Montreal, and am a Francophile, I have a reasonable command of the French language. I told the technician that her discovery was really interesting, thanks in part to serendipité, namely serendipity. I assumed that serendipity was a cognate, readily understood in many languages, but all that I received was a blank stare. The technician who made the discovery had no idea what serendipité meant; no surprise, as it is not a French word. I looked up the origin of the word and learned that it derives from Farsi, was coined in 1754 by Horace Walpole, and is based on the Persian story of The Three Princes of Serendip, who routinely made accidental good fortune findings. Nevertheless, serendipity, regardless of its origin, has affected my career many, many times.

I will introduce serendipity to this autobiography by talking about a memorable teaching experience as a new faculty member at University of California, San Francisco (UCSF), an experience that allows me to explain why I am distributing poems throughout this piece. The teaching experience was indeed memorable, but not in a particularly positive way. My first lecture assignment for the UCSF medical students was on spinal cord reflexes, a lecture previously given by Howard Fields, with whom I had completed a postdoc after returning to the United States from London (see “Science with Howard Fields”). I looked at Howard’s existing syllabus and considered it remarkably thin. So I completely rewrote it, filling in many details, not limiting the lecture to Ia afferents, and to alpha and gamma motoneurons. I added information about gamma trails and gamma plates, and so on. When I showed it to Howard, he immediately said, “Much too much,” but I ignored him. Howard was right; the lecture did not go well. Halfway through the lecture several students interrupted me and asked whether this level of detail was necessary; whether gamma trails and plates are really clinically relevant; and, of course, whether the details would be on the exam. Not surprisingly perhaps, my first teaching evaluations were not encouraging. Particularly painful was the following comment: “Dr. Basbaum seems to be pretty smart, but maybe he should be doing something different.”

Well, serendipity stepped in the following year. First, I revised the syllabus, returning it closer to Howard’s. But for reasons that I cannot recall, the night before the lecture, I wrote a short poem summarizing key features of the lecture, and read it at the end of the lecture. The poem clearly improved my reviews, but hopefully, how I adjusted the lecture also helped. Being an entertaining lecturer should never be sufficient. A second short poem on polysynaptic reflexes followed, after which the students expected poems for all of my lectures. So, in this autobiography, I take the opportunity to put them together, sadly for lectures that are no longer assigned to me. Now I only give the pain lecture, and it has been reduced from 4 to 1.5 hours. Perhaps pain is not particularly important in a medical school curriculum.

Ode to Spinal Cord Reflexes, with Apologies to Supraspinal Control

Of motoneuron activation I have often inquired,

While preparing the spinal reflex lecture at home by the fire.

Can feedback alone maintain muscle tone,

Or is the system controlled from up higher?

I listed with burning desire,

As the muscles responded with ire.

You must be insane, if you think the brain

Is in every stretch reflex required.

Gamma motoneurons, you see, are inspired,

To maintain the tone that’s desired.

When the spindle pole muscles contract, So the Ia’s react,

And the alpha motoneurons continue to fire.

Thus, contraction’s sustained,

Without help from the brain.

And one has the tone that’s desired.

The second hour of the lecture turned to polysynaptic reflexes, emphasizing the evolutionary significance of a simple polysynaptic circuit:

On the Crossed Extensor Reflex

If you contract your ipsilateral extensors when you step on a pin,

Without the crossed extensor reflex,

Imagine how deep that the pin would go in!

And to summarize the second half of the lecture, which covered polysynaptic reflexes:

Beyond the Monosynaptic Reflex: Timing Is Everything

This lecture on spinal cord reflexes, I agree, was far too didactic.

So to read you a poem would be anticlimactic.

I need some more time to dream up a new tactic.

Of course, it always takes longer when it’s polysynaptic.

Growing Up in Montreal

I was born in Montreal, suffice it to say, years ago. My grandparents, Sophie and David on my mother’s side, and Anna and Nija (a nickname) on my father’s side, were born in Europe and came to Canada at the turn of the 20th century. Both my mother (Freda) and my father (Ben) were born in Montreal. Of the four children in our family, two of my siblings, an older brother, Mel, and a younger sister, Eleanor (Chava), sadly died several years ago. The youngest of my siblings is Nissa. Her very interesting life story is recounted later in this piece. Neither of my parents attended college (my mother couldn’t even complete high school because of diphtheria), but they were very strong proponents of a strong education. The high school system in Montreal was divided on religious grounds, with both Catholic and Protestant schools, as well as some that taught in French and others in English. I attended an English Protestant school, but French lessons began in the third grade, and I took to the language quickly.

I thoroughly enjoyed learning and speaking French, which undoubtedly contributed to the decision to send my kids to a French bilingual school in San Francisco. Although we moved around a lot in Montreal while I was growing up, we finally settled down in the Western part of the city, and I attended a large high school, with more than 2,000 students. But, West Hill High School, with well over 35 students in every class, did provide a great preparation for college. Compared with costs in the United States, university in Canada is inexpensive, and it was traditional for students in Montreal to attend McGill. Of course, this is also very different from the more common tradition in the United States, where students can’t wait to leave home for college. I lived at home during my first three years at McGill, and only lived near the campus in my senior year.

We were raised in what could be called an Orthodox Jewish family, with a kosher home, but religion was not a particularly strong influence on my life. In contrast, religion definitely influenced Nissa’s life. After attending journalism school at Carlton University in Ottawa, she moved to Newfoundland, where she ran a newspaper. Nissa prefers that I not constantly retell my story about how I learned that she had converted to the Anglican church, but for posterity here goes. I received a call from Nissa, perhaps 40 years ago, while she was in Newfoundland. She said that she had some very important and certainly unexpected news to tell me, that she found Christ. “In Newfoundland!?” I asked. “Who would have guessed?” It’s not funny, she quickly replied.

Indeed, it was not. After studying in London and Northern Ireland, but wanting to be ordained, something that at that time, for a woman, was not possible in the UK, she returned to Canada. She attended the University of Toronto, where she met Robin, also an Anglican priest, and they have two children, Rebecca and Ben. After serving as the parish priest in Oakville and then Niagara on the Lake (both in Ontario), she was appointed dean of the Cathedral in Kelowna, British Columbia. One of my favorite stories occurred when Nissa and Robin visited us in San Francisco, when the 1989 earthquake hit. They were driving downtown and the car started shaking; they initially thought there was a problem with the car. But when they saw bricks falling from some buildings, they realized what had happened. Robin’s memorable line was that “there will be a great sermon coming from this experience.” I am certain that there was. Very sadly, as I am writing this piece, Nissa and Robin had to abandon their home in Kelowna, because of uncontrolled wildfires.

McGill and Expo 1967

The earliest example of serendipity influencing my career path occurred when I was an undergraduate at McGill University. It was the summer of 1967 and I applied for a position at Expo ’67, the World’s Fair. I was on the waiting list to be a guide at the Australian Pavilion, a dream summer job. Unfortunately, time was running out, so instead I answered an ad for a summer research technician position in the laboratory of the renowned pain researcher, Ronald Melzack, a professor in the Psychology Department at McGill, an amazing place that included D. O. Hebb of Hebbian synapse fame. I had taken Melzack’s undergraduate course on motivation, but I knew little to nothing of the pain research ongoing in his lab. I accepted the position, and one week later heard that the Expo ’67 position was mine. I seriously considered switching, but my father convinced me that having accepted the Melzack offer, I should stay the course. I listened to my father, a decision that profoundly influenced my career in research. Timing of the Melzack position relative to the Expo ’67 offer was truly serendipitous.

Interestingly, although my experience with Melzack continued through my senior year at McGill, it never led to a joint publication. However, that interaction definitely introduced me to the complexity of the pain experience. More important, perhaps, the study in which I was involved probably triggered my longstanding interest in the descending control systems through which the brain regulates the transmission of “pain” messages at the level of the spinal cord. Two years before, in 1965, Melzack and Wall published their now-famous Gate Control Theory of Pain (Melzack and Wall, 1965). Most of the model focused on circuits in the dorsal horn through which large- and small-diameter afferent fibers regulate the flow of information in the dorsal horn, information that underlies a pain experience provoked by an injury. Largely ignored, however, is that the model also included a Central Control Trigger (CCT), namely a pathway from the spinal cord to the brain that engages supraspinal circuits that, in turn, descend to and control spinal cord processing.

What was unusual was that the ascending pathway in the CCT was hypothesized to be via dorsal column axons, which traditionally carry non-nociceptive (non-pain-provoking) information. My task in the Melzack lab, during that first summer and for a subsequent honors thesis, was to test the model by training food-deprived cats in a classic Pavlovian-type model. A noxious stimulus that normally would provoke paw withdrawal is applied to the paw. If, however, the stimulus is paired with a food reward, then the noxious stimulus becomes a conditioned stimulus. Continual pairing of the food and the noxious stimulus very quickly led to inhibition of the paw withdrawal to the noxious stimulus. Instead, the cat immediately dropped its head to the food delivery device.

My task was to train the cats and then perform dorsal column lesions, which were intended to disrupt the CCT that Gate Control Theory hypothesized underlay the altered behavior of the cat. Sadly, the results did not support the hypothesis, which perhaps explains why I have never published a paper with Melzack. However, I did write an obituary that was published in Pain (Basbaum, 2020), an obituary that describes what a remarkable scientist he was, someone who constantly reminded me that nociception and pain are not the same thing. Melzack also wrote Eskimo (not a great word these days) children’s stories. As noted in the following sections, it took many years before I actually turned my attention from nociceptive processing to the neurobiology of pain, which, of course, is a cortical percept and thus very different from the circuits, which according to Ron, “merely” carry the information to the brain.

The Move to the University of Pennsylvania

The big question was what to do after graduating from McGill. Medical school was definitely on my mind. But my research experience in the Melzack lab convinced me to apply to the doctoral program in the Psychology Department at Penn. This was a tumultuous time: 1968, which has to be one of the most memorable years in the past century: first flight to the moon; both Martin Luther King Jr. and Robert Kennedy were assassinated; Lyndon Johnson decided not to run for a second term, but his landmark Civil Rights legislation was passed; and a taste of freedom came with the Prague Spring in Czechoslovakia. Vietnam was raging, which unquestionably contributed to the now infamous Democratic Convention at which Hubert Humphrey was nominated to run against Richard Nixon. This was also the year of the Tet Offensive in Vietnam, and to find new soldiers, the lottery was introduction (a form of conscription based on your birthday). As a Canadian, I was not subject to the draft, but pretty much every other Penn graduate student my age was. I remember the day that the newspaper published the list of birthdays, in the order in which individuals would be required to enlist. I looked through the long lists in the middle of the paper, but couldn’t find my birthday. So I checked the front page: I was fourth on the list, and were I American in 1968, this autobiography might have been much, much shorter.

Few of my colleagues know that my degree is actually in psychology, perhaps because I did all of my research in the Anatomy Department at Penn. Other than taking many psychology courses in my first year, I really didn’t spend much time with the psychology faculty. I did meet Carol Garten, who came to the Psychology Department from Bryn Mawr. By Christmas of the first year at Penn, we were a couple, and at the end of the year, one week after the first moon landing, we were married in Peekskill, NY, where her parents lived and where she grew up.

There is a famous story about our relationship that has been repeated many times, including at Carol’s memorial, by her sister Toby. Carol and I were visiting Carol’s parents a couple of months before we married. Carol’s mother was not someone you could tell an off-color story to, and she was definitely traditional.

We were having lunch, when Carol’s mother asked, “Basbaum; isn’t that German for some kind of tree?”

“It is,” I said.

“What kind of tree?” she asked.

I said that I wasn’t certain, but that I thought that Bas meant lilac. “Well, that’s interesting,” she said. “You know that Carol’s last name (Garten) means garden. When you are married, the lilac tree will be in the garden!” Without missing a beat, although regretting my speedy response, I replied, “The lilac tree has already been in the garden!” Carol’s mom turned around, walked out, and didn’t talk to me for two weeks.

My knee-jerk response to my future mother-in-law about the significance of my last name, as well as my admittedly inappropriate response upon hearing that Nissa had discovered and turned to Christ, is unfortunately, something that I rarely can prevent. I am an inveterate joke teller and punster, and many of the jokes would be considered off-color. I do enjoy provoking laughter and I do have an ability to tell jokes with accents from countries around the world, French (Quebecois and France), Italian, Scottish, German, Yiddish, and so on. Years ago, when I was first appointed chair of the Anatomy Department at UCSF (see “The Move to San Francisco”), a very close faculty member and friend, Gail Martin, pulled me aside and offered the following advice: “You know, Allan. Now that you are chair, you can’t tell those jokes anymore; I have my lawyer on speed dial.”

Doctoral Research at Penn

I began my doctoral research under the mentorship of Mel Levitt, whose lab was in the Anatomy Department at Penn. Mel studied primate behavior, with a focus on cortical mechanisms that process somatosensory, including pain, information. Unfortunately, Mel did not receive tenure, so he had to leave Penn, at which point I was left without a thesis advisor. That serendipitously led to the appointment of Eliot Stellar as my doctoral adviser. Eliot, famous for his studies on the neurobiology of feeding behavior, had no research experience in the pain area, but I continued my studies under his mentorship. What is significant is that Eliot started the Institute of Neurological Sciences, which I believe was the first neuroscience program in the country. I was definitely one of the first doctoral students in this program, around the same time that the Society for Neuroscience was formed (1969). Peter Strick, now head of the Neuroscience Program at the University of Pittsburgh, was another graduate student at the birth of that program. Peter and I actually lived in the same small apartment building and shared a wall. Rent was only $96 a month, but the graduate stipend was only $2,400 a year.

Autotomy: A Model of Neuropathic Pain

Although Mel had to leave, one of his observations in primates did influence what proved to be the basis for the second paper that I published. Mel noted that rhesus monkeys would attack their digits after multiple dorsal rhizotomy, which severed all primary afferents in the dorsal roots, completely denervating the limb. The simplest explanation was that the animals were attacking an insensate limb. But I wondered whether a phantom limb–type condition had developed, one associated with an unpleasant, even painful experience that the monkey tried to block. To test this hypothesis, I turned to the rat and performed multiple dorsal rhizotomies, denervating the hindlimb. As in the primate, that surgical procedure led to the rats attacking the denervated hindlimb. The question that I asked was whether unilaterally superimposing different subtotal spinal cord lesions could prevent the biting of the hindpaw that occurred. In other words, could severing a pathway that carries “pain” information to the brain, but does not produce a motor defect, interfere with a phantom limb–like chronic pain condition?

My ability to make lesions of the spinal cord, which was questioned subsequently (see “My First International Association for the Study of Pain Meeting”), is owed to the expertise of two of my amazing Penn mentors, John Liu and William “Bill” Chambers. In fact, a subtotal lesion did prevent the biting of the denervated limb, without producing paralysis. When I presented these results to Fred Kerr, a well-regarded neurosurgeon at a national anatomy meeting, and suggested that this was a “neuropathic pain” condition, I was strongly advised to come up with some other term for the condition. “The clinicians will never buy it,” he said. So, the manuscript describing the results only referred to “Disorders produced by multiple dorsal rhizotomy” (Basbaum, 1974). Five years later Pat Wall (see volume 3) and colleagues revisited the phenomenon and gave it the name that persists today: autotomy (Wall et al., 1979).

Multisynaptic Ascending Spinal Cord “Pain” Pathways

With the ability to make spinal cord lesions, my doctoral thesis project turned to a very different question. Traditional textbooks teach that “pain” is transmitted by a straight-through pathway from the spinal cord to the brain, namely through the crossed spinothalamic tract. But I noted that several of the rats in which I performed spinal cord hemisections were still responsive to noxious stimuli applied to the contralateral limb. I wondered through what other routes “pain information” could get to the brain. To address the question, I performed two spaced hemisections, one on each side of the cord, thus cutting all long pathways. Before the surgery the animals were trained to move their head into a light beam to turn off a noxious stimulus to the hindlimb. Using this approach, I found that despite the spaced hemisections, the rats could still respond to a noxious stimulus and concluded that it a multisynaptic system must carry the information in the absence (or perhaps even in the presence) of the long ascending pathways (spinothalamic and spinoreticular).

Only during my postdoc years in London, with Pat Wall, did I meet William (Bill) Noordenbos, the head of neurosurgery in Amsterdam. Most important, after meeting Bill, I learned about his book Pain, which was his thesis (Noordenbos, 1959). In this book, Bill wrote about “pain” pathways, and he hypothesized that short, multisynaptic pathways could explain the return of pain after cordotomy, the surgical procedure that supposedly cuts the long ascending spinothalamic and spinoreticular “pain” pathways. Clearly, my thesis studies confirmed, at least in the rat, the Noordenbos hypothesis. But what I also learned subsequently and wrote of recently in an article entitled the “History of Spinal Cord ‘Pain’ Pathways” (Basbaum, 2022), this conclusion was, in fact, made many, many years before by Austrian scientists, Karplus and Kreidl (1914) who performed the same experiment in cats. That discovery convinced me that I needed to be a better reader of prior literature (difficult as I can’t read German literature), but I took some solace in the fact that my findings had been “preconfirmed.”

Another study that I performed during graduate school is also worth highlighting, as it not only introduced me to neuroanatomical research but also taught me another important lesson about publishing. With Peter Hand, a superb neuroanatomist in the Veterinary School at Penn, I took advantage of the introduction of the Fink-Heimer method to study anterograde axon terminal degeneration. Previous tracing studies relied on the Marchi method, which only identified areas of demyelinated axons. The Fink-Heimer silver method was an improved Nauta method that could also identify the degenerating terminals of unmyelinated axons. In these studies in rats, I uncovered an unusual projection pattern of primary sensory neurons in the dorsal column nuclei, one that we called “bricks” because of the rectangular pattern of degeneration that we observed (Basbaum and Hand, 1973). Not long after publishing these results in the Journal of Comparative Neurology, I attended an American Association of Anatomy meeting in Dallas and met Aldo Rustioni, a wonderful neuroanatomist and friend from the University of North Carolina. We went to lunch and were discussing spinal cord organization studies, and then Aldo asked if I had seen the very recent publication from Peter Hand. “Yes,” I replied, “I was the first author!” That was my introduction to the significance of senior authorship. I try now to be much more attentive to other contributors to a paper’s publication.

Of course, the spinal cord has been the major focus of my research, and not surprisingly, I was assigned the lectures on basic spinal cord anatomy and physiology. And following the “success” of my first poem reading to the medical students, they expected a new poem for every subsequent lecture. A poem on the organization of the spinal cord followed. And my graduate student research with Peter Hand, which introduced me to somatosensory neuroanatomy, led years later to a second poem about the homunculus.

Praise the Lord for the Spinal Cord

Funiculi are the columns and fasciculi are the tracts

Which just about covers all the white matter facts.

Via spinal cord pathways, information accesses the brain

So that we all may experience touch, joint position sense, and pain.

In this lecture you learned that if your arm you vibrate

You’d be activating myelinated axons that ascend cuneate.

But, if your penchant is directed at those areas that do thrill us,

You’d be stimulating large fibers that course in gracilis.

Dorsal columns course ipsilateral; spinothalamic tract is crossed.

And after anterolateral cordotomy, pain, and temperature are lost.

From cerebral cortex, the corticospinal tract crosses, creating a complex boulevard.

Which is how a spinal hemisection provokes Le Syndrome Brown-Sequard.

These many ascending and descending pathways are why we cannot afford

To relinquish the functions performed by the cord.

Sure, the brain is important, but the spinal cord’s central.

So Come Blow Your Horns, be they dorsal or ventral.

And let us end by rephrasing the words of the Lord

Honor Thy Mother … Don’t Cut the Cord!

You Are Only as Sensitive as Your Postcentral Gyrus

Buried in the cortex, in the postcentral gyrus

Is a somatotopic map, of which we can inquire as

To form and to function and overall size

Of the parts of the body from which sensations arise.

The map reflects density of peripheral innervation.

Thus, a distorted homunculus is no aberration.

The map is essential for tactile sensation;

Indeed, there is no perception after S1 ablation.

If you amputate a limb, a phantom persists.

This is no illusion; it really exists.

The eyes say, “Absurd!” but the mind says, “I feel!”

Because it’s the map in the brain that makes things seem real.

It has oversized fingers and large luscious lips,

An exaggerated tongue, but no Valkyrian hips.

Unless you’re a pig, the nose is quite small;

Some parts of the body are hardly represented at all.

There is only minimal cortex for tendons and bones,

But there’s a whole lot of space for erogenous zones.

You see, it may be a body designed from above …

But, it’s a body that only your mother could love.

Postdoctoral Fellowship with Pat Wall

After Carol and I received our doctorates at Penn, the question was where to do postdoctoral research. I very much wanted to work in Patrick Wall’s lab at University College London, so we made an agreement that Carol would find a postdoc mentor in London (she ended up working with George Gray of Gray’s Type I and II synapses), but that she would get to choose the second postdoc. The serendipitous consequence of that arrangement explains how I ended up in San Francisco (see “The Move to San Francisco”).

I have often emphasized that my time in Pat Wall’s lab at University College London had an enormous impact on my career, not only because of the technical skills that I picked up, but more important, because I also had the opportunity to work with someone who was truly a visionary and creative scientist. Pat and I could be recording from spinal cord neurons in the cat, when we might encounter a neuron with odd response properties. Rather than ignoring the odd neuron and moving on, Pat could completely change direction and aim to figure out what’s going on. Getting excited about an unexpected finding, and pursuing its significance, rather than concentrating purely on hypothesis-driven research, I believe, does have an important place in research. Serendipity not only can lead to a change in a research direction, but also certainly can lead to unexpected breakthroughs. As Ulrike Heberlein told me, despite the preference of most National Institutes of Health (NIH) study sections, she likes to do hypothesis-seeking research.

Following the pioneering collateral sprouting studies of Liu and Chambers (1958), Pat and I asked a question about the extent to which, in the presence of considerable injury, primary afferents can reorganize their connections with spinal cord neurons. Chambers and Liu isolated a single dorsal root (by dorsal rhizotomy of several rostral and caudal roots) and reported extensive sprouting into denervated areas of the dorsal horn, a result that was contentious, and by many, ignored.

Before I arrived in London, in 1972, however, Pat and Gene Merrill published a paper reporting that there are dorsal horn neurons that can be electrically activated from distant dorsal roots, but not by natural stimulation (Merrill and Wall, 1972). They proposed that these neurons normally are innervated by silent synapses. With this background, Pat and I revisited the sprouting question, recording from the spinal cord in a cat in which a single dorsal root had been isolated by rhizotomy, basically the same preparation that revealed collateral sprouting. As predicted, we found that the functional reach of the isolated root had significantly extended. In fact, some dorsal horn neurons now had split receptive fields, receiving input from more rostral, intact afferents, as well as from the sprouting, isolated afferents (Basbaum and Wall, 1976). In many ways, our finding provided a foundation for the remarkable activity and injury-dependent reorganization that Michael Merzenich (see volume 7) and colleagues reported in the somatosensory cortex (Kaas et al., 1983). Of course, Mike has argued that the reorganization involves circuit changes in the cortex itself, rather than influences from changes at spinal cord, brainstem, or thalamic levels.

Beginning to Study Descending Controls

While in the Wall lab, I also initiated a series of studies that in many ways was the introduction to my long-standing research into pain control mechanisms. Three years before I arrived in London, Reynolds (1969) described the analgesic effect of electrical stimulation in the periaqueductal gray (PAG). Particularly striking about his finding was that the analgesia could be produced without motor side effects or effects on food intake. As the analgesia was associated with a decrease of noxious stimulus-evoked reflexes, I decided to study the pathways through which I hypothesized were the PAG-derived descending circuits that generated the pain control. Of course, I had considerable experience making spinal cord lesions, so the study was pretty straightforward: implant stimulating electrodes in the PAG, demonstrate analgesia, and then ask whether subtotal spinal cord lesions could interfere with the pain relief. In a relatively short time, we found that lesions of the dorsolateral funiculus (DLF) of the spinal cord in the rat completely blocked the pain relief, without introducing motor deficits. Most important, the midthoracic lesions blocked the analgesia when testing hindlimb and tail, but they did not reverse the analgesia of the forelimbs. That important difference ruled out an alternative hypothesis as to the basis of the pain relief. Specifically, as stimulation of the ventrolateral PAG is also rewarding, one proposal was that the reward effectively “masked” the pain that was experienced. Because we could selectively block the pain control of the hindlimbs, preserving that of the forelimbs, it was clear that the analgesia was not secondary to reward (Basbaum et al., 1977).

Morphine and Stimulation-Produced Analgesia

Timing and, of course, more serendipity, I guess, are everything. Around the same time that we were performing these studies and following the discovery of the opioid receptor (Lowney et al., 1974), endorphins were described (Hughes et al., 1975). Subsequently, Huda Akil (see volume 8) and David Mayer in the John Liebeskind lab at University of California, Los Angeles (UCLA) reported that the opioid receptor antagonist, naloxone, not only blocks morphine-induced analgesia but also the analgesia produced by PAG stimulation (Akil et al., 1976). Those observations turned our attention to the circuits through which opiates (notably morphine) exert their analgesic effects. I first asked whether DLF lesions interfered with the analgesia produced by systemic morphine. In fact, bilateral DLF lesions completely reversed the tail-flick blockade produced by systemic doses up to 10 mg/kg. Interestingly, higher doses would reinstate the blockade, almost certainly via a direct action on spinal cord neuronal processing, an observation consistent with the report of Tony Yaksh that spinal administration of opiates can be powerfully analgesic (Yaksh and Rudy, 1976). An interesting sidenote is that our first paper describing these DLF results was coauthored by John O’Keefe, a good friend from my days at McGill and at the time a faculty member with a lab adjacent to Pat Wall’s. Years later John won the Nobel Prize for his studies of hippocampal place cells.

Interacting with Patients: Learning from Peter Nathan

Unquestionably, one of the most impactful influences on my career was when Pat Wall introduced me to Peter Nathan, a neurologist at the National Hospital for Neurology and Neurosurgery at Queen’s Square in London. Peter was a true Renaissance man. In addition to being a first-rate consulting neurologist who saw a cross section of patients, including among the most difficult chronic pain patients, from throughout the United Kingdom, Peter was also a neuroanatomist who along with the neuropathologist, Marion Smith, studied the anatomy of spinal cord pathways implicated in pain processing. Peter also wrote interesting biographies and was a major financial supporter of the highly successful play, Chaucer’s Tales, and he gave all his profits to charity.

For more than two years, I sat next to Peter every Wednesday morning and received firsthand experience with patients. I tell my students that for the first three months, I just listened to patients, but the students don’t believe me. Most important, I quickly learned that a preclinically studied animal (whether mouse or monkey) is not a human and that the human pain experience is far greater than the magnitude of the injury. And because I often saw the same patients over several months, I also learned what worked and what did not, as well as the heterogeneity of the patients, even those ostensibly with the same injury. Most memorable were the postherpetic neuralgia (PHN) patients, a classic neuropathic pain condition. Opiates were not particularly effective and gabapentin was years away from its discovery. The antidepressant, amitriptyline (a serotonin and norepinephrine reuptake inhibitor, and a cholinergic blocker) had just been introduced for neuropathic pain.

But in my experience, what proved to be remarkably effective, particularly in patients with PHN of the first division of the trigeminal nerve, was local anesthetic (bupivacaine) injection into the supraorbital notch. This injection reliably blocked the ongoing and evoked pain of the forehead. In fact, pain relief occurred in close to 100 percent of patients, But, most interestingly, in some patients, the patient remained pain free for up to three weeks. The pain always returned, but a subsequent injection was also effective. That observation convinced me of the critical significance, indeed necessity, of peripheral afferent input, to sustain neuropathic pain. I have seen comparable results in patients with phantom limb pain; local anesthetic injection of the stump not only can eliminate stump pain, but the phantom would also disappear. Those observations are consistent with a longstanding premise described by Livingston, namely that injury-induced changes in the spinal cord can for a short period independently sustain the pain after peripheral nerve injury, but a peripheral driver is necessary (Livingston, 2012). Of course, we now refer to this phenomenon as central sensitization (Woolf, 1983).

My experience with Peter Nathan convinced me that basic science pain researchers must also learn directly from patients living with chronic pain. Not only will researchers better understand the complexity of the pain experience and appreciate which treatments are effective and which are not, but they also will appreciate how chronic pain influences quality of life and family interactions. And most important, they will also be able to interact with clinicians. I have been fortunate to have brilliant physician-scientists, neurologists, anesthesiologists, and dermatologists complete research fellowships in my lab and have always encouraged students and postdocs in my lab to shadow the pain physicians at the pain clinic. Fortunately, many do. To emphasize the importance of patient interactions, the HEAL Initiative created a video in which I discussed the importance of seeing patients (http://heal.nih.gov/news/stories/p).

My First International Association for the Study of Pain Meeting (Florence, Italy)

Not long after I joined Howard Fields’s lab in San Francisco (see “The Move to San Francisco”), Howard encouraged me to present the DLF story, which had just been published in Pain, at the first meeting of the International Association for the Study of Pain, in Florence, Italy. That’s a meeting that one cannot turn down. So, Carol and I and our London-born daughter, Katherine, who was only one year old, went to Florence. The talk that I gave was all of 15 minutes. After a few simple, supportive questions, a well-known and respected physician scientist, Arthur Taub, who studied pain, stood up and said that he didn’t believe our story. He said that making selective lesions of the DLF in the rat is impossible. He argued that there would inevitably be damage to other pathways. He pointed out, correctly, that the published manuscripts only included sketches of the lesions, not the original histology. I was pretty devastated; nobody was going to believe the postdoc who was telling this story.

Fortunately, there is a happy ending to this tale. Near the end of the meeting, Ron Dubner, who I had met while working in Pat Wall’s lab, said that he would love to hear more about the DLF story and so he invited me to visit the National Institute of Dental Research, where he oversaw a large pain research group. I eagerly accepted and showed up a couple of months later. I expected to give a one-hour talk, but questions kept coming. After about four hours Ron said, “Oh, Allan, it turns out that Gary Bennett, a fellow in the lab, was about to do some surgeries in rats. Would you be willing to show them how to create the DLF lesions?” Apparently, there was an ulterior motive to Ron’s invitation to me to come to the National Institutes of Health (NIH). Not to be proven wrong, I went to the operating room and operated on three rats. What they learned quickly, and what I had previously learned from John Liu at Penn, is not to use scissors to make the lesion as that will produce bleeding and unintended damage to adjacent tissue. Rather, the lesion is created with jeweler’s forceps. Target the region of interest and squeeze the tissue for about 15 seconds. This approach effectively crushes, rather than cuts, the targeted pathways and completely avoids bleeding. After an hour or so, the rats awoke from the anesthesia and immediately ran around, with no motor signs obvious. That convinced Ron and his lab that it is indeed possible to make selective DLF lesions, and Ron eventually spread the word. But in my subsequent papers, I did include the histological verification.

The Move to San Francisco

While in London, Carol met John Heuser, who was a postdoc in Bernard Katz’s (see volume 1) lab. John was offered a position at UCSF in the Physiology Department, and he invited Carol to do a second postdoc in his new lab. Carol was an electron microscopist who, from her work in George Gray’s lab, was very interested in synaptic architecture. So the offer was superb. Carol also had an offer to work with Tom Reese at the NIH, which was great as I had an offer to work with Steve Gobel at the National Institute of Dental and Craniofacial Research (NIDR), in the pain research unit that was headed by Ron Dubner. But for reasons that I can’t remember, Tom encouraged Carol to join John’s lab. My problem was that I knew nobody in San Francisco. (To be honest, I had never been to California and thought that the Golden Gate Bridge interconnected San Francisco and Los Angeles). Anyway, serendipity stepped in again. Pat Wall reached out to Howard Fields, who was setting up a lab in the Neurology Department at UCSF. Long story short: I joined Howard’s lab and the rest is truly history. My move to San Francisco was the beginning of a very long and productive research collaboration with Howard, and most important, the beginning of what is now a 50-year, very close friendship.

Making the move to San Francisco, however, was not all that straightforward, for several reasons. Most memorable, of course, is that our daughter, Katherine was born in London.

Carol’s pregnancy and Katherine’s birth were unforgettable. First, Carol was amenorrheic, and we were told that she probably couldn’t become pregnant without a lot of medical intervention. In what was to be our last year in London, we decided to take a two-week vacation, skiing in Austria. Carol had a “cold,” but our doc said that being in the mountains would be best for her. Unfortunately, Carol broke her leg near the end of our trip and was treated with a nonsteroidal anti-inflammatory drug apparently used in horses, not one that should be prescribed to humans, particularly pregnant ones. When we returned to London, Carol was placed in a cast and then she complained to our physician that she not only had a mild cough but was also nauseous. “Post-influenza colic,” the physician concluded. At which point Carol asked whether breast enlargement was also associated with postinfluenza colic. A subsequent pregnancy test confirmed that it was definitely not colic. The problem was that we had no idea how pregnant she was. Early days of ultrasound guessed that she would deliver in mid-August of 1974. Well, a month later, we were still waiting, and my mother was convinced that there were problems with the pregnancy. Katherine, in fact, was born September 28. That was two weeks before we were scheduled to return to the United States, tickets already purchased.

The problem was that as a Canadian citizen, it was not easy for me to get back to the states. So Carol left with Katherine and stayed with her parents in Peekskill, New York. I was busy dealing with immigration. When interviewed at the American Embassy, while applying for a Green Card, I knew that my fingerprints had been sent to every city in which I had lived, including Philadelphia. Apparently, immigration folks were looking for some criminal history that would prevent me from getting the Green Card. I asked what crimes would be a problem: “Type A crimes: murder, rape and trafficking in drugs,” was the reply. “Not a large number of unpaid parking tickets?” I sheepishly asked, all of which I had collected at Penn, remembering what my father-in-law had warned me when he learned that I never paid them. “Not to worry,” the agent told me. So, finally, I made it to the states, two months after Carol left and we moved to San Francisco, with a two-month-old daughter in tow.

Within weeks of arriving in San Francisco, the question as to the meaning of my last name again came up. I was walking by the neurology office, when the chief administrative officer, a rather formidable German woman, asked me, “You are Dr. Basbaum, yes?”

“Yes,” I said, and then she asked, “What is the meaning of Basbaum?”

I told her that I thought it meant lilac tree, at which point she laughed and stated firmly that: “Bas is not a lilac! Bas is nussing! You are Dr. Nussing Tree,” a name that she repeated every time I walked by her office: “Here comes Dr. Nussing Tree!”

It took many years for me to learn the actual meaning of my name. A letter from a distant family member in Brazil, the country to which many of my distant European relatives had emigrated instead of going to Canada. Anna Basbaum explained that the name was originally “Vaisbaum” (i.e., “white tree”). Often V’s become B’s, which is why I remain Dr. White Tree, with a “B.”

Science with Howard Fields

Howard Fields had set up an electrophysiology lab to study spinal cord processing in the cat. He had previously published a series of important studies on the properties of spinoreticular neurons (Fields et al., 1977), a topic that I recently discussed in a review of spinal cord projection neurons that carry “pain” messages to the brain (Wercberger and Basbaum, 2019). Given the recent focus on descending controls and the identification of the DLF pathway, Howard and I turned our attention to the effects of electrical stimulation of neurons in the rostral ventral medulla (RVM), which contains the serotonergic neurons that are the origin of the descending DLF pathway. We demonstrated that RVM neurons project to the spinal cord via the DLF (Basbaum et al., 1978; Basbaum and Fields, 1979) and in an earlier paper, that electrical stimulation profoundly inhibits the firing of dorsal horn neurons that receive pain-provoking input and that DLF lesions blocked the inhibition (Basbaum et al., 1976). Specifically, we observed profound inhibition of the so-called wide dynamic range neurons of lamina V of the dorsal horn and minimal to no effect on the lamina IV neurons, which respond only to innocuous stimulation.

Serendipitously, perhaps, these electrophysiological studies occurred not long after the introduction of a new anterograde tracing method, autoradiography, using transport of tritiated amino acid, a technique that was significantly improved over silver degeneration methods. You didn’t need to make a lesion, and autoradiography was far more sensitive. The protocols not only were incredibly difficult but also required generating emulsion-coated slides of sectioned tissue and weeks of transport and then emulsion development in the darkroom. The problem of great sensitivity had its own issues, namely distinguishing transported signal from background noise; but we persevered.

Our studies, in the cat, were designed to target the reticular formation of the medulla, specifically the nucleus reticularis gigantocellularis. Our objective was to map projections to the thalamus, as part of the spinoreticulothalamic “pain” pathway that Howard’s previous spinal cord electrophysiological studies had investigated. We used a beveled needle to inject the tritiated leucine, which would be taken up by neurons, incorporated into protein, and then anterogradely transported, we hoped, to the thalamus. Inadvertently, and yes, serendipitously, instead of aiming the bevel rostrally, we turned it 90 degrees, resulting in injections that targeted the midline, including the nucleus raphe magnus.

We certainly observed significant projections rostrally, but analysis of the caudal medulla, notably the trigeminal nucleus caudalis and the spinal cord dorsal horn, revealed extensive terminations in superficial layers, laminae I and II (Basbaum et al., 1976). As previous tracing studies concluded that there was no descending projection to the superficial laminae, our findings were initially questioned and were considered to be an artifact of the autoradiographic technique. Time proved our findings correct, however, and our observations were followed by our many studies and that of others that examined the controls exerted from the RVM (and midline serotonergic nucleus raphe magnus) on “pain” responsive neurons, not only in lamina V but also in lamina I, which was predicted from the projection to the superficial dorsal horn. Perhaps fortunately, my studies of the brainstem anatomy convinced Henry “Peter” Ralston, who preceded me as chair of the Department of Anatomy at UCSF, to assign the brainstem lecture to me, which prompted the following poem that ended that lecture.

The Brainstem Cranial Nerve Review

Midbrain, medulla, bridged by the pons

Sur le pons d’Avignon, our neuroanatomy course goes on and on.

But to help with your studying, messieurs et mesdames

Here’s a review of the brainstem for the final exam.

If you stick out your tongue, it should come out very straight.

But with a lesion of the XIIth nerve, it will almost certainly deviate.

And since intact strong tongue muscles the weak override,

The tongue will stick out on the paralyzed side.

Branchial IX, X, XI exiting nerves are contiguous,

Their cell bodies located in nucleus ambiguus.

Glossopharyngeal’s not pure; it’s a sensory-motor mixed bag,

Its afferent component might, in fact, make you gag.

VII and IX transmit tongue taste bud information and as the textbooks have taught us,

There’s also a Xth nerve taste component for the epiglottis.

The facial nerve, yes that’s VII, is particularly hard to get straight,

Because it hooks over VI, before it exits with VIII.

Can you imagine if Hemingway had suffered VIIth nerve woes?

His great novel might have been titled, For Whom Bell’s Palsy Tolls.

And with no corneal reflex to protect him, he would have so ruined his eyes,

That all he’d have won was the “No Bell Palsy” prize!

Turning to vision, oculomotor is III, Edinger-Westphal constricts,

Trochlear is IV and abducens is VI.

Laterally, medially, in myriad ways,

Through the paramedian pontine reticular formation, the brain controls conjugate gaze.

And MLF, III, IV, VI, and vestibular connect,

To maintain eye position when you reposition your neck.

But if the world starts to spin and you can’t navigate,

It’s likely there’s damage to vestibular VIII.

Last but not least, is the Vth cranial nucleus;

Its anatomical organization does nothing but confuse us.

Don’t ask me why descending tract axons carry trigeminal “pain.”

I only teach … I had no hand in the design of the brain.

Could We Stay in San Francisco?

After a couple of postdoc years in San Francisco, we turned our attention to faculty positions. We considered positions at Columbia in New York, but our visit was not at the most ideal time. New York was a pretty rough place in the mid-1970s, and since we had a two-year-old with us, crime was a concern. There was a wonderful opportunity in the Anatomy Department, which was headed by Michael Gershon, of enteric nervous system fame. However, what clinched our decision not to move to New York came, I guess serendipitously, when I raised our concerns to a Columbia faculty member, whose name will go unmentioned. This individual said that there was no reason to be concerned about crime. She carried a $20 with her at all times and perhaps had lost $100 a year to muggers. That part of the startup package convinced us to stay on the West Coast.

After a visit to Irvine and another interesting offer of faculty positions for both Carol and me, UCSF asked if we would like to stay. The chair, Peter Ralston, offered me a faculty position. Not much of a startup: $25,000 and a 360-square-foot lab, renovated from half of a former men’s restroom. We joked that this lab offered a novel way to do “uranyl” acetate staining of grids for electron microscopy. The lab was on the 13th floor; no superstitious concerns here, although San Francisco did skip 13th Avenue when it named its streets. The lab did have a small, 60-square-foot office, with a great view of the Pacific Ocean. But the lack of a window in the lab proved annoying to my first graduate student, Michelle Moss, who felt that we should restructure the lab and office so that everyone could enjoy the view. Knowing that that was impossible, I went to Sears and purchased an inexpensive painting of a window and hung it in the lab. But Michelle got the last laugh. She said that I should hang the window in my office so that I could get cross-ventilation!

A story that Michelle recounted about her first attendance at Society for Neuroscience is also memorable. Michelle was listening to a small crowd of neuroscientists discussing pain mechanisms, and she tried to engage but was completely ignored. Apparently, she overheard someone mention my name, at which point she spoke up and said that she was a graduate student in my lab. That was followed by someone exclaiming: “Wow, Allan Basbaum. He’s semifamous!” I still do not know whether “semifamous” is something of which I should be proud. More likely, it indicated that I had a lot of work to do.

During this time, our studies with Howard continued, and in my own lab, we introduced electron microscopy and immunocytochemistry, a technique largely pioneered for the nervous system by a very close friend and colleague, Tomas Hökfelt. But, after several years at UCSF, some opportunities to move on appeared, in particular, a position at the University of Washington (UW), where John Bonica had established the first Multidisciplinary Pain Clinic and where he founded the International Association for the Study of Pain. Long story short is that Carol, who had a soft-money, in-residence position at UCSF, which was also in the Anatomy Department, was not offered a hard-money position at UW. That was our bottom line, so we stayed in San Francisco. The dean, however, recognized that my scientific kindred spirits were not the cancer and cell biologists next door to me on the 13th floor, but the neuroscientists in the newly established Keck Center for Neuroscience. So, I moved down to the newly renovated eighth floor, where I was surrounded by an amazing group of outstanding neuroscientists, including Steve Lisberger (see volume 12), Alisson Doupe, Michael Merzenich, Christoph Schreiner, and Ken Miller. The energy in the Keck Center was fantastic and unquestionably contributed to my continuing efforts to take a multidisciplinary approach, involving neuroanatomy, electrophysiology, and pharmacology, to dissect the spinal cord circuits that process pain messages.

More Serendipity After the Winter Conference on Brain Research

My communications with John Liebeskind, while in London, definitely led to one of the most serendipitous and particularly significant events in my career. Soon after joining Howard Fields’s lab, I received a call (I almost wrote “email,” but email didn’t exist yet), from John Liebeskind, asking me if I could fill in for him at the Winter Conference on Brain Research (WCBR) meeting, a ski meeting in Keystone, Colorado. I knew nothing about the meeting, but agreed to attend. Having grown up in Montreal, I was very familiar with snow, but I was a hockey player. I did not ski at all. At the Keystone meeting, I gave a 30-minute evening talk about our findings on brain stimulation produced–analgesia and the neuroanatomical connections from the medulla to the spinal cord. A few questions were asked but nothing unexpected.

But the next morning was incredibly memorable. While standing in the ski lift line, another WCBR attendee, recognizable by the WCBR armband that everyone else thought was a radio station, approached me and introduced himself. It was Fred Plum, the editor-in-chief of the Annals of Neurology, not a journal that I regularly, or I must admit, ever read. He said that he was interested in the research that I presented the night before and asked if I would be willing to write a review for the journal. I thanked him and said, “Sure.” Only after returning to the lab and telling Howard about the invitation did I realize how significant that invitation was. As a neurologist, Howard was much more excited about the opportunity. Together we put together the review “Endogenous Pain Control System,” which not only reviewed our neuroanatomical and functional studies of descending controls but also included our hypothesis that morphine analgesia resulted from activation of the same descending control system that could be triggered by electrical stimulation of the PAG (Basbaum and Fields, 1978).

Thanks to the artistic talent of another postdoc in Howard’s lab, Stewart Anderson, the review included a diagram that illustrated our view of the circuits through which activity of PAG neurons engaged the raphe neurons of the RVM and the projections of the latter neurons to the dorsal horn. This was still the very early days of endorphins, but we did include a hypothetical circuit in which enkephalin release from inhibitory interneurons in the PAG somehow engages the descending control network. As opioids were inhibitory and activation of the PAG neurons that project to the raphe was required, we hypothesized that a disinhibitory circuit functioned in the PAG. Specifically, we proposed that the disinhibition involved enkephalin-mediated inhibition of GABAergic interneurons that act directly on the PAG-nucleus raphe magnus neurons. That figure was updated years later in an Annual Review of Neuroscience paper that Howard and I wrote, and it continues to be cited (Basbaum and Fields, 1984). Not surprisingly, details of the intrinsic circuitry in the raphe have greatly increased, and of course, there is now evidence for descending inhibitory as well as facilitatory actions that derive from the RVM. Howard, Mary Heinricher and Peggy Mason’s studies of RVM derived “on” and “off” cells are a beautiful illustration of the complexity of the circuit that we had considerably underestimated (Fields et al., 1991).

Substance P and Pain Processing

Following the demonstration that opiates exert their antinociceptive effects, in part, by regulating sensory-neuron-derived release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) (Jessel and Iversen, 1977), our laboratory studied peptide actions in a variety of acute and chronic pain models. Our earliest foray into transgenic mouse technology involved creation of a mouse in which the preprotachykinin gene that codes for substance P and other tachykinins was knocked out (Cao et al., 1998). The study was led by an outstanding graduate student, Yu-Qing Cao, who is now an associate professor at Washington University, and among the world’s experts in migraine pathophysiology. The initial analysis of the substance P knockout mouse was somewhat disappointing. Based on the literature demonstrating a profound substance P-mediated increase of activity in dorsal horn nociresponsive (i.e., presumptive pain-generating) neurons, we expected to observe a significant decrease in the behavioral response to a noxious stimulus, but that was not what we found.

Instead, it appeared that substance P only comes into play under suprathreshold pain conditions. However, the knockout condition did result in opiate sparing, in which the dose of morphine required to reduce pain was reduced. We published the results of this study in Nature and interestingly, the minimal baseline effect of deleting substance P turned out to be consistent with later clinical studies that found no utility in treating chronic pain with antagonists of the neurokinin1 receptor, which is targeted by substance P. Subsequently, Pat Mantyh and I published several papers on the functional relevance of the target of substance P, namely the NK1 receptor (Abbadie et al., 1997; Mantyh et al., 1995). Nevertheless, the limited effects of deleting substance P on pain behavior remain a mystery. Perhaps the most memorable result of our knockout study was that it led to a minireview of our study by a close colleague, Clifford Woolf. Well, at least the title of the minireview in Neuron was memorable and admittedly creative: “Null Mutations Lacking Substance: Elucidating Pain Mechanisms by Genetic Pharmacology” (Woolf et al., 1998). Fortunately, however, one of the authors of that minireview, Simona Neumann, decided to do a postdoc in my lab!

My lab’s very definite move into transgenic mice, including global and Cre-mediated knockout mice, was the motivation for the following poem that I wrote for a plenary lecture that I presented at the Vienna conference of the International Association for the Study of Pain (IASP). The topic was transgenic technology and its application to pain research.

Of Knockout Mice … and Humans

As a graduate student I worked in primates, and with Pat Wall I studied cats

And since moving to San Francisco, I turned to pain research in rats.

But now the peptide circuits that I study are in a 20 micron slice

Figuring out what happens when substance P is lost in preprotachykinin knockout mice.

Of course, some clinicians in the audience may question my advice,

That pain in humans can be helped by studying behavior in a slew of knockout mice.

I remind them that morphine’s efficacy in patients we can remarkably predict

By monitoring an opioid’s ability in mice to inhibit a heat-evoked tail flick.

Yes, Marilyn Monroe was a knockout, we all can agree.

And without question the greatest knockouts were at the hands of Mohammed Ali.

But to relieve pain, studying pain mechanisms in a knockout mouse still seems to me

A better approach to future therapy than continuing anterolateral cordotomy.

After the knockout mouse story was published, we continued to examine conditions in which substance P derived from nociceptors would come into play. Of particular interest was our Nature report of an N-methyl-D-aspartic acid (NMDA)-receptor-mediated regulation of substance P from primary sensory neurons (Liu et al., 1997). Of course, the NMDA receptor was not only implicated in memory formation in the hippocampus but also contributes to what I refer to as “maladaptive memory” in the dorsal horn of the spinal cord. Specifically, injury-induced persistent hypersensitivity has at its basis an NMDA-receptor-mediated sensitization of dorsal horn “pain” processing circuits. When we first investigated the receptor, it was assumed to exist only on postsynaptic neurons, In a series of neuroanatomical studies, however, we demonstrated that the receptor is, in fact, expressed at high levels in primary sensory neurons (Liu et al., 1994).The result was quite surprising as the implication was that glutamate release from sensory neurons could exert a facilitatory perhaps autoreceptor-mediated action on transmitter release from the same afferents. Another very close colleague and friend, Roger Nicoll (see volume 10), not surprisingly, didn’t buy into the possibility of presynaptic NMDA receptors. In fact, Roger considered that believing in presynaptic facilitation was heretical. However, when we demonstrated that substance P release from nociceptors is, in fact, regulated by presynaptic NMDA receptors, Roger relented slightly. Of course, presynaptic NMDA receptors have since been demonstrated in other areas of the central nervous system (CNS).

Peripheral Pain Processing Mechanisms: Science with Jon Levine

My interest in the contribution of substance P was unquestionably an important contributor to a very productive collaboration that I had with Jon Levine, a remarkable scientist. Jon, a rheumatologist who is a physician and holds a doctorate, is interested in inflammatory disease. Jon not only treats patients but also runs a large preclinical lab and has even published many important studies on the pathophysiology of postoperative dental pain. Our early studies addressed the peripheral mechanisms that contribute to the neurogenic inflammatory process, through which the release of chemicals from the peripheral terminals of primary sensory and sympathetic efferent neurons generates a profound inflammatory response. We first used the experimental arthritis model in rats. In a Science paper on the pathophysiology of the disease, we demonstrated that the level of substance P was particularly high in joints that developed the most severe arthritis and, more important, perhaps, that injection of substance P into a joint that normally develops less severe arthritis, namely the knee, would increase disease severity (Levine et al., 1984).

Subsequent studies reported that substance P levels are also high in arthritic joints of patients (Pritchett, 1997). In related studies, we demonstrated that the sympathetic nervous system also exerts a pathophysiological contribution to inflammation and pain (Levine, Dardick et al., 1986). The rat studies also led to an important clinical study in patients with pain associated with rheumatoid arthritis. Here, we demonstrated that guanethidine-induced sympathectomy, localized to the painful limb, could significantly reduce the ongoing pain (Levine, Fye et al., 1986). Just as Peter Nathan and Howard introduced me to the neurologist’s perspective on clinical pain, which definitely focuses on CNS processes, so Jon taught me about the important peripheral contribution of primary afferents and sympathetic efferents to clinical pain. Of course, those studies predated our recent focus on neuroimmune contribution to pain and itch (see “The Neuroimmune Contribution to Pain Processing”).

The Complete Opposite of Serendipity

Unfortunately, good things eventually come to an end. In 2000, Carol developed ovarian cancer. Although her oncologist said that she might survive six months, in fact, she lived for another six years, during which time, although cycling through every chemotherapy possible, her lab flourished. Her studies of mucin gene regulation and bacterial influences on epithelial cells (Lemjabbar and Basbaum, 2002) and on the effects of tobacco smoke on mucin genes (Gensch et al., 2004) are particularly notable. In fact, Carol cloned several mucin genes (Muc2, Muc5) for which the Cystic Fibrosis Foundation named a postdoctoral fellowship in her honor. To say that Carol was dedicated to her research is an understatement. To study the gene for CFTR, the cystic fibrosis transmembrane conductance regulator, she often went down to meet arriving boats at Fisherman’s Wharf at 5:00 a.m., where she picked up shark rectal glands, which are rich in CFTR. Try to explain to friends that your wife was picking up shark rectal glands at 5 a.m. at the wharf.

Another amusing story relating to Carol’s research is worth telling. Very soon after the Monica Lewinsky saga occurred, I suggested that perhaps the world was wrong in their conclusion as to what was on the famous dress. Rather, I suggested that perhaps Bill C. had sneezed on her, and that it was mucus! As Carol had the probes to determine if I was correct, I said that she could be famous. Interested in passing the proposal along, Carol quickly emailed Ken Adler, a major mucin research colleague in North Carolina, and relayed my proposal to probe the dress for Muc2, Muc5, and so on. Within 30 seconds, Ken emailed back that my suggestion was reasonable, but that a greater likelihood of success would arise if the dress were probed for Suc2, Suc5, and such.

The little story about Mucus genes truly illustrated the joy that Carol had in her research and with her colleagues. But when she died, I was lost. For almost 25 years, she and I came to the lab together; we didn’t work together and carefully avoided having lunch together. But getting home and seeing our two children, and discussing the science that happened during the day, had ended. At this time, I wondered what direction to go and seriously entertained the idea of moving to industry. I have served on several advisory boards, but it was at Rinat Neurosciences, headed by Arnon Rosenthal, where I consulted regularly. In fact, for one morning every week for almost two years, I attended regular roundtable discussions with Rinat scientists. This was an unusual arrangement, but one that the dean endorsed as he recognized that I needed a change. It was a wonderful experience, very different from the usual advisory board sessions. In fact, the meetings were more like a group meeting, where science was presented, argued, and discussed. Within a few months, I was offered a position as vice president at Rinat, but I decided that industry was not my cup of tea. I didn’t want someone else’s money and objectives to limit what I could do, no matter how important the indication was (obviously pain) and how cutting edge was the science.

Once again serendipity stepped in, however, thanks to the dean. Recognizing how important a change of environment would be for me, he suggested that I move my lab to the new Mission Bay campus. Here were entirely different surroundings, new buildings, and most important, a completely new daily driving routine and even better weather. The move was extraordinarily helpful. The lab was moved in less than two days and was up and running soon after. And my research studies with David Julius, who had already moved his lab from Parnassus to Mission Bay, began what has proven to be a continuing collaboration and friendship. And as noted below, remaining at UCSF was key, years later, to eventually meeting and marrying Marcia (see “A New Life With Marcia”).

David Julius, TRPV1, and the Nobel Prize

Of course, we all know that David Julius received the Nobel Prize for his discovery of the gene that codes for and the structure of TRPV1, the receptor targeted by capsaicin, the pungent ingredient in chili peppers. The history of the rationale for the search for the capsaicin receptor is particularly interesting. Many years ago, Hungarian scientists demonstrated that injection of capsaicin into neonatal rats would kill small-diameter, presumed nociceptive primary sensory neurons (Jancsó et al., 1977). These animals had dramatically reduced pain behavior to noxious heat stimulation. Recognizing the potential significance of this from a translational point of view, several pharmaceutical companies, notably Sandoz in the United Kingdom, worked hard to identify the receptor. But they failed. After his arrival in San Francisco, David attacked the problem. As a postdoc in Richard Axel’s lab, David used expression cloning and identified the 5HT1c receptor gene (Julius et al., 1998). At UCSF, David used the same approach and succeeded in cloning the capsaicin receptor (Caterina et al., 1997). Originally called VR1, the name changed to TRPV1, when it was appreciated that TRPV1 was a member of a very large family of TRP channels.

After David’s initial publication, our laboratories began a long and continuing collaboration on the functional relevance of the channel to acute and persistent pain. What David recognized is that many members of the TRP family are characterized not only by their expression in primary sensory neurons, and their responsiveness to temperatures, but also that many respond to natural products, with capsaicin epitomizing this phenotype. To date, we have published 15 papers together, not only on TRPV1 but also on other TRP channels (TPRA1), an irritant receptor (Bautista et al., 2006), and TRPM8, a cold and menthol receptor (Bautista et al., 2007), on the pain-provoking properties of a host of toxins (Osteen et al., 2016) and most recently on the location of the TRPV1 channel that regulates core body temperature (Yue et al., 2022). In several studies, we have taken advantage of the remarkable neuron killing properties of resiniferatoxin, which is about 1,000 times more potent than capsaicin and can kill TRPV1 afferents in the adult (Cavanaugh et al., 2009).

David and I have also published four reviews, one of which was published in Cell and is my most highly cited paper (Basbaum et al., 2009). These collaborations were not serendipitous, but illustrative of the incredible collaborative culture at UCSF, where the scientific strengths of different laboratories readily come together. Let me end this section with some practical advice. As David found, birds express the TRPV1 channel, but it is nonfunctional, presumably allowing the birds to investigate many plants. Of course, birds also like to eat from bird feeders, but so do squirrels. Well, as squirrels have a functioning TRPV1 channel, all that you need to do is add some cayenne to the bird food in your feeder and the squirrels will quickly stay away.

Ongoing Science at UCSF: The Neurochemistry of Pain Processing

Following our studies of the contribution of TRPV1 to pain processing, our laboratory continued to address the incredible molecular complexity of the sensory and spinal cord circuits that transmit injury messages that are interpreted by the brain as painful, as well as circuits that underlie the neurochemical control of nociceptive circuits in the dorsal horn. Of particular interest is our study of the very dense population of PKCγ-expressing interneurons located in inner lamina II of the dorsal horn. In a Science paper, we reported that knockout of PKCγ dramatically reduced the pain hypersensitivity produced in a neuropathic pain model, namely partial sciatic nerve section (Malmberg et al., 1997), in part via an influence on a subset of NMDA-receptor regulated dorsal horn circuits (Martin et al., 2011). Other studies examined the contribution of different glutamate transporters (VGlut2; Scherrer et al. 2010, and VGlut3; Seal et al., 2009), dorsal horn glycine receptors (Basbaum, 1998), as well as several very understudied molecules, for example, hippocalcin-like 4 (Alvaro et al., 2020), aquaporin 1 (Shields et al., 2010) and TR4, a testicular orphan nuclear receptor (Wang et al., 2013).

We also reported that dorsal horn calcitonin-gene-related peptide (CGRP), long considered to derive exclusively from primary sensory neurons, is also expressed in a population of lamina III interneurons and contributes to mechanical sensitivity (Löken et al., 2021). Most recently, we demonstrated that sensory neuron derived ACVR1, a receptor that to date is associated with a profound clinical phenotype, namely fibrodysplasia ossificans progressiva, is an important contributor to the pathophysiology of nerve injury-induced pain (Yu et al., 2022). Particularly productive and enjoyable has been a longstanding collaboration with Patty Phelps at UCSF. I know little to nothing about embryonic development of spinal cord circuitry, but together we have been studying the migration and function of lamina I neurons and the interesting contribution of reelin and DAB1 (Akopian et al., 2008).

Of course, as I have worked for years on opiate-induced mechanisms of pain control, it is not surprising that our laboratory also investigated the differential contribution of the multiple opioid receptor subtypes. Particularly rewarding was a series of studies with Greg Scherrer, a postdoc who trained with Brigitte Keiffer in Strasbourg, and who is now on the faculty at the University of North Carolina. Greg and I were intrigued by the many reports that the mu (MOR) and delta (DOR) opioid receptors dimerize and that this dimerization could underlie the regulation of pain processing at the level of primary sensory neurons (Gomes et al., 2004). Our anatomical studies, however, suggested that dimerization of the receptors in sensory neurons was highly unlikely (Scherrer et al., 2009). In fact, in double-label studies using an antibody against the mu receptor, in a delta receptor reporter (GFP) mouse, we found coexpression in fewer than 5 percent of sensory neurons. Rather, the mu receptor predominated in unmyelinated peptidergic afferents and the delta receptor predominated in the nonpeptidergic MrgprD subpopulation of unmyelinated afferents, as well as in larger, myelinated afferents. And, most important, our pharmacological studies found that an action at the mu receptor regulated heat-provoked pain behaviors and an action at the DOR regulated mechanical pain. Our paper did provoke a rather heated discussion as it also provided evidence that the reported pain-relevant regulation of substance P trafficking from primary sensory neurons to the dorsal horn via the DOR (Guan et al., 2005) is unlikely to occur as substance P and DOR are not found in the same neurons.

Functional Neuroanatomical Tracing: What’s All the Fos About?

Without question, one of the most significant influences in the approaches that our laboratory has taken to understand pain processing, particularly at the level of the spinal cord, was the Nature report of Stephen Hunt, on the use of c-fos expression to monitor the activity of CNS neurons (Hunt et al., 1987). For the record, I was one of the reviewers of that wonderful paper. Once it was published, we incorporated Fos expression into many of our studies, from changes in the spinal cord after injury (Chi et al., 1993) to the regulation of neuronal activity by a variety of analgesics, including morphine (Presley et al., 1990). I did have fun writing a short review of Fos studies in a paper titled: “What’s All the ‘Fos’ About?” (Basbaum, 1994). At the same time, in addition to introducing autoradiography to study descending projection systems, we constantly incorporated new tracing methods into our toolbox. Particularly productive were several earlier studies that used pseudorabies virus (either directly or in a Cre-dependent fashion) to map circuits that engage specific pain transmission neurons, for example, in the spino-parabrachial-amygdalo pathway (Jasmin et al., 1997).

But our laboratory has also developed our own protocols. In a collaboration with Daniel Menétrey, while on sabbatical in Paris, we generated an unusual modification of the traditional wheat germ agglutinin (WGA)-HRP tracer. Here we replaced the HRP with an apoprotein of the HRP, which was enzymatically inactive (Basbaum and Menétrey, 1987). As a result, it was possible to combine this new tracer with other HRP-linked tracers. More recently, with Joao Braz, a brilliant scientist who joined my lab as a postdoc from Paris and who continues to serve as my right hand in the lab for more than 20 years and 50 joint manuscripts, we generated a remarkable transgenic mouse that permits transneuronal tracing of complex, multisynaptic circuits in the CNS. In this mouse, we are able to trigger anterograde transneuronal expression of WGA in a Cre-dependent manner (Braz et al., 2005). Finally, we continue to use a slew of AAV and HSV viruses to dissect CNS circuits. Most recently, we used retrograde labeling to ribosomal profile spinal cord projection neurons (Wercberger et al., 2021). In these studies, we identified several novel genes that define the spinoparabrachial population, which led to our conclusion that projection neurons are not organized as labeled lines that transmit distinct modalities (i.e., heat, mechanical, cold), but that the neurons are polymodal. Our recent in vivo calcium imaging of projection neurons in awake mice supports that conclusion (see “Long-Term Spinal Cord Imaging in the Awake, Behaving Animal”).

Gabergic Transplant Treatment of the “Disease” of Neuropathic Pain

I have often spoken of the difficulty of raising funds for fundamental pain research, emphasizing that the problem is that people “die in pain, not of pain.” In other words, because the general public considers chronic pain to be a symptom of some other disease, somewhat understandably, their donations for research reach laboratories that study the disease that permanently injured or killed their loved ones (e.g., cancer, multiple sclerosis, heart attack, spinal cord injury). The family rarely donates to laboratories that study pain. Of course, the patients who experience these conditions often have ongoing, difficult to treat chronic pain. In my opinion, the conclusion that pain is a symptom of many diseases (e.g., osteoarthritis) is correct. But that conclusion is not correct for the neuropathic pain conditions that can follow damage to the nervous system.

Rather, neuropathic pain, in my opinion, is a disease of the nervous system, one generally of hyperexcitability secondary to loss of inhibitory controls, in the spinal cord and at higher levels of the nervous system. This designation would include post-stroke pain, pain after spinal cord injury, chemotherapy-induced neuropathic pain, and certainly phantom limb pain. The latter condition is particularly striking, as the pain is experienced in a limb that no longer exists. In many respects, chronic neuropathic pain is comparable to epilepsy, where there is hyperexcitability of cortical circuits, secondary to loss of inhibitory controls, and its manifestation is seizures. Not surprisingly, the first-line therapy for many neuropathic pains, although far from adequate, is anticonvulsants, which of course, are the first-line pharmacotherapy for seizures.

Given this perspective, we asked whether we could introduce a different approach to neuropathic management, namely one that is directed at treating the disease. To this end, Joao and I initiated a program that followed studies of John Rubenstein, Arnold Kriegstein, and Arturo Alvarez-Bullya and colleagues, who transplanted GABAergic inhibitory neuronal precursors from the medial ganglionic eminence of the embryonic mouse into the brain of seizure prone mice (Baraban et al., 2009). The transplants significantly reduced the seizure incidence, presumably by reestablishing inhibitory controls. In our studies, we transplanted the cells into the dorsal horn of mice that exhibited profound mechanical and thermal hypersensitivity after peripheral nerve damage, either partial transection of the sciatic nerve, or following paclitaxel chemotherapy. Electron microscopic studies brilliantly performed by my Australian colleague, Ida Llewellyn-Smith, who worked with us for two months for many years, demonstrated that the transplant integrated remarkably into the host spinal cord, extended axons, and made synapses with host neurons. The host formed synaptic contacts with the transplant (Llewellyn-Smith et al., 2018). Most important, the transplants restored inhibitory controls in the spinal cord and completely reversed the mechanical hypersensitivity and even ameliorated the persistent scratching that occurs in a chronic model of neuropathic itch (Braz et al., 2014).

In related studies we reported that transplanting the cells into the anterior cingulate cortex (ACC), which codes for the affective component of the pain experience, also ameliorated behavior indicative of the experience of pain, not just reflex endpoints (Juarez-Salinas et al., 2019). This approach is now in the clinic; five patients with focal epilepsy have been transplanted, and it is my hope that the company, Neurona Therapeutics, will eventually use the approach to treat different neuropathic pain conditions. Soon after Neurona’s formation, I served on its Scientific Advisory Board and remain enthusiastic about the technology.

The Neuroimmune Contribution to Pain Processing

The complexity of pain processing mechanisms grows with every new publication. Of particular interest is the increased emphasis on neuroimmune mechanisms, a subject that we enthusiastically are now addressing. Our studies focus on neuroimmune mechanisms in the generation of chronic pain, notably the neuropathic pain that can follow nerve damage. There is now considerable evidence for an important contribution of spinal cord microglia, which many studies have shown are “activated” following peripheral injury (Milligan et al., 2005). What was not known are the factors that initiate the microglial response. Using an RNASeq analysis of dorsal root ganglion neurons after peripheral nerve injury, we found that nerve-injury induced de novo synthesis of macrophage colony stimulating factor 1 (CSF1) in sensory neurons is both necessary and sufficient for the activation and proliferation of spinal cord microglia and for their contribution to the development of nerve injury-induced mechanical hypersensitivity (Guan et al., 2016).

And in a follow-up study, we demonstrated that this neuroimmune phenotype is sexually dimorphic, findings consistent with earlier reports of Jeff Mogil and colleagues at McGill (Sorge et al., 2015). Specifically, we found that male microglia are far more responsive to CSF1. In fact, although more than 1,200 genes are altered after intrathecal CSF1 injection in male mice, only 90 are altered in female mice (Kuhn et al., 2021). Furthermore, we found that the CSF1 significantly increased regulatory T (Treg) cell number in spinal cord meninges. Most interesting, in Treg-deficient mice, we found that intrathecal CSF1 in female mice not only activated microglial cells but also provoked hypersensitivity following peripheral nerve injury. That finding also paralleled the report that in the absence of T cells, microglia are contributors to nerve injury–induced hypersensitivity in female mice. Where we do not agree, however, is that we cannot find evidence that activated T cells actually penetrate the spinal cord to influence dorsal horn “pain” processing. Rather, our recent studies suggest that activation of meningeal Treg cells is critical to nerve injury–induced pain processing.

Ongoing Research and New Directions

As noted above, Ron Melzack once chided me at a meeting, saying that our work was great, but the studies are all about nociceptive processing, not pain. Admittedly our studies of spinal cord processing and descending control mechanisms that regulate spinal cord nociceptive processing did not get at the pain experience. So, I agreed with Melzack and indeed always teach medical students that “The Bane of Pain Is Plainly in the Brain.” Indeed, to underscore the complexity of pain processing and the importance of the brain, I wrote a short piece on the topic (Basbaum, 2018), as well as the following poem

The Bane of Pain Is Plainly in the Brain

Pain is an intricate potion,

Of sensations, cognitions, emotions,

Acute pain may be terrible

But it’s persistent pain that’s unbearable;

And rarely responds to mere lotions.

Though pain may not be easy to bear,

There’s often a reason for pain being there.

It’s critical to know,

Lest a cancer unbeknownst grow.

Pain signals a need for repair.

You learned of children with Congenital Insensitivity to Pain.

They’re unaware when they have fractures or sprains.

These children are rare,

But they need constant care.

Or their injuries will not be contained.

You see, A deltas and C’s are essential,

To establish the painful potential.

But shake your hand or vibrate,

And you may close Melzack and Wall’s Spinal Gate

So that the pain is no longer sequential.

In fact, there are myriad ways to control pain,

Which is perhaps why cordotomy’s on the wane.

Find out what the morphine dose is,

Even consider hypnosis.

Remember pain’s not a stimulus; it’s a perception of the brain.

In this regard, find a pregnant woman and ask her,

Is LaMaze merely a ploy to distract her?

Or when labor pain

Is not “perceived” by the brain,

Are the endorphins a relevant factor?

Speaking of endogenous opioids—there are numerous classes.

Some reportedly are as potent as grass is.

So, if you’re in pain

Just depend on your brain

Because the endorphins are the true opiates of the masses.

From the Spinal Cord to the Brain

Despite Melzack’s entreaties, it was actually years before our research turned to pain processing in the brain. My transition to the brain began with a very interesting collaboration with Vikaas Sohal, a neuroscientist and psychiatrist at UCSF. Our studies focused on the contribution of the ACC, a region of the brain implicated in the affective, or emotional component of the pain experience. The project was led by Karuna Meda, a joint neuroscience graduate student in Sohal’s lab and my lab (Meda et al., 2019). That study integrated behavior, optogenetics, and slice physiology and demonstrated that chronic pain–related aversion did not correlate directly with overall ACC hyperactivity, but rather to changes in the activity of specific pathways that engage ACC circuits, include those arising in the basolateral amygdala and dorsomedial thalamus. That study emphasized that to understand the basis of pain affect, one needs to examine the circuit changes within the ACC, not merely its overall level of activity. Our recent, calcium imaging and Fos studies of the effects of general anesthetics on ACC activity and pain processing provided results consistent with those conclusions (Weinrich et al., 2023; see “Calcium Imaging and General Anesthesia Mechanisms”).

Despite my rather late interest in brain mechanisms and pain affect, as a new faculty member, I was nevertheless assigned to give the limbic lectures, where emotions, of course, are processed. I did write a poem that illustrates the complexity of cognitive and emotional experiences and highlights rather dramatic approaches to treatment.

Neuroanatomy Can Be Stimulating, Especially in the Limbic System

Let me tell you a story about a Med Student named Fred

Who became so depressed that he wished he were dead.

When medication failed the doctors instead

Implanted electrodes in Fred’s mixed-up head.

Poor Fred …

The original plan was to make an electrolytic lesion

In the temporal lobe, near the amygdala region.

That idea was abandoned since there’s really no reason,

Stimulation techniques can be infinitely more pleasing.

Through a hole in Fred’s head the surgeons dropped electrodes towards

The mesolimbic pathway that signals reward.

Nucleus accumbens releases gobs of dopamine, and thus stimulation affords

A feeling so marvelous that Fred’s “joie de vivre” was restored.

Interestingly, the electrodes also evoked memories of indescribable smells.

Just where they came from Fred could not tell.

But Fred was so taken with the sensations olfactory

That his depression was almost completely refractory.

As Fred continued to improve and his psyche restored

He was suddenly inspired and shouted, “Good Lord!”

If I could only recall where my memories are stored

I might possibly pass the Part I Medical Boards.

Indeed, Fred passed the Boards and is doing just well.

Did a residency in psychiatry and neurosurgery, Do Tell!

No longer depressed, no more visions of Hell.

He just has to put up with an occasional odd smell.

So, if you’re depressed, try this new operation.

Turn yourself on with some self-stimulation.

It may not be as natural as Zen meditation,

But its morbidity is much less than frontal cortex ablation!

Calcium Imaging and General Anesthesia Mechanisms

Unquestionably, Karuna’s findings and a plethora of studies on the ACC were the impetus for a major technical change in the lab’s approach, highlighted by our introduction of calcium imaging. A postdoc in the lab, Jarret Weinrich, led our foray into the brain. Our initial plan was straightforward: use calcium imaging with miniscopes to monitor activity of neurons in the ACC, so as to better understand the ACC circuits that underlie pain affect. As noted earlier, the prevailing view, based on both clinical (ablation) and imaging (fMRI) studies was that reducing activity of the ACC can reduce the affective component. We introduced GRIN lens-based calcium imaging of neural activity in the ACC, but our first studies were disappointing. We were recording under isoflurane anesthesia and found that the ACC was quiet, in fact, silent, which provided absolutely zero insight into relevant circuits. But these initial recordings once again proved serendipitous. Jarret reminded me of the unusual properties of ether, compared with contemporary general anesthetics. Specifically, stages of anesthesia can be recognized during ether application, beginning with analgesia and amnesia, well before the patient is unconscious (Snow, 1847).

We actually received approval to study ether by the IACUC, but the office of Environment, Health, and Safety strongly discouraged its introduction into the lab, for pretty obvious reasons. So Jarret proposed that we study the dose-dependent action of more contemporary general anesthetics. Most interestingly, when we studied nitrous oxide, which has analgesic properties and has been used in dental and labor procedures, we unexpectedly found profound activation of excitatory neurons in the ACC (Weinrich et al., 2023). Clearly this paradoxical finding of an analgesic activating ACC neurons necessitated a reevaluation of the circuits in the ACC through which pain affect is generated. The clue to what might underlie the paradox was revealed when we studied the effect of a noxious stimulus (laser-evoked heat to the paw) in the presence or absence of nitrous oxide. Not surprisingly, the laser increased activity, however, in the presence of nitrous oxide, the increase was much reduced compared with the increase over baseline. This finding suggested that the extent to which ACC activity underlies pain affect is more a function of the difference between the noxious stimulus–evoked activity relative to baseline activity. We hypothesized that the activity provoked by the laser stimulus relative to spontaneous activity may, in fact, represent a biomarker of the affective component of the pain experience. And interestingly, we suggested that that activity may underlie the phenomenon of connected consciousness, in which there can be perceived pain in an anesthetized, immobile patient presumed to be unconscious (Sanders et al., 2017).

Long-Term Spinal Cord Imaging in the Awake, Behaving Animal

Having introduced calcium imaging, we turned our attention back to the spinal cord. Although trained as a spinal cord physiologist with Pat Wall, I have always appreciated the major limitation of the approach. Specifically, with only rare exceptions, all studies are performed in anesthetized animals, and they are performed acutely, making it impossible to follow the activity of neurons over time, so as to study the transition from acute to chronic pain. Very recently, with brilliant postdocs, Biafra Ahanonu and Andrew Crowther and a fabulous neuroscience graduate student, Mariela Rosa-Casillas, we have solved the post-laminectomy fibrosis problem, which makes long-term imaging possible (Ahanonu et al., 2023). The problem of excessive movement of the spinal cord has also been addressed, so that now we not only can record long-term images from the same population of spinal cord neurons, but also the recordings can be performed in the awake, behaving mouse. Immediately obvious, and admittedly not unexpected, was the increased excitability of dorsal horn neurons, including the presence of spontaneous activity and more pronounced firing in the awake versus the anesthetized state.

With this new ability, we are also now able to study the organization of dorsal horn circuits that process injury messages, before and after tissue or nerve injury, while correlating behavior. We are also addressing the longstanding question of the polymodality of dorsal horn projection neurons in superficial dorsal horn, not only in response to pain-producing algogens but also itch-provoking pruritogens, including histamine and chloroquine. Particularly exciting, although challenging, is our plan to concurrently record from spinal cord and brain regions (e.g., amygdala or ACC) so that we can interrogate mechanisms by which the brain makes decisions based on activity in populations of spinal cord projection neurons. Specifically, if there are no labeled lines for pain and itch, then the brain must decode activity across the projection neurons. Concurrent recordings from brain and spinal cord in the awake, behaving animal will hopefully provide insight into how those decisions are encoded.

Development of Novel Analgesics: Collaborating with the Chemists

This collaborative culture at UCSF is incredibly well-illustrated in our very recent work with UCSF chemists, in a DARPA-funded collaboration in which we seek to identify novel pain pharmacotherapeutics. The major objective is polypharmacology, specifically to develop nonopioid analgesics that concurrently interact with multiple targets in an additive or ideally in a synergistic fashion. Our laboratory has been working with UCSF chemists and biochemists, headed by Brian Shoichet, who use in silico screening to identify novel receptor ligands. Brian and colleagues screen against a cryostructure of a known analgesia target or by homology screening of an existing analgesic. Remarkably, they typically screen more than 300 million and, more recently, more than 2 billion structures and then narrow down the search, based on binding, PK, and other factors. The top candidates are synthesized, and to identify the most potent analgesics, our lab studies their effects in wild-type and a variety of knockout mice.

Of course, we are particularly interested in analgesics with the best therapeutic window. Especially notable is our recent discovery of several molecules that target the alpha2 adrenergic receptor. These novel ligands are analgesic in a variety of acute and chronic pain models and, most important, they do not show sedative effects at doses that are profoundly analgesic (Fink et al., 2022). By combining neuroanatomical and pharmacological approaches, we also focus on the loci where the novel drugs act. In other studies, we have identified novel ligands that are effective analgesics, including novel cannabinoid 1 receptor agonists (Tummino et al., 2023) as well as novel agonists that engage the EP4 receptor (Gahbauer et al., 2023), which is the target of pain-sensitizing prostaglandins.

The Lure of Industry

Not surprisingly, perhaps, my search for novel analgesics introduced me to small and large pharma. The need is obvious: 100 million people in the United States experience pain in a given year. And for about a third, the pain seriously interferes with quality of life. Of course, the drive to develop something as good as (and hopefully that can replace) opioids has provided a particularly strong incentive for venture capitalists to look for opportunities to translate laboratory findings into a successful company. Unfortunately, my success in the pain world has been less than outstanding. An earlier company in which Clifford Woolf and I engaged with several other colleagues failed when a microglial targeting effort proved ineffective for postherpetic neuralgia. Sadly, that was definitely an example of reverse serendipity. In fact, most of the scientists involved were not in favor of beginning the clinical trial, but the venture capitalists were insistent.

Very recently, I was a cofounder of Coda Biotherapeutics, which was developing chimeric receptors that could be targeted selectively to, for example, primary sensory neurons and activated by an oral drug that had no target other than the chimeric receptor. The logic of Coda’s approach is one that I have advocated for years. Specifically, there are many drugs that are effective against pain, but when administered systemically, they are severely limited by inevitable adverse side effects, particularly when the drug enters the CNS. Opioids offer the best example. Morphine is very effective for pain, but misuse liability, constipation, and, of course, respiratory depression are difficult to avoid. Ideally, the Coda chimeric drug would exert an effect only on the receptor, blocking pain, but not inducing adverse side effects. Disappointingly, despite impressive results, the recent difficulty in raising additional funds led Coda’s demise.

I continue to emphasize the principle upon which Coda was developed, and it is a principle that I teach medical students. As I have said very often, oral and other systemically administered drugs “don’t know where to go.” Thus, side effects are inevitable. As part of a TikTok for Science effort organized by graduate students in the Quantitative Biology program at UCSF, I agreed to create a 50-second video that emphasizes this principle. Specifically, I agreed to answer the question “How does the ibuprofen know where to go?” As I knew and still know almost nothing about TikTok, my first effort was not too successful. Marcia, to whom I am now married and who is a complete nonscientist, deemed the video of my answer to the question, “Boring!” Knowing my penchant for writing poems, she suggested that I write a poem, which I did and videotaped myself reading it. “Better, but not good enough,” Marcia said. “You need to Rap it!” I also know little about Rap, but I am game. So, for those interested, please check this video out: https://www.tiktok.com/@qbi_ucsf/video/6977811026590878982 As to the words of the poem:

How Does the Ibuprofen Know Where to Go?

You injure your knee, the knee’s inflamed, and boy it hurts like hell,

So, you take a pain reliever that you hope will make you well.

Into your mouth go ibuprofen pills, but they’re not looking for your knee.

The pills will travel everywhere, of that I guarantee.

You see the ibuprofen has no idea where to go, and so I must advise.

Ibuprofen will work everywhere, so stomach and other side effects could definitely arise.

You see, it’s the side effects from oral ibuprofen that limit what dose is needed for your knee.

And taking more pills won’t solve the problem; of this your stomach will certainly agree.

Alternatively, treat the injury directly, for example, a medicated patch placed on the knee;

Side-effects less likely, and with luck, you’re now pain free.

Memorable Events: The Berlin Dahlem Conference and Nagorno-Karabakh

I have often noted that one of the wonderful benefits of science is the opportunity to attend national and international meetings, where science is not only presented and discussed, but where lasting friendships are made. I believe that I have a close colleague in most of the major cities in the world, and even in some of the less-well-known cities. And often the meetings at which we interact take place in fabulous settings.

Serendipity unquestionably led to perhaps my most memorable international meeting, which Jean-Marie Besson and I organized. For many years, Jean-Marie led the most significant pain research group in France, and it was in his lab that I spent a wonderful sabbatical year. In 1988, we met in Berlin to plan a Dahlem conference, to be held in Berlin the following year. Dahlem conferences were unusual—only 40 attendees, many of whom are not in the field to be discussed. The hope was that bringing scientists from different disciplines, who meet for a week of largely informal discussions, could move the field in ways that do not occur with traditional get-togethers. Well, it turned out that one year later was exactly the date that the Berlin Wall came down, or at least opened up. Attendees arrived in Berlin in November 1989, expecting that the meeting would be canceled. In fact, the meeting went on as planned and was very successful, resulting in a book that included papers submitted ahead of time, as well as several rapporteur reviews of the discussions that took place.

But the evenings after the discussions ended proved most memorable. We went to the wall, hammer in hand, carved out pieces, listened to music, saw East German guards walking on top of the wall, but without guns, and watched as throngs of East Germans crossed the border. I remember seeing two East German and two West German soldiers literally pick up and carry a small Skoda (a two-stroke, single cylinder Czechoslovakian car) that got stuck at the border, into West Berlin. The crowd went nuts. I still have pieces of the wall in my office. Disappointingly perhaps, the initial title of the book (Towards a New Pharmacotherapy of Pain: Beyond Morphine) was overly optimistic. Morphine, sadly, is still the most powerful pain reliever available, and we continue to seek something better. So we dropped “Beyond Morphine” from the title of the book (Basbaum and Besson, 1991).

On a more somber note is a meeting that I attended more than 20 years ago, in Nagorno-Karabakh, a small enclave in the middle of Azerbaijan, populated by Armenians, but largely isolated. My dear friend, Vania Apkarian, with whom I recently cowrote an amicus brief concerning the Dobbs decision at the Supreme Court, wanted to make more people aware of the concerns surrounding Nagorno-Karabkh, which in 1994, had won a battle for independence from Azerbaijan. Vania organized a small meeting, in Stepanakert, the capital. We were housed in a hotel that survived the war, but it was rather run down and had little running water, and electricity often resulted in lights and slides disappearing in the middle of talks. But we met the people who lived in Nagorno-Karabakh, especially the children who loved the candy and even the flashlights that we were told to bring as gifts. I also remember the rather old Russian plane that took us from Yerevan, Armenia, where a post-election-attempted coup initially kept us in our hotel, to Nagorno-Karabakh. The return bus trip was even more eventful. We had to stop for hours at the border with Azerbaijan, so Ze’ev Seltzer organized the building of a large sculpture on the border, made from whatever attendees could collect (rocks, branches, leaves). Unfortunately, these positive memories are very sadly smothered by the recent war in Nagorno-Karabakh, in which Azerbaijan has retaken control. I know that Vania is devastated and is organizing a philanthropic effort to raise funds for the citizens who need support. My thoughts will always be with them.

A Memorable, but Embarrassing Event, and Forgettable Recognition

There is an oft-repeated illustration of the fact that my ability to communicate in French is not perfect. Although I am reasonably fluent in French, and in fact, have presented lectures in French, including a memorial to Jean-Marie Besson at a French Pain Society meeting in Nantes, what I clearly miss is an appreciation of French slang, and especially the evolution of the meaning of specific words. Years ago, I was at a meeting in Italy, with my late wife, Carol, and we were saying goodbye to Jean-Marie. I shook hands with Jean-Marie and said “Au revoir, a la prochaine.” Then Jean-Marie shook hands with Carol, at which point I said, “Jean-Marie, tu peux baiser ma femme,” which literally means you can kiss my wife (presumably on the cheeks). What I did not know is that a slang adoption had significantly changed the meaning of baiser. Translated to its contemporary meaning, what I said was, “Jean-Marie, you can f@&! my wife.” Jean-Marie’s glasses fell from his head. He laughed out loud, and then corrected me. I soon learned that I could not attribute my mistake to Quebecois French “un baiser” still means “a kiss,” but the slang version of the verb is what is now common both in France and in Quebec.

Carol and I did achieve some interesting royal recognition, but not necessarily recognition to put in your CV. My friends jokingly referred to Carol as the Queen of Mucus and me as the King of Pain! There are certainly many colleagues in the field who are better deserving of the title of King of Pain, but it did lead to a wonderful family event. As a gift for my 70th birthday, Marge and Thom Limbert, the brother and sister-in-law of Marcia’s son-in-law, Jake Limbert, wrote and sang a song “The King of Pain.” This song is an obvious take off on Police’s “King of Pain,” but their song instilled considerable humor by including phrases captured from some of my YouTube lectures on pain, including Placebos work! Where’s the pain? In my mind, of course.

The song is available at https://on.soundcloud.com/D2HNh. (I am not sure where they found the 1980s picture of me with an afro.)

Allan Basbaum Turns 70, and He’s the King of Pain

Lyrics by Marge Limbert; music by Tohm Limbert (and the Police).

There was a little post doc in a lab that day;

He’s the same old thing as yesterday.

There’s a last-minute present from an airport shop;

There’s a mouse he’s got and its pain will stop.

Chorus

I have stood by his bar, he’s pouring Tanqueray.

With the pain and itch neurons running round his brain, I guess. We’re always hoping that he’ll end his reign,

But, it’s his destiny to be the King of Pain

Chorus

There’s a little postdoc at the lab that day (he’s Canadian).

He’s the same old thing as yesterday (he’s Canadian).

There’s an interview with Charlie Rose (he’s Canadian.)

There’s a dreadful joke turning friends to foes (he’s Canadian).

Chorus

There’s a golfer who’s trapped in the sand his ball (he’s Canadian).

There’s a researcher altering his protocol (he’s Canadian).

There’s a jazz standard played by a dorky dad (he’s Canadian).

There’s a transgenic mammalian in his science lab (not Canadian).

Chorus

There’s a condo in Soma with modern;

There’s a short man braggin’ ’bout his peer review clout.

There’s a smart man eating lunch at Panda Express;

There’s a PhD made into a bobble head.

Chorus

There’s a boss having parties to reward his lab (he’s Canadian).

There’s a Sharks fan now who cheered on the Habs (he’s Canadian).

There was a little post doc in a lab that day.

He’s the same old thing as yesterday.

King of pain, king of pain, he will always be king of pain, he will always be king of pain.

Of course, it has been a while since I was a postdoc, but the birthday song was great fun. Unfortunately, after reading Empire of Pain: The Secret History of the Sackler Dynasty, by Patrick Radden Keefe, which is a remarkable book that tells the story about the Sacklers, Purdue Pharma, and the opioid epidemic, I learned that the book includes a pejorative reference to Russell Portenoy as the King of Pain. In my opinion, Russ has made many significant contributions to the clinical effort to treat chronic pain. If he is the King, then it is for those positive contributions.

The UCSF Environment: Amazing Faculty, Students, Postdocs, and Administrative Colleagues

I have often told my students and postdocs that being a scientist and pain researcher is my hobby. One student, Racheli Wercberger, thought that was great, and asked “When will it be my hobby?” I really do consider the science that I do every day to be equivalent in many ways to a delightful hobby, something that I look forward to doing, but definitely one that I take seriously. Of course, the hobby is significantly enhanced by my good fortune at being on the faculty at UCSF. Collegiality among the faculty, outstanding trainees, and an incredibly open and interactive research environment are the hallmarks of this place. Doors (and minds) are always open and establishing a collaboration is incredibly easy.

A few years ago, I looked back at my CV and realized that I had published with close to 40 UCSF faculty, highlighted, unquestionably by my collaborations with Howard, Jon, and David. In contemporary publications, technology is often significant, and it explains why papers now have many authors and a slew of approaches. The ability to engage others who are experts with different technologies is critical. At UCSF that is easy. The contrast with the way science was published in the past century is obvious; many fewer authors on papers, and as one of my graduate students commented after her lab meeting report on a paper published in the 1980s: “Not only did the manuscript from the last century have many fewer authors, but Figure 1 only had 1 figure!” “That’s why it’s called “Figure 1,” I said. Now, of course, every paper has 20 authors and Figure 1 has 20 tiny postage-stamp-size images.

Needless to say, the success of the laboratory owes much to the faculty at UCSF. Without an amazing administrative staff in the Anatomy Department, headed by Stephanie Louie, and without my executive assistant, Linda Toschi-Chambers, my responsibilities as chair for the past 25 years would have made the success of the laboratory impossible. And as department chair, I have received wonderful support from several deans, most recently Talmadge King, and the chancellor, Sam Hawgood. The greatest credit, however, must go to the incredible students, postdocs, and research technicians with whom I have had the good fortune to work. Many of the trainees have gone on to successful academic positions, including at Loyola University (Dan Cavanaugh), University of Pittsburgh (Brad Taylor), University of North Carolina (Greg Scherrer), Washington University (Yu-Qing Cao), and McGill University (Reza Sharif-Naieni). Additionally, Dana Rohde and Igor Mitrovic are both on the teaching faculty at UCSF. Many others chose industry (a common decision in the Bay Area), including many in leadership positions (Andrew Ahn, head of migraine research, Teva; Annika Malmberg, vice president, research, Sarepta Therapeutics; William (Bill) Martin, global therapeutic area head, neuroscience, Johnson & Johnson; and, last but certainly not least, Susan Hockfield, who was president of MIT. Many continue to hold positions in venture capital, science communication, and other posts in the educational field. Particularly striking is the remarkable breadth of countries from which the scientists in the lab originated: Great Britain, Ireland, Hungary, France, Iran, Israel, Canada, Sweden, Turkey, Norway, Spain, South Korea, Brazil, Venezuela, Germany, Japan, China, Australia, Russia, India, Serbia, Croatia, and, of course, the United States. Many languages are spoken, but the common one is the language of science. Lab meetings are engaging and always useful, during which we present ongoing research, exciting new discoveries, and creative technology, and most important, are never afraid to discuss problems, even experiments that failed. We alternate research meetings with a journal club, where everyone quickly realizes that if you have about 15 “reviewers,” no manuscript would ever get published.

Life and Work Outside the Lab

In addition to overseeing a research lab at UCSF, as well as being chair of the Anatomy Department since 1998, I have thoroughly enjoyed engaging in professional work outside the university. I served as treasurer of the IASP, and several years later, lost an election (fortunately) for president. I have been a member of the Board of Scientific Counselors at the National Institute for Dental Research (now the NIDCR), which for years was the home of one of the strongest pain research groups, led by Ron Dubner, who sadly died very recently.

As of this writing I am completing a four year stint on NINDS Council and continue as a member of the MDWG (the Multidisciplinary Working Group) that advises the executive committee of HEAL (Help End Addiction Long-Term). The latter committee was created by Congress and has dispensed significant funds to basic and clinical pain and addiction research efforts to address the ongoing opioid epidemic. Because there is no NIH Pain Research Institute, undoubtedly related to the fact that chronic pain cuts across the interests of almost all existing NIH Institutes, the effort of HEAL is particularly significant. At this time, I also serve as cochair of the Scientific Advisory Board of the Facial Pain Research Foundation, which is dedicated to finding a treatment for trigeminal neuralgia, and as chair of the IASP Publications Committee, which advises on policy for IASP Pain publications, including Pain, Pain Reports, and PRF (Pain Research Forum). I have also served on the advisory boards for small and large pharma, advising on novel pain therapeutics. Importantly, my outside activities are not limited to scientific enterprises. I was appointed to the board of the French American International School, which my daughter and son attended, and I served as president of the board for 10 years. No doubt that service is what led to my receiving the Chevalier French Order of Merit from the French government (not quite the Legion D’Honneur).

As noted earlier, many of my trainees followed my love of science and are in successful careers in academia and industry, and even as teachers in high school science. But it did take a while for the hobby to be firmly established. When I was setting up my first lab, I was probably impatient with the folks in the lab. I often walked through my 360-square-foot lab urging everyone to finish up their experiments, finish the injection, mount the sections, evaluate the slides, and take pictures. Apparently, I said that “I could do that in 10 minutes” once too often, and one day I came into the lab to see that everyone was wearing a t-shirt that said, “Allan does it in 10 minutes.” So that was the last time I used that phrase, and over the years, I have calmed down.

On the one hand, I still get excited when new ideas and results are presented at lab meetings, and I thoroughly enjoy putting research findings into print. I appreciate the challenge faced by students and postdocs and enjoy seeing their success. On the other hand, I have to say that I was taken aback at the 2022 SfN meeting, when I was approached by a young student at the Pain and Itch Social. This student introduced herself as my scientific great-granddaughter! Indeed, she was a graduate student in Greg Corder’s lab at Penn. Greg not only did his graduate work in a former postdoc’s lab, namely Brad Taylor, but Greg was also a postdoc in the lab of another postdoc, Greg Scherrer. Clearly, I have been doing science for a long time, but I still enjoy it. But I can’t promise that I’ll continue until I meet my great-great-grandchild in pain research.

Katherine and Jesse

My kids unquestionably grew up in an environment very different from many of their friends. From the time we arrived in San Francisco, Carol and I each worked six days per week, splitting the weekends. Vacations were rare, but we did travel together, with Katherine and Jesse, who was born five years later. I thought that Katherine and Jesse might continue our science tradition. Well, not quite. Katherine completed a theater degree at the University of California, San Diego. But even the theater majors had to take a science course, and Katherine not surprisingly took a neuroscience course. I remember her calling me one day saying that she and her dorm mates had a neuroscience exam and they needed help.

“Did I know anything about the NMDA receptor?” she asked.

“A little,” I said.

After a one-hour telephone tutorial, she did well on the exam, but she did not pursue neuroscience. Interestingly, however, after being convinced that an acting career was not ideal, she went to Tufts, where she received training as a registered dietician. That curriculum, of course, required her to take several basic science courses, physiology, and even molecular biology. Times did change. I remember her calling to tell me about a really interesting paper that she read on epigenetics! She is now a very successful dietician nutritionist at the University of Virginia and has been married for several years to Tony Noble.

My son, Jesse, followed a very different path. In fact, at Oberlin, Jesse did major in molecular biology and comparative English literature and also volunteered several times in my lab. I thought that he might consider medical school. Not at all. After working with immigrant workers in Oberlin and then in Portland, Rhode Island, he moved to New York where he became a private investigator for the Bronx Defenders, a public defender’s office. That experience convinced him to get a law degree. He attended Hastings College of Law in San Francisco, now called University of California College of the Law, because of the terrible legacy of its founder.

While in law school, Jesse was editor-in-chief of Law Review and then he clerked in Philadelphia for a senior judge, who had clerked for Thurgood Marshall. After a short stint in a major law firm, and another clerkship in Los Angeles, Jesse decided to become a public defender. He is married to an immigration attorney, Kate Mahoney, who he met in law school. They are both committed to using the law to the benefit of those who normally cannot afford it. Recently, after many years as a public defender, Jesse took a position in the state attorney general’s office, where he is a deputy attorney general. Needless to say, I was pretty impressed, but according to Jesse, there are many deputy attorney generals.

A New Life with Marcia

About two years after Carol died, dermatology chair, Bruce Wintroub, who at the time I only knew through endless committee meetings, asked me if I was “dating.” He said that there was someone who he wanted me to meet. No thanks, I said. Bruce would ask every three months, and finally, I agreed. So, Bruce and his wife, Marya, organized a dinner at their home and invited four friends. I was nervous as all get-out. But Marcia (Fortnoff), who lived a few blocks from Bruce and Marya and whose older daughter Kate was best friends with their daughter Mollie, was incredibly engaging. After dinner, we talked and talked. Marcia’s husband Ken had died a year before Carol, so in many ways we had a lot in common. We did start to “date” and three years later decided to get married. Marriage likely would have happened earlier, but we didn’t want to ruin the excitement of the pending marriage of Marcia’s oldest daughter, Kate, to Jake Limbert. Interestingly, we were married at City Hall by Gavin Newsom, then the mayor of San Francisco and now California’s governor, through a connection that Keith Yamamoto had. The “service” in his office was brief, but Gavin was gracious. Memorable was that when we walked out of his office, Marcia turned to me and said, “Boy, he’s handsome.” Interestingly, we just saw the movie Barbie, which includes Barbie’s boyfriend, Ken, and his friend, Allan, which of course, are the names of Marcia’s two husbands.

Marcia could not be more different from Carol. First, while Carol was a successful scientist with whom I could discuss the latest findings in my lab, Marcia was a court reporter and then a headhunter in the legal world. Marcia believes in pretty much every alternative therapy that exists, including acupuncture, which I believe is an exotic placebo. But placebo, in my opinion, is a word that needs to be replaced. Specifically, when I suggest to friends that many, if not all, successful alternative or complementary therapies are a placebo, the natural assumption is that I am implying that nothing was wrong in the first place. Far from it, of course. Placebos can be very effective particularly against pain, which is a percept of the brain. In my pain lecture to the medical students, I tell them that at home I can use the “f” word, but not placebo. We need a new word.

Our families have blended incredibly well. Most enjoyably, our sphere of friends, and notably their exceptionally varied backgrounds, have grown. Not surprisingly, many of my closest friends are scientists, but Marcia’s friends include many lawyers, artists, hair stylists, and chefs, and we meet regularly. Marcia and I together have four grandchildren, all of whom fortunately, live in the Bay Area. Marcia’s older daughter, Kate, is a psychotherapist and is an expert in couples therapy. Kate’s husband Jake is interim vice president of Supply Chain and Support Services at UCSF. Marcia’s younger daughter, Chase, is a social worker and Veterans treatment specialist. She works with veterans who have pending criminal cases and helps them get diverted to Veterans Treatment Court and connected to VA services. Chase’s husband Agustin is also a public defender, and one of the most ardent baseball fans I have ever met, attending both Giants’ and A’s games, as well as soccer games in San Jose. Kate and Jake have two girls, Willa (11) and Hazel (7), and Jesse and Kate have a son, Aengus (6), who we call Gus, and a daughter, Maeve (3).

Sadly, COVID has limited the times that Katherine and her husband Tony can visit from Charlottesville, but hopefully, passing of the pandemic will allow for more visits in the near future. We have a second home in Napa, which was built when Carol was ill, as a place to get away. However, in 2017, the home was destroyed in one of the too many fires in Napa Valley. Fortunately, the insurance companies were outstanding, and we rebuilt the home. Marcia and I don’t get there very often, but our children and grandchildren thoroughly enjoy it. As a fun aside, after the fire, the insurance agent insisted that everything depreciates. I argued that art, which is one of the areas in which Marcia and I completely agree, never depreciates. I reminded the agent of the Saudi Arabian prince who recently purchased a Da Vinci painting for $450 million; clearly paintings appreciate in price! Probably terrified, the agent asked me: “You didn’t have a Da Vinci in Napa, did you?” Fortunately for her, I didn’t.

Should I Retire?

Having been involved in pain research for more than 50 years, I do have to look into the mirror and ask whether it is time to pass the torch, not only the scientific one, but also the administrative one. As Marcia, knows I need to be busy. My nonscience hobbies include playing jazz piano, and I still take lessons, and I am a golfer. After our home in Napa burned down, I was invited to join Bruce Wintroub and two other friends and play every weekend in Richmond. I am actually improving and thoroughly enjoy the weekly four hours of camaraderie.

I have, in fact, discussed a transition with the dean (not quite as dramatic as the television series Succession), but a discussion that is nevertheless relevant to the Anatomy Department faculty. In fact, about 15 years ago, I seriously considered stepping down. The department was populated by many senior faculty, so there was little that the chair could do; space was occupied and there was no hiring. When a senior faculty member had funding issues, putting out fires predominated. But I stayed on, and after many retirements, the department was truly reborn. We have hired many young, dynamic scientists (interestingly only a couple of neuroscientists). Rather, the department’s strength is in cell and development biology, stem cells and cancer. Two years ago, we created an Aging Research Institute, headed by Leanne Jones, whom we recruited from UCLA, and Saul Villeda, whose studies of blood factors that influence aging have truly revolutionized the field. A wonderful gift made possible the creation of the Bakar Aging Research institute (BARI). The Institute is now a vibrant research enterprise, with faculty from many departments focused on the biology of aging. There is hope for me yet.

In Summary: A Gift to Readers—PRM

As it is unlikely that all readers will enjoy reading my autobiography, I am ending with a final poem that I hope will be of interest to most SfN members. Needless to say, we are all overwhelmed by emails. Unfortunately, although the great majority can be immediately deleted, many contain messages that we need to address. But often, for many reasons, we can’t answer immediately our email. My concern, however, is that the message will get lost. The oppressive effect of COVID made communication even worse, as in person interactions led to even greater numbers of emails arriving every day. To reduce the potential negative impact of the increased electronic communication, I created PRM, which stands for Please Remind Me. Specifically, when I want to highlight a message that I must not forget, I forward it immediately to Linda, my administrative assistant, with PRM in the subject line. Every Wednesday and Friday afternoon, I receive a list of the PRMs, so that important messages and relevant dates when an answer is required never get lost or forgotten. That simple solution has greatly improved how I deal with the ridiculous number of emails, only some of which need an immediate response.

PRM (Please Remind Me) Is a Gem

Well, COVID has unquestionably changed how we work; it’s all email and Zooming forever.

But prioritizing what to do hasn’t changed, our colleagues still hate to hear “Oh, whenever.”

Some work still needs to get done, so you should try PRM,

You won’t forget a key task, and avoid more mayhem.

Every Wednesday and Friday, you’ll receive updates of the PRM lists.

You’ll probably recognize some needy individual, who you thought no longer exists.

Some emails seemed unimportant, others portend coming doomsday.

Those can’t wait till December, so answer them today.

This reminder method can work miracles; some make my assistant LOL

Especially when I refuse to address them, as they are the emails someone sent from hell.

So give it a try with your colleagues, adopt PRM.

It could alter your life; it’s truly a gem.

The last few years have been tough, but working together we did COVID survive.

Everyone’s amazing; staff, faculty, students, and postdocs continue to thrive.

We are now really “rounding the corner” and now have reasons to cheer.

So, my PRM for everyone is to have a very successful rest of this year.

Selected Bibliography

Abbadie C, Trafton J, Liu H, Mantyh PW, Basbaum AI. 1997. Inflammation increases the distribution of dorsal horn neurons that internalize the neurokinin-1 receptor in response to noxious and non-noxious stimulation. J Neurosci. 17:8049–60.

Ahanonu B, Crowther A, Kania A, Rosa-Casillas M, Basbaum AI. 2023. Long-term optical imaging of the spinal cord in awake, behaving animals. bioRxiv 2023.05.22.541477.

Akil H, Mayer DJ, Liebeskind JC. 1976. Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist. Science 191:961–62.

Akopians AL, Babayan AH, Beffert U, Herz J, Basbaum AI, Phelps PE. 2008. Contribution of the Reelin signaling pathways to nociceptive processing. Eur J Neurosci. 27:523–37.

Alvaro CG, Braz JM, Bernstein M, Hamel KA, Craik V, Yamanaka H, Basbaum AI. 2020. Hippocalcin-like 4, a neural calcium sensor, has a limited contribution to pain and itch processing. PLoS One 15:e0226289.

Baraban SC, Southwell DG, Estrada RC, Jones DL, Sebe JY, Alfaro-Cervello C, Garcia-Verdugo JM, Rubenstein JL, Alvarez-Buylla A. 2009. Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice. Proc Natl Acad Sci (USA) 106:15472–77.

Basbaum AI. 1974. Effects of central lesions on disorders produced by multiple dorsal rhizotomy in rats. Exp Neurol. 42:490–501.

Basbaum AI. 1988. Distribution of glycine receptor-immunoreactivity in the spinal cord of the rat: Cytochemical evidence for a differential glycinergic control of lamina I and V nociceptive neurons. J Comp Neurol. 278:330–36.

Basbaum AI. 1994. Immediate early genes: What’s all the Fos about? Commentary: APS Journal 3:49–52.

Basbaum AI. 2018. The bane of pain is mainly in the brain. In: Think Tank: Forty neuroscientists explore the biological roots of human experience, 128–34. Ed. Linden DJ. New Haven, CT: Yale University Press.

Basbaum AI. 2020. In memoriam: Ronald Melzack. Pain 161:877–79.

Basbaum AI. 2022. History of spinal cord “pain” pathways including the pathways not taken. Front Pain Res (Lausanne). 3:910954.

Basbaum AI, Bautista DM, Scherrer G, and Julius D. 2009. Cellular and molecular mechanisms of pain. Cell 139:267–84.

Basbaum AI, Besson JM, Eds. 1991. Towards a new pharmacotherapy of pain. New York: Wiley.

Basbaum AI, Clanton CH, Fields HL. 1976. Opiate and stimulus-produced analgesia: Functional anatomy of a medullospinal pathway. Proc Natl Acad Sci (USA). 73:4685–88.

Basbaum AI, Clanton CH, Fields HL. 1978. Three bulbospinal pathways from the rostral medulla of the cat: An autoradiographic study of pain modulating systems. J Comp Neurol 178:209–24.

Basbaum AI, Fields HL. 1978. Endogenous pain control mechanisms: Review and hypothesis. Ann Neurol. 4:451–62.

Basbaum AI, Fields HL. 1979. The origin of descending pathways in the dorsolateral funiculus of the spinal cord of the cat and rat: Studies on the anatomy of pain modulation. J Comp Neurol. 187:513–32.

Basbaum AI, Fields HL. 1984. Endogenous pain control systems: Bulbospinal pathways and endorphin circuitry. Ann Rev Neurosci. 7:309–38.

Basbaum AI, Hand PJ. 1973. Projections of cervicothoracic dorsal roots to the cuneate nucleus of the rat, with observations on cellular “bricks.” J Comp Neurol. 148:347–59.

Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EH, Basbaum AI, Julius D. 2006. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–82.

Basbaum AI, Marley NJE, O’Keefe J, Clanton CH. 1977. Reversal of morphine and stimulus-produced analgesia by subtotal spinal cord lesions. Pain 3:43–56.

Basbaum AI, Menétrey D. 1987. Wheat germ agglutinin-apoHRP gold: A new retrograde tracer for light- and electron-microscopic single- and double-label studies. J Comp Neurol. 261:306–18.

Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. 2007. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448:204–208.

Basbaum AI, Wall PD. 1976. Chronic changes in the response of cells in adult cat dorsal horn following partial deafferentation: The appearance of responding cells in a previously non-responsive region. Brain Res. 116:181–204.

Braz JM, Juarez-Salinas D, Ross SE, Basbaum AI. 2014. Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch. J Clin Invest. 124:3612–16.

Braz JM, Nassar MA, Wood JN, Basbaum AI. 2005. Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor. Neuron 47:787–93.

Brown JL, Liu H, Maggio JE, Vigna SR, Mantyh PW, Basbaum AI. 1995. Morphological characterization of substance P receptor-immunoreactive neurons in the rat spinal cord and trigeminal nucleus caudalis. J Comp Neurol. 356:327–44.

Cao YQ, Mantyh PW, Carlson EJ, Gillespie A-M, Epstein CJ, Basbaum AI. 1998. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392:390–94.

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. 1997. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 389:816–24.

Cavanaugh, DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ. 2009. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci. (USA) 106:9075–80.

Chi SJ, Levine JD, Basbaum AI. 1993. Effects of injury discharge on the persistent expression of spinal fos-like immunoreactivity produced by sciatic nerve transection in the rat. Brain Res. 617:220–24.

Fields HL, Clanton CH, Anderson SD. 1977. Somatosensory properties of spinoreticular neurons in the cat. Brain Res. 120:49–66.

Fields HL, Heinricher MM, Mason P. 1991. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci. 14:219–45.

Fink EA, Xu J, Hübner H, Braz JM, Seemann P, Avet C, Craik V, Weikert D, Schmidt MF, Webb CM, Tolmachova NA, Moroz YS, Huang XP, Kalyanaraman C, Gahbauer S, Chen G, Liu Z, Jacobson MP, Irwin JJ, Bouvier M, Du Y, Shoichet BK, Basbaum AI, Gmeiner P. 2022. Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor. Science 377:eabn7065.

Gahbauer S, DeLeon C, Braz J, Craik V, Kang HJ, Wan X, Huang X-P, Billesb⊘lle CB, Yongfeng Liu Y, Che T, Ishan Deshpande I, Jewell M, Fink EA, Kondratov IS, Moroz YS, Irwin JJ, Basbaum AI, Roth BL, Shoichet BK. 2023. Docking for EP4R antagonists active against inflammatory pain. Nature Comm. 14:8067.

Gensch E, Gallup M, Sucher A, Li D, Gebremichael A, Lemjabbar H, Mengistab A, Dasari V, Hotchkiss J, Harkema J, Basbaum C. 2004. Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK. Biol Chem. 279:39085–93.

Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA. 2004. A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci. (USA) 101:5135–39.

Guan J-S, Xu Z-Z, Gao H, He S-Q, Ma G-Q, Sun T, Wang L-H, Zhang Z-N, Lena I, Kitchen I, Elde R, Zimmer A, He C, Pei G, Bao L, Zhang X. 2005. Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia. Cell 122:619–31.

Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, Guan AK, Evans-Reinsch Z, Braz J, Devor M, Abboud-Werner SL, Lanier LL, Lomvardas S, Basbaum AI. 2016. Injured sensory neurons de novo express CSF1 and induce DAP12-dependent neuropathic pain and DAP12-independent microglial proliferation. Nature Neurosci. 19:94–101.

Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. 1975. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258:577–80.

Hunt SP, Pini A, Evan G. 1987. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation Nature 328:632–34.

Jancsó G, Kiraly E, Jancsó-Gábor A. 1977. Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones. Nature 270:741–43.

Jasmin L, Burkey AR, Card JP, Basbaum AI. 1997. Transneuronal labeling of a nociceptive pathway, the spino-(trigemino-)parabrachio-amygdaloid, in the rat. J Neurosci. 17:3751–65.

Jasmin L, Wang H, Tarczy-Hornoch K, Levine JD, Basbaum AI. 1994. Differential effects of morphine on noxious stimulus-evoked Fos-like immunoreactivity in subpopulations of spinoparabrachial neurons. J Neurosci. 14:7252–60.

Jessell TM, Iversen LL. 1977. Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature 268:549–51.

Juarez-Salinas DL, Braz JM, Etlin A, Gee S, Sohal V, Basbaum AI. 2019. GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness. Brain 142:2655–69.

Julius D, MacDermott AB, Axe Rl, Jessel TM. 1998. Molecular characterization of a functional cDNA encoding the serotonin 1c receptor. Science 241:558–64.

Kaas JH, Merzenich MM, Killackey HP. 1983. The reorganization of somatosensory cortex following peripheral nerve damage in adult and developing mammals. Annu Rev Neurosci. 6:325–56.

Karplus JP, Kreidl A. 1914. Ein Beitrag zur Kenntnis der Schmerleitung im Ruckenmark. Pflugers Arch. 158:275–287.

Kuhn JA, Vainchtein ID, Braz J, Hamel K, Bernstein M, Craik V, Dahlgren MW, Ortiz-Carpena J, Molofsky AB, Molofsky AV, Basbaum AI. 2021. Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice. Elife 10:e69056.

Lemjabbar H, Basbaum C. 2002. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med. 8:41–46.

Levine JD, Clark RE, Helms C, Moskowitz MA, Basbaum AI. 1984. Intraneuronal substance P contributes to the severity of experimental arthritis. Science 226:547–49.

Levine JD, Dardick SJ, Roizen MF, Helms CH, Basbaum AI. 1986. The contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis. J Neurosci. 6:3423–29.

Levine JD, Fye K, Heller PH, Basbaum AI, Whiting-O’Keefe Q. 1986. Clinical response to regional intravenous guanethedine in patients with rheumatoid arthritis. J Rheumatol. 13:1040–43.

Liu CN, Chambers WW. 1958. Intraspinal sprouting of dorsal root axons; development of new collaterals and preterminals following partial denervation of the spinal cord in the cat. AMA Arch Neurol Psych. 79:46–61.

Liu H, Mantyh PW, Basbaum AI. 1997. NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386:721–24.

Liu H, Wang H, Sheng M, Jan LY, Jan YN, Basbaum AI. 1994. Evidence for presynaptic N-methyl-D-aspartate autoreceptors in the spinal cord dorsal horn. Proc Natl Acad Sci. (USA) 91:8383–87.

Livingston WK. 2012. Pain and suffering. Ed. Howard Fields. Seattle, WA: IASP Press.

Llewellyn-Smith IJ, Basbaum AI, Bráz JM. 2018. Long-term, dynamic synaptic reorganization after GABAergic precursor cell transplantation into adult mouse spinal cord. J Comp Neurol. 516:480–95.

Löken LS, Braz JM, Etlin A, Sadeghi M, Bernstein M, Jewell M, Steyert M, Kuhn J, Hamel K, Llewellyn-Smith IJ, Basbaum A. 2021. Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity. Elife 10:e59751.

Lowney LI, Schulz K, Lowery PJ, Goldstein A. 1974. Partial purification of an opiate receptor from mouse brain. Science 183:749–53.

Malmberg AB, Chen C, Tonegawa S, Basbaum AI. 1997. Preserved acute pain and reduced neuropathic pain in mice lacking PKCγ. Science 278:279–83.

Mantyh PW, DeMaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE, Simone DA. 1995. Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268:1629–32.

Martin WJ, Malmberg AB, Basbaum AI. 2011. PKCgamma contributes to a subset of the NMDA-dependent spinal circuits that underlie injury-induced persistent pain. J Neurosci. 21:5321–27.

Meda KS, Patel T, Braz JM, Malik R, Turner ML, Seifikar H, Basbaum AI, Sohal VS. 2019. Microcircuit mechanisms through which mediodorsal thalamic input to anterior cingulate gyrus exacerbates pain-related aversion. Neuron 102:944–59.

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Presley RW, Menétrey D, Levine JD, Basbaum AI. 1990. Systemic morphine suppresses noxious stimulus-evoked fos protein-like immunoreactivity in the rat spinal cord. J Neurosci. 10:323–35.

Pritchett JW. 1997. Substance P level in synovial fluid may predict pain relief after knee r replacement. J Bone Joint Surg Br. 79:114–16.

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Joanne Berger-Sweeney

BORN:

Los Angeles, California

September 21, 1958

EDUCATION:

Wellesley College, Wellesley, MA, BA, Psychobiology (1979)

University of California, Berkeley, CA, MPH, Environmental Health Sciences (1981)

Johns Hopkins School of Public Health, Baltimore, MD, PhD, Neurotoxicology (1989)

National Institute of Health and Medical Research (INSERM), Paris, France, Postdoctoral, Neurophysiology (1989–1991)

APPOINTMENTS:

Environmental Scientist, Environmental Science Associates, Berkeley, CA (1982–1984)

Assistant to Full Professor, Department of Biological Sciences, Wellesley College, Wellesley, MA (1991–2010)

Director and Codirector, Neuroscience (formerly Psychobiology) Program, Wellesley College (1992–1996 and 2004–2006)

Associate Dean of the College, Wellesley College (2004–2010)

Professor of Biology, Adjunct Professor of Psychology, Professor (secondary) of Public Health and Community Medicine, Tufts University, Medford/Boston, MA (2010–2014)

Dean of the School of Arts and Sciences, Tufts University, Medford, MA (2010–2014)

President and Professor of Neuroscience, Trinity College, Hartford, CT (2014–present)

HONORS AND AWARDS:

National Science Foundation Young Investigator Award (1994)

Fogarty Senior International Fellowship to Switzerland (1994)

Class of 1966 Associate Professor (endowed), Wellesley College (2001)

Fellow, International Behavioral Neuroscience Society (2002)

Fellow, Faculty for Undergraduate Neuroscience (2004)

Allene Lummis Russell Professor of Neuroscience (endowed), Wellesley College (2004–2010)

Lifetime Mentoring Achievement Award, Society for Neuroscience (2006)

Honorary Member, Phi Beta Kappa (2011)

Fellow, American Association for the Advancement of Science (2012)

Alumni Achievement Award, Johns Hopkins School of Public Health (2015)

Posse Star, Posse Foundation (2017)

Member, American Academy of Arts and Sciences (2018)

Joanne Berger-Sweeney has conducted research on the neurobiology of learning and memory. With interests in behavior, pharmacology, toxicology, and the cholinergic system, her scientific work has focused on Alzheimer’s disease and Rett syndrome. She did the proof-of-concept work on Razadyne, one of the most widely used Alzheimer’s drugs in the world. She transitioned to academic administration, where she became the first African American and the first woman to serve as president of Trinity College since its founding in 1823.

Joanne Berger-Sweeney

Early Years

Growing Up in La La Land

I was born and raised in Los Angeles, in a close-knit and supportive family. I loved skateboarding, beaches, my family, and movies, and I especially loved musicals. Our home was filled with music as my mother played the piano and organ beautifully. To me, growing up in L.A. was a privilege, and I believe it was, in great part, why I have a bright and sunny attitude about life.

Los Angeles was a complex and interesting multiracial environment. You could go throughout different parts of the city and encounter people of all races and ethnicities. This was in the 1960s and 1970s, well before that kind of diversity seemed to spread throughout the rest of the country.

My parents placed a high value on education and encouraged my budding career as a scientist. I’ve always had a love of science and math, although there were no other scientists in our immediate family. My father, Paul Sweeney, was an attorney, and my mother, Arminta Parks Sweeney, served as executive director of the Angeles Girl Scout Council. My two brothers, Paul and John—eight and seven years older than me, respectively—followed our father’s footsteps into the legal profession, and today they are both practicing attorneys in Los Angeles.

Family History

Throughout my childhood and high school years, my mother would wake me up each morning by whispering in my ear, “You can be anything you want to be.” From as far back as I remember, I was aware that our family had a proud history of involved and engaged African American citizens. On my father’s side, I can trace back to my great-great-grandfather, Jacob Pruett, who spent 40 years of his life in slavery and then became one of the first African American men ever to vote in the United States. Jacob’s granddaughter, Alberta, was a trailblazer as well—she was the first African American invited to serve on the board of the Girl Scouts of New York City. Alberta’s husband, my grandfather, was one of the first African American men to graduate from Oberlin Seminary and was minister of the largest Black Methodist Church in Harlem in the 1950s and 1960s.

On my mother’s side, my second cousin was the poet Sterling A. Brown. My mother’s parents were both college educated, and I was told that my maternal grandmother’s parents attended Clark College in Atlanta (now Clark Atlanta University)—one of the country’s first historically Black colleges—when it was a two-year college, after slavery. So, I believe that on my mother’s side, I am fourth-generation college educated, and on my father’s side, I am at least the third generation to attend college. In other words, education was highly valued and promoted in our family.

Image 1: With my mother, Arminta Parks Sweeney, as a young child, circa 1960

I learned my family’s history through stories that were shared to give us pride in who we were and where we came from because, of course, there might be external influences telling you that maybe you’re not as smart as someone else. I think my parents felt it was particularly important to instill that sense of pride in their children, so that each of us knew where we were from and hence would gain a sense of how far we could go. The expression “I am where I am because I stood on the shoulders of giants” conveys well what my brothers and I learned growing up in our family.

My father grew up in Harlem and was a basketball star in his youth. He served in the military before heading to Atlanta to attend Clark College, where he met my mother, a fellow student, who was born and raised in Atlanta. She was younger than my father but a year ahead of him at Clark because his military service delayed the start of his college career. After my mother graduated at age 19 with her bachelor’s degree, majoring in sociology and minoring in music, she earned her master’s degree in sociology at Atlanta University while my father finished his undergraduate degree. My brother Paul was born while my parents were still in Atlanta, and then they moved to Washington, D.C., where my father attended Howard University School of Law. My brother John was born while they lived in Washington, D.C., and it was seven years later that I would appear on the scene, after my family had established new roots in Los Angeles.

Go West!

Family lore has it that on the day my father graduated from law school in 1954, he packed up his bags to drive cross-country to set up life in Los Angeles. My mother, with the two boys in tow, took the train to join my father a little later. My father felt that California was the land of opportunity, where our family would be perceived differently than they were in Atlanta, D.C., or New York City, where he was raised. My cousin, who is a lawyer who studies lawyers, has reminded me of how few Black lawyers there were in the United States at that time—about 2,000 in the 1950s. My father graduated number two in his law school class at Howard, where Thurgood Marshall, the first Black U.S. Supreme Court justice, was an alumnus. My father, a few years later, was taught by some of the same professors as Justice Marshall.

My parents became deeply involved in the fabric of their new California home. My father’s first job was at the Urban League before he went into private practice. My mother spent most of her career working for the Girl Scouts before eventually becoming executive director of the Angeles Girl Scout Council. They both had deep roots in the church and depended on community. Social networks existed long before Facebook, and my parents were very successful in using theirs to help themselves and others. My parents took risks and seized the opportunities that their education afforded them. They developed and used their networks to the fullest, and those networks supported their children and inspired them to learn.

Church and Civil Rights Movement

I was raised during the civil rights movement, and we attended one of the largest and most prominent Black Methodist churches in Los Angeles, Holman United Methodist Church. We regularly welcomed well-known guest speakers, including the Reverend Dr. Martin Luther King Jr., Archbishop Desmond Tutu, and the Reverend Jesse L. Jackson. These leaders came to speak at our church, where our preacher was the Reverend James Lawson, a well-known civil rights activist. I grew up thinking that going to church was a social justice and civil rights activity. At some point, my brothers stopped going to church, and my father was no longer attending by then—my parents divorced when I was around 13 or 14 years old. But my mother and I continued attending every week. It was a very proper, dignified service with classical music and African American spirituals, but no gospel music, and it was a very important part of my upbringing, particularly with that focus on engagement and activism.

Early Love of Science

At school, my propensity for science was apparent from an early age. I felt a great sense of anticipation before dissections in science class, finding it fascinating to see how all the different parts of a frog’s body worked together. At some point in either middle or high school, I received a math and science award sponsored by Bank of America. I also recall another, though less formal, moment of recognition during middle school. We were typically seated alphabetically, and it so happened that sitting next to me was the cutest guy in the class, a basketball player who eventually went on to play professionally. I always did well on tests, which I would say is self-perpetuating; when you do well, you think you’re smart, and so you continue to do well. I remember this handsome classmate looking over at my exam, and I thought, “Fine, go ahead, you’re cute.” At the time, it struck me that when you’re smart, people pay attention to you—including the cutest guy in the class, even if it’s just to take a look at your answers.

Image 2: Attending service at Holman United Methodist Church with Rev. James Lawson, civil rights activist, bottom left, 2015

Girl Scouts

Being a Girl Scout was a formative and tremendously positive experience for me. I started as a Brownie and continued all the way through the Senior Girl Scout level. Because my mother led the region’s Girl Scout Council, it probably would have been embarrassing if I did not remain a Girl Scout, but I enjoyed it, and it was one of those activities that shaped how I saw the world. I grew up in a Black neighborhood and in a Black church, and Girl Scouting included going away to camp, where I would interact with people from many different backgrounds. Those experiences gave me a love of outdoors, campfires, and camp songs. In L.A., you’re 30 minutes from the ocean and an hour from the mountains, and those are wonderful places to go camping.

Of course, I also sold cookies and actually had an unusual cookie-selling experience, no doubt because of my mother’s role with the organization. I had the opportunity to go on The Carol Burnett Show to sell Girl Scout cookies to the star, which was great fun. Somewhere in the television archives, I expect there’s footage of that segment of Carol Burnett graciously receiving a Girl Scout cookie delivery from 13-year-old me and me graciously accepting her cash!

High School

Before junior high school, my family moved from Baldwin Hills, where many Black doctors and lawyers lived, to Inglewood, where L.A.’s airport is located. We moved because of Inglewood’s excellent public schools, which at the time were primarily white, so that I could enroll in a better school. After we moved, however, Inglewood experienced the phenomenon that was referred to as “white flight.” One of the first weekends we lived there, someone rang our doorbell and my mother opened the door to find a woman on the front step who looked shocked to see my mother. Apparently not knowing what else to do, the woman handed my mother a flyer and walked away. The flyer read, “Keep our neighborhood white.” My mother, who had a great deal of confidence, simply said, “How ridiculous that is.” I was very much attuned to how my mother handled that kind of situation.

When I began attending Morningside High School, the student population was more than 60 percent white, and by the time I graduated, it was down to less than 20 percent. Funding for public schools decreased significantly as white residents moved or enrolled their children in private or parochial schools. This also was the time when gangs were starting in L.A.; the Crips and the Bloods were making their presence known in my high school when I was in my sophomore and junior years.

My mother begged me to transfer to a parochial school. But I knew all my classmates, who watched out for the “smart one,” I had close friends I did not want to leave, I was a cheerleader, and I was determined to remain at Morningside High through graduation. Later, I realized that it probably was the reputation Morningside had about three years before my graduation—as one of the best schools in the state of California—along with my high grades that must have factored into my being accepted for admission by Stanford University and Wellesley College. By the time I graduated from Morningside High, its reputation was no longer the same, not by a long shot.

American Field Service Experience in Malaysia

My mother was always looking for activities that would broaden my horizons. One such opportunity came during my senior year of high school, through the AFS-USA student exchange program, then known as American Field Service. I went through an extensive interview process, at the high school level and up to the national level, which included being asked questions about current issues and civics. The program invited two students from Morningside High to participate, and I was the second one selected.

Applicants had been asked to indicate countries where they were interested in being placed, and I believe I listed France, Italy, and Spain, but I was selected to go to Malaysia. That location assignment may have had to do with AFS’s process for determining matches, which included asking how we would handle different theoretical situations and then matching an individual’s characteristics with a host country and family. AFS must have determined from my responses that I was a student who would be able to acclimate well in Asia.

Leaving L.A. for Malaysia was my first big travel experience, and this was in the mid-1970s, very different from today, when people hop on planes to go all over the world. Before then, the one time I had been out of the country was with my family on a visit to Tijuana, Mexico, just over the southern California border. The trip to Malaysia was long; we flew first to Seoul, South Korea, and then to Hong Kong before arriving in Malaysia. After we were picked up at the airport, unfortunately, the car we were riding in struck and killed a bicyclist who was traversing a large, unlit highway. It was a dramatic and unsettling way to arrive in the country. But I soon met my very welcoming Malay hosts, a Muslim family in the town of Seremban, 40 miles south of Kuala Lumpur, and I believe that experience changed the course of my life.

The father in the family was the head of state for Seremban, and, because there is no separation of church and state, he was both the religious and the governmental head of state. It was a more formal environment than I was used to, and the family guided me about certain rules and what was polite. We ate with our hands at meals, and we would use or pass items only with our right hand because the left hand was considered dirty. We washed at least twice a day because it was hot and muggy and also because it is very much a part of the Muslim prayer ritual.

I learned that the population in Malaysia is made up of Malays, the native people; Chinese, who emigrated there; and Indians. I realized during my stay that the Malay people knew I wasn’t Malaysian, and they assumed I was Indian. The Indian people knew I wasn’t Indian or Chinese, and they assumed I was Malay. Nobody thought I was American because for them, Americans were white. While I was there, they didn’t know quite what I was or where I came from, but everyone was warm and friendly.

Among four children in my Malay family, the eldest was a daughter who also was an AFS student and had gone to live with a family in Europe while I was hosted by her family. The next oldest was a daughter about my age, who helped shepherd me around, and she had two younger brothers. I attended high school there for about a month until the summer recess began; it was part of the British system of school, and we wore school uniforms. Most days after school, I played badminton with my best friend.

I think it was toward the end of my stay that I heard that a number of host families did not want to host a Black girl from the United States and that my host family was one of the few families willing to take a student regardless of race. Living overseas with a family from a different culture—and a different religion, in the case of my AFS family—really broadens your perspective. It opens your mind and opens your heart in such a way that you cannot go through life and think, “I don’t want people to immigrate to the U.S.,” or “I have a prejudice against people of Muslim heritage.” Living side by side with a family, when they have taken you in as a high school student, changes your perspective on life and what it means to be a global citizen, to be engaged with other people in the world.

The experience also sparked a travel bug in me and kindled a desire to live in different places, something I would later do in Paris, Edinburgh, and Zurich. I also have had two opportunities to serve on the AFS-USA Board of Directors, and my daughter, who lived in Ghana one summer through the AFS program, also has served as a young member of the AFS Board of Directors.

But back to when I was selected as an AFS student, I remember that I had to miss the last stretch of my senior year of high school because of the program’s timeline. I was the salutatorian of my class at Morningside High, and my best friend was the valedictorian; I still remember how incredulous her mother was that I would miss being there in person for graduation. But that is what happened because I was on a plane to Malaysia before graduation. And my best friend from high school and I are still good friends.

My Undergraduate Years

My mother thought that it would be very cool if her smart, unconventional daughter from Los Angeles attended one of the prestigious Seven Sisters women’s liberal arts colleges on the East Coast. For a Black girl from L.A. in the 1970s, this was indeed an unconventional choice. I also had a bit of my father’s sense of adventure—that desire to set off for the opposite coast—so, at the age of 16, after returning from Malaysia, I flew cross-country to attend Wellesley College. I had never been to Massachusetts before I stepped off the plane to matriculate at Wellesley.

My mother had put me on the plane in Los Angeles, and my brother, Paul, picked me up at the airport in Boston. Paul had graduated from Columbia Law School and was working as an attorney in Washington, D.C. Because he was on the East Coast, it was arranged that he would come up to Boston to deliver me for my first semester at Wellesley. I still remember Paul driving me through different parts of Boston and how different it all looked in contrast to L.A. It was almost as if there were lines and barriers: this was the white neighborhood, this was the Black neighborhood, and this was the Irish or Italian neighborhood. In L.A. in the 1970s, I hadn’t seen anything that felt as stark as that. Also, I remember I was struck by the sight of so many old buildings, including when we drove past Harvard University. But, Wellesley, I was pleased to find, was beautiful in spite of its old buildings; the campus was spread across 500 acres, including a lake, and I thought, “Thank goodness I chose this place.”

Life isn’t always easy, and things don’t always go as planned. Sometimes, you need to figure out how to get back up when you are knocked off your feet. In November of my first year at Wellesley, my mother died unexpectedly of an aneurism at the age of 46. I was 3,000 miles from home, and I had just turned 17 that fall. My mother had been the most supportive mom you could imagine. As I experienced that devastating loss, Wellesley surrounded me like a mother and supported me through a very difficult time.

My mother had instilled in me that I could be anything I wanted to be and that I could do anything I wanted. And, despite a D in my first chemistry course in my first year of college, I was not going to be deterred from being a scientist. So, it was a rough start at Wellesley, but I plugged along and got back on my feet. I soon discovered my passion, in part due to some good luck. In my sophomore year, Wellesley hired a young, enthusiastic assistant professor in the Biology Department to teach in the emerging field of psychobiology. This professor, Howard Eichenbaum, spoke very fast, especially for a Californian like me. He was extremely smart and enthusiastic, and he wanted to figure out how memory worked. His enthusiasm was infectious, and my imagination was captured.

Liberal Arts Values

As an undergraduate, I also became infused with liberal arts values, developing skills involving communication, critical and analytical thinking, and teamwork and leadership, as well as a deep sense of civic responsibility. In liberal arts education, breadth is as important as depth, and it leads you to bring together ideas that nobody ever thought of bringing together before. The liberal arts are about empowerment and mentorship and knowing that people really care about you and your development. Wellesley was a powerful liberal arts sisterhood.

I also had the opportunity to do hands-on experiments as an undergraduate. I still remember what happens when you stimulate the hypothalamus of a live animal, as I suspect anyone who is a behavioral biologist will remember as well. I was a solid B student. I wasn’t an academic superstar, but I graduated in the first full class of psychobiology majors because I was willing to try something new and interdisciplinary.

Graduate and Doctoral Studies (and Work in between)

After my undergraduate years, I went back to California and completed a master’s degree in public health in environmental health sciences at the University of California, Berkeley. After completing my studies, I worked at ESA, an environmental engineering consulting firm in Berkeley, and consulted for several years. At ESA, I was an environmental analyst splitting my time between office work and fieldwork while evaluating hazardous waste sites and wastewater quality in agricultural runoff. I had been advised not to start working, with the warning, “You will never go back to graduate school.” But I did not mind making an unconventional choice. And I believe that working outside of the academy—since most of my career has been in academia—included some of the best years in my life and instilled in me the importance of careful analysis, delivering your product on time and on budget, and customer service.

After about three years of full-time work, I decided to go back to pursue a doctorate at Johns Hopkins University in a newly formed program in neurotoxicology, the study of poisons that affect the brain. I saw this program as combining a bit of my undergraduate background in psychobiology/neuroscience with my master’s field of environmental toxicology. My first laboratory rotation at Hopkins wasn’t the best. I struggled with some of the medical school courses, and my first rotation adviser told me that I might consider doing something else, in other words, not being a scientist. But I didn’t listen, and I found a new adviser.

Lucky Rotations

My second rotation, I was lucky. That rotation was in the Department of Psychology on the Homewood campus of Johns Hopkins, with Professors Gary Wenk and David Olton, which led to my first publication in neuroscience. In addition, I had fun doing the work, which was the start of my focus on the cholinergic system and memory. That continued to be a theme of my research for more than 30 years. More important, I was beginning to learn the principles of good science and expecting the unexpected result. David Olton also made me a much better scientific writer.

In my next step toward becoming a scientist, I was very, very lucky. My third and final rotation was in the laboratory of Dr. Joseph Coyle (see volume 10), who was the head of the Child Psychiatry Department. He had appointments in neuroscience, public health, toxicology, and pharmacology. Yes, he was a bit of a wunderkind at Hopkins.

Great Scientists and Human Beings

In Joe Coyle’s laboratory, I started to see an important pattern. Of course, we scientists look for patterns, and I learned that great scientists can also be great human beings. In that lab, I met great human beings who worked competitively and cooperatively while pushing the frontiers of science. Our weekly lab meetings were critical thinking experiments for all of us. We gained insight into various projects, and we spurred one another to excel. It was a team effort. I learned the difference between hypothesis-driven science and descriptive science, as well as the importance of each in a particular situation. Also, in Joe Coyle’s lab, I had the opportunity to work with one of the most creative and caring mentors, Christine Hohmann, who was a postdoc in the laboratory. We continued to probe the cholinergic system, this time primarily in development and understanding how cholinergic dysfunction could be involved in conditions as diverse as Down syndrome and Alzheimer’s disease (AD).

Merging Research Interests

In the mid-1980s, there was evidence that cholinergic dysfunction was associated with AD. But it was not by any means an accepted theory that manipulating the cholinergic system would have any effect on the course of the disease. I had been working in Joe Coyle’s lab on an AD model, which consisted of making small, discrete legions of the basal forebrain of rats.

We were beginning, at that time, to understand acetylcholine that acts as a neuromodulator in cortex; a neuromodulator modifies the excitatory or inhibitory effects of a primary neurotransmitter. Small, discrete legions of the basal forebrain and medial septum disrupted the broad diffuse cholinergic projections to the neocortex and hippocampus, respectively, mimicking the diffuse cholinergic losses in neocortex and hippocampus that are seen in AD. There also was evidence that these small, discrete basal forebrain lesions in rats caused changes in behavior, specifically working memory deficits. And a hallmark of AD is deficits in working memory or short-term memory. Therefore, we hypothesized that enhancing cholinergic functions in cortex would alleviate memory deficits in AD.

Also, a note about modeling a human disease in nonhumans: First, you need to think about what aspect of the disease you wish to model—the behavior, the neurochemistry, the neuroanatomy, or the genetics. Different models will serve you well, depending on which of those different areas you aim to address. Rarely will you find a nonhuman model that mimics the full plethora of human disease characteristics.

In Joe Coyle’s lab, I found the perfect lab to merge my interests in behavior, pharmacology, toxicology, and the cholinergic system, and I ended up staying in his lab for my dissertation.

When Bonnie Davis, MD, approached Joe Coyle about testing the effects of a long-acting acetylcholinesterase inhibitor, for which she had the patent, we hypothesized that it could boost the cholinergic function as a treatment for AD, and we had the animal model in which to test this new drug, galanthamine.

As a side note, I share here the formation and breakdown of the neurotransmitter acetylcholine to better understand the effects of galanthamine. Acetylcholine is formed in the presynaptic terminal by the enzyme choline acetyltransferase. It interacts postsynaptically with nicotinic and muscarinic receptors. It is degraded by acetylcholinesterase in the postsynaptic terminal. Therefore, blocking acetylcholinesterase should prevent degradation of acetylcholine and boost cholinergic functions.

The drug galanthamine is a selective, competitive, reversible, long-acting cholinesterase inhibitor that also stimulates nicotinic receptors. It is able to pass through the blood-brain barrier and boost central cholinergic functions. It turned out to be effective clinically and was approved by the Food and Drug Administration in 2001. It continues to be used to treat individuals with AD. Galanthamine went through a couple of name changes and also is known pharmaceutically as Razadyne. For a number of years, it was one of the most widely prescribed drugs to treat AD in the world. It may seem obvious now that cholinesterase inhibitors improve cognitive function in some patients with AD, but it certainly was not easy to publish papers at that time about the cholinergic system and AD. I remember we had a paper rejected from Science because it didn’t support the plaques and tangles theory of AD. But with 924 clinical trials and 7,740 papers between the 1980s and 2020, the majority of studies indicate that cholinesterase inhibitors induce an improvement in cognitive function in mild to moderate AD.

Proof-of-Concept Work

When I think back on being a second-year graduate student, I remember how we would get a little white vial of powder, labeled galanthamine, and we had to figure out how much to use, what to dissolve it in, what dose and route of administration were appropriate, how long it was effective, and, foremost, whether we had a good model of AD. This was what I did as a graduate student; I conducted experiments probing the cognitive and neurochemical effects of an acetylcholinesterase inhibitor and the dose response curves and medicinal chemistry of altering different functional subgroups on the galanthamine molecule, and I examined the effectiveness of the newly designed drugs. I was looking for appropriate doses and timing and routes of administration to maximize beneficial effects of the drugs while minimizing side effects. I also was examining fundamental principles of the involvement of the cholinergic system in working and reference memory. Based on my work in graduate school, I had four papers published between 1988 and 1991 showing that galanthamine was effective in reversing the working memory deficits induced by focal basal forebrain lesions in rats, and that was the proof of concept that galanthamine was behaviorally relevant and effective in an animal model with minimal side effects. Simultaneously, I was teasing out the effects of the cholinergic system on different aspects of memory. I found this work incredibly exciting, and both of these are important themes in my later research. I was interested in basic research questions that had clinically relevant implications.

It was those early animal experiments, combined with the strong will of Bonnie Davis, who had the patent for galanthamine, that were critical in moving the drug through the pharmaceutical medicine machine to become a clinically relevant treatment. Only years later did I understand that the work that I had done in graduate school was clinically relevant and served as proof of concept for this treatment for AD. And if you ask me whether my scientific work was basic research, I would say, “Not always.” If you ask whether it was translational research, I would respond, “Sometimes.” Indeed, the dichotomy between basic and translational research often is irrelevant. And if you ask me if this scientific work had an impact, I would say, “Absolutely yes.” Was it exciting? I would respond, “Enthusiastically yes!” Whether or not galanthamine was a cure for AD, it certainly helped millions and millions of people.

Heeding Some Advice (but Not All)

A second theme of my dissertation work that had a long influence on my career is something that came about through discussions with Christine Hohmann, one of Joe Coyle’s postdocs at the time and my day-to-day supervisor. She shared with me that the genome of the mouse was being mapped. “If I were you,” she said, “given your interest in behavioral neuroscience, I would focus on mouse behavior rather than rat behavior.” And that led me to become a neuroscientist with an expertise in mouse behavior, which subsequently led to one of my favorite titles among my scientific publications, “Mice Are Not Little Rats,” with Karyn Frick, but that comes later.

Also, while I was part of Joe Coyle’s laboratory, I met another one of his postdocs, Laure Ory-Lavollée, who was a pharmacist and a native Parisian. She convinced me that I wanted to do a postdoctoral fellowship in France. In the meantime, others were telling me I should not do a postdoc in Europe because it would be difficult to reenter the U.S. scientific market. But I really wanted to live in Paris. I mentioned earlier in the section about growing up in L.A. that I loved musicals, which includes the classic An American in Paris. Who wouldn’t want to live in Paris after watching Gene Kelly and Leslie Caron dance around the City of Lights? So, off to Paris I went, to the INSERM, the National Institute of Health and Medical Research.

However, heeding some of the advice that I had received, I negotiated up front with the French laboratory that I would need to come back to the Society for Neuroscience (SfN) meeting each year to maintain my contacts in neuroscience and to be a part of the U.S. scientific network.

Postdoctoral Study

American in Paris

It was an unconventional but thoughtful choice to go to Paris. I had a wonderful life there. I also fell in love with someone who would later become my husband. I did some good science in the laboratory of Dr. Yvon Lamour—yes, his last name does mean “love” in French. I continued to work on the cholinergic system—this time the neurons of the medial septum, which project to the hippocampus. And I used in vivo electrophysiology techniques to understand the bursting patterns of these cells, with the generous support of my mentor there, Marie-Hélène Bassant, who was a much better electrophysiologist than I would ever be. As a side note, it is just as important to find out what you are not great at doing as to understand what you do well. Electrophysiology was not my strong suit.

After two years in my postdoc in Paris, I saw an ad in Science magazine for an assistant professorship at Wellesley College, my alma mater. It was the position that Howard Eichenbaum, my former professor and mentor, was vacating—he was leaving for a position at the University of North Carolina at Chapel Hill (UNC). At that time in 1991, as I was completing my postdoc in Paris, I interviewed at research-intensive universities and liberal arts colleges, as well as at a major pharmaceutical company. I liked the people with whom I interacted at Wellesley College the most; they articulated a good balance between work and personal life. I knew I could do world-class science there because Howard, my predecessor, had done so, and I thought it offered me an appropriate work-life balance. Although several colleagues questioned my ability to pursue a high-quality research career at a liberal arts college, I chose this unconventional path. In 1991, I returned to Wellesley as an assistant professor of biology, and Howard, my predecessor and undergraduate adviser, helped me negotiate my start-up package as he was leaving for his new role at UNC. He was a mentor, through and through.

Science at a Liberal Arts Institution

My Own Family and My Own Lab

I loved science, but I also wanted a full, well-rounded life. Six months after arriving for my position at Wellesley, I married my life partner, Urs Berger, a fellow scientist whom I met in Paris. Urs is now a retired neuroscientist and music archivist, and we have two wonderful children, Clara, 27, and Thomas, 23. And back in the 1990s, women in science were sometimes told that you weren’t supposed to have children, at least not if you were serious about research. Also, we heard, “Never, ever bring your children to a scientific meeting.” But I did …

As a faculty member, I understood that I had chosen to pursue a career at a liberal arts college and that I would need to devote time to teaching and to my students; it wasn’t a research university. I realized that to succeed, I would need to integrate my teaching and research as much as possible. Also, I recognized that a focus on AD was not really conducive to research at a small liberal arts college. This research was highly competitive, required too many resources, and moved at a pace that I was not likely to be able to keep up. But I had a few strategic advantages, including many smart, enthusiastic undergraduate students. Also, animal per diem costs were considered as part of the overhead at Wellesley. In other words, I didn’t have to add animal per diem costs to my external research grants; I could write smaller, lower cost grants to do my behavioral work. Those were two important factors, especially for someone interested in behavioral neuroscience, which is very labor-intensive and very animal-intensive. I wanted to continue my focus on the cholinergic system, learning and memory, and pharmaceutics, and, of course, to use mice as my model organism—although I would do an occasional experiment in rats. Also, I knew that to continue doing cutting-edge research, I was going to have to rely on having collaborators inside and outside of Wellesley College. I chose to focus on research quality over quantity.

Amazing Students

I had an amazing resource at Wellesley: bright, ambitious, hardworking undergraduate students. The first student who came to work in my Wellesley laboratory was Beth Buffalo, who earned a doctorate and went on to serve as chair of physiology and biophysics at the University of Washington. Others who came to or through the laboratory, or with whom I had interactions, included Anne Churchland, PhD; Dorothy Jones-Davis, PhD; Laura Schaevitz, PhD; Darlene Gabeau, MD/PhD; and far too many amazing women scientists than I can name here. My experience was a case of the students being smarter than the professor—and, for professors reading this, it really is okay if your students are smarter than you are.

Image 3: Alongside bright, talented students and collaborators at an SfN meeting, circa 2000

New Collaborations, Discoveries, Publications

In 1992, shortly after my return to Wellesley College as a faculty member, Doug Lappi and Ron Wiley approached me with a new tool that they had developed. It was an immunotoxin that could specifically target cholinergic cells of the basal forebrain of rats. Other toxins that I had worked with as a graduate student damaged both cholinergic and noncholinergic cells in the basal forebrain. Here was an opportunity to target cholinergic cells and test the hypothesis of whether the memory impairments were associated with lesions to cholinergic neurons or more general neuronal loss in the region.

Working with Stephan Heckers, a brilliant anatomist as well as a neurologist, I hypothesized that the cholinergic neurons in the medial septum and nucleus basalis were critical to working memory in the rat. But, I was wrong. And at that time, it was big news that the basal forebrain cholinergic system, when damaged specifically and discretely, did not induce working memory deficits. It appeared that the loss of cholinergic projections to the hippocampus and neocortex was not sufficient to induce the memory losses that I had documented previously in my graduate work. This new immunotoxin tool allowed us to ask and answer a question definitively, and we were able to publish this novel finding in the Journal of Neuroscience. And so, here, three years into this unconventional choice of pursuing a research career at a small liberal arts college, I had a publication in a prestigious journal. This discovery, along with others, led to successfully receiving a National Science Foundation (NSF) Young Investigator Award. This unconventional career choice definitely was paying off.

I also want to mention some very special fellow researchers with whom I worked in the early 1990s: Mark Baxter and Karyn Frick. Mark was a graduate student at UNC at the time and was interested in the immunotoxin research on the cholinergic system and memory that we were doing. Karyn soon joined the laboratory and was my first postdoctoral fellow at Wellesley College. Both had come from David Olton’s lab at Johns Hopkins, and our scientific connections led to friendships that continue today. Now Karyn is a distinguished professor of neuroscience at the University of Wisconsin-Milwaukee, and Mark is a professor of pathology and comparative medicine at Wake Forest University.

Rett Syndrome

Another topic of my research was Rett syndrome, a genetic disorder primarily affecting girls. By the late 1990s, the MECP2 gene that was associated with Rett syndrome had been identified. What was critical for me happened in 2003, when Rudolf Jaenisch, the geneticist at Massachusetts Institute of Technology (MIT), created a mouse model in which this gene, Mecp2, was deleted, and he described it as a mouse model for Rett syndrome. I had published papers as a graduate student suggesting that the cholinergic dysfunction in the developmental period was associated with Down syndrome and Rett syndrome, but here was an opportunity to test the hypothesis in a genetically modified mouse. Rett syndrome is a rare developmental disorder, and I thought at the time that working in the Rett field was less crowded than AD and the learning and memory fields. I had a chance to do important work, even at a small liberal arts college. It was important to find the right niche.

Persistence

A related story demonstrates the role of persistence in science. I had read in Nature magazine about Jaenisch’s mouse model for Rett syndrome. Because I had developed an expertise in mouse behavior, I thought that perhaps this was a niche for me. So, I first sent an e-mail to Jaenisch, proposing that I behaviorally test his Mecp2 mice. I sent numerous e-mails for three months, but I just couldn’t get through to him—he was simply too busy. However, I was very nice to his assistant every time I called. Eventually, she called me and said, “I am going to make this meeting happen.” And when I got Rudolf Jaenisch on the phone, he could not have been nicer. He agreed immediately to give me four to six breeding pairs of his Mecp2 mice. Of course, this was a different era; he put the mice in containers and sent them off in a taxi cab from MIT to Wellesley, which was about a 30-minute ride. This provided me with an incredibly precious resource, Mecp2 mice, and that was the foundation of my colony for the next 10 years.

Generalization in a Hyperspecialized World

We published about 20 manuscripts on Rett syndrome, pharmacology intervention, and how to improve behavior, neurochemistry, and neuroanatomy. First, we showed that Mecp2 mice replicated many of the behavioral and neurochemical characteristics of girls with Rett syndrome; in other words, they were a good animal model of the condition. Then, over a course of about 10 years, I, along with numerous collaborators, looked at cholinergic drugs to improve behavioral and respiratory symptoms in Mecp2 mice and developed potential therapeutics in humans. I was at the right place at the right time with the right skill set and enough persistence to contribute to the collaborative research efforts to improve the lives of girls with Rett syndrome. At this point, most people would say my work was translational. But I was constantly reading and thinking about basic mechanisms, blurring the lines between basic and translational studies. One thing that is clear is that when you study a disease, you can’t have a narrow focus. There were cholinergic deficits in girls with Rett syndrome, but there were also a number of other neurochemical abnormalities. I needed to understand numerous aspects of brain development, metabolic regulation, and respiratory functions to contribute to research that would improve the lives of these girls. Through my research on Rett syndrome, I became a more broad-based scientist, providing careful analysis of the evidence, reformulating hypotheses when the data didn’t fit the original hypothesis, and describing what I found, even when it didn’t fit my hypothesis. I was as adamant about publishing negative results and results that didn’t fit our hypothesis as I was in publishing evidence that fit our predictions.

Throughout my career in neuroscience, I have felt a pressure to “Specialize! Specialize! Specialize!” “Become an expert in a very narrow field.” But as a person with a liberal arts background, I saw the value in generalization and breadth and in making unexpected connections in a hyperspecialized world. David Epstein’s book Range: Why Generalists Triumph in a Specialized World really resonated with me. I believe that the zigzags in my early career and taking the time to discover my personal strengths and letting my interests propel the breadth of my research have served me well, both on the bench and in academic administration.

People and Structures Matter

Returning now to the people and structures that helped make my career in science. I must mention Drs. Jim Townsel and Joe Martinez, who were such an important part of my research life and keeping me involved in cutting-edge research during summers at the Marine Biological Laboratory (MBL) in Woods Hole. They cofounded, and led for many years, the SPINES Program, which originally referred to the Summer Program in Neuroscience, Ethics, and Survival Skills, and now refers to the Summer Program in Neuroscience, Excellence, and Success. This program focuses on educating graduate and postdoctoral fellows from underrepresented backgrounds to succeed as leaders in neuroscience. I taught in a primarily undergraduate student setting at a liberal arts college, so the summer program provided an incredible opportunity to interact with and influence graduate students and postdoctoral fellows. I took on an assignment that many researchers would avoid, teaching students English grammar and how to develop a persuasive, clearly written scientific argument.

Jim and Joe were excellent neuroscientists who cared deeply about creating a stronger, more diverse population of neuroscientists for the future. I will not try to list the successes of the SPINES program and the hundreds of outstanding neuroscientists who have been touched by this program and our special summers together at the MBL.

My scientific career also was very much a family affair. Without the support and patience of my husband, with whom I fell in love in Paris, and our kids, I could not have spent long hours in the laboratory or dragged them around the world to scientific meetings and sabbaticals in Zurich and Edinburgh. As a side note, my last sabbatical in 2008 was with Richard Morris in Edinburgh, which was an incredible life experience. Additionally, Joe Coyle continued to support and mentor me throughout my career, and I continue to have scientific and personal collaborations with Christine Hohmann, who is a beloved professor at Morgan State University.

Image 4: My husband, Urs, and our two children at SfN, circa 2003

Another important element of my success was my ongoing involvement in the SfN. As an associate professor at Wellesley, I was director for a training program for diversity in neuroscience. From there, I was elected onto Council, was treasurer for SfN, and served as chair of the Professional Development Committee, as well as on the Committee on Committees, nominating other people to committees. Currently, I serve on the SfN’s selection committee for the Gruber Neuroscience Prize. My association with SfN has given me as much in development opportunities as I have given service to SfN.

Transition to Administration

In 2004, I left teaching and bench science full time to pursue an administrative career, primarily because of a desire for a broader impact beyond the bench and beyond science. It was an unconventional choice to leave a successful career at the bench to become an administrator. For 10 years, I did retain an active laboratory, combining it with my administrative work. One of the reasons that I decided to move into administration was that I saw in my classes so few Black women—Wellesley is a women’s college—and I wondered what I could do to change that, not only in my lab but also across the institution. I saw administration as a way to innovate, to create, and to push my agenda of excellence forward, at a faster pace and to a broader audience.

I served in administration at Wellesley for six years and then became dean of the School of Arts and Sciences at Tufts University, a position I held for four years. My fabulous postdoc, Laura Schaevitz, came with me from Wellesley to Tufts. Laura is now senior vice president and head of research at Recursion. You may note a recurring theme of this chapter is working with smart, dedicated mentees, who have continued on to very successful careers in science.

Also, I believe that my skills as a scientist were quite helpful in my becoming an administrator. These include the abilities to analyze a problem deeply, to base decisions on research and data, and to experiment, in other words, to try something new to see if it works. Analyzing nonverbal behaviors was another useful skill that transferred from the laboratory to higher education leadership. In the lab, I watched a great deal of rodent behavior and had to infer the meaning; now I am more likely to watch nonverbal cues in humans and infer meaning of human behavior.

When you think of leadership, words that likely come to mind are strength or power. When I think of leadership, I think of a funny video you may have seen—it was originally a Super Bowl commercial for a technology company—where workers are in the process of building a plane while flying it. That’s my view of leadership, building a plane while flying it. Leadership is exhilarating, scary, complex, and never boring. It is sometimes frustrating but also often satisfying.

In 2014, I became the president of Trinity College, one of the premier liberal arts institutions in the country, located in the capital city of Hartford, Connecticut. I left my laboratory behind and found my new home and the opportunity to shape higher education at Trinity, primarily an undergraduate liberal arts institution. We also have a small Graduate Studies program—including the opportunity to earn a master’s in neuroscience—and we are one of the few liberal arts colleges with an engineering program. All of us at Trinity—in the administration, faculty, and staff—are focused on our mission to prepare students to be bold, independent thinkers who lead transformative lives.

Image 5: My inauguration as the 22nd president of Trinity College, 2014

About administration, I like to say that it is not about having power; it’s about taking responsibility. To share some examples of what success looks like to me in my current role: I see it in a smart, curious, and engaged student body of 2,000-plus students. As well, since I arrived at Trinity, we have increased by 50 percent financial aid for undergraduate students and dramatically enriched the socioeconomic, racial, and international diversity of our student body. Success also means more engaged, community-oriented faculty and staff who help to shape those transformative lives. And we’ve been able to increase faculty of color at Trinity by 14 percentage points in the past three years. Success also means focusing on student outcomes. Six months after graduation, 96 percent of the students in the Class of 2022 knew what their next step was going to be—employment, graduate education, or fellowship. Success also means balanced budgets because that is something that you have to think about as an administrator.

Also, for me, success means extending Trinity College’s connections beyond our campus. During the past year, we have celebrated Trinity’s bicentennial year with the theme “Committed to the future since 1823.” Throughout our yearlong celebration, we are taking time to examine and discuss our college’s past, present, and future identity, both internally and as part of our wider communities, including within our home city of Hartford and more globally. In recent years, ways in which we have strengthened our connections in Hartford and beyond include the establishment of an innovation center and the Liberal Arts Action Lab, part of Trinity’s Center for Hartford Engagement and Research. We also have forged a unique partnership with the global technology firm Infosys—an unprecedented collaboration between a liberal arts college and a global tech giant.

While I have served as Trinity’s president, I have had wonderful opportunities and recognition along the way, including being elected to the American Academy of Arts and Sciences. I have been honored as a top Women in Business leader in Connecticut by Hartford Business Journal. And I currently serve as chair of the board of directors of Hartford HealthCare, the second-largest outpatient and hospital system in the state.

Obviously, I believe in getting involved and trying to make changes from the inside. I have tried to live out Wellesley College’s mission of “Women who will make a difference in the world.” And I have always remembered my mother’s words of encouragement about being able to be anything I wanted to be.

Mine is a story of science, and I hope that it is also clear that it is a story of scientists—people who influenced and shaped me, befriended me, collaborated with me, and were my promoters. As well, my journey is a reflection of my parents’ story and their pioneering spirits. I was one of the only African Americans graduating from Johns Hopkins with a science doctorate my year. I was the first African American woman to move through the ranks to become a tenured full professor in biology at Wellesley College, the first African American to be elected to the Council and then treasurer of the SfN, and the first woman president and the first African American president of Trinity College.

To paraphrase David Copperfield (title character of the Charles Dickens novel), I might ask, “Am I the heroine of my own life?” Or as Isaac Newton might have pondered, “Am I standing on the shoulders of giants?” I tell young and aspiring neuroscientists that they need to be the heroines or heroes of their own stories. Don’t try to live someone else’s life.

Lessons Learned

I offer here some of the lessons that I have learned:

Your mentors don’t have to look like you; they do need to care about you and promote you. They need to open doors and networks to support you.

Administration isn’t about power; it’s about responsibility.

Generalization has its advantages.

Most important, help others along the way.

As much as I have enjoyed my career in the research laboratory, I recognized that I needed to do more to be satisfied. I had the possibility to do more, and I seized some of those opportunities to move beyond the bench. I was prepared to do so because I had taken on progressively more responsibility as part of my scientific career, including with the SfN. I felt that I could innovate, create, and, yes, disrupt more as an administrator than as a bench scientist. And, quite honestly, I felt that my science career, at the time I moved away from the bench, had already made a significant impact and helped millions of people with AD and Rett syndrome.

Acknowledgments

Thank you to Kathy Andrews who edited this narrative into a readable chapter; Tom Yelich who relentlessly hunted down references and checked them for accuracy; and Sonya Adams for copyediting. Most of all I acknowledge the collaborators, students, mentors, and friends who have made my successes possible.

Selected Chronological Bibliography

Wenk, G., Sweeney, J., Hughey, D., Carson, J., & Olton, D. (1986). Cholinergic function and memory: extensive inhibition of choline acetyltransferase fails to impair radial maze performance in rats. Pharmacology, Biochemistry, and Behavior, 25(3), 521–526.

Sweeney, J. E., Höhmann, C. F., Moran, T. H., & Coyle, J. T. (1988). A long-acting cholinesterase inhibitor reverses spatial memory deficits in mice. Pharmacology, Biochemistry, and Behavior, 31(1), 141–147.

Sweeney, J. E., Höhmann, C. F., Oster-Granite, M. L., & Coyle, J. T. (1989). Neurogenesis of the basal forebrain in euploid and trisomy 16 mice: an animal model for developmental disorders in Down syndrome. Neuroscience, 31(2), 413–425.

Sweeney, J. E., Puttfarcken, P. S., & Coyle, J. T. (1989). Galanthamine, an acetylcholinesterase inhibitor: a time course of the effects on performance and neurochemical parameters in mice. Pharmacology, Biochemistry, and Behavior, 34(1), 129–137.

Sweeney, J. E., Bachman, E. S., & Coyle, J. T. (1990). Effects of different doses of galanthamine, a long-acting acetylcholinesterase inhibitor, on memory in mice. Psychopharmacology, 102(2), 191–200.

de Bilbao, F., Senut, M.C., Sweeney, J., Jazat, F., & Lamour, Y. (1991). Etude comparative chez le rat âgé des déficits comportementaux et des modifications morphométriques des neurones contenant de la galanine dans la région septale médiane [Comparative study in aged rats of behavioral deficiencies and morphometrical modifications of galanin containing neurons in the medial septal area]. C R Acad Sci III, 312(10), 503–509.

Sweeney, J. E., Lamour, Y., & Bassant, M. H. (1992). Arousal-dependent properties of medial septal neurons in the unanesthetized rat. Neuroscience, 48(2), 353–362.

Bachman, E. S., Berger-Sweeney, J., Coyle, J. T., & Hohmann, C. F. (1994). Developmental regulation of adult cortical morphology and behavior: an animal model for mental retardation. International Journal of Developmental Neuroscience, 12(4), 239–253.

Berger-Sweeney, J., Berger, U. V., Sharma, M., & Paul, C. A. (1994). Effects of carbon dioxide-induced anesthesia on cholinergic parameters in rat brain. Laboratory Animal Science, 44(4), 369–371.

Berger-Sweeney, J., Arnold, A., Gabeau, D., & Mills, J. (1995). Sex differences in learning and memory in mice: effects of sequence of testing and cholinergic blockade. Behavioral Neuroscience, 109(5), 859–873.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (1996). Discovering Neurons: A Compilation of Classic and Novel Laboratory Exercises in Neuroscience. New York: Cold Spring Harbor Laboratory Press.

Berger-Sweeney, J., & Hohmann, C. F. (1997). Behavioral consequences of abnormal cortical development: insights into developmental disabilities. Behavioural Brain Research, 86(2), 121–142.

Ricceri, L., Calamandrei, G., & Berger-Sweeney, J. (1997). Different effects of postnatal day 1 versus 7 192 immunoglobulin G-saporin lesions on learning, exploratory behaviors, and neurochemistry in juvenile rats. Behavioral Neuroscience, 111(6), 1292–1302.

Arters, J., Hohmann, C. F., Mills, J., Olaghere, O., & Berger-Sweeney, J. (1998). Sexually dimorphic responses to neonatal basal forebrain lesions in mice: I. Behavior and neurochemistry. Journal of Neurobiology, 37(4), 582–594.

Hohmann, C. F., & Berger-Sweeney, J. (1998). Cholinergic regulation of cortical development and plasticity. New twists to an old story. Perspectives on Developmental Neurobiology, 5(4), 401–425.

Hohmann, C. F., & Berger-Sweeney, J. (1998). Sexually dimorphic responses to neonatal basal forebrain lesions in mice: II. Cortical Morphology. Journal of Neurobiology, 37(4), 595–606.

Berger-Sweeney, J., McPhie, D. L., Arters, J. A., Greenan, J., Oster-Granite, M. L., & Neve, R. L. (1999). Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Research. Molecular Brain Research, 66(1-2), 150–162.

Hohmann, C. F., Richardson, C., Pitts, E., & Berger-Sweeney, J. (2000). Neonatal 5,7-DHT lesions cause sex-specific changes in mouse cortical morphogenesis. Neural Plasticity, 7(4), 213–232.

Berger-Sweeney, J., Stearns, N. A., Murg, S. L., Floerke-Nashner, L. R., Lappi, D. A., & Baxter, M. G. (2001). Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior. Journal of Neuroscience, 21(20), 8164–8173.

Frick, K. M., Burlingame, L. A., Delaney, S. S., & Berger-Sweeney, J. (2002). Sex differences in neurochemical markers that correlate with behavior in aging mice. Neurobiology of Aging, 23(1), 145–158.

Ricceri, L., Hohmann, C., & Berger-Sweeney, J. (2002). Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical morphogenesis in rats. Brain Research, 954(2), 160–172.

Berger-Sweeney, J. (2003). The cholinergic basal forebrain system during development and its influence on cognitive processes: important questions and potential answers. Neuroscience and Biobehavioral Reviews, 27(4), 401–411.

Berger-Sweeney, J. (2003). Using mice to model cognitive deficits in neurologic disorders: narrowing in on Rett syndrome. Current Neurology and Neuroscience Reports, 3(3), 185–187.

Berger-Sweeney, J. and C. F. Hohmann. (2003). Dysplasias. In The Corsini Concise Encyclopedia of Psychology and Behavioral Science. Eds. W. E. Craighead and C. B. Nemeroff. New York: Wiley.

Branchi, I., Bichler, Z., Berger-Sweeney, J., & Ricceri, L. (2003). Animal models of mental retardation: from gene to cognitive function. Neuroscience and Biobehavioral Reviews, 27(1-2), 141–153.

Frick, K. M., Stearns, N. A., Pan, J. Y., & Berger-Sweeney, J. (2003). Effects of environmental enrichment on spatial memory and neurochemistry in middle-aged mice. Learning & Memory, 10(3), 187–198.

Tsai, G., Ralph-Williams, R. J., Martina, M., Bergeron, R., Berger-Sweeney, J., Dunham, K. S., Jiang, Z., Caine, S. B., & Coyle, J. T. (2004). Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proceedings of the National Academy of Sciences of the United States of America, 101(22), 8485–8490.

Schaevitz, L. R., & Berger-Sweeney, J. (2005). Neurogenesis of the cholinergic medial septum in female and male C57BL/6J mice. Journal of Neurobiology, 65(3), 294–303.

Berger-Sweeney, J., Zearfoss, N. R., & Richter, J. D. (2006). Reduced extinction of hippocampal-dependent memories in CPEB knockout mice. Learning & Memory, 13(1), 4–7.

Picker, J. D., Yang, R., Ricceri, L., & Berger-Sweeney, J. (2006). An altered neonatal behavioral phenotype in Mecp2 mutant mice. Neuroreport, 17(5), 541–544.

Nag, N., & Berger-Sweeney, J. E. (2007). Postnatal dietary choline supplementation alters behavior in a mouse model of Rett syndrome. Neurobiology of Disease, 26(2), 473–480.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2007). Observational methods used to assess rat behavior: behavioral patterns. Cold Spring Harbor Protocols, 2007.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2007). Observational methods used to assess rat behavior: general principles. Cold Spring Harbor Protocols, 2007.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2007). Observational methods used to assess rat behavior: neurological testing. Cold Spring Harbor Protocols, 2007.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2007). Testing spatial and nonspatial learning using a morris water maze. Cold Spring Harbor Protocols, 2007.

Stearns, N. A., Schaevitz, L. R., Bowling, H., Nag, N., Berger, U. V., & Berger-Sweeney, J. (2007). Behavioral and anatomical abnormalities in Mecp2 mutant mice: a model for Rett syndrome. Neuroscience, 146(3), 907–921.

Berger-Sweeney, J., Schaevitz, L., and Frick, K. M. (2008). Neurochemical systems involved in learning and memory. In Neurobiology of Mental Illness, 3rd edition. Eds. D. S. Charney and E. J. Nestler. Oxford: Oxford University Press.

Nag, N., Mellott, T. J., & Berger-Sweeney, J. E. (2008). Effects of postnatal dietary choline supplementation on motor regional brain volume and growth factor expression in a mouse model of Rett syndrome. Brain Research, 1237, 101–109.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2008). Dissection of rat brains. Cold Spring Harbor Protocols, 2008.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2008). The nissl stain: a stain for cell bodies in brain sections. Cold Spring Harbor Protocols, 2008.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2008). Perfusion of brain tissues with fixative. Cold Spring Harbor Protocols, 2008.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2008). Sectioning of brain tissues. Cold Spring Harbor Protocols, 2008.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2008). Subbing slides. Cold Spring Harbor Protocols, 2008.

Han, L., Picker, J. D., Schaevitz, L. R., Tsai, G., Feng, J., Jiang, Z., Chu, H. C., Basu, A. C., Berger-Sweeney, J., & Coyle, J. T. (2009). Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II. Synapse, 63(8), 625–635.

Nag, N., Baxter, M. G., & Berger-Sweeney, J. E. (2009). Efficacy of a murine-p75-saporin immunotoxin for selective lesions of basal forebrain cholinergic neurons in mice. Neuroscience Letters, 452(3), 247–251.

Nag, N., Moriuchi, J. M., Peitzman, C. G., Ward, B. C., Kolodny, N. H., & Berger-Sweeney, J. E. (2009). Environmental enrichment alters locomotor behaviour and ventricular volume in Mecp2 1lox mice. Behavioural Brain Research, 196(1), 44–48.

Nag, N., Ward, B., & Berger-Sweeney, J. E. (2009). Nutritional factors in a mouse model of Rett syndrome. Neuroscience and Biobehavioral Reviews, 33(4), 586–592.

Ward, B. C., Kolodny, N. H., Nag, N., & Berger-Sweeney, J. E. (2009). Neurochemical changes in a mouse model of Rett syndrome: changes over time and in response to perinatal choline nutritional supplementation. Journal of Neurochemistry, 108(2), 361–371.

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2010). Choline acetyltransferase staining in brain sections. Cold Spring Harbor Protocols, 2010(8).

Paul, C. A., Beltz, B., & Berger-Sweeney, J. (2010). Staining for acetylcholinesterase in brain sections. Cold Spring Harbor Protocols, 2010(8).

Schaevitz, L. R., Moriuchi, J. M., Nag, N., Mellot, T. J., & Berger-Sweeney, J. (2010). Cognitive and social functions and growth factors in a mouse model of Rett syndrome. Physiology & Behavior, 100(3), 255–263.

Berger-Sweeney J. (2011). Cognitive deficits in Rett syndrome: what we know and what we need to know to treat them. Neurobiology of Learning and Memory, 96(4), 637–646.

Katz, D. M., Berger-Sweeney, J. E., Eubanks, J. H., Justice, M. J., Neul, J. L., Pozzo-Miller, L., Blue, M. E., Christian, D., Crawley, J. N., Giustetto, M., Guy, J., Howell, C. J., Kron, M., Nelson, S. B., Samaco, R. C., Schaevitz, L. R., St Hillaire-Clarke, C., Young, J. L., Zoghbi, H. Y., & Mamounas, L. A. (2012). Preclinical research in Rett syndrome: setting the foundation for translational success. Disease Models & Mechanisms, 5(6), 733–745.

Schaevitz, L. R., & Berger-Sweeney, J. E. (2012). Gene-environment interactions and epigenetic pathways in autism: the importance of one-carbon metabolism. ILAR Journal, 53(3-4), 322–340.

Schaevitz, L. R., Nicolai, R., Lopez, C. M., D’Iddio, S., Iannoni, E., & Berger-Sweeney, J. E. (2012). Acetyl-L-carnitine improves behavior and dendritic morphology in a mouse model of Rett syndrome. PloS One, 7(12), e51586.

Schaevitz, L. R., Picker, J. D., Rana, J., Kolodny, N. H., Shane, B., Berger-Sweeney, J. E., & Coyle, J. T. (2012). Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders. Developmental Neurobiology, 72(6), 891–905.

Schaevitz, L. R., Gómez, N. B., Zhen, D. P., & Berger-Sweeney, J. E. (2013). MeCP2 R168X male and female mutant mice exhibit Rett-like behavioral deficits. Genes, Brain, and Behavior, 12(7), 732–740.

Schaevitz, L., Berger-Sweeney, J., & Ricceri, L. (2014). One-carbon metabolism in neurodevelopmental disorders: using broad-based nutraceutics to treat cognitive deficits in complex spectrum disorders. Neuroscience and Biobehavioral Reviews, 46 Pt 2, 270–284.

Berger-Sweeney J. (2023). Diversity in neuroscience: how this moment is different. Journal of Neuroscience, 43(46), 7724–7726.

Patents

Berger-Sweeney, J., with Dr. R. Neve. 1998. U.S. Patent # 08/729348, Transgenic non-human mammal expressing Flag-APP-CP100 fusion protein, an animal model of Alzheimer’s disease.

Berger-Sweeney, J., with Dr. B. Davis. 2015. U.S. Patent Application # 61801768, Treatment of Rett syndrome, an autism spectrum disorder.

György Buzsáki

BORN:

Kaposvár, Hungary

November 24, 1949

EDUCATION:

University of Pécs, Hungary, MD, Medicine (1974)

University of Western Ontario, London, Postdoc, Neuroscience (1981–1982)

University of Texas, San Antonio, Postdoc, Neuroscience (1980–1981)

Academy of Sciences, Budapest, PhD, Neuroscience (1984)

APPOINTMENTS:

Assistant-Associate Professor, Institute of Physiology, University of Pécs, Hungary (1975–1988)

Associate Professor in Residence, Department of Neurosciences, University of California, San Diego (1989–1990)

Professor, Board of Governors Professor, Center for Molecular and Behavioral Neuroscience, Rutgers University (1990–2011)

Biggs Professor of Neuroscience and Physiology, NYU Neuroscience Institute, New York University (2012–present)

HONORS AND AWARDS (SELECTED):

Krieg Cortical Discoverer Award, The Cajal Club (2001)

Elected member, Hungarian Academy Sciences (2001)

The Hans-Lukas Teuber Lecture, MIT, Boston (2009)

The Talairach Lecture, Organization of Human Brain Mapping (2010)

Brain Prize, Lundbeck Foundation, Denmark (2011)

Elected Member, Academia Europaea (2012)

Most Cited Researcher, ISI (2006–present)

Board of Editors, Science AAAS (2014–present)

Doctor Honoris Causa, University of Aix-Marseille, France; University of Kaposvár, Hungary; University of Pécs, Hungary (2015, 2017)

Elected Member, National Academy of Sciences, United States (2017)

Special Lecture, Society for Neuroscience (2019)

Ralph W. Gerard Prize (2020)

Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience (2021)

György Buzsáki defined synaptic-cellular mechanisms of hippocampal sharp waves and theta and gamma oscillations. His theories and innovative methods have turned studies of brain rhythms into one of the most active research areas. Buzsáki’s work changed how we think about information encoding (“neural syntax”) in healthy and diseased brains. His most influential work is known as the two-stage model of memory trace consolidation. During learning, inputs transiently modify hippocampal network. In turn, the time-compressed tagged events are repeated hundreds of times during sleep to consolidate memories. Buzsáki has been a strong advocate for studying spontaneous brain activity in its natural state, such as sleep and for brain-body interactions as the evolutionary source of cognition. His demonstration that in the absence of changing environmental signals, cortical circuits continuously generate self-organized cell assembly sequences, specific to recall or the animal’s route planning, is a breakthrough for the neuronal assembly basis of cognitive functions.

György Buzsáki

One’s accomplishments are judged by others rather than by the first-person reminiscence of the storyteller because we all suffer from source-memory problems (i.e., whether an idea was genuinely ours or creep into our brains unnoticed). Thus, autobiographies should not be trusted as a reliable source of events because of the unreliability of memory “traces.” If our memories were accurate representations of life events (analogous to movies), we could regard them as “things” that could be made, reliably recalled, replaced, repaired, exchanged, cloned, or even stored for eternity in some immortalized format and downloaded into someone else’s brain. However, this movie metaphor is misleading. A movie, once created, exists in isolation and does not interact with anything or anywhere else anymore. It can be watched many times without altering its content. In contrast, when our life experiences are relived, they inevitably are mixed with experiences acquired between the last and the currently recalled events. Such perpetual modification of the trace may go on even without conscious recall in our sleep. This is the neuroscience of memory, the field I have been trying to contribute to and against which personal recollections should be evaluated. But perhaps instead of this long paragraph, I should have introduced my problem more poetically: “When we remember something, do we remember the thing itself or just the last time we remembered it?” (Jorge Luis Borges, Funes the Memorious).

Upbringing

I was 11 years old when I killed my best friend. The next day, I went to school as if nothing happened. Neither my classmates nor my teachers asked any questions, and our neighbors, who surely knew about the details of the previous day’s events, did not accuse me of wrongdoing. I did not commit the crime alone but with my family’s involvement. It was my father who stabbed my friend’s heart with a sharp bayonet he kept in a special drawer since his days in the army. I only assisted. This was the norm of life in my part of the world back then. My best friend, whom we killed on that cold January day in 1960, was Rüszü, our pig. During his life, he and I were bonded friends. Rüszü was always eager to get out of his pen and follow me to our favorite destination, a small, shallow bay of Lake Balaton, Hungary, just across the street from our house (Figure 1). Although many readers may regard pig slaughtering as a barbaric practice, it played an essential role in the lives of Europeans for centuries. First, home breeding and slaughtering of pigs was an economic necessity. Second, a pig slaughter feast was a social event, often linked to a family wedding or christening. Third, and perhaps most important, the entire pig was processed from skin to intestines and nothing was discarded. Instead, the various parts were treated with time-tested methods, such as smoking, and there was a strict choreography for their consumption, starting with fresh meat in winter months, followed by smoked ham at Easter, and ending with pork rinds with onion or scallion in warmer months. When I disliked some parts, my father firmly reminded me that food I was trying to refuse was part of our beloved pig and no part should end up as trash under any circumstance. We must remember and respect the animals we killed.

Only many years later, I began to confront myself with the events of that January day, especially because in our profession, we face the same moral dilemma with our laboratory animals. In my childhood, people had a close and caring relationship with their farm animals. I can say with confidence that today, this is true for our laboratory animals. Animals in the wild are eaten up alive by others, die of hunger, freeze to death, or succumb to disease. In contrast, our laboratory animals live in a comfortable environment with plenty of nourishing food, often surrounded by their littermates. At some point in their lives, we sacrifice them under humane conditions. We give them life and take it away. This is exactly what our imagined Gods do to us. God allows us to enjoy a few happy moments before “calling us back home” when, according to him (her, they?), our time is up. Of course, we are not Gods and thus do not have the same rights, but the analogy remains. If we put aside the analogy, the next moral issue is whether we have the right to exploit other animals for our benefit. Perhaps nobody has a good answer, but I feel this reasoning is a bit of hypocrisy. We do this to our young all the time. We rob them of their freedom and send them to war to sacrifice their lives for us. How is this practice different from sacrificing animals we care for and love while they live? I am writing these lines at a time when in Ukraine, Sudan, and other parts of the world, thousands of young lives are extinguished regularly under the banner of high moral values. It is in this larger cultural, historical context within which we have to make judgments. Such contexts shape our brains and morals, and unless we are acutely aware of this truth, we may rush to quick conclusions about our students and associates coming from different cultures. Emphasizing this cultural embeddedness of the brain in today’s polarized world when we deny opportunities or break our colleagues’ careers in the name of “here and now” morals is as important as ever.

My childhood included many animals: turtles, a family of hedgehogs, fish in a toilet tank, pigeons, barn owls, and rabbits, in addition to our family’s cats and chickens. Lake Balaton was the source of many happy moments in my early life. It provided everything I needed: swimming during the summer, skating in the winter, and fishing most of the year around. I lived in complete freedom, growing up in the streets with other kids from the neighborhood. We made up rules, invented games, and built fortresses from rocks and abandoned building materials to defend our territory against imagined invaders. We wandered around the reeds, losing ourselves only to find our way out, developing a sense of direction and self-reliance. My parents had only one rule: “Be home before it gets dark.” The definition of darkness was, of course, negotiable. I grew up in a child’s paradise, even if those years were the worst times of the communist dictatorship for my parents’ generation.

Fig. 1. The house of my childhood. In my memory store, it was a “huge palace” with spacious large rooms, and this is how I described its features to my daughters. Not surprisingly, they were disappointed when I showed it to them sixty years later. To clarify my betrayed memory, I had to explain to them that the brain always calculates ratios and that subjective spatial scale is proportional to the number of steps we take. This is why my palace shrank. (Picture taken in 2019.)

Summers were special. My parents rented out our two bedrooms, bathroom, and kitchen to vacationers from Budapest, and we temporarily moved up to the attic and I was sent for a few weeks to stay with my maternal grandparents in Szekszárd. My grandpa was a farmer and a jack-of-all-trades. I undoubtedly inherited my manual dexterity from him. He was a happy, proud, and forward-looking individual. That is until the day when a group of people with red armbands showed up and “nationalized” all their land and property, forcing grandma and grandpa to join “collectivized farming” under the glorious Stalinist socialist plan. This was the first and last time I had seen my grandpa cry. My only benefit from the tragedy was that he started to talk about his life. As a young cavalryman, he fought in the infamous 12-battle war in the Isonzo River valley during World War I, where his beloved brother was killed. During World War II, he survived the battle of Stalingrad and became a prisoner-of-war (POW). He told me how they had to march day and night through Ukraine, sleeping while walking and being prevented from falling by fellow POWs. While serving in the army, my grandfather had a sidekick, György Buzsáki, who was 19 years younger than him. György, mainly out of respect for my grandfather, married his only daughter.

I have never met my paternal grandfather. He died at a young age as a war hero and received a “knight” award (Vitéz Buzsáki). The honor of the Vitéz prefix of my grandfather became a significant burden on my father in the Stalinist era. My grandmother raised her four children alone in a deserted old farmhouse. Their source of water was the rain and a shadoof next to the pigsty and a giant chestnut tree that provided shade (and leaves falling into the well). When I enquired why there were frogs in the well, I got the answer that if the frogs were alive, the water was drinkable. Satisfied with the answer I always enjoyed pulling up the bucket and drinking from this special water.

The rest of my summer days were spent in Siófok. Once my father told me that one of the vacationers was a “scientist-philosopher” who knew everything. I wondered how it would be possible to know everything. I took every opportunity to follow him around to figure out whether I could discover something special about his head or eyes. But he appeared to be a regular guy with a good sense of humor. I asked him what Rüszü thought about me and why he could not talk to me. He gave me a long answer with many words that I did not understand, and at the end, he victoriously announced, “Now you know.” Yet I did not and kept wondering whether my pig friend’s seemingly affectionate love was the same as my feelings for him. Perhaps my scientist knew the answer, but I did not understand the words he used. This was the beginning of my problem with words used in scientific explanations. Only much later I realized that too often, when we do not understand something, we often make up a word or two and pretend that those words solve the mystery. I guess I became a scientist as a consequence of striving to understand the true meaning behind explanations. Of course, there were other reasons as well.

A short walk from us lived an electrician who generously allowed me to hang around in his workshop. He was patient enough to explain to me why there is a coil in a bell. I assume it was his advice to my parents to present me my first scientific book How Does the Transistor Work? as a Christmas present. This book was a dialogue between the Curious Kid and the Big Smart Head with many cartoon illustrations and offered explanations of difficult concepts. I read it multiple times until I memorized every word. Not having access to such a piece of wonder as the transistor, I built a crystal detector radio, soldered wires to the earpiece of a broken telephone set, and stretched a wire antenna between the apricot tree and the pigsty. And voila, I could listen to the local radio through the sizzling membrane of the earpiece in our abandoned chicken coop (my “workshop”), which was much more fun than sitting next to my parents’ radio in the house. Once my electrician adviser and I rode our bikes to a huge antenna tower outside Siófok. There, an engineer showed us what I thought was surely a magic trick. He connected strangled wires to a light bulb which lit up and dimmed depending on how he was folding the wires. If he told me he was God, I would have believed him. Unfortunately, my friendly adviser was electrocuted later that year by touching a bare wire and standing barefoot in his shack. After that sad event, my parents tried to talk me out of everything that had to do with electricity. But I had already tasted the apple, and my life was about to change in a major way.

My mother always wanted to return to the city, which meant Pécs for her, where she spent a few years of her youth and “which will provide the necessary education and culture” for me and my sister, Judit. Mom was the progressive member of our family and tried to fulfill her dreams through her children. Without her dedication and sacrifice, I wonder how my life would have been shaped. While my parents were packing our belongings, I joined my good friends from the neighborhood for a last soccer game. Trying to save the ball from entering the goal, I jumped on it and tried to turn it backward, at which moment the laws of physics decided what happened next. I flew forward, hitting the telephone pole, which served as part of the goal head first. My friends walked me home. I lay down on a bed that was still left in the house and the world disappeared for two days. When I vaguely regained consciousness, I overheard my worried parents’ conversation about whether to unload the truck or take me to the hospital and leave my mother with me while my father carried out the move. Feeling guilty about the situation, I stood up and bravely stated that I was okay and ready to go. During the four-hour drive, I vomited profusely several times and arrived at Pécs in miserable condition. I had my first concussion with retrograde amnesia. The story I just told is but a reconstruction from the feedback I learned from my parents and the information they got from my buddies.

My Education in Pécs

Pécs greeted me with plusses and minuses. Our apartment was much smaller and without a garden, and there was not even a park nearby, not to mention the absence of my forest and Lake Balaton in Siófok. My classroom’s floor was soaked with black wood tar and whenever I fell in a fight, the proof stayed on my clothes the whole day.

But there were plusses as well. Pécs, which lies on the sunny slopes of the Mecsek mountains in Hungary’s southwest, has one of the oldest universities in Europe (founded by Pope Urban V in 1367 as Universitas Quinque Ecclesiensis) and has been a major cultural center. It has a rich architectural heritage from the 150-year Ottoman occupation, including my favorite domed Mosque of Pasha Gazi Kasim in the city center. I soon discovered a youth club and joined the Radio Fox Hunting Club (aka Amateur Radio Direction Finding, ARDF). The hunters needed to have knowledge about triangulation by a directional antenna and good orientation and running skills because the cunning “foxes” (i.e., the enemy radio stations) broadcast only intermittently from various hidden locations in diverse, wooded terrain. When rotating the directional antenna, the radio signal changed in strength so that by running fast to another location while the transmission was still on, a skilled hunter could determine the likely direction and location of the fox. You get the picture. The critical ingredients for success are good running skills and of course a sophisticated receiver, which each competitor had to build. The club became my second home, where I acquired the skills to build a functioning device. One day, beeps of di-di-di-da-da came from one of the rooms. This was the first time I heard the Morse code. I was mesmerized when the operator told me he had a conversation with another ham in New Zealand. Conversation by beeps? I assumed that our operator did not speak English or Maori, and presumably, the operator in New Zealand did not understand Hungarian. Instead, I was informed that they “spoke” to each other with dots (short pulses) and dashes (long pulses) through a universal language in which most words consist of three letters called Q-code. I was instantly hooked. To be part of such a wireless conversation, all I had to do was to memorize the Morse code and the Q language, learn more about electronics, feedback, and feedforward circuits to stabilize oscillator frequencies, pass exams, build a transmitter and receiver, and set up a wire antenna between the chimneys of our house and the neighbors. Then, I could communicate with any short-wave (10 to 80 m bands) ham radio around the globe. And that is precisely what I did during my high school years. I had radio contacts with a few famous people, including Yuri Gagarin (UA1LO), U.S. Senator Barry Goldwater (K7UGA), King Hussein of Jordan (JY1), and Queen Noor (JY1H). The aviator Howard Hughes was also a ham radio operator (W5CY). Hams are not exceptional among neuroscientists—for example, the late W. Ross Adey (the University of California, Los Angeles, UCLA), John Hopfield (Princeton University), Terry Sejnowski (Salk Institute), and Fritz Sommer (UC Berkeley).

In learning Morse code, the biggest hurdle is recognizing the silent gaps in the sea of dots and dashes separated by short spaces. Packing and separating messages is the most crucial thing in any coding system, be it speech, written language, computer language, or spike transmission in the brain. In Morse code, letters are separated by silent periods of the duration of a dot, while words have boundaries of at least two dots’ length of silence. Without silent gaps, the di’s and da’s are just nonsense noise. Reading neuronal messages is even more complicated because action potentials are all just dots, and they come from many sources simultaneously. I had so much fun in the radio club, and the problems of oscillations, coding, and communication have bugged me ever since.

The good news in the summer of 1964 was my successful entrance test and acceptance to a newly created special math-physics curriculum in the Széchenyi Gymnasium. It was a competitive class with a bizarre mixture of outstanding and less knowledgeable communist teachers. Our math teacher was an energetic young woman; she hosted “problem-solving” evenings and weekends in her tiny sublet, posted math problems on our bulletin board for extra credit, and prepared us for math competitions. She gave us P. A. Larichev’s Collection of Problems in Algebra. By the end of our sophomore year, my good friend László and I had solved all 1,000 problems. Our teacher declared that we were math gurus and sent us to a mathematical Olympiad contest. This was a pivotal moment in my life. I could solve only one of the five problems. Then, during lunch after the test, I met the true geniuses. They enthusiastically discussed those “easy problems,” clearly having fun, and I felt I was among Martians. But I did not feel defeated; on the train ride back home, I felt elevated and relieved by the realization that I just eliminated math as a career option. Instead, I could concentrate on my radio hobby.

These were my best high school years. I had time for everything, from competitive swimming early in the morning to radio connections in the evening and studying for school in between. Like most of my friends, I became under the spell of hippy culture and pop music. With three of my trusted classmates (trust was a precious commodity of friendship in those days), we often listened to the short-wave broadcasts of Radio Free Europe and BBC, frequently jammed by the Hungarian authorities by frequency interference. Once there was a music quiz on BBC with a prize, which I solved and mailed the solution to the London address provided by the DJ. Two weeks later, he announced my name and address for winning the Satisfaction record by the Rolling Stones.

This was the year 1966, the tenth anniversary of the 1956 Hungarian Uprising. Every criticism of the regime was forcefully retaliated. We hated the system, represented locally to us by our communist teachers and most prominently by the school principal. She was a math teacher and occasionally substituted for our beloved young teacher. We often shouted out the solution loudly before she finished scribing a problem on the blackboard. We enjoyed making fun of her, and she was visibly upset by our misbehavior and sent my buddy László out to the corridor (a well-established form of punishment). László walked to the darker end of the corridor (where construction was going on) and sketched a scaffold on the wall with the principal hanging from it. To add emphasis to his anger he added a caption: “This is how every communist will end up.” The next day the secret police showed up at the school, taking writing samples from each of us. László was missing from school that day and the following days. He hid in the mountains until he was hungry enough to return home. In the meantime, three of his closest friends were taken to the police station, and we were interrogated for hours and asked to write everything about our connections to the Imperialist West. I was told firmly that they knew everything about me, including the decadent infiltration of my mind by BBC. When I finished, they took the page and asked me to write another, more detailed version. This went on for a few times. Late that night, they showed me a lengthy document with my name on the last page and forced me to sign it without allowing me to read its content. I signed and was released at 6 a.m. At the political trial, I had to read “my confession” but proudly stated to the judge that those sentences were not mine. This upset our principal who was ex officio attending the proceedings. The 17-year-old László was tried as an adult and received six years of imprisonment.

My own punishment was not delayed much. In the all-teacher conference, the principal demanded that my grades be decreased in all subjects. I got “good” in physics (that hurt the most), geography, history, and geometry. We also got a grade for social behavior. I got a grade of 2 (the worst was 1), something nobody has ever heard of. Those midterm grades were my worst ever. The principal’s punishment aimed to reduce my chances of getting into any university. If this was not enough, the entire math-physics class was disbanded, and we were dispersed into classes with vocational curricula (5+1 or 4+2, meaning one or two days working in a workshop or at a farm). As a result, in my senior year of high school, I learned nothing new. I lost an entire year of my youth at a time when the brain is a sponge and absorbs knowledge at an unprecedented speed. Things improved a bit when the principal retired and was replaced by a jovial successor. He told my mother that if I “behaved well” my future would not be lost. But I did not behave.

By the Prussian tradition of Hungarian education, we had to take final examinations (Matura or baccalaureate) at the end of high school. It just happened that the first Western pop group that ever visited my town was the British Nashville Teens and their concert was timed for the night before my Matura. I could not miss that event! I arrived at the concert with my friends and showed them secretly my small Union Jack banner. When the group played their biggest hit “Tobacco Road,” I displayed my enthusiasm by waving the British flag. In no time, I was pulled down from the middle of the theater over the heads of many other spectators by the secret police, who happily tested the efficacy of their rubber batons on my body and drove me to prison.

My mother was demanding but also the tiger protector of the family. She wanted her children to become “somebodies.” She worked as a secretary with no high school diploma for most of her life. After moving to Pécs, she started to work as a typist in the Law School, reaching the rank of executive secretary of two consecutive deans. A vital background knowledge here is that in addition to the regular Law School degree, the university also issued degrees to those who attended a “corresponding” class whose members typically showed up only for their oral examinations. Members of this group were mainly cadres of the establishment, such as police and military officers and people with the right party connections. My mom knew all these people because she handled their exam books. Luckily, one of those individuals was a high-ranking officer of the city police. Informed by my sister, who also was at the concert, about my “disappearance,” my mother called that person and begged him to release her son. My mother saved me, as she did on several more occasions. The following morning, I was released exhausted. Yet, I got all A’s on my Matura exam. As an act of congratulation, the teachers offered me coffee. I liked the taste of the coffee with sugar and asked for another double espresso. When leaving the room, I saw our geometry teacher, who also functioned as the party secretary of the gymnasium, rushing toward me. “There will be consequences for your provocation last night,” he warned me and left. The coincidence of these several factors triggered a feeling that I never had before. Palpitation, accelerated breathing, stomach cramps, and subsequent insomnia, which were all signs of fear and vulnerability, lasted for several weeks. The positive outcome of this new feeling was that I never drank coffee again, although I am aware that caffeine was only a minor contributor to my anxiety.

With my ham radio obsession, my hope was to continue my studies as an electrical engineer at the Technical University in Budapest. However, my parents argued otherwise, mainly because of the cost of living in Budapest (even though education was free), which they could not afford. So I reoriented myself and applied for medical school. But after my Nashville Teens hiccup, I was unsure I would have a chance. After my oral admission exam in physics, I was told that Professor Ernst wanted to see me. The professor instantly said to me that he had conceived the physics problem and that only 2 of the 800 applicants had a perfect solution. He did most of the talking and at the end, he said, “See you in September.” As I learned later that day, Jenö Ernst, the professor of biophysics, was the most powerful professor in the medical school. Thus, the fact that he shook my hand meant my likely acceptance. In November 1944, he and Professor Kálmán Lissák greeted the Red Army when they arrived in Pécs. Lissák was a Nobel Laurate Otto Loewi student in Graz, Austria, and Walter Cannon’s assistant at Harvard. He had returned to Hungary to become chair of physiology in the Medical School before World War II. During the Nazification of Hungary, Lissák hid his Jewish friend Jenö Ernst and, in return, Ernst protected Lissák during the postwar communism. Their bond became a significant factor later in my neuroscientist career and served as an example that trust and friendship can override ideological and religious differences.

Medical School and Endre Grastyán

The Medical School of Pécs has produced a remarkable group of neuroscientists, including János Szentágothai, the legendary neuroanatomist. Yet, the two-year anatomy curriculum was just too much for me. While my friends were having fun at the School of Engineering in Budapest, learning exciting stories about radio transmission and electronic oscillators, I spent most of my time studying the unending details of bones and ligaments. But one day during a physiology class, the lecturer Endre Grastyán talked about something truly fascinating. I could not help but wonder about the parallels between the content of that lecture and control operations in electronic circuits. After his introductory lecture on the brain, my life in medical school acquired a new meaning. I wanted to get closer to him and learn more about his creative thinking. After my physiology examination, I applied to volunteer in his lab, a practice similar to the medical doctor/doctoral programs in the United States. The best training in Grastyán’s laboratory occurred through my participation in the regular lunch discussions that could go on for several hours. It was during these lunch tutorials that I first learned about the hippocampal “theta” rhythm, which has become my obsession ever since. This was a natural fit for me, given my interest in amplitude, frequency, and single-sideband modulation of radio waves.

I spent most of my time in the Physiology Department. Thanks to Lissák, the chair, the department enjoyed many exceptional privileges. Nearly every faculty member spent one to several years in Western Europe or the United States. Grastyán spent two years in the Brain Institute at UCLA in 1957–1958, and even young faculty could occasionally attend conferences. Lissák encouraged and supported publications in Western journals, which was not a norm in most institutions in Hungary. Even just thinking about the possibility that one day I could cross the Soviet-bloc border was a strong motivation for me to work in the department. Occasionally, we had famous visitors from great institutions, and I had the privilege of being their personal student guide. Sir John Eccles spent several days with us. I had the extraordinary luck of sharing a train ride with the cybernetician and roboticist Grey Walter from the Burden Neurological Institute in Bristol from Budapest to Pécs. I learned about his Machina speculatrix tortoise firsthand. The hippocampus researcher Robert Isaacson (from the University of Florida, then the University of Binghamton, New York) visited several times. Bob and I forged a lifelong friendship, and he supported me in many ways when I came to the United States. E. Roy John from New York University also visited for a week. One day, Walter Freeman from the University of California, Berkeley, gave a seminar on his olfaction maps in our small library. Grastyán, this gentle, polite person, kept interrupting his talk, asking one question after another, drilling the famous U.S. professor for more than two hours. To me, it looked like a boxing match. I wondered why Grastyán invited this person whom he now wanted to execute on the spot. On the way to dinner that night, Professor Freeman told me how much he enjoyed the honest atmosphere of the seminar with sincere questions. I realized then, and there that scientific debate is a reversed truce. You are the defender of truth and only the truth—diplomacy should be put aside. I often think of these moments these days when colleagues congratulate each other about the wonderful lecture they gave instead of offering useful critique. Scientific debate is not personal. It is the essence of progress. I like questions after which I cease breathing in surprise and spend days searching for an answer.

At the end of the year, my mentor Grastyán left for the United States to spend nearly two years in E. Roy John’s laboratory at New York University. By that time, I already befriended his disciple Professor György Karmos, who kindly took me in. Karmos had perhaps the most sophisticated neurophysiology lab in Hungary then, including a “computer of average transients.” Do not think of a computer but a machine that digitized analog signals and averaged them. My first assignment in the Karmos lab was to examine the variability of sound-evoked responses in the auditory cortex as a function of behavior. I measured the trial-to-trial amplitude variability of the various evoked components and compared them to the baseline before the stimulus. The baseline varied more than the evoked components, however, and we had the “paradox” finding that the early and largest evoked components had the smallest variability. This was the first time I faced the fascinating issues of brain “state,” “context,” and “spontaneous” activity, problems that remained with me forever. I presented my “evoked response paradox” at a student conference in 1973. I have since seen various iterations of this fundamental observation (e.g., Churchland et al., 2010).

Other than finding a home in the Physiology Department, my six years in the medical school were uneventful. I became a tour guide in my city, worked as a trash collector at a camp site, and was a doorman in an international youth camp for two summers at Lake Balaton. For another summer, I was a bell boy in a hotel. These jobs gave me extraordinary opportunities to occasionally meet people from the Western world and practice my English. A key event of these jobs was meeting Brenda Morrison, an English psychiatrist who spent two days in Balaton on her way to a congress in Vienna. To my great luck, it was pouring rain on those two days, and I had a chance to discuss and compare life in Hungary and the West with her. A month after our meeting, Brenda kindly invited me to spend a month in the Guy’s Hospital in London. This was an exceptional opportunity, but I needed to get an exit visa. Again, my mother helped out. Her dean helped me to find the key person and compose a letter to the Ministry of Defense to temporarily suspend my military duty requirement and allow me to travel. To my surprise, I received permission and with the support of our dean, I was allowed to do my elective training in surgery at Guy’s Hospital. Brenda’s son lent me his bicycle and I discovered many parts of London. The contrast between London and my world was hard to comprehend.

Although I was certain that I wanted to become a brain physiologist (the term “neuroscientist” was not coined yet) from the day when Grastyán gave his introductory lecture, now in my sixth year, I had to think about my real options. Earlier that year, I won the Russian language competition in the Medical School, and as a reward, I could spend my Internal Medicine rotation in Lvov (or Lviv), Western Ukraine. Although I did not gain much knowledge about medicine there, I learned a lot about human relationships. Before, I hated everything that was Russian. But in Lviv, I met many wonderful Russian and Ukrainian students, and I realized that there is a huge difference between people and political formations. One of the greatest things about being a scientist is meeting talented people from so many different nations and discarding stereotypes.

Decisions about jobs in medical school were made in July while I was in Lviv. When I returned home, the bad news awaited me: my hoped-for position was given to the party secretary of our class, and there were not many vacant positions left anywhere in the country. There I was, the first-ever member of my extended family with a graduate degree and, in fact, the second (after my sister) with a high school diploma. By all standards, as a descendant of farmers from both sides of my family, the socialist system was designed for me and similar others of the society. A tiny minority, members of the super-well-organized Communist Party hijacked the otherwise noble intention of the socialist doctrine. Under the banner of equality, inclusion, and moral purity, they rapidly formed a totalitarian bureaucratic state in which the victims became precisely those members of the society for whom their ideology promised prosperity. The implementation of the system failed for obvious reasons. First, there are always opportunistic members in a society, who have an uncontrollable desire to be in a leadership position, irrespective of the ideology. I often amuse myself and silently predict which of my colleagues in the United States would undoubtedly have become leaders in a communist regime, irrespective of their current beliefs. The second peril is “self-censorship.” This factor is perhaps the most dangerous because of its large scale and everyday effect. We condemn the actions of colleagues even when we agree with them and praise those we fear and dislike beyond what the authorities expect from us. Third, we elect underqualified persons into leadership positions to show that we are loyalist. In turn, new leaders with insufficient experience hire people with even less experience, which is known as “negative selection.” The nondeserving rulers become fearful of their prospect of survival, and their actions focus on preserving their comfort while forgetting their original mandate. These hidden “rules” worked at every level of society, and science was no exception. But politicizing science and redefining history (almost everything was invented by the “Soviet scientists,” according to my school books), instead of evaluating and acknowledging scientific contributions strictly based on intellectual merit and societal utility, was a grand failure. Censorship of science is harmful to the progress and well-being of societies, as the collapse of the Soviet system illustrates.

Instead of research, I found one job option: to become a resident in a thermal hospital specializing in rheumatoid diseases in a small town. Another option was a drug company in Budapest (GYKI; the compound GYKI 52466, a widely used noncompetitive AMPA receptor antagonist, was developed there). I learned how to canulate the tail vein of mice, and after hundreds of mice, I could do the procedure blindfolded. I started reading extensively about animal behavior, triggered mainly by the Nobel Prize for ethology in 1973. Detailed observations of the animal’s behavior were the needed antidote for Pavlov’s passive brain idea and Skinner’s recipe to study cognition by lever presses. I returned to Pécs every weekend to continue my experiments, now focusing on behavior. At the company, I pointed out the inadequacies of the testing apparatuses for drug screening and suggested alternative paradigms to my superiors. But I was told that “this is a drug company and we use internationally accepted and verified tests.” Well, if no innovation was needed, I wondered, “What am I doing here?”

Military Service

In this low moment, the draft notice from the military was a welcome event. I had to get through with my military training at some point anyway and so the timing appeared perfect. Our sergeant took every opportunity to humiliate the “doctor privates,” and he made sure that our uniforms got muddy during the cruelling morning exercises only to get punished if in the afternoon he spotted a piece of dirt on our boots. It gradually sneaked up into my brain that the entire goal of the initial military training was to break our egos and push us to the lowest levels of human existence. It took even longer to comprehend how constructive and valuable it was. Rebuilding ourselves from the ashes was a cathartic exercise. I am grateful to my sergeant and army experience, which made me a better person. I occasionally comment to my students that a month in the gulags would make graduate school look like a piece of cake.

By the end of my military service, I received good news. The party secretary of the Physiology Department “defected” to the Netherlands, and I could fill the vacancy. My monthly salary as an instructor was 2,420 forint (approximately $80).

Fig. 2. Ethograms of learning experience in the rat. Top: Frequency of occurrence of different behaviors and sequential relationships among behaviors in session 1. Bottom: Session 10. The diameter of each circle is proportional to the frequency of behaviors. The width of the connecting arrows is proportional to the number of occurrences of each sequence type. 1, drinking; 2, run to bar; 3, bar pressing; 4, run to drink; 5, turn left; 6, turn right; 7, rearing; 8, sniffing; 9, grooming; 10, stop or freeze. (Buzsáki et al., 1979).

Department of Physiology, University of Pécs

Besides teaching, I was busy in the laboratory with my ethological experiments. I was lucky to be able to borrow a videotape recorder, and I spent long hours replaying every detail of rat behavior, from ear pricks to grooming syntax (Figure 2). In 1977, I had the good luck of spending a few weeks at the Nencki Institute of Experimental Biology (founded by Jerzy Konorski) in Warsaw. I trained two dogs to go to place A or B, signaled by loudspeakers from either location. They learned it in a day. The next day, I placed one loudspeaker above the start position and two tones indicating locations A and B. To my disappointment, the performance of both dogs remained poor even by the end of my term in Warsaw. Back in Pécs, I designed an analogous experiment for rats and found similar results. I made a discovery, or so I thought. The rabbit’s fur always coincides with the meat in the appropriate ecological niche, so the fox chasing the fur will get the rabbit’s meat every time. Only in the lab can we change this contingency. Soon, I realized that others had already made similar observations (Breland and Breland, 1961; Seligman, 1970).

In the East, one of Pavlov’s students, Piotr Stevanovitch Kupalov observed that his freely behaving dogs extensively investigated the metronome (CS) placed in the window sill even at the expense of losing food (US) placed at another part of the room. In the West, the literature on “autoshaping” also argued that the CS does not become a substitute for the US but rather becomes a new goal (Brown and Jenkins, 1968), which acquires significance for the animal through its active investigation. The brain is not a passive absorber but an investigator. My first contribution to this topic was translating part of Kupalov’s work into English. A year later, I was delighted to receive an invitation from the editor of the Journal of Experimental Analysis of Behavior, founded by B. F. Skinner, to write a review on East versus West views on behavior. The main message of my first-ever review was that the doctrine that any stimulus can be linked equipotentially to CS (Pavlov) and that any behavior can be shaped by the reinforcer (Skinner) is simply false. Instead, signals and reinforcers provide an affordance for implementing innate tendencies. We do things to perceive our surroundings. This old message remains important today, with the revival of the Skinnerian philosophy under the label of “reinforcement learning” (anything can be linked and shaped by the reinforcer), the rapid spread of head-fixed preparations, and using virtual reality “environments” (Grastyán and Vereczkei, 1974; Buzsáki, 1982, 1983).

To my surprise, many bright students wanted to work in my lab. They were only a few years younger, and we shared similar worldviews. To relate my newly learned knowledge about evolutionary constraints to behaviors, I designed an experiment that mimicked our feeling of “imprisonment” behind the Iron Curtain. Rats had to press a lever for food at intervals longer than 10 seconds. The timer was reset if they pressed at, say, at 9.8 seconds. This is a difficult task (known as DRL) even for humans. Doing nothing for food is a counterprepared behavior. We built a six-compartment apparatus, in which the “rooms” contained various things, such as a running wheel, wood shavings, and toys. Half of the rats could mediate time by visiting the rooms at will (freedom group). The other half was confined to one compartment with just a lever. Members of the freedom group learned the task well, adopting stereotypic visits to the different compartments between presses. The performance of the confined group remained consistently poor. After the asymptotic execution of the task, we changed the contingencies. By enjoying the new freedom, the performance of the previously confined rats increased rapidly. In contrast, the now-confined animals pressed the lever prematurely and kept jumping out from the lever-containing compartment. The calory cost of their jumps and presses was several times higher than the calory gain obtained with the few pellets during each session. Subsequently, we repeated the experiments in animals that underwent fimbria-fornix lesions. Surprisingly, the lesioned group’s performance was less affected by the freedom-confinement change. The sad conclusion of the experiment was that brain damage is the solution to tolerating confinement. I presented our findings at an Intermozg (Russian for Interbrain) meeting in Pécs, and Ezras Astratyan, the founder of the Institute of Higher Nervous Activity, Moscow, was my chair. Nobody asked a question after my talk but my friends warned me: “Be careful, they understood you.” It took a long time to write up this story, and another four years from submission to publication (Acsádi et al., 1986). My ethologist “career” culminated in my writing a little book on animal learning (in Hungarian; Buzsáki, 1984).

Parallel with the behavioral experiments, I continued to work with Grastyán’s lab on the relationship between hippocampal activity, locomotion, eye movements, CS responses, and my refined behavioral parameters. I already had a mini question to address the existing debate in conditioning. Reward and US were believed to be the main motivators of behavior but how they exerted their impact on behavior was a mystery. The dominant theory was “stimulus substitution.” But I thought that a cat or dog is not so stupid to recognize that the loudspeaker is not palatable. Others promoted the view that the CS-US contingency offers an affordance to investigate and learn about the CS. Clever people on both sides of the debate designed various experiments to “convincingly” support one or the other hypothesis, but without an objective arbiter, the arguments remained just arguments. With electrodes in the brain, however, we could ask the brain. During eating, drinking, and other times of consummatory behaviors theta oscillations were absent. Conversely, when the animal investigated the signal, theta was always present, clearly revealing that the CS was not a substitute for US. I realized how unending psychological arguments can be a shortcut by looking at the brain, the source of all behaviors. Brain activity is an objective judge. I should examine not only behavior but also the brain. By studying the electrical activity of brain networks, I could also satisfy my curiosity about information transmission beyond the Morse code and sender-receiver communication.

Electrophysiology Is Cool

I inherited Karmos’s 12-channel pen recording electroencephalogram (EEG) after he left to head an Institute in Budapest. Following Grastyán’s pioneering work on theta oscillations and the orienting reflex, other groups linked this prominent hippocampal pattern to attention, arousal, and information processing. Those ideas could be contrasted with another influential hypothesis, advanced by Cornelius (Case) Vanderwolf that theta oscillations in the rat occur during intentional or voluntary movement. To “defend” my mentor and “disqualify” Vanderwolf’s view, I designed various paradigms to demonstrate that theta can be induced in the immobile cat in response to the CS. Of course, there always remained the possibility that the cat was prepared to move, and with such reasoning, the problem was shifted to the territory of “intentionality” and volition. Moreover, the cat is not a rat. The latter factor was my main motivation to switch to rodents, despite the technical challenges associated with the smaller head of the rat. By the time I was performing those experiments, virtually every term in the psychological vocabulary had already been claimed to relate to theta. Thus, to come up with the ultimate single correct correlate seemed hopelessly remote. I suspected that those behavioral-cognitive terms were hypothetical constructs with fuzzy boundaries, which may not correspond to any particular brain mechanism. Perhaps it would be safer to work on something more tangible.

I was already familiar with Per Andersen’s (University of Oslo) (see volume 4) beautiful evoked field response/population spike experiments in rabbits, and I had just found out that such experiments could also be done in the waking rat. I read the reprint by Winson and Abzug (1977) at a barber shop while waiting for my haircut. I got so excited that I left before my turn and rushed back to the lab to check what components I needed to start recording evoked responses from the rat hippocampus. I had to build head stages from dual MOS-FET buffers to use smaller diameter but higher impedance electrodes. With the afforded input-output measurements, I could study the impact of sleep and waking, learning, and the interactions of various hippocampal inputs on output functions in the paradigm that I designed for the autoshaping experiments. We soon replicated and expanded Andersen’s experiments with entorhinal input stimulation, identifying the sequence of fiber volley potential, extracellular field PSP (input), and population spike (output). To our surprise, when we used the same approach by stimulating the hippocampal commissure, although the CA1 responses behaved as expected, we did not see a population spike in the dentate gyrus, no matter the stimulus intensity. That baffled me, and I began to think that the commissural fibers also terminated on interneurons and, in turn, such fast inhibition could have overridden the anatomically known excitatory inputs on the granule cells. However, this hypothesis required further investigation.

Finding Treasure in Pécs and Making Contacts with the Academic World

As a young man, I pretended I had a free life and never thought of anchoring myself to a place or person. That is until I met the most beautiful and most brilliant woman in the world. When you find someone whose soul resonates with yours, and you realize that every moment you spend with her feels like a gift of life, you are sure you found true love. Veronika Solt and I got married in October 1978. My life as a scientist did not change but acquired a different meaning. A better one.

By the late 1970s, Hungary began to depart from other Soviet-bloc countries in various ways, allowing visits to Western countries, at least for artists and scientists to “represent the achievements of the socialist system.” I hitchhiked to Florence, Italy, to present our work on the interaction between the commissural and entorhinal inputs in the hippocampus at the European Neuroscience Association meeting (a predecessor of FENS). My first truly international meeting was an extraordinary experience to meet authors of papers whose works I have already read. Among them were Menahem Segal and Bruce McNaughton, who have remained my friends and fierce competitors to this day. Bruce was going through every panel of my poster and told me that he was working on a manuscript on the same topic, an event that happened many times over the years. There is a term for this today: “being scooped.” For me, it was delightful news that someone at the other end of the world found something similar. What a relief it was.

My key link to the world of neuroscience was Magdeburg in Eastern Germany. There, Professor Hansjürgen Matthies was the director of the Magdeburg Medical Academy. Because of his party connections, he was allowed to organize an annual symposium on learning and memory, where most of the speakers were from beyond the Iron Curtain. Here I met Helmut Haas, Cornelius (Case) Vanderwolf, Joe Martinez, James (Jim) McGaugh (see volume 4), Rodolfo Llinás (see volume 5), and Susan Sarah—all friends who made a big difference in my later life. After the Berlin Wall was brought down, I was invited back to Magdeburg to deliver the Hansjürgen Matthies Honorary Lecture in 2015.

Although my rat experiments were going well, I was ready to learn more and asked Grastyán to recommend a suitable lab in the United States. My plan A was to work in the laboratory of W. Ross Adey. Plan B was any other lab, anywhere. Adey was the head of the Space Biology Laboratory at UCLA, also a ham radio operator, and the first neuroscientist to use digital computers for the analysis of the EEG, a perfect match for my interests. Grastyán wrote to Ross, but a few months later, he told me that Adey’s lab may not fit me well. I had not thought much about this comment for decades, but in 2021, I received a package from an old colleague in Pécs, who saved some of the relics from Grastyán’s desk. In it was a letter from Adey, explaining that he was eager to host me: “I can promise him excellent experience in a very new and exciting area of molecular biology … of learning and memory”). For reasons I will never learn, Grastyán did not mention Adey’s response to me. Perhaps my mentor thought that I would have a better opportunity. Yet, I occasionally wonder how my scientific trajectory would have evolved if I had the chance to join Adey’s lab, especially because we are currently working on the impact of GHz radiation on brain activity, a specialty of Adey’s lab in the 1960s. In 1979, Grastyán received a letter from Eduardo Eidelberg, a neurosurgeon, from the University of Texas at San Antonio. Eidelberg and Grastyán overlapped at UCLA in their younger years and had mutual respect. I immediately wrote to Professor Eidelberg and thanked him for his offer. There was no offer, of course, and he had never heard of me, but Grastyán’s word was enough for my acceptance. I still had to undergo several clearance hurdles until I eventually received an exit permit stamp on my passport and the U.S. J-1 visa.

Another rewarding event in 1980 was the International Union of Physiological Sciences (IUPS) meeting in Budapest, with 6,000 scientists (Figure 3). I attended many memorable lectures and met several of the speakers. I had the opportunity to show my single-unit recordings to Per Andersen, who said that he had never seen such nice large amplitude extracellular units in the hippocampus. This praise meant a lot to me. He introduced me to Carol Barnes, who with Bruce McNaughton, was spending sabbatical time with him in Oslo. I invited Carol for dinner at a restaurant with great gypsy music. Carol brought two other gentlemen with her, whose name I could not quite make out during the introduction. They asked me about my work and I explained to them that I just finished an experiment on long-term potentiation (LTP) of the commissural input to CA1. I politely enquired whether they were familiar with LTP and related plasticity phenomena at which point Carol clarified that her friends were Tim Bliss and Graham Goddard (Carol was Graham’s student). You can imagine the complex mixture of my embarrassment and pleasure meeting such giants.

Fig. 3. IUPS meeting in Budapest, 1980, with my wife, Veronika Solt, and Evgeny Sokolov, the most prominent Soviet researcher on the orienting response.

During the meeting, I managed to exchange enough U.S. dollars and Deutschmarks from my acquaintances to purchase a plane ticket from London to New York City. I could pay for the London flight with Hungarian currency. The stopover in the United Kingdom allowed me to participate in the Fourth European Neuroscience Meeting, Brighton in September 1980. There, I met Fred (Rusty) Gage, marking the beginning of our lifelong friendship. When I arrived in New York City, I figured out how to use the coin telephone and called Bob Isaacson, hoping that he would explain to me which subway I should take to find him. I did not know that New York City and New York State were different, and only there I realized that Binghamton was a seven-hour bus ride from the city. Never mind, I found the 42nd Street Bus Terminal and took a red-eye Grey Hound bus ride to Binghamton. The next day, I visited Bob’s lab, gave a seminar, and met the students and postdocs who gave me a crash course about life in the United States. Bob was generous enough to purchase a plane ticket for me to San Antonio, Texas. My life in the United States began to take shape.

First Postdoc: University of Texas Health Science Center, San Antonio

During our first meeting, I explained my research plan on the hippocampus to Professor Eidelberg (or Eduardo after the first five minutes). He told me that his grant was for spinal cord research, but he had an extra room where I could conduct my experiments, provided that I prepare single fibers from the dorsal root of the spinal cord twice a week. I should call him when I had the fiber with electrophysiological proof so he could take over the experiment. That was a generous deal, but he warned me, “young man, the only thing you will be able to show is that Ramón y Cajal was right.” For me, that was not such a bad outcome. He had no student or postdoc but two technicians, who occasionally helped me with histology and developing my 35-millimeter films.

I continued the work I started in Pécs searching for direct proof of feedforward inhibition. Steve Fox and Jim Ranck (1975) had already hypothesized that fast-firing cells in the hippocampus were inhibitory interneurons. My aim was to record these putative inhibitory cells and show that they respond before activation of granule cells or pyramidal cells. Collecting the needed instruments took a while, but I had my lab up and running in a few weeks.

I missed my wife and family. They had no telephone at home so exchanging letters was the only way of communication. The content of the second letter from my wife was devastating. Her exit visa application was denied. My secret plan was to work in North America for a few years but certainly not without my wife, and I contemplated returning to Hungary before the end of the year. To distract from my anxiety, I spent more and more time in the lab. On Christmas Eve, I found four beautiful interneurons, each firing 2–3 milliseconds before the population discharge of the pyramidal cells. In my excitement, I overdeveloped the film, and the spikes were barely visible. For today’s readers, the evoked responses were displayed on the oscilloscope screen, and for documentation, we took screenshots with a camera (later by Polaroid). I continued to search for putative interneurons in the coming months, showed that they fired rhythmically with theta waves, and collected convincing evidence that excitatory inputs excite both interneurons and principal cells; however, either because the synapses on the interneurons were stronger or because the charge time of the membrane of interneurons was faster, interneurons fired first and, therefore, could prevent or delay the discharge of their innervated principal neurons. In addition, I could show that activation of interneurons by commissural stimulation attenuated the entorhinal input-evoked responses. In the papers published with Eduardo, we concluded that “interneurons of the hippocampal formation can be directly driven by various afferent inputs,” and also that “the excitability of the principal cells depends upon the relative strengths of the inputs to these two cell types” (Buzsáki and Eidelberg, 1982; p. 603; Buzsáki 1984; p. 145). Within a year, Roger Nicoll’s (see volume 10) group at the University of California at San Francisco reported that in the hippocampal slice preparation, orthodromic stimulation always evoked higher amplitude inhibitory postsynaptic potentials (IPSPs) in CA1 pyramidal cells than antidromic stimulation, another strong support for feed-forward inhibition. With the emergence of immunocytochemical identification of interneurons, anatomical evidence for feedforward inhibition was firmly provided. The case was settled. Feed-forward inhibition has become a standard part of today’s neuroscience, rarely referring to the original papers. Yet, to my great honor, a citation of my Ralph Gerard Prize (2020) reads: “As a young scientist in the early 1980s, he introduced the concept of feedforward inhibition, which is now a widely recognized property of neural circuits.” Roger Nicoll was a member of the jury. He remembered, and this mattered more to me than anything else. After all, the biggest honor one can get in our profession is acknowledgment from those handfuls of people whose work we admire.

The year 1980 marked the beginning of Glasnost and perestroika in Eastern Europe. Perhaps because of such an “opening,” my wife’s appeal was granted, and she got an exit visa in January. She bought a ticket to New York City, I went to the Hospital’s Credit Union, borrowed $1,200, and bought an old used car, a Fiat 128, which looked very much like my father-in-law’s Soviet Lada. On the way to New York, I visited William (Skip) Levy and Oswald Stewart at the University of Virginia in Charlottesville, and Barry Komisaruk at Rutgers University, Newark, New Jersey. In New York City, I met Jim Ranck, Steve Fox, and John Kubie (whose works I knew by heart) and Jon Winson at Rockefeller University.

Jon Winson put me up in the Abby Aldrich Hall guestroom at Rockefeller, next to the library (a reminder: I was just a postdoc from behind the Iron Curtain). That place was more elegant than the Presidential Suite of a Westin Hotel. When my dear Veronika arrived, she created the false impression that her husband won the lottery. Only the battered Fiat car was a reminder of my postdoc status. While driving in Brooklyn the next day, I hit a pothole and lost a tire. Never mind I had a spare. On the way back to San Antonio, we had to change the front tires four more times. It turned out that the pothole collision broke the car’s suspension. Luckily, we did not know it until we reached Texas, so we did not panic and cancel our travel plan. That plan included a lot. We visited the Isaacsons, James (Jim) Sprague (see volume 1) at the University of Pennsylvania, whom I had met earlier; Fred King, the director of the Yerkes Primate Center in Atlanta, Georgia; and Morton Mishkin at the National Institutes of Mental Health (NIMH) in Bethesda, Maryland. Mort was already a superstar, so I was surprised to learn that his office was in the basement with water dripping through the ceiling. Mort also spent some time at the Nencki Institute, Warsaw, so he was well aware of the financial situation of East Europeans. After my seminar, he handed me an honorarium of $100 in cash. That was enough for a Peking duck dinner with my wife, gasoline expense to Texas, a night in New Orleans, and $40 reserve for a potential emergency tire replacement. Later, I learned from several of my colleagues on our trip that the Federal Bureau of Investigation (FBI) had inquired about a potential spy from the Soviet bloc. Bob Isaacson jokingly told to Fred King that the FBI was not after the Hungarian but rather that Fred was the target of a covert investigation. These days, FBI agents occasionally visit my lab and ask me about potential spies working in my lab.

At the University of Texas Health Science Center (UTHSC), Veronika became a nonregistered medical student but had the same clinical responsibilities as the regular students. This was a super-generous gesture of several professors, for which we are eternally grateful. During the summer, we drove to California with our Fiat. In San Diego, I visited Larry Squire (see volume 11), Stuart Zola-Morgan at the VA Hospital and Max Cowan (see volume 4) at the Salk Institute, who introduced me to Larry Swanson (see volume 11) and David Amaral. I was impressed by the high density of neuroscientists in a single city. The scientific highlight of my trip was UC Irvine. Both Jim McGaugh and Charles (Chuck) Ribak invited me to give two separate seminars. Jim put us up in the luxurious Laguna Beach Hotel and invited us for dinner at his house. In my Anatomy Department seminar, I met strong resistance to the idea of feedforward inhibition. Our intense debate electrified Chuck to devote his next several years to providing the needed structural evidence with my colleague László Seress from Pécs, whom he invited as a postdoc. The last leg of our trip was the San Francisco area. At my seminar at UC Berkeley, there were only six people: Walter Freeman, the olfactory physiologist; John Garcia, the discoverer of “taste aversion learning”; Mark Rosenzweig (see volume 5), a pioneer of neuronal plasticity; my host Joe Martinez; and his two students. I reminded myself that quality overrides quantity. We also drove to Stanford and visited Richard Thompson, the dominant neurophysiologist of learning and memory of the day. He kindly invited me to join his lab as a postdoc, but his lab was a bit of a disappointment in terms of technical sophistication. Moreover, by that time, I had already committed to joining Brian Bland’s lab in Canada. Just a week before my departure to the United States, I had received a letter from Brian (a student of Case Vanderwolf) to join his lab for two years. Brian had just returned from Per Andersen’s lab, full of energy and ideas, and he had received excellent funding from the Alberta Heritage Foundation. While in San Antonio, I kept corresponding with my university at Pécs and the authorities to allow me to stay abroad longer.

Second Postdoc: Canada

In retrospect, it is truly amazing how much support I received from my U.S. colleagues. It is unheard of today that a postdoc is invited to give a departmental seminar for an honorarium and stay with the family of the faculty. Perhaps, it was my exotic status of being an Eastern European or a salutation to Grastyán that secured me those privileges. We crisscrossed the country, assuming that our trip was perhaps the last one in the United States. We had one more long drive ahead of us though. We packed our belongings in the Fiat, said goodbye to our friends, and arrived in Calgary on Canadian Thanksgiving Day and stayed with the Blands. Veronika and I slept in the next day, and Brian served us breakfast in bed! Unfortunately, later that day, he had to deliver devastating news. The Alberta Heritage Foundation has terminated its postdoc program. The implication was that I had no funding. Yet, I did not panic. I was trained under uncertainty, and, importantly, we were young. I planned to contact as many Canadian neuroscientists as possible Brian and I knew and offer my services. The first and last person I called was Case Vanderwolf, whom I met in Magdeburg. Case agreed to take me in. So we sat back into our Fiat and drove on the Trans-Canada Highway for five days from Calgary to London, Ontario. I spent a good part of each day fixing our car.

University of Western Ontario

The Department of Psychology at the University of Western Ontario (today Western University) was in a modern building surrounded by old houses in the architectural style of Oxford. Case had no student that year, only a technician, and I was the only postdoc. But to my great luck, Lai-Wo (Sten) Leung had just joined the faculty in the Department of Physiology and helped me a lot with novel quantification methods. Case’s lab had a pen-recording EEG, two oscilloscopes, stimulators, and a most precious four-channel FM tape recorder. Luckily, the psychology student lab had more equipment, some of which I could borrow. I have already learned how to sharpen and insulate tungsten microwires from Eidelberg, I just had to build an impedance meter and a microdrive to record single units from behaving rats. I trained rats to run several turns in a running wheel to activate a sound, which signaled the availability of a water reward at the opposite end of the box. I wanted to study single-neuron correlates of the theta waves so I needed long theta trains that occurred reliably during running. For a while, I was scared to write Grastyán that I was working with Case Vanderwolf, whose views on the hippocampus were diametrically opposite to his. Case was smart in different ways from Grastyán. He was a detail-oriented careful investigator. Although he was acutely aware that the brain serves cognition, he refused to accept any claim on memory or spatial map until all other motor, autonomic, and hidden variables were excluded. I agreed with him that it is super important to monitor those variables, but I had already formed the opinion that action and cognition are not completely separable. Searching for “pure” cognition in an animal that does not behave was perhaps a hopeless endeavor.

Working with freely moving, drug-free rats increased my confidence in my previous findings. For any comparison, the same animal retained its own control, and this within-subject design has remained my main approach throughout my entire career. Identifying putative interneurons and pyramidal cells was much easier because the repeatable behavioral correlations provided additional help to identify waveform and firing pattern differences. The recordings were inspected on the oscilloscope screen and broadcasted through a loudspeaker. The ear is a Fourier analyzer, and the smallest changes can easily be detected. I first extended my previous observations on the relationship between firing patterns of different hippocampal neuron types and theta oscillations while simultaneously studying their correlations with fast (gamma band) rhythm. But the most fascinating pattern was a strong, synchronous population pattern, which I called sharp wave burst and later sharp wave-ripple. I have been enthralled by the beauty and power of this pattern from the first moment I heard its buzzing sound. I felt as if I had been listening to a group of orchestra musicians idly tuning their instruments. The next moment they united in the thrilling harmonies of Beethoven’s Fifth Symphony. Studying the neuronal correlates of sharp wave ripples, I learned why synchrony is a unique brain operation. It can bring about enormous power surges at no extra energy cost. If one listens to one instrument at a time in an orchestra, even the first violin, the actual melody of the piece may be hard to identify. This is more so in the brain. When listening to the spike sounds of individual neurons, we cannot detect the occurrence of a sharp wave ripple. But when we listen to many neurons, one cannot miss it. I wondered what the function of such collective action might be. The brain must have a good reason to go to the trouble of producing such unusual population activity. My first thought was that it was a teaching signal to induce plasticity in the neocortex, but it took four decades of further work in many laboratories to get a clearer picture. Instead of writing three papers on theta, gamma, and sharp waves, I decided to publish the three interconnected stories in a long paper with 21 figures (Buzsáki et al., 1983).

During the summer of 1982, two key things happened. Veronika was allowed to visit Canada by the Hungarian authorities for a month. Second, Bob Isaacson wrote me a kind letter, offering me an assistant professor position. This was an exceptional opportunity, and we discussed it extensively with my wife. The stakes were high. If we both stayed, she had to start all over her medical studies. If I stayed in the United States and she returned to finish her remaining year and a half, there was a good chance that the authorities would classify me as a “dissident” with no option to return to Hungary. She would not be able to return to the United States. We chose a third option. She flew back to Hungary at the end of the summer, and I also returned at the end of the year. Did we really make a decision or float on the waves of life?

Case Vanderwolf was an exceptionally warm-hearted mentor. I often spent the weekend at his house where he and his wife, Judy, prepared meals based on medieval recipes. Every summer, they made a canoe trip in Northern Ontario and invited us along with Case’s daughter and a couple from Toronto to their annual trip. The seven of us were flown by a seaplane and landed on a big lake in the middle of nowhere. Only Case and Judy knew how to handle a canoe properly and only Case had an idea (and a map) of where we were. He always warned us ahead of time when a waterfall was expected, at which point we had to portage our canoe and gear (i.e., our tents, food, clothing) on our heads from the upstream to the downstream parts of the river. After sunset, we pitched a tent, made fire, and cooked dinner. The backpack with the food had to be placed as far as possible from the tent in case hungry bears would come by. And they did. One night, my wife left the tent and faced a sizable bear from a close distance. Luckily, the bear had another agenda than to attack an innocent Hungarian. After the third day, my wife and the couple from Toronto were discussing how to kill Case for all this torture, but we postponed carrying out the plot because of our fear that we would never make it back to civilization without him. With time, however, we adapted to the daily routine, and at the end of our venture, we all concluded that that was the best trip in our lives. Case’s training reminded me of my good sergeant in the army. And one more detail: On the first day of our trip, Case declared that the rule of wilderness is skinny-dipping and he showed the way. We justified our following by thinking that there would be one less thing to dry each day. I am sure if I did such a thing with my lab members today, I would appear on the front page of the New York Times and lose my job. But back then and there, this was completely acceptable with no prejudice, and things functioned just as well.

Leaving Canada

In October, one day after submitting our manuscript, I packed the few things I had and drove the Fiat back to the United States to visit Bob Isaacson and tell him my decision. From there, I drove to New York City, bought a ham radio transmitter, I gave away my faithful Fiat wreck to a Hungarian acquaintance, and ordered a car from the Schiphol Airport, Amsterdam. In those days, transporting cars was the best way to convert dollars to Hungarian currency because citizens spending more than one year abroad were exempt from paying the 60 percent tax.

In New York City, I developed a fever and by the time I arrived in Amsterdam, it got worse. I picked up the car, an Audi diesel (the cost of diesel was half the regular gasoline in Hungary), and drove to Hungary in one stretch. At the Hungarian border, the “authority” informed me that, as a Hungary citizen, I was not allowed to drive a car with a foreign license plate inside the country. I asked for tools to remove it but he gave me a hateful look and told me to return to him after removing the plate. It was the middle of the night and raining and I was shivering in fever. After a good while, a Belgian truck arrived and the driver helped me to remove the license plate. I arrived in Budapest the following day and spent a week in bed in my in-law’s apartment with pneumonia. It was not a welcoming beginning to my restart in Hungary.

Starting a New Life in Pécs

The three and a half years I spent in Pécs after returning from the United States were perhaps the most formative years of my life. Being aware of the financial and technical limitations, I deliberately designed experiments that were difficult technically and could not be done faster, even in a large lab in the United States. One of those experiments was to identify the state-dependent changes in the distributions of the current sinks and sources involved in hippocampal theta oscillations. The first step was to collect high-spatial-resolution data with a stationary (control) electrode in the CA1 stratum oriens and from all other layers successively. I used my running track paradigm to “clamp” behavior and compare theta during level pressing and running. Each experiment took an entire day with frequent failures because cerebrospinal fluid short-circuited the drive or the rat was not motivated enough to run beyond 50 trials. Case Vanderwolf donated his four-channel FM tape recorder to me (my most expensive piece of equipment) so I could record everything on tape. The analysis step was an even bigger challenge. Although we received our first computer, a PDP-11, from Roy John, New York University, we did not have an analog-digital converter. I found a solution at the Kodaly Institute of Music in Budapest, dedicated to preserving folksongs in digital format. So I carried my tape recorder to Budapest on a train, converted the data onto punch tape, and used the punched tape in Pécs to feed our PDP-11. Even with this clumsy process, our paper was the first current-source density description of hippocampal theta oscillations. We also showed that theta waves are asymmetric and that the degree of asymmetry varied with speed in a layer-dependent manner.

By the time I resumed my position in the Department of Physiology, Grastyán had replaced Kálmán Lissák as the director. He hated his director role and often cited Plato as an excuse: “One of the penalties for refusing to participate in politics is that you end up being governed by your inferiors.” One such “inferior” was a “Moscovite” (this was a reference to Hungarians who obtained a doctorate in the Soviet Union), who got confused about ion concentrations inside and outside the neurons during his talk at a summer course. After the talk, a young participant commented on the talk in a genius way. Everyone in the room, except the Moscovite speaker, realized that the young participant made fun of him. He was Peter Somogyi, who already held appointments in Budapest and Oxford by then. After the talk, we immediately bonded and have remained trusted friends.

Our plan to return to the United States got a further push when Veronika learned after her graduation that she did not get any of the jobs she applied for in Pécs, despite being a top student. Grastyán helped out (again!) by offering a temporary instructor position for my wife in the Physiology Department but allowed her to work in the Internal Medicine Clinic. In early 1983, I received a letter from William (Chip) Levy from the University of Virginia offering me a research associate position. At the U.S. Embassy, however, the Consul firmly told me that she issue me only a J-1 visa, which meant that we had to return to Hungary for two years before changing our visa situation. This unexpected verdict felt devastating then but, in retrospect, we should have been thankful because this event forced us to follow plan B, which was planning our future in Hungary. From the sales of the Audi and our small apartment and loans from our relatives and friends, we bought a share of a house in the nice, hilly part of Pécs. We had enough room to host journal clubs with my students regularly. Our beautiful daughter, Lili, was born a year later.

Grastyán Turns 60

Endre Grastyán turned 60 in 1984. Case Vanderwolf and I thought organizing a hippocampus meeting in his honor would be a lovely birthday present. This was the first-ever meeting I organized. The speakers included William Levy, Fernando Lopes da Silva, John Kubie, Jim Ranck, Ian Wishaw, Brian Bland, Stan Leung, Klaus Reymann, Bob Muller, Steve Fox, Case Vanderwolf, John O’Keefe, Bob Sainsbury, Vincent Bloch, Richard Morris, Rob Sutherland, and Tim Bliss (Figure 4). This team was the cream of hippocampal physiology research of the day (Per Andersen could not attend). I also invited a dozen Soviet scientists but nobody came because a year in advance was too short for passing through the multilevel bureaucracy. The scientific highlight of the meeting was Jim Ranck’s premier presentation of his discovery of head direction cells in the postsubiculum, neurons that fire only when the head points in a certain direction in the environment, regardless of the animal’s location. We recorded all the discussions, which I transcribed and published along with the submitted manuscripts in a volume Case and I edited a year later (Buzsáki and Vanderwolf, 1985). There was an interesting discussion about the theta phase relationship of spikes. Whereas I observed that, on average, spikes of pyramidal cells prefer the trough of the theta cycle, John O’Keefe argued that place cell spikes could occur at any phase, perhaps escaping from the background control. Case emphasized the importance of two types, cholinergic and noncholinergic, theta oscillations. In turn, O’Keefe commented that perhaps we should “speculate about the possibility that in fact there are various phase relationships that can occur between these two EEG patterns, and may be part of the function of the EEG is to create interference patterns as a function of the different phases of these two theta waves” (Buzsáki and Vanderwolf, 1985, p. 386). Nine years later, O’Keefe cracked the puzzle with the discovery of spike “phase precession.” A memorable comment on my work came from Tim Bliss: “My point about sharp wave was that it is a naturally occurring phenomenon which satisfies the two conditions, high frequency and high strength” (Buzsáki and Vanderwolf, 1985, p. 395). All speakers referred to Grastyán’s pioneering work, and I was happy to see how much he enjoyed interacting with all the participants.

Fig. 4. Symposium for Endre Grastyán’s 60th birthday. Vasváry Villa, Pécs. First row, William Levy, Fernando Lopes da Silva, John Kubie, Jim Ranck, Endre Grastyán, György Buzsáki, Ian Wishaw, Brian Bland, Stan Leung; second and back rows: Klaus Reymann, Bob Muller, Steve Fox, Case Vanderwolf, John O’Keefe, Bob Sainsbury, Vincent Bloch, Richard Morris, Rob Sutherland, Ferenc Kekesi, István Mészáros, József Czopf, Lajos Vereczkei, László Molnár, Mark Molnár, and others. (Missing from the picture: Eric Halrgen and Tim Bliss.)

University of Binghamton, New York

Although I could not accept the job at the University of Binghamton, Bob Isaacson invited me back to teach a graduate course on human neuroanatomy. It was planned as a full semester course, but the graduate school allowed me to condense it to two months. The month before my expected trip, Antonio Giuditta (Universitá di Napoli, whom I met in Magdeburg) sent his postdoc, Adolfo Sadile, to my lab to study whether DNA synthesis was involved in LTP. As a control, we used low-frequency stimulation (1 Hz), and we found long-term depression of the evoked responses: “The decrease in PSA [amplitude of population spike] became significant 5 min after the stimulus trains” (Sadile et al., 1991, p. 85). During the second week of our work, I was summoned by the military, as a reservist, for an exercise. After we built a tent hospital in the Bakony mountains and were expecting casualties from an imagined “attack by the imperialists,” a political officer summoned me for an “interview.” The officers in the room presented the conspiracy theory to me that NATO sent Adolfo Sadile to spy on secrets of the Hungarian Army through me. When I asked how NATO would know in advance that I would be drafted, they were puzzled but not much. I was scared to mention that I had a planned trip to the United States and just hoped that the communication between the military and the secret police was poor. It was. Two days before my planned departure, the exercise ended and all reservists were released.

I went to the Pathology Department and requested a cadaver brain for my course. At JFK Airport in New York City, the customs officer asked about the content of my carry-on bucket, and I told him I was carrying a human brain for teaching purposes. I showed him a certificate that the specimen contained no dangerous substances, and he was satisfied. My students in the course were overwhelmed with happiness being able to inspect, handle, explore, and cut a real brain and to learn about blood supply, the Willis circle, the meninges, ventricles, cranial nerves, and of course the Brodmann areas of the brain.

University of Lund, Sweden: Brain Tissue Transplantation

Our lives with Rusty Gage intersected again. Rusty felt a bit isolated at Texas Christian University and went to work with Anders Björklund (see volume 10) in Lund, Sweden. The Björklund lab was already a leader in neuronal sprouting and transplantation. Their work ushered many clinical trials with tissue transplants in Parkinsonian patients. Rusty introduced me to Anders at a meeting. They explained how they removed the fimbria-fornix to access the vascularized surface of the thalamus, which is an excellent substrate for transplanted embryonic tissue. In my lab, I was also removing the fimbria-fornix but to examine the impact of subcortical inputs on hippocampal oscillations. We immediately formed a plan to determine whether embryonic hippocampal or septal transplants in the fimbria-fornix cavity could restore hippocampal function. Anders kindly offered me a visiting scientist position that allowed me to visit his department and learn their techniques. I made several trips to Lund, my income tripled, and I was able to buy our first color television. Rusty taught me his already perfected surgical methods, I replicated them in Pécs, completed the physiological investigations there, and brought the brains back to Lund for histological analysis. Every experiment offered something unexpected, and we published several interesting papers about the electrical activity in the transplanted tissue and the restored or malfunctioning patterns in the host brain. I thought this collaboration with Anders and Rusty would continue forever, giving me a comfortable life (and income) in my Pécs laboratory.

An important collateral of my Lund days was my introduction to Tamás Freund (see volume 11). Both Anders and Rusty knew Tamás, who at that time was working with his mentor Peter Somogyi in Oxford. I mentioned to Tamás that epileptiform activity always develops in the transplanted hippocampal tissue, a sign of impaired inhibition. Tamás was eager to investigate and soon reported a discovery to me. The axon-initial segment of transplanted pyramidal cells was devoid of chandelier interneuron boutons. The spike output of the pyramidal cells was without control, which explained the epileptic activity. In the discussion of our paper, we made the tentative (and incorrect) suggestion that epileptic activity kills chandelier interneurons. I corrected this conclusion decades later at Tamás’s 60th birthday party. By that time, we had learned that GABAergic interneurons are born in the ganglionic eminence and chandelier cells migrate to the hippocampus in late embryonic days. Because we transplanted the hippocampus at embryonic day 15, our tissue probably did not contain a single chandelier neuron.

One night in Lund, Rusty got a call from Robert (Bob) Katzman, who had just become the chair of the Neuroscience Department at the University of California, San Diego (UCSD). Bob offered Rusty a tenured job. By then, we had established our sincere friendship and started thinking about how we could continue working together. After returning to Pécs, I found a flyer in our library in which the National Academy encouraged young researchers to apply for scholarships working abroad and even listed a couple of foundations. That was quite a policy change. So I started to apply to every foundation I could find in the United States without much success. I also tried the new JD French Alzheimer’s Foundation (JDFAF). I had no credentials in Alzheimer’s disease (AD), but after learning that the foundation was dedicated to the neurosurgeon John (Jack) Douglas French, the first director of UCLA’s Brain Research Institute, whom Grastyán and Eidelberg knew well, I became hopeful. I already heard about his wife, Dorothy Kristin French, the New York Metropolitan Opera diva. When Jack was diagnosed with AD, Dorothy devoted her life to the cure of the disease, and with her Hollywood friends, she founded the JDFAF. My application about AD was pretty vague, but it explained how cholinergic inputs may affect hippocampal and thalamocortical operations. Rusty and Eidelberg kindly wrote letters of support. When I met Mrs. French later, she told me that Eidelberg also wrote her a personal letter saying a few things about me, but she liked the sentence that “this crazy Hungarian likes to dance.” To this day, I want to believe that this was the reason why I got a $100,000 grant, which allowed me to join Rusty at UCSD in 1986.

Wonderful UCSD Years

We spent four unforgettable years in San Diego. Our daughter Lili and the Gages’ daughters Cheka and Alex were similar in age. My wife and Rusty’s wife, Mary Lynn, became close friends. We spent many weekends together, celebrated many family birthdays, and our daughters attended the same Montessori school.

UCSD was a very welcoming environment. To my great surprise, in the first week after my arrival, a nice gentleman, Theodore (Ted) Bullock (see volume 1) was looking for me and told me that he had read my ethology papers. Learning that someone at the other end of the world read Eastern European journals was a strange feeling. But Ted was an exceptional person. He became my unsolicited mentor on physiological issues at UCSD. He introduced me to Bob Galambos (see volume 1) (who discovered echolocation in bats) and Reginald (Reggie) Bickford. Reggie was a student of both Lord Edgar Adrian and W. Grey Walter. Reggie retired in 1980 but kept his lab gadgets in a shipping container, which became my treasure box. The most important piece he donated to me was a computerized 16-channel EEG mapping device with a printer. This was precisely the equipment I was dreaming about. Case Vanderwolf had already shown that cortical electrical activity has both cholinergic and noncholinergic components, and my JDFAF grant was about the impact of the nucleus basalis on the thalamocortical system. I had to build a running wheel apparatus and a 16-channel miniaturized preamplifier. This innovation was made possible by the great electronic shop in the Physics Department at UCSD, where I spent a great deal of time. Quad-MOSFET chips had just become available, and I could stack them into a cube that was easily carried by an adult rat. Sixteen screws in the skull above the neocortex provided a two-dimensional map, and I also recorded unit firing from the cortex, thalamus, or the nucleus basalis (NB). I could record only up to 30 seconds of data with Reggie’s EEG machine, but that was state-of-the-art. I did depth profiles of the neocortical LFP (local field potential), combined with lesions of NB or parts of the thalamus. I showed that “damage to the NB resulted in a dramatic increase of slow delta waves,” whereas thalamic lesions affected sleep spindles (Buzsáki et al., 1988, p. 4007).

After the paper was accepted, I got a call from Mircea Steriade from Laval University, Quebec City, who was one of the reviewers: “Why does a Hungarian want to destroy my career?” was his opening sentence. Mircea, a Romanian, was the undisputed leader of thalamocortical rhythms back then and believed that the thalamocortical projection was solely responsible for the neocortical arousal. After our telephone discussion, he invited me to visit his lab and we wrote a 61-page chapter on the basal forebrain cholinergic system (Steriade and Buzsáki, 1990). The results and the methods I established were suitable for asking questions in aged animals, especially because cholinergic impairment was believed to be a cardinal problem in AD. With my undergrad student volunteers, we could record cortical maps from the same animal for up to 16 months and found that the most reliable correlate of aging was a thalamocortical rhythm, which I called high voltage spindles (HVS).

I made many friends at UCSD. Phil Groves and his postdoc, Jim Tepper, taught me their way of intracellular recordings. Bob Terry was my adviser on AD-related issues, Marta Kutas (of Hungarian origin) and Steve Hillyard on cognitive topics. Larry Squire, David Amaral, and Stuart Zola-Morgan were my hippocampus buddies. Their super-energetic student, Wendy Suzuki (I was a member of her committee) organized Hippocampus Pizza dinner discussions at the Salk Institute. Francis Crick and the neurophilosopher Pat Churchland (see volume 13) were frequent partners in these debates. Pat sent her graduate student Adina Roskies (now a distinguished professor of philosophy at Dartmouth College, New Hampshire) for a rotation in my lab to learn how to record neuronal spiking activity from hippocampal neurons. Ted Bullock introduced me to his collaborator Walter Heiligenberg, a student of Konrad Lorenz. Walter and Ted studied the jamming avoidance of the electric fish Eigenmannia. The key thing I learned from Walter is that sensation starts with an action. Walter’s wife, Zsuzsa, was a piano teacher from Budapest, and the organizer of music life in San Diego. Famous musicians who gave concerts in the San Diego Symphony often ended up for dinner in Walter’s and Zsuzsa’s home in Del Mar. We spent many nights together with Walter, Zsuzsa, and their three children, who mixed English, German, and Hungarian, during the party conversations. Walter’s good friend was Mark Konishi (see volume 6) from CalTech who often came down to cook dinner for the parties. Mark liked to reminisce about his early life in Japan, which resonated with my childhood in Hungary in multiple ways. Unfortunately, Walter was killed in a plane crash while on his way to deliver a lecture at the University of Pittsburgh. He was 56.

IBRO Satellites in Pécs, 1987

The Second World Congress of Neuroscience (IBRO) was held in Budapest in August. I submitted two applications for organizing satellite events in Pécs. The first proposal was about synaptic plasticity in the hippocampus with Helmut Haas (then in Zürich), whom I met twice in Magdeburg, and the second was about brain tissue transplantation with Rusty Gage, Anders Björklund, and Albert Aguayo. When both applications got accepted, I started to panic. How do I tele-organize such important events from San Diego? My ex-technician and two of my ex-students in Pécs helped me out. I arrived in Hungary with $5,000 cash in my pocket (nota bene: it was illegal for Hungarian citizens to possess foreign currency) and brought two micromanipulators, which were ordered by my colleagues in the Department of Physiology, worth $6,000, for which I expected to receive Hungarian forints from the university. Helmut brought 10,000 Swiss francs in his briefcase. We expected about 120 participants, all major players in the plasticity field for the first satellite. Helmut and I arrived three days earlier to check out everything from hotel rooms to the planned concert in the cathedral. But one major item was missing: poster boards. After calling every person I knew for information, one lead was to the House of Armed Forces and I even got the name of the chief officer. Entering his room, I explained that this international conference reflected the salutation of the scientists of the world to the achievements of our great socialist system. I also placed an envelope on his desk. He opened the envelope (it contained 10,000 forints, approximately a month of salary), slid it into his drawer, and asked how many boards I needed. Helmut was shocked to see military trucks in front of the conference hotel and soldiers setting up the poster boards. Helmut and I paid for the hotel rooms, lunches, and dinners, including the gypsy band, with cash for the three days and expected to be arrested by the authorities at any time.

A good part of the symposium was dedicated to long-term plasticity. One of our originally scheduled speakers was Graham Goddard, who had drowned early that year while attempting to cross a storm-swollen river in New Zealand’s Arthur’s Pass National Park. Graham was 48 years old and had already established his fame with the discovery of kindling. Helmut and I thought it appropriate to dedicate our satellite event to his memory and asked his friend, Tim Bliss, to give a lecture in Graham’s honor. Tim’s emotional talk discussed the different forms of plasticity and their relationship to epilepsy. Tim admitted that he never liked the term he coined (LLP, long-lasting potentiation), and other abbreviations like LTE were equally difficult to pronounce, whereas LTP (long-term potentiation), the term introduced by Graham, was so much easier to utter. He suggested switching from LLP to LTP honoring Graham Goddard and LTP became the standard abbreviation after the Pécs satellite. That memorable moment of the meeting was worth the effort of organizing it. Today’s neuroscience students only know about LTP.

We ended the satellite with an excursion to the Villány wine region, where I paid for the dinner and wine with the money I borrowed from my parents. I had not yet received the reimbursement for the micromanipulators from the university and ran out of cash. Yet, I still had to run another satellite after the main IBRO event in Budapest. One great talk at the main meeting was by Rodolfo Llinás, who talked about low threshold Ca²⁺ spikes and how thalamic neurons can spike not by excitation but by rebounding from inhibition. That was really cool, I thought. After his talk, Peter Somogyi and I managed to “steal” him from the audience, and Peter shared his homemade sausage-filled sandwiches with us while we were picnicking on the grass. In the afternoon, I bumped into Tamás Freund, who was planning to come to our transplantation satellite, and I told him that I had no money to support the event. Tamas ran home, brought back his family’s entire savings, handed me a big envelope, and said: you pay it back when you can. He not only saved our symposium but also taught me about trust and the real meaning of friendship.

The transplantation symposium was designed to be a small event, mostly discussing strategies. One speaker from Havana, Cuba, showed a movie in which Fidel Castro watched Parkinson’s patients who received adrenal medulla transplants and were playing basketball after their recovery. Many questions were asked but few answers were given. Rusty had to fly back to the United States early the next day and the Cuban speaker offered her services. Picture this: an American neuroscientist, whose father was a decorated U.S. Navy pilot commanding officer, riding in a Soviet Lada car, property of the Cuban Embassy. I survived both meetings and was happy that I ventured into them.

Grastyán told me how much he enjoyed the plasticity satellite. Yet, I was surprised that he did not ask questions and a bit disappointed that he did not come to our social events. He suggested that I submit my Doctor of Science degree to the academy because he wants me to become his successor. Although I felt that nothing was a bigger honor than hearing this gesture from him, I politely responded that he should perhaps think about others as well in case my candidacy was not approved. He then gave me a long explanation of why he returned to Hungary from the United States, despite the opportunities he was offered. That was the last conversation with my dear mentor. He died of lung cancer in a year. He was a chain smoker. A few months later, Rusty and I invited Jan Bures from Prague to San Diego and I talked to Jan about my bad feelings regarding my last conversation with Grastyán. Jan put it plainly: “You are obliged to your talent and have to exploit it. Von Neumann may have ended up as a high school math teacher in Hungary.” The comparison was exaggerated, but I got the point.

My First Promotion

Parallel with the nucleus basalis and thalamic studies, we continued our transplant experiments with Rusty. We observed that after the fimbria-fornix lesion, chronic epileptiform events inevitably emerged in the hippocampus. It seemed that such a preparation was suitable to study the impact of neuronal transplants on hippocampal excitability. Nearly all tissue transplants made things worse and induced seizures. Eventually, we succeeded in suppressing epileptiform events by transplanting embryonic locus coeruleus directly into the deafferented hippocampus. Despite this small success, I was confused about my research direction. I did not quite understand the structure of academia in the United States and had uncertainties about my future. The grant proposals we had written with Rusty were successful. Yet, Rusty also recognized that this direction alone was not a sustainable research goal. His group had rapidly switched to studying nerve growth factors and applying genetic engineering methods. I felt that my focus on neuronal circuits and the in vivo methods I tried to improve were not interesting enough. Job advertisements were almost exclusively for researchers using in vitro methods, the dominant electrophysiology technique of the day.

Rusty had a more optimistic view, and he sponsored my green card (permanent U.S. residency) application. At the same time, he suggested to Bob Katzman to offer me an in-residence faculty position. I was heartened when the faculty unexpectedly recommended me the title of associate professor, a jump from a postdoctoral scholar. This was great news.

Lucky Number 13

My new title did not come with a startup package or new space but with the responsibility to raise funds for my salary and research. But when I began applying for grants, one rejection followed the next. One NSF reviewer’s main comment was that the “sole goal of this application is to secure a faculty position to G.B. in the US.” I did not understand why this was a crime. Bob Katzman kindly included me in their AD program project renewal with just one experiment and a small budget, yet the reviewers recommended removing me from the project. I applied for a grant from the Epilepsy Foundation of America. I did not receive it, but the rejection letter included an encouraging line that my application was scored high and, therefore, I should reapply. I did at the next round, only to get a second rejection letter. My JDFAF grant was about to run out. My wife worked as a volunteer in the Department of Medicine with no salary. One night, after reading a bedtime story to my daughter, I was watching my sleeping beauty and, with the prospect looming of not being able to pay the mortgage in a few months, was thinking, “What kind of a father I am, who cannot provide support for my family?”. Such desperate moments are never forgotten but become part of you, making you stronger after each failure. I shared my desperation with Roger Traub, who was visiting me at UCSD from IBM. Roger encouraged me by saying that my work should be funded eventually. His emotional support coincided with my 12th rejection.

Justin Zivin, a neurologist colleague, submitted a program project to NIH, and I was part of that proposal. My project received the best score from the site visit team, and I felt encouraged. Then, during the spring of 1989, I received good news. Our application with David Amaral and Peter Rapp to study the behavioral, physiological, and anatomical changes following intraventricular infusion of nerve growth factor in aged monkeys was funded by the Alzheimer’s Disease and Related Disorders Association (ADRDA). A month later, I received the “pink sheet” from NIH, indicating that the score on my RO1 application was in the fundable range. It was the same proposal that had been rejected by the Epilepsy Foundation twice. Our program project with Justin was also funded by the summer. Things miraculously rebounded. The important lesson I learned from these and many other similar experiences is that resilience to defeat and humiliation is the most crucial ingredient of a scientist. I have written two books, each with 13 chapters. My current laboratory at NYU is on the 13th floor. Our apartment in New York City is also on the 13th floor (Okay, it says 14th in the elevator because 13th floors do not exist in residential buildings). I like the number 13 (and I am not Judas).

Two-Stage Model of Memory

Amid my uncertainties about research directions, there were occasional sunny days. The denervated (fimbria-fornix lesion) hippocampal preparation offered some unexpected advantages. The sharp wave ripples were transformed into large amplitude interictal spikes and single-pulse stimulation of the entorhinal inputs evoked a unique spatiotemporal event with multiple population spikes that I could study with the 8 or 12 recording sites implanted along the long axis of the hippocampus. Following tetanic stimulation of the entorhinal input, the response amplitudes did not uniformly increase, but a new, unique spatiotemporal pattern was induced. The genuinely unexpected thing was that after such induction, the spontaneously occurring population events (“exaggerated” ripples) in the CA1 region were virtually identical to those of the evoked responses, except that no dentate responses preceded the spontaneous CA1 events. Reversing the stimulus polarity and recruiting a different set of perforant path axons induced another unique spatial-temporal constellation of spontaneous events. The repeated spontaneous patterns were present only during immobility and nonREM, the same brain states that promoted sharp wave ripples. This was a eureka moment, and I knew I was onto something important. I saw a potential caricature of what happens during learning and memory. The neocortical information during learning may modify the synaptic connectivity in the CA3 recurrent system, and the spontaneous sharp wave ripples replay the newly formed pattern over and over during nonREM sleep. This was a potential explanation for the puzzle why episodic memories can last forever after a single experience. I shared my excitement with Rusty and rushed to the third floor to outline my new idea to Phil Groves. Phil became so excited that he organized an impromptu seminar the following week, and I used the blackboard to outline my future two-stage memory model. The small audience included Phil, Reggie, Bob Livingston, Pat Churchland, the freshly arrived faculty Terry Sejnowski, Steve Hillyard, and Francis Crick (Rusty was out of town). We went on from 10 A.M. until lunch with exciting discussions and diversions, and I knew that I had to write about the discovery soon, although I was unsure about the format. Pat suggested a review, which I eventually did. She and Terry generously devoted a chapter to the two-stage model in their book The Computational Brain (Churchland and Sejnowski, 1992).

Trip to Oxford

Tamás Freund received a fellowship from the Italian pharmaceutical company FIDIA to study the protective effects of gangliosides in the ischemic brain in the Neuropharmacology Unit, Oxford, with A. David Smith and Péter Somogyi. Although several “static” experiments have been performed before and after global forebrain ischemia, there was no information about the dynamic changes that occurred in the brain during and following the ischemic challenge. I built the necessary equipment in San Diego and carried it to Oxford. In two days, we were recording before, during, and after ischemic attacks. In addition to electrical activity, we recorded local tissue O₂ level and temperature with a microprobe developed by the company (Ottosensors) of my engineer friend from Vienna, Otto Prohaska. Before leaving Oxford, I gave a seminar discussing my ideas on sharp wave ripples and the two-stage model of memory formation. Because Tamás and I worried a bit that some of the variability of the results was due to anesthesia, Tamás flew to San Diego, where we replicated the critical aspects of the experiments in freely moving rats.

Shortly after my return to UCSD, I received a letter from David Smith. David, the founding editor of the IBRO journal Neuroscience, invited me to join the editorial board. This was an unexpected honor. In addition, David suggested that I submit my planned review of my memory model to Neuroscience. I already had an outline, but the final product took another year to finish while I had to attend to other priorities.

Hesitation and Choice

After receiving three grants, my financial security looked okay, at least for a while. I had one graduate student, Melissa Hsu, who was interested in ischemia. I volunteered to teach a course for a group of underrepresented minority students, was an adviser for two medical students, and became the chair of admissions for graduate studies (thanks to David Amaral), my first major administrative duty. I published 12 papers in 1989 and received an accelerated promotion from the department. Everything looked good for me. The situation was somewhat different for my wife. Veronika kept working as a volunteer even after she passed the Educational Commission for Foreign Medical Graduates (ECFMG) exams (today they are called USMLE). In her residency interviews, she was encouraged to rate the University of Southern California highest to “match” their program. We discussed many variations of how to handle our family affairs, mainly because Lili was about to enter elementary school. Living separately in two cities or living together halfway between San Diego and Los Angeles were not attractive options. Until that point in our marriage, my wife supported my ventures, following me around the world. It was my time to give back to her.

Paula Tallal and Ian Creese from UCSD were offered to direct a new center at Rutgers-Newark, and my friend Jim Tepper suggested they recruit me. I liked their vision of the center and the proximity of the University of Medicine and Dentistry of New Jersey (UMDNJ), a potential workplace for Veronika. She applied to the psychiatry program at UMDNJ and had to submit her match rankings in April. One day before her deadline, I called Ian, asking when I should expect a written offer from Rutgers, and explained our urgency. He told me there were routine administrative steps to be followed, but he assured me everything was on track. I was not sure what “everything” meant because we had not even discussed my salary, space, or title. Veronika matched shortly at UMDNJ, and my options came down to one choice, the outcome of which depended on Ian’s and Paula’s handshakes. When I arrived at Rutgers in 1990 as a full professor, I received everything they offered me verbally.

Bob Katzman retired from his position as chair, and the department was in search of a new leader. Leon Thal was one of the applicants, and he promised me tenure in case he became the new chair. Ted Bullock was super generous and offered half of his lab space for me at Scripps. During my years in Newark, I often fantasized about how much easier it would have been to recruit postdocs with a lab right on the beach. Despite such attractions, we decided to move to the east coast. Rusty threw an unforgettable goodbye party for us. At that point, we had coauthored 29 papers and several additional chapters, but life laid new paths before us.

Twenty Peaceful Years at Rutgers University, 1990–2011

Rutgers-Newark is ethnically the most diverse university in the United States in the heart of this old city in New Jersey. When I arrived in 1990, I had three rooms in three different buildings, a graduate student (Melissa Hsu) and a postdoc (Zsolt Horváth). Melissa remained a UCSD student. Zsolt drove his family in his old Oldsmobile (we called it Zsoltmobile, which was passed onto two more generations of postdocs) from San Diego to New Jersey. I soon recruited another postdoc from Pécs, a neurosurgeon from China, and Anatol Bragin (a collaborator of Olga Vinogradova from Moscow), and the six of us started the lab. I had already given up on the transplant work and wanted to focus on circuit analysis, where my engineering mind felt comfortable. This required expanding in two directions: intracellular recordings and large-scale monitoring of spiking activity.

First 10 Years

THE INTRACELLULAR PROJECT

Our intracellular program was conceived in San Diego, when Nobuaki Tamamaki (then from Kyushu University) visited UCSD. He mentioned a new Japan-supported program, the Human Frontier Science Foundation (HFSP) that called for international collaboration. I invited Tamás Freund, Helmut Haas, and Richard Miles (from Paris) to join Nobu and me. The main goal was to characterize the physiological properties of morphologically identified inhibitory interneurons in the hippocampus. We got the award, my first one at Rutgers, which, with renewal, kept us together for six years. My job was in vivo characterization. I trained a neurosurgeon postdoc to impale neurons, examine how their properties were related to various LFP patterns, label the neurons with neurobiotin, and reconstruct the entire dendritic and axonal tree. Beginner’s luck was with us, and soon we labeled a chandelier neuron in CA1. I faxed a few pictures of the axon arbor to Peter Somogyi, who got on a plane to visit us and trained us to reconstruct the axon connections with a neurolucida tube, and we wrote the outline of a paper, all in a week. Our neuron was the first chandelier cell in the rat. It contacted more than 1,000 pyramidal cells, exceeding previous estimations based on Golgi studies by several-fold.

The second project aimed to reconstruct the axon arbors of pyramidal neurons and granule cells in different hippocampal regions in both the dorsal and ventral hippocampus to quantify the distribution of axons in different layers and estimate the magnitude of convergence and divergence of pyramidal neurons. This four-year project has remained a key reference for intrahippocampal pyramidal neuronal connectivity. Luck struck again when we found a peculiar, never-before-seen interneuron, which we called the “back-projection cell” (Figure 5). The neuron’s cell body was in the CA1 region, but its axons crossed the hippocampal fissure and projected back to the CA3, and possibly dentate regions. This pattern was opposite to the well-known trisynaptic excitatory traffic in the hippocampus. Floyd Bloom, the editor-in-chief of Science, highlighted our findings in his Society for Neuroscience Plenary Lecture and, subsequently, many types of long-range interneurons have been described in the forebrain.

The project for interneurons yielded several new types and new papers. However, the search for interneurons in the apical dendritic layers failed. Instead of healthy-looking interneurons, postdoctoral fellow Anita Kamondi (today professor of neurology at Semmelweis University, Budapest) recorded only variable amplitude, often wide waveform spikes from mystery structures. We first thought the variable amplitude reflected poor impalement and leakage of a dying neuron. One afternoon, the fire alarm went off, and we had to evacuate. An hour later we returned and the recording still showed the same pattern with burst of spikes during sharp wave ripples. Suspecting that recordings were from dendrites, postdoc László Acsády, who came from the Freund lab, carefully examined the reconstructed pyramidal neurons, and each time we found that activated glia attached to the dendrite at the estimated depth of penetration. These were the first anatomically verified intradendritic recordings in the hippocampus. The results suggested that “sharp wave bursts facilitate dendritic electrogenesis” (Kamondi et al., 1998; p. 3925) and that Ca²⁺ spikes in distal dendrites contribute significantly to the extracellularly recorded theta currents. With time, we became experts with intracellular recording in vivo, and it remained our auxiliary technique for many years to come. Postdoc Darrell Henze succeeded in recording simultaneously intracellularly and extracellularly (with tetrodes or silicon probes) from the same neurons. These recordings included our first widely shared dataset that served as ground truth for perfecting unit clustering programs in many laboratories (https://crcns.org/data-sets/hc/hc-1) and biophysical modeling of extracellular spikes with Christoph Koch’s lab at CalTech. Over the years, we collected intracellular data from more than 450 neurons in the hippocampus, entorhinal cortex, and neocortex. Add three more decades, and we could study the membrane properties of CA1 pyramidal cells in freely moving mice.

Progress in a dozen or so labs on hippocampal interneurons matured enough by 1995 to write the first synthesis. Tamás Freund, Richard Miles, and I discussed an outline of a potential review. This was boosted by the first interneuron meeting I organized with Phil Schartzkroin (University of Washington) and Tamás Freund. It was a satellite event of SfN’s annual meeting in San Diego on a Mississippi steamboat in Mission Bay. The text Tamás and I wrote on the anatomy and physiology of interneurons, respectively, got longer and longer, and we contemplated turning it into a book. David Amaral, the founding editor of the Hippocampus journal, came to our rescue by offering the pages of an entire issue of his journal. Tamás came to Rutgers for a month, and we worked day and night to meet the short deadline. Wiley brought 400 copies to the SfN meeting in 1996 to promote the journal and large color posters featuring our cover design. All copies and posters were gone in two days and our monograph became a citation classic (Freund and Buzsáki, 1996).

By this time, Peter Somogyi had already done fundamental observations of hippocampal interneuron types in vitro and planned to expand his remarkable expertise to in vivo reconstructions. He sent Thomas Klausberger to my lab to learn intracellular recording and labeling. Thomas worked super hard, but finding interneurons routinely and labeling them reliably proved not to be a high-throughput direction. We were also doing juxtacellular labeling of neurons, a method also with compromises. When Thomas returned to Oxford, he perfected the juxtacellular method and carved out a remarkable niche in the interneuron field with many admirable experiments.

Fig. 5. Celebrating our “back-projection” interneuron paper (Sik et al., 1994). Front: Daniel Carpi. Left to right: Maan-Gee Lee, Zoltán Nádasdy, Arne Ylinen, Markku Penttonen, Attila Sik, G. B., and Melissa Hsu (partially visible is James Chrobak).

LARGE-SCALE NEURONAL RECORDING PROJECT

Our large-scale neuronal recording program started with meeting Jerry Pine, a great physicist and maverick from CalTech who sought me out with a proposal to build and test a “cultured neuron probe,” a combination of the neuronal transplants, electrode-neuron interface, and control device. It was a silicon structure with 16 wells into which dissociated fetal septal or hippocampal neurons could be placed one by one before implanting into the hippocampus with the hope that the graft neurons could contact the host brain and that, through stimulation of the well neurons, the host brain could be affected. Anatol Bragin, an avid tennis player, loved to ping floating neurons into the probe wells, imagining that he was playing “microgolf” under the microscope. During our collaboration, Jerry introduced me to Ken Wise. Ken, a Bell Labs alumnus, was a professor of electrical engineering and a creator of the Micro-Electro-Mechanical Systems (MEMS) program at the University of Michigan. Ken envisioned silicon micromachining to replace traditional microwires with implantable silicon electrodes for neuronal recordings. I put my bet on this emerging new method, knowing that a metal microwire has only one useful spot, the tip, whereas the rest of it is just bulk that replaces neuronal tissue. In a silicon probe, virtually the entire surface can be recorded from hundreds of sites. Ken and I found a remote table at a CalTech dinner and came up with four-shank and six-shank designs that night. All the early probes were designed for acute experiments and were wire-bonded to a large printed circuit board (PCB). At Rutgers, I cut and filed the PCB to its smallest possible size, soldered the leads under the microscope, and attached it to a microdrive so that it could be chronically implanted in a rat. The next time I met Ken and showed him the “mutilated” PCB and my stacked 24-channel MOSFET preamp, he appeared in disbelief. This started our 30-year collaboration and friendship. The new probes allowed us to record up to 50 neurons at a time, a leap from the typical one to three neurons of the day, and investigate the “time-varying organization of neuronal populations” during sharp wave ripples. With the new approach, we had our first major paper 18 months after I joined Rutgers, which demonstrated that “powerful depolarization of the excited interneurons results in high-frequency firing of these cells which, in turn, determine the precise timing of pyramidal cell discharge” (Buzsáki et al., 1992, p. 1027). Ken’s group created the “Michigan probes,” which turned into the NeuroNexus company, and his technology is the direct precursor of today’s Neuropixels.

The linear silicon probes also allowed for the simultaneous recording of LFP in different layers in cortical structures and quantifying the direction of current flow between extracellular compartments (i.e., current source density analysis). We could zoom into the neuronal substrates and mechanisms of theta, gamma oscillations, sharp wave ripples, neocortical spindles, slow oscillations, and other network patterns. We studied information exchange across brain regions assisted by the various brain oscillations and their phase-amplitude coupling and published a barrage of papers on these topics. Xiao-Jing Wang (from the University of Pittsburgh) spent the summer of 1995 in my lab, and we published an influential computational model on gamma oscillations (Buzsáki and Wang, 1996). The large-scale recording project has expanded in several ways and over the years has become the strength of the lab.

To exploit our geographical situation and be part of a bigger community, Bruce McEwen (see volume 8) from Rockefeller University and I founded the NY/NJ Hippocampus Club in 1991. In our monthly events, students, postdocs, and lab leaders from the New York City and New Jersey labs gathered either in our center at Rutgers or Rockefeller. The presenters were students or postdocs and the presenting lab paid for the drinks and pizza (which we brought from New Jersey to save money). The club survived and prospered for eight years. Bruce and Ian Creese (my codirector) nominated me to become the chair of the Biomedical Section of the New York Academy of Sciences, which became another excellent opportunity to interact with neuroscientists beyond our small community at Rutgers-Newark.

To our great happiness, our second daughter, Hanna, was born in 1992, just before my wife started her child psychiatry rotation. She received a two-week (!) break for her maternal leave. Her residency program kept her busy, so sharing the responsibility of parenting was a must, which was eased a lot by the long visits of either my mother or my in-laws. I hardly ever discussed my work, grant, and paper rejections with my wife those days. When I arrived home, there were other duties and problems to solve while we were working hard on two careers and raising children and trying to fit into a society so different from the one in which we were brought up kept us busy. Driving kids back and forth to school and afternoon programs are familiar exercises to parents in the United States. I often wondered how much more productive young people could be if preschools were available at the workplace and school kids could rely on efficient and safe public transportation, as are the norms of life in other industrial countries. This parental dependence was so different from my childhood, with all the freedom I had. More importantly, as kids, we learned much more about each other outside school than during classes, and that early imprinted experience was an essential preparation for understanding the true nature of friendship and human interactions later in adult life.

My first featured lecture invitation was the Bottazzi Lecture at the 43rd Annual Meeting of the Italian Physiological Society in Sorrento, just before the presentation of the venerable John Zachary (J. Z.) Young (see volume 1) from University College London. J. Z. was an honorary member of the Stazione Zoologica in Naples and a lover of Italy. He made me swear that I would bring back my family to Sorrento someday. A few years later, after visiting Adolfo Sadile in Naples, we spent a few days on the Amalfi coast with my family, staying in a beautiful hotel with mosaic floors and frescoes on the wall. My elder daughter (12 years old at the time) was not happy with the surroundings and complained that the hotel was “such an old fashion” place and so different from the spectacular hotels in Atlantic City, New Jersey, and Las Vegas. That night, my wife and I decided we needed to provide some European education to our daughters. Just before Hanna entered elementary school, my wife paused her job (already working in private practice), and we left for my sabbatical in Paris in 1999.

Sabbatical in Paris

If it were up to me, I would make it mandatory that every person in every country should spend time in another culture. In Paris, our daughters discovered in no time that the cultural and fashion center of the world was not Millburn, New Jersey. Hanna went to a French school, while Lili attended an elegant international high school on Avenue Victor-Hugo. My hosts, Alain Berthoz at Collège de France and Yehezkel Ben-Ari at Port Royal Medical Center, treated me extremely well. Alain had a huge machine shop, and with the engineer, we designed our C-shape super-light microdrive prototype, which we proceeded to use for a decade. For years, Ben had worked on a phenomenon known as giant depolarizing potential (or GDP), an in vitro network-driven membrane oscillations with superimposed fast action potentials. I reasoned that GDP must be the in vitro equivalent of sharp wave bursts in vivo. Ben’s argument was that they were distinct because GDPs disappear after a week in the postnatal life of rats. I thought the best way to settle the issue was to join his lab and perform in vivo experiments on rat pups. Ben’s lab was full of activities. My desk was next to our rig, surrounded by offices of students and postdocs, including Rosa Cossart and Christophe Bernard. Rustem Khazipov was my main experimenter buddy. He applied his patch-clamping experience in vitro, and we soon succeeded in demonstrating the first patch-clamp recordings in vivo, coupled with silicon probe recordings. The earliest pattern we observed in the hippocampus was a sharp wave burst reminiscent of giant depolarizing potentials observed in vitro, and it persisted beyond the first week of life. Theta oscillations emerged during the second week, as Brian Bland had already shown, but ripples appeared only three weeks postnatally. The reviewers of our manuscript liked our story, but two of them complained that they expected that work with Buzsáki as the senior author should have been done in the behaving pup, whereas our experiments in Paris were performed under anesthesia. When I returned to Rutgers, Xavier Leinekugel from Ben’s lab came with me. We spent a year replicating our results in behaving pups and the resubmitted work was accepted (Leinekugel et al., 2002).

Although sharp waves were the earliest first pattern in the hippocampus, they were often coupled with a rhythmic neocortical pattern, as we observed with Rustem, who also joined us at Rutgers. We termed this rhythmic pattern “early spindle” because it was the earliest organized neocortical activity. In the somatosensory cortex, each spindle was invariably triggered by muscle twitches, limb jerks, or whole-body startles: “the interaction between movement-triggered sensory feedback signals and self-organized spindle oscillations shapes the formation of cortical connections required for sensorimotor coordination” (Khazipov et al., 2004, p. 758). With this work, we provided evidence that the baby kicks in the womb, which is important for normal development of the fetus by teaching the brain about the shape and size of the growing body. Rustem continued his work as a group leader at the Institute of Mediterranean Neurobiology (INMED) in Marseille and founded the Institute of Neuroscience of Kazan State Medical University in Kazan, Tatarstan. After Xavier and Rustem, more than a dozen French researchers joined my lab in subsequent years. My sabbatical time was well invested.

Building Our House

My sabbatical in Paris divides my two decades of tenure at Rutgers University. But there was another dividing event as well. Before moving to Paris, we sold our house and bought a run-down ranch in a nearby town with a good public high school. In Paris, my wife and I began to read extensively about contemporary architecture and interior design. One late night, visiting the book section of the Virgin Megastore on the Champs-Elysées, we found a book on glass houses by Peter Forbes, a student of Ludwig von Mises, and we knew immediately what kind of house we wanted to build. Peter Forbes is based in Florence, Italy, and has a reputation for designing ecofriendly structures. Peter alerted me to one of his trainees, who was an architect teaching at Rutgers, and the three of us designed our new home. I became a contractor, handyman, electrician, plumber, and interior designer, all at the same time. My wife and I built a kitchen, two bathrooms, stairs, and furniture in the living room and our study, and we helped the workers in every possible way. It was a great teamwork. The original ranch house was ugly, and my daughters would not even give their address to their classmates and did not invite anyone to visit. But once the new house was shining, my younger daughter overheard the conversation between a young girl and her father in the street saying, “This is the coolest house” (https://www.youtube.com/watch?v=tiLW-K935rI). From then on, both my daughters loved their new palace.

Close to the finish line, I was carrying two buckets full of tiles while climbing a ladder. I almost made it to the top when I lost my balance, flipped backward, and landed on the concrete floor head first. My wife and Hanna left for food shopping minutes earlier. When I regained consciousness, I could move my left hand to my ear, and I felt something flowing. I mentally traveled back to a surgery lecture in my medical school, when our professor explained that hemorrhage in the ear canal is a signature of a scala media fracture and is deadly. Fearing that the end was coming, I crawled on one side to the telephone in the living room and called 911. Firemen arrived and broke through the front door. The next thing I remember was seeing many shoes around me and, sad faces of my wife, daughter, and strangers. I broke six vertebrae, and my left otolith and damaged my shoulder. Only two days later when I recovered from spinal diaschisis and had my first urination in the emergency room I felt alive again. I learned how to sleep (or at least rest) with my eyes open because when I closed them the whole world started to spin around me. After I was discharged from the hospital, my lab came to my rescue. America Online internet service had just become available in New Jersey. Anton Sirota, my faithful graduate student, worked hard to establish a connection between my bed at home and the lab. When I started walking again, I told myself that from now on every day is a gift of life. I should be nice to everyone and grateful for everything. But of course, with time, I just got back to my old self and continued doing everything the same as before my second head concussion. Yet, I noticed that my creativity improved. Of course, this may be just my imagination and the alternative to head concussion-induced improvement is that I started to cherish previously unnoticed moments of life with increased optimism.

Second Decade at Rutgers

At about the same time when I moved to Rutgers, David Tank became the group leader at Bell Labs in Murray Hills, New Jersey. David’s house was only a few minutes from ours, and we have spent several parties together. David put together an extraordinary team, including Winfried Denk (the codiscoverer of two-photon laser scanning microscopy), Karel Svoboda, Michael Fee, and David Kleinfeld. My monthly visits to Bell Labs and the unique opportunity to spend time with these super-bright physicists were the intellectual highlights of my regular life. When they moved to in vivo preparations, Karel often showed up in our lab to learn about intracellular recordings. I spent many days in his lab to learn about the new imaging technique that catapulted them to fame in just a few years. Thinking that imaging is essential for progress in systems neuroscience, postdoc Hajime Hirase built our two-photon rig, with the generous help of Rafael Yuste (Columbia University). Although the original plan was to monitor neurons, we had better luck with imaging pericytes and astrocytes. Our astrocyte imaging was the first in vivo, and we showed that population bursts of neurons can selectively affect some but not other processes of astrocytes. Hajime took his experience to his future lab at RIKEN, Tokyo, and devoted his career to studying glia.

When Bell Labs was shamefully discontinued by corporate interests, the researchers spread. Karel moved to the newly built flagship institute of the Howard Hughes Medical Institute, the Janelia Research Campus in Virginia, and invited me to become a visiting scientist. I had a small experimental room there for six years, with full support of Jeff Magee with whom I had already interacted for a decade. My official funding from HHMI was for a project to enable chronic recordings from at least 64 sites using multiplexed technology. This was an important goal because mice rapidly became the species of choice in neuroscience. Postdoc Sebastien Royer (now a professor at KIST, Seoul, Korea) moved from the Rutgers lab to Janelia, and I traveled to visit him and Jeff biweekly or monthly. Soon after the discovery of optogenetics, Sebastien, Jeff, and I thought that perturbing circuits in a neuron-specific manner is what systems neuroscience needs. We learned how to thin and sharpen glass fibers with hydrofluoric acid (a fatally dangerous chemical) and to attach the fibers to the shanks of our silicon probes. In less than a year after the landmark optogenetics paper of Ed Boyden and Karl Deisseroth, we were making light-driven artificial place cells, followed by specific silencing of parvalbumin and somatostatin-expressing interneurons. These experiments demonstrated that “perisomatic and dendritic inhibition have distinct roles in controlling the rate, burst and timing of hippocampal pyramidal cells” (Royer et al., 2012, p. 769).

When miniature signal multiplexers became available, my postdoc Antal (Toni) Berényi built the first 64-channel system for mice and soon a 512-channel device for rats. With that, our expensive 128-channel recording systems with myriads of cables and occupying half of the room became obsolete overnight and was replaced by Toni’s system, which was smaller than a desktop computer and cost only a few thousand dollars. With Toni, we also asked how we could affect epileptic seizures noninvasively by transcranial electric stimulation (TES): “Closed-loop TES can be an effective clinical tool to reduce pathological brain patterns in drug-resistant patients” (Berényi et al., 2012, p. 738). Upon his return to Hungary, Toni Berényi founded his company Neunos for epilepsy management, which was recently acquired by BlackRock, Inc.

One day, a mathematician and graduate student in robotics from University College London, Ken Harris, visited Rutgers’ String Theory group and my lab in exploration of postdoc options. After graduation, Ken got a job at Lloyd Bank, a typical career path for math students. A few months later, he asked me whether the postdoc position was still available in my lab. Ken joined us soon, accepting a budget cut from his salary of more than 60,000 British pounds to $28,000. To me, this indicated his dedication! I told Ken that the most important problem in neuroscience was the separation of extracellularly recorded units. Ken immediately got to work and perfected József Csicsvári’s unit cluster-cutting algorithm. Postdoc Michaël Zugaro and his partner Lynn Hazan, a software engineer, were already working on our NeuroScope development. A good part of our weekly lab meetings was devoted to questions and wishes of lab members to perfect both NeuroScope and Ken’s program, which became KlustaKwik. After extensive testing, we shared both programs with the neuroscience community, which were improved further by the many contributing labs.

In the meantime, Ken absorbed a tremendous amount of neuroscience knowledge and realized that the clustering of neurons was not the most important problem. We worked on a variety of topics until Ken zoomed in on a key question, the mechanisms of cell assembly formation. We found that spike timing of “pyramidal cells can be predicted more accurately by using the spike times of simultaneously recorded neurons” within the “temporal window [that] matches the membrane time constant of pyramidal neurons, the period of the hippocampal gamma oscillation and the time window for synaptic plasticity” (Harris et al., 2003, pp. 552; 555).

Anton Sirota (now a professor at Ludwig-Maximilians-Universität, Munich, Germany), Kenji Mizuseki (now a professor at Osaka Metropolitan University, Japan), Kamran Diba (now a professor at University of Michigan), Shigeyoshi Fujisawa (now a professor at RIKEN, Tokyo), and George Dragoi (now a professor at Yale University) overlapped with Ken and Eva Pastalkova, marking an especially productive epoch of the lab. Kamran observed that neuronal sequences during sharp wave ripples are a palindromic game; playing the same place cell sequences either forward before exploring the environment for “planning upcoming trajectories” or reverse “run sequences at the end of the trial could facilitate backward associations” (Diba and Buzsáki, 2004, p. 1242). A further boost for the functional significance of sharp wave-ripples came from the experiments in which we showed that their elimination led to serious memory impairment (Girardeau et al., 2009). In addition, the high spatial resolution of the silicon probes allowed us to realize that the compact cell body layer of the hippocampal CA1 region was in fact two layers as if the layers of the neocortex were squeezed into a narrow layer. In parallel, Anton’s work demonstrated how hippocampal theta oscillations entrain local gamma rhythms in wide neocortical areas.

The replay experiments lead to frequent lab discussions of whether the brain starts out fresh as a tabula rasa and gets modified postnatally by experience or whether there are functionally preconfigured modules from which experience can choose. Harime’s, Ken’s and George’s experiments were more compatible with the idea that brain dynamics create a “realm of possibilities” and experience can match some of these preexisting patterns. A fascinating question was whether the activity of hippocampal place cells is determined by sensory inputs spike by spike or generated by an internal program. Postdoc Eva Pastalkova and I designed a two-choice memory experiment in which the rat was trained to run in a wheel for 15–20 seconds between trials and to keep in mind which part of the maze it planned to go. Based on these experiments, we hypothesized that “during recall, imagination, or action planning,

the sequence identity is determined by the intrinsic dynamics of the network” and that “neuronal algorithms, having evolved for the computation of distances, can also support the episodic recall of events and the planning of action sequences and goals” (Pastalkova et al., 2008, p. 1327). We performed parallel experiments in the prefrontal cortex (Fujisawa et al., 2008), which showed similar sequentially organized neuronal assemblies, and we also found that the hippocampus and prefrontal cortex work hand-in-hand in action planning and memory tasks. Because assembly sequences reliably predicted elapsed time, we hypothesized that “mechanisms that evolved for spatial navigation also support tracking of elapsed time in behaviorally relevant contexts” (Itskov et al., 2011, p. 2828). Our observation prompted Howard Eichenbaum (Boston University) to call hippocampal neurons “time cells,” initiating a novel branch of hippocampal research.

Rhythms of the Brain

In research papers, scientists write to other specialists often in language understandable only to the superspecialists. However, experimental findings from the laboratory gain their power when they are understood by people outside the trade. As brain oscillations have begun to be understood by their spiking contents, there was a need to bring together two large but independently studied areas: the microscopic spiking and the mesoscopic local field potentials. I felt the urge to do it but did not quite know how to start. To support my sabbatical visit to Paris, I applied for a Fogarty International grant. After the initial rejection, the revision was approved but only after I had already returned to the United States. The foundation kindly agreed to split it into halves, and I spent parts of two summers in Ben-Ari’s lab, now in Marseille. Ben kindly let us rent his medieval apartment in the historic harbor of Marseille. While my family and visitors were playing cards each night, I began to outline a book about brain rhythms, six years before it eventually got published. Halfway through the writing, I received an invitation from Science to write a review about brain oscillations. I was already prepared and Andreas Draguhn (University of Heidelberg) and I submitted the manuscript in six months (Buzsáki and Draguhn, 2004). The published book (Rhythms of the Brain, 2006) was well received. Its punchline summary, that “brains are foretelling devices and their predictive powers emerge from the various rhythms they perpetually generate” (p. vii) resonated with neuroscientists, cognitive scientists, physicists, and engineers alike. Predictive coding became a household phrase in brain research. Justification of the role of neuronal rhythms in brain communication was an uphill battle. In a general sense, communication is an agreement between a sender and receiver. This “agreement” is called the cipher known to both parties. A key aspect of the cipher is a procedure by which the messages are broken down into smaller chunks. Chunking of messages by agreed rules allows the coding and “deciphering” of virtually infinite combinations from a finite number of chunks. This small set of rules, usually referred to as syntax, “governs the combination and temporal progression of discrete elements into hierarchical relations that allow the generation of messages” (Buzsáki, 2010, 365). I reasoned that the potential substrate for a neuronal syntax in the brain is the constellation of neuronal rhythms. Honestly, I never dreamed about the combined impact that the book and the review had on the field. But I am happiest about the moments when a young researcher tells me that the reason why they chose to study neuroscience is because they read the rhythm book.

One person who read the book was Richard (Dick) Tsien (see volume 11) at Stanford University. Dick already had a reputation for his formidable memory and his ability to summarize one’s complicated talk in three short sentences. My first lengthy conversation with Dick was at a Jacque Monod Conference in Roscoff, France, in 2005. After my plenary talk, Dick asked me to sit next to him at dinner and warned me to get prepared. Dick expects yes or no answers to his questions, which are often not straightforward in neuroscience. At the end of dinner, we promised each other that we would continue our conversation. And we did so on multiple occasions, including an event in Shanghai. On a walk to the conference venue, Dick was explaining something enthusiastically, immersed in thought, and only watching the red light turning to green but not the traffic. A cab rushing through the already red light was approaching Dick at a high speed at which point I instinctively grabbed his jacket and pulled him back to the sidewalk. Dick likes to think that I saved his life, and I like to believe it. Independent of this incident, Dick and I were already discussing how wonderful it would be to work together in the same institute. Not knowing about each other’s intentions, both Dick and I were invited to interview for the director position at the Helen Wills Neuroscience Institute at the University of California, Berkeley. At the same time, Rodolfo Llinás recommended both of us to replace his director role at New York University. Dick was offered both jobs and turned down Berkeley. I was the runner-up at Berkeley and was supported by both Mu-ming Poo (see volume 13) and Robert Knight who represented two ends of the scientific spectrum in the institute. The prospect of leading this extraordinary institution felt great for my ego. As an alternative, Dick suggested to join him to build the new Neuroscience Institute at NYU. My hesitation between the prestige in California and the opportunity to work in New York City peacefully lasted only for a weekend. Monday, I withdrew my application from UC Berkeley and accepted the offer at NYU.

Lab Life and the Challenge of Recruiting Colleagues

Our small center at Rutgers-Newark was a far cry from the large neuroscience community of UCSD, the Salk Institute, and the Scripps Research Institute. Recruiting good students and postdocs was a challenge. The best strategy has proven to be reaching out to my colleagues and begging them to send their young to my lab. I met József Csicsvári when he was still a high school student and told him to study engineering and computer science. He did and applied to our graduate school at Rutgers after he got his degree in Budapest. Anton Sirota was referred to my lab by a Russian scientist who spent a year in my lab at Pécs. Both József and Anton spent eight years with me as graduate students and postdocs. Hungary, France, Finland, and Japan, and more recently Spain, China, Germany, and Iran are the countries from which I recruited most of my lab members. Personal-level recruitment has always been the most effective strategy for me. During my second visit at Collège de France in 2008, I shared a large desk with several students, including Adrien Peyrache (now a professor at McGill University) and Gabrielle Girardeau (now group leader at Institut National de la Santé et de la Recherche Médicale, Paris) who joined my lab after they graduated along with Lisa Roux (now a group leader at Université de Bordeaux) and several other French scientists. I met Antonio Fernandez-Ruiz (now directing his own lab at Cornell University) at a summer course I organized in Barcelona, and who recruited several more Spanish investigators to the lab. I have always helped postdocs coming from abroad to obtain their own support from national and international grant agencies. In this process, they learn the challenge of grant writing, and acquire stronger self-confidence and independence when they arrive and start their projects.

The most important ingredient of a successful working environment is that all members feel safe. Feeling safe, giving, and receiving moral support from others is especially critical in an environment where young and often naïve people gather together from different parts of the world with different cultures and value systems. By design, I never had a lab technician in my lab. Instead, the chores are divided among us. Each person is a “mini-boss” in charge of the computer network, surgery room, histology, machine shop desk, organizing lab meetings, seminars, and journal clubs, so that they can reprimand the violators and can expect to be reprimanded by others in case of misbehavior. Perhaps the most difficult thing for a lab leader to do is to “implant” ideas into the heads of others so that the student or postdoc believes that the idea is their own. Scientists are the best workforce in the universe because they work on their ideas and therefore are willing to venture into never-explored territories and tolerate high levels of uncertainty. I worked with them to write their own grant proposals whether it was for a fellowship or a K99. I designed my lab at Rutgers so that everyone’s desk was in a single large room, next to the labs and my office, and I always kept my door wide open, as an invitation to walk in. I have had lunch with lab members every day. Participation is completely voluntary without any pressure or agenda. Animated lunch discussions in which we all feel like equal partners are the best and easiest way to learn about each other, the difficulties of everyday private life, frustrations, and dreams. In addition, this is an opportunity to address bigger questions of our science, which rarely enter the discussion of our papers but which offer a broader perspective or framework within which we can conceive new experiments and discuss what we find. Lectures and seminars are tailored for an abstract average person with the naive assumption that the audience retains all the details and follows the logic of the lecturer. In contrast, the essence of small-group conversation is to question the fundamental logic, a quest for clarification and simplification, and a search for explanations and answers without a rigid agenda, in which the focus is not on covering large chunks of material but on understanding the critical details.

Accepting a new member to my lab is an unwritten contract between that member and me that I will take responsibility for nurturing and guiding them to the next level of their lives whether it is a postdoc position, faculty job, or industry. Members typically “calibrate” their abilities in comparison with others during their tenure in the lab and there is rarely a discrepancy between their expectations and my judgment. Our weekly lab meetings, lasting longer than two hours, are the best forum to evaluate each other. The presented progress reports and the fierce but honest discussions are our most constructive activities. I sincerely hope that no lab member has ever left a lab meeting feeling that they were ridiculed or even slightly ashamed. Instead, the feedback provided by these “many eyes see more” discussions often help to guide useful modifications and improvements of the strategies.

I evaluate people slowly perhaps because I often witnessed the pattern that a student’s or postdoc’s performance may appear “mediocre” for two or three years only to rebound unexpectedly with a discovery. This is the nature of scientific investigation. I never had to fire a student or a postdoc. Perhaps I could not. It is tempting for a lab leader to team up with people with complementary skills for a planned project. Yet, in my experience, good collaborations emerge from social interactions. Taste for the same type of movies, playing tennis or other sports, or just drinking coffee or tea together provide the foundation of trust that can lead to more efficient collaboration than rational logic. Feeling comfortable with a fellow lab member at any moment inside and outside the lab is far stronger a drive than the potential benefits of the collaboration. Failing together is often as much a reward as succeeding. Several marriages and lifelong friendships have been sparked from such interactions in the lab over the years. Nothing pleases me more than seeing that my “kids” get along with each other (Figure 6). For me, the success of mentoring is not only measured by the academic ranks achieved by my mentees but also by their happy family lives and the photos they send me about moments of their private lives. Science is a social endeavor.

Fig. 6. Nine lab alumni (now professors around the world) dining in Verona, Italy, May, 2023. Left to right: Antonio Fernandez-Ruiz, Sebastien Royer, Kamran Diba, Gabrielle Girardeau, Adrien Peyrache, Karim Benchenane (“honorary member”), George Dragoi, Lisa Roux, and Anton Sirota.

An Unexpected Call

Returning to my room from the conference hall at the Santa Fe Institute in February 2011, I found a message from Denmark to call back the number. I recalled that a few months earlier I had submitted a recommendation for my friend Peter Somogyi for the new Brain Prize from the Lundbeck Foundation. Secretly hoping that my nominee got the prize, I called back the number. As I was listening, I got a bit confused as to why the caller congratulated me, but it slowly sank in that I was one of the three winners. I wondered who had nominated me. As I learned later, nobody did. However, when the committee’s selection came down to two names, Peter Somogyi and Tamás Freund, some members felt that I also belonged to that group. Rewarding our trio was a nod to the excellence of Hungarian neuroscience over a century.

New York University Langone Medical Center

Our move from Rutgers to NYU happened overnight. Several lab members already lived in New York City and they established our first “colony.” Within a month after we all moved to NYU, we were running experiments.

NYU offers a friendly collaborative environment. Postdoctoral fellow Dion Khodagholy developed the “NeuroGrid,” an organic, conformable recording device to record from many cortical sites (Khodagholy et al., 2015). After testing the functionality of NeuroGrids in rodents, in virtually no time, we were able to test them also in patients with epilepsy, thanks to our fruitful collaboration with neurosurgeon Werner Doyle and neurologist Orrin Devinksy. We forged new collaborations with several NYU colleagues, including Dick Tsien, Robert Froemke, Dayu Lin, Rodolfo Llinás, Michael Long, Bernardo Rudy, Bob Machold, Anli Liu, Sage Chen, David Heeger, John Rinzel, Tony Movshon, Xiao-Jing Wang, and Dan Sodickson. We continued our tool developmental efforts with the engineering group at the University of Michigan, now headed by Professor Euisik Yoon, leading to innovative μLED probes that allow for optogenetic probing of a single neuron or a few neurons as well as several other devices.

Our New Framework

After I received the Cortical Discoverer prize from the Cajal Club in 2001, I was invited to write a review for a prominent journal. I thought that the best way to exploit this opportunity was to write an essay asking whether the dominant framework in neuroscience is on the right track. My main argument was that many terms in neuroscience are inherited from folk psychology and are often used in two ambiguous ways: both as the thing-to-be-explained (explanandum) and the thing-that explains (explanans). I warned that a framework dictated by human-centric introspection might not be the right roadmap for neuroscience and argued that there should be another way of carving up the brain’s “natural kinds.” A month later, I received the rejection letter: “Dear Gyuri, … I hope you understand that for the sake of the journal we cannot publish your manuscript.” Yet, the issues I exposed in the manuscript kept bugging me and after moving to NYU, I decided to expose my views to a broader audience in the form of a new book (The Brain from Inside Out, 2019). Ever since the time of Aristotle, thinkers have assumed that the soul or the mind is initially a blank slate, a tabula rasa on which experiences are painted. This view has influenced thinking in Christian and Persian philosophies, British empiricism, and Marxist doctrine. In the past century, it has also permeated psychology and cognitive science. This “outside-in” view portrays the mind as a tool for learning about the true nature of the world. The alternative view—one that has defined my research—asserts that the primary preoccupation of brain networks is to maintain their own internal dynamics and perpetually generate myriad patterns of neural activity. When such preexisting nonsensical patterns are linked to actions and potentially useful environmental signals, they acquire significance to the organism. Thus, learning is more of a matching process rather than a de novo computation. In addition to receiving feedback about the influence of the book from neuroscience colleagues and beyond, a cherished bonus was the 2020 Prose Award from the Association of American Publishers.

Balance, symmetry, and normality dominate our thinking and culture, perhaps because of their simplicity. Similarly, in neuroscience, we seek for and tend to present “typical” or “representative” neurons and dynamic patterns. But when with our large-scale recordings we began to collect data by the hundreds and thousands, and quantified the results, a very different picture emerged. We and others found that at many physiological and anatomical levels in the brain, “the distribution of numerous parameters is in fact strongly skewed with a heavy tail, suggesting that skewed (typically lognormal) distributions are fundamental to structural and functional brain organization” (Buzsáki and Mizuseki, 2014, p. 264). The brain is not composed of numerous similar components and is not as plastic as it previously seemed, but rather component diversity and nonegalitarian organization ride on the backbone of a preconfigured connectivity and dynamics characterize neuronal networks. Such preexistence is often referred to as attractors, manifolds, or neural schemata. This insight not only had implications for how we now collect, analyze, and interpret observational data but also gave rise to a different type of thinking.

During the past decade, we operated mainly under this new framework. Although the centerpiece of our work has remained the hippocampus, we reached out to its partner structures to better understand its computation. Expanding our hippocampal work to the head direction system was a rewarding experience, and the findings provided evidence that mechanisms that appear to be controlled externally are in fact self-organized and present even during sleep (Peyrache et al., 2015). A series of experiments was devoted to examine the extent to which apparently learned and newly synthetized neuronal patterns were preconfigured (Grosmark and Buzsáki, 2016; McKenzie et al., 2021; Valero et al., 2022). The new thinking led to our investigations of the embryonic origin and constraints of neuronal connectivity and physiological interactions in the adult brain. In contrast to the dominant framework that portrays neural systems in which sensory inputs sculpt connectivity and dynamic patterns through activity-dependent plasticity (“neurons that fire together, wire together”), we showed that “neurons born together, wire and fire together” (Huszár et al., 2022, p. 1210) is an alternative scenario. Even more surprising revelations were ahead of us. While many laboratories have investigated sharp wave-ripples as a cognitive biomarker, in reality, sharp waves evolved much earlier than the complex neocortex that reads out the mnemonic content of hippocampal sharp waves. We discovered that this very pattern also serves to reduce interstitial glucose in the body, and thus “two seemingly distinct processes—cognition and whole-body metabolism—are linked together” in the brain by hippocampal sharp wave-ripples, and “mnemonic and metabolic processes are regulated simultaneously within an organism” (Buzsáki and Tingley, 2023, p. 204).

I tend to believe (or at least pretend) that the most recent manuscript we happen to be working on is the most important. After working on hippocampal sharp wave ripples for decades, our recent work finally seems to make sense of this remarkable brain pattern. A general wisdom is that experience needs to be somehow tagged during or shortly after learning, but the brain mechanisms responsible for such triaging have yet to be searched for in earnest. Now we found that the sharp wave ripple is the selecting mechanism. Only when sharp wave ripples tag a particular experience will that experience be replayed over and over during subsequent sleep. Sharp wave ripples are thus a post hoc editing mechanism that selects aspects of experience to be preserved for future use (Yang et al., 2024). Thus, my excuse for not mentioning potentially important events in our lab life during the past several decades and omitting names of numerous talented students and postdoctoral fellows and colleagues whose hard work was so important to my scientific life is that not enough sharp waves emanated in my brain during critical events or when attempting to recall those events. As a substitute, I refer the reader to a 2019 photograph (Figure 7), when most previous and current lab members came together to celebrate our friendship (the excuse being my 70th birthday). Further sources of information include the Neurotree (https://neurotree.org/neurotree/tree.php?pid=5038) and our lab alumni web page (https://Buzsákilab.com/wp/labmembers/group-photos/).

Fig. 7. Group get-together in 2019. First row: Mihály Vöröslakos, Kamran Diba, Xiao-Jing Wang, G. B., Azahara Oliva, Anna Conti, Farnaz Sharif, Ekin Kaya, Veronika Solt (my wife). Second (intermittent) row: Xiaoyang Long (guest), Kenji Mizuseki, Anton Sirota, Manuel Valero, Karim Benchenane, Shengjia Zhang (guest), Andrea Cumpelik, Yiyao Zhang, Laura Green, Jolin Chou, Stephanie Rogers, Rachel Swanson, Maria Asplund (visitor), Derek Buhl, Dirk Isbrandt, Viktor Varga. Third row: David Sullivan, David Tingley, Andres Grosmark, Jennifer Gelinas, Yoshikazu Isomura, Lisa Roux, James Chrobak, Zifang (Frank) Zhao, Fan Wu, Darrell Henze, Luke Sjulson, Heather Read, Gabrielle Girardeau, George Dragoi, Antonio Fernandez-Ruiz, Behnam Tayebi (guest), József Csicsvári. Fourth row: Ken Harris, Dion Khodagholy, Yuta Senzai, Thomas Hainmüller, Erik Schomburg, Ipshita Zutshi, Peter Rozman, Dan English, Roman Huszár, Dan Levenstein, Xavier Leinekugel, Kathryn McClain, Eliezyer Fermino de Oliveira, Omid Yaghmazadeh, Asohan Amarasingham, Adrien Peyrache, Sebastien Royer.

Missing alumni from the picture: Gyula Acsádi, László Acsády, Costas Anastassiou, Péter Barthó, Mariano Belluscio, Antal Berényi, Liang Cao, Angus Chadwick, Boldizsár Czéh, András Czurkó, Ronny Eichler, Shigeyoshi Fujisawa, Tomoyuki Furuyashiki, Caroline Geisler, Oleg Godukhin, Palmer Greene, Lynn Hazan, Esther Holleman, Bo Hu, Ingrid Inema, Gábor Jandó, Julien Chuquet, Anita Kamondi, Roustem Khazipov, Svenja Kiljan, Charles King, Thomas Klausberger, Lianne Klaver, Bernát Kocsis, Marie Lacroix, Maan-Gee Lee, John Long, András Lörincz, Lisa Marshall, Dun Mao, Sam Mckenzie, Michaele Migliori, Lenäic Monconduît, Sean Montgomery, Zoltan Nádasdy, Simal Ozen, Edit Papp, Eva Pastalkova, Jagdish Patel, Markku Penttonen, Peter Petersen, Michele Pignatelli, Jonathan Platkiewicz, Marie Pollard, Pascale Quilichini, Michael Repucci, David Robbe, Florbella Rocha-Almeida, John Schulman, Attila Sik, Zoltan Somogyvári, Marisol Soula, Eran Stark, Marie Vandecasteele, Lajos Vereczkei, Brendon Watson, Lucia Wittner, Aarne Ylinen, Michaël Zugaro. For new members since 2019, see (https://Buzsákilab.com/wp/labmembers/group-photos/).

Postlude

Describing one’s life story is like illustrating evolution in a one-minute movie as if there was a well-thought-out plan from viruses to invertebrates to humans, without the myriads of branch points and dead ends. In an autobiography, we tend to ignore those blind alleys to save pages and emphasize only the rare positive highlights. Yet, I am grateful for every bit of hardship I have encountered in my life. I know those “negative” experiences made me a better person and offered opportunities to take alternative, often better, paths. Of the highlights, the most memorable event for me was my plenary lecture celebrating the 50th Anniversary of the Society for Neuroscience in Chicago in 2019. Nearly all of the 7,000 seats in the lecture hall were taken, and the fire marshal prevented more people from entering, marking the highest attendance in the history of the society, according to the organizing committee. A bonus was that “Buzsáki lab” was the most frequently tweeted name of the meeting. What can be a higher honor than so many of my respected colleagues devoted 60 minutes of their lives to my presentation?

I have lived the life of a gypsy, moving from one place to another and building 17 labs. Once a Hungarian friend from Transylvania, who had spent his prime years of education in Canada and now lives in the United States, asked me the question: where is home? I answered that home is what you build with your sweat and tears, like the one I built for my family in New Jersey. But that house is sold, and I have become a full-time New Yorker. Perhaps the correct answer is that my home is the lab. There are only two difficult things in life. The first is to figure out what keeps us moving. The second is to be able to make a living with that hobby. I succeeded in both, mainly because I found a partner who supported me in my ventures and I have two lovely daughters, without whom life would be just emptiness.

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John H. Byrne

BORN:

Englewood, New Jersey

February 15, 1945

EDUCATION:

New York University Tandon School of Engineering, BS (Electrical Engineering, 1968)

New York University Tandon School of Engineering, MS (Bioengineering, 1970)

New York University Tandon School of Engineering, PhD (Bioengineering, 1973)

APPOINTMENTS:

Assistant to Associate Professor, Department of Physiology, School of Medicine, University of Pittsburgh (1976–1981, 1981–1982)

Vice Chair (Neuroscience), Department of Physiology, School of Medicine, University of Pittsburgh (1981–1982)

Associate to Full Professor, Department of Physiology and Cell Biology, McGovern Medical School of The University of Texas Health Science Center at Houston) (1982–1985, 1985–1987)

Professor, Department of Neurobiology and Anatomy, McGovern Medical School (1987–present)

Chair, Department of Neurobiology and Anatomy, McGovern Medical School (1987–2018)

Director, Neuroscience Research Center, UT Health Science Center at Houston (1992–present)

June and Virgil Waggoner Chair, McGovern Medical School (2001–present)

Director, Office of Postdoctoral Affairs, UT Health Science Center at Houston (2005–2018)

HONORS AND AWARDS (SELECTED):

NIH Research Career Development Award (1978)

NIMH Research Scientist Development Award (Level II) (1986)

Javits Neuroscience Investigator Award (1986, 2023)

Treasurer, Society for Neuroscience (1992–1993)

NIMH Research Scientist Award (1993)

President’s Scholar Award for Research, The University of Texas Health Science Center at Houston (1998)

Fellow, American Association for the Advancement of Science (2001)

Hebb Award, International Neural Network Society (2004)

President’s Award for Mentoring Women, UT Health Science Center at Houston (2006)

Award for Education in Neuroscience, Society for Neuroscience (2007)

President, Association of Medical School Neuroscience Chairpersons (2008–2009)

Innovations in Health Science Education Award, The University of Texas System (2012)

President’s Scholar Award for Teaching, UT Health Science Center at Houston (2014)

Member, Alpha Omega Alpha Honor Society (2017)

The University of Texas System Regents’ Outstanding Teaching Award (2017)

John Byrne’s work has focused on the understanding of the cellular and molecular mechanisms underlying behaviors and their ability to be modified by learning. He has done so by using a combination of biophysical, biochemical, molecular, and mathematical modeling techniques. His work on operant conditioning is particularly significant because it constitutes the first detailed mechanistic analysis of this major form of associative learning and provides the basis for a comparative analysis of the mechanistic interrelationships among different forms of learning. Another novel aspect of his research program is his pioneering use of complementary empirical and mathematical modeling approaches to the understanding of memory. In addition to his research, Byrne has taken a leadership role in the community of neuroscientists and has organized and participated in outreach activities at the local and national levels. He is also a dedicated and innovative educator. He is an author or editor of 15 books, including a graduate text on cellular and molecular neuroscience. In addition, he is the developer of an open-access web-based neuroscience electronic textbook.

John H. Byrne

John H. “Jack” Byrne

It is a great honor to write an autobiography for this series. Perhaps my story will resonate with others and provide some insight and guidance for their own careers. Perhaps also this chapter will provide some insight into an era during which great progress was made in understanding mechanisms of learning and memory by exploiting the technical advantages of invertebrate model systems. So, like most autobiographies, let’s start this voyage at the beginning. But if you choose not to read further, here is the bottom line. The extent to which I have had a successful career in brain science is due to having some brains, putting in hard work, having great mentors and collaborators, choosing the right boat, being in the right place at the right time, having a supportive spouse and family, and having other good luck.

When I was a boy, my father told me of his harrowing experiences dodging U-boat torpedoes as a captain of a Liberty ship transporting cargo to England during World War II. It is my good fortune that he made it home. He chose the right boat, as many others on those convoys were less fortunate. Pop (as we called him), John James Byrne (b. 1915), was the son of Charles John Byrne (b. 1876), a native of Dublin, Ireland. Charles worked in New York City as a poultry inspector. Tragedy struck when he died of a heart attack in a doctor’s office in 1935, just two weeks after he canceled his life insurance policy. His (and my) good fortune was marrying my grandmother, Roseanna Blanchfield, in 1908, who was also born in Dublin (b. 1878). Charles and Rosanna had six children; my father was the fifth. After high school, Pop pursued a maritime career, first working as captain of charter fishing boats out of Sheepshead Bay, New York, as a tugboat captain in New York Harbor, and then as a captain of Liberty ships.

My mother, Lillian, was born in 1914 on a houseboat on the Hudson River just south of the George Washington Bridge on the New Jersey side. She was one of the five children of Katherine (Winkler, b. 1886) Schwartzman and Frank Schwartzman (b. 1884). The Winklers lived in Moravia, now part of the Czech Republic. In 1885, they emigrated to the United States and established a dairy farm in New Jersey, where my grandmother Katherine Winkler was born. The Schwartzman family emigrated to the United States in 1852 from Bavaria after the family mill was destroyed by fire. Grandfather Frank Schwartzman was a successful fishing boat captain and also reportedly had a side business as a “rum runner” during Prohibition. He owned several fishing boats operating out of New York Harbor in the 1920s and 1930s, including the 189-foot steam fishing yacht Colonia. On one fishing trip, Frank Schwartzman and the Colonia rescued 34 men from a vessel at the point of foundering off of Coney Island (New York Times, October 21, 1930). Frank Schwartzman died of a brain tumor in 1937. His two sons continued the maritime tradition with son Frank becoming an oil tanker captain and Howard becoming a ship pilot on the Panama Canal.

Boats and the sea were a common thread in the early lives of my father and mother. Indeed, John James Byrne and Lillian Schwartzman met on a fishing boat. They were married in 1943. After World War II, my father retired from the Merchant Marine to raise a family, and the couple moved to Freeport, a small town on the south coast of Long Island about 30 miles from New York City. My father also began a new career as an electrical contractor and started the Byrne Electric Company.

I was a baby boomer (b. 1946) and the second of six children. At Holy Redeemer elementary school, I was not particularly concerned about high grades; Bs, or even Cs were fine. My priority was to have as little to do with schooling as possible, and at the same time work as much as I could on odd jobs, such as mowing lawns, raking leaves, shoveling snow, and delivering newspapers and magazines. Work was a bit of a necessity, because there were times when customers of Byrne Electric failed to pay their invoices and sometimes things got rather tight. It was ironic that our home electricity was once turned off by the power company because we failed to pay our electric bills. So, to get anything extra, you were on your own. I did contribute to the family by helping my father on the job. I was mostly a gofer and someone who held the flashlight, but I learned something about electricity and electrical circuits. At a young age, I also had an interest in learning how things worked. I would disassemble bicycle backpedal brakes, lawn mower and outboard motors, and old vacuum tube radios to see what was inside and discover how they worked. In retrospect, that was the beginning of a trajectory of discovery ultimately leading me to science.

During elementary school, my parents both became interested in amateur radio, and they dragged me and my older sister along. We both learned Morse code and radio theory necessary to pass the Federal Communications Commission (FCC) exam for General Class amateur radio operator licenses. That experience allowed me to learn more about electronics and the principles of voltage, current, and resistance. (Little did I know that I was also learning about basic principles of heat transfer, solute diffusion, and fluid flow.) In those days, amateur radio enthusiasts built much of their own equipment. I built a transmitter from scratch and used it to communicate with other “hams” around the United States and the world.

Parochial school went only to the eighth grade, so by then, I needed to decide whether to go to a parochial high school or enter the public-school system. It was an easy decision for me. I had had enough of the dogma, rigidity, and occasional physical abuse. (A nun once pulled me down to the floor by my ear to punish me for something I did not do.) And then there was the issue of the Holy Ghost, a concept I could never understand.

At Freeport Junior High School, I was exposed to two inspiring teachers, one in algebra and the other in social studies. I excelled in those courses and enjoyed getting good grades. When it was time to move on to 10th grade at Freeport High School, I was pleased to learn that my teachers had recommended me for the honors program. Here, I had the opportunity to continue to enjoy learning in an environment with a group of other highly motivated students. Looking back, I was extremely fortunate to have had the opportunity to be exposed to such an enriched academic environment. I regret that so many students are less fortunate. Public schools in Long Island, like those in Freeport and nearby Baldwin and Merrick, were excellent and included a diverse body of students. Some Freeporters in that era who went on to successful careers in the arts and sciences included Carolyn Boriss-Krimsky (my home roommate in high school), Arthur Davidson, Lou Reed, and Harold Varmus. Freeport High School was fertile with opportunities. I joined the Mask and Wig Club, eventually becoming technical director of the high school senior variety show. I joined the math club and eventually became its president. I cofounded the high school amateur radio club and became its president. The faculty adviser for the radio club was Mr. Parker, who was also in charge of the Industrial Arts program. He would be frequently contacted by outside companies looking for help from high school students. He told me about a summer job at Columbian Bronze Company, a firm that was known for its ship propeller manufacturing but that had begun to market marine radio telephones and depth finders. They had a need for a student with an electronics background who could troubleshoot and repair defective devices.

It was on to college after the summer job at Columbian Bronze. My background with electronics naturally led me to electrical engineering. I was not particularly interested in going to an away school, so I looked for local schools. One that attracted me was the Polytechnic Institute of Brooklyn (Poly, now New York University Tandon School of Engineering). I became a commuter; taking the Long Island Rail Road back and forth between Freeport and Brooklyn. Poly had great strengths as an engineering school, but socializing was limited because most of the students were commuters, and it was as far from a party school as you could get. Indeed, there was only a single female freshman in my entering class. So all socializing was local. Fortunately, there were several other commuter types like me from Freeport who attended local colleges like Adelphi and Hofstra Universities and some friends from high school who had local jobs. We frequented local bars and clubs and dated some of the high school seniors. That’s where I met Susan. We went out during her senior year and that summer. We went our separate ways, but four years later got back together and have been together ever since. The successes that I describe here would not have been possible without her love and support.

My expertise with radio telephone repair at Columbian Bronze led me to a job repairing radio telephones with American Hydrofoil Lines during the summer of 1964. American Hydrofoil ran hydrofoil boats for commuters between Port Washington, Long Island, and Wall Street, and passengers between 34th Street and the 1964 World’s Fair in Flushing, Queens. Sometimes, I filled in as a deckhand. On one occasion, I worked on a private charter to take Richard Nixon to the World’s Fair. That was my first interaction, albeit minimal, with a celebrity. In the summer of 1965, I landed a job with the Computer Simulation Laboratory at the U.S. Naval Training Device Center in Sands Point, Long Island. There, I was exposed to large-scale analog computer simulations of ship docking and helicopter flight. The unit was being relocated to Orlando, Florida, but my boss John Cavallari opted not to move and instead accepted a position as director of the electronics lab in the department of medical physics at Memorial Sloan-Kettering Cancer Center in New York City. He invited me to work with him again the following summer. Working at Memorial was a great experience, because I was exposed to the field of biomedical instrumentation. Working in a clinical setting also exposed me to medicine and the realization that so little was known about treatments and cures for many diseases. I have not forgotten the sadness I felt when seeing the hairless young children receiving radiation treatment on the machines we maintained. I was also becoming interested in neuroscience, because my mother was diagnosed with multiple sclerosis. It was discouraging to learn how little was known about its cause, mechanisms, and effective treatments.

I did not realize it at the time, but my hard-work ethics, electronics background, and life experiences was moving me toward a career in biomedical sciences. I just needed some direction. A chance encounter with a Poly student whom I had worked with at the Naval Training Device Center the previous summer set me on the trajectory of a life in neuroscience. While waiting for an elevator one day in the fall of 1966, he told me about a part-time job for an electronics technician, which was available at NYU Medical School. I called the number he gave me and spoke with Eric Kandel. Kandel invited me for an interview and offered me the job. Needless to say, it turned out to be more than a job; it was a compass pointing to the future.

NYU and the Golden Age of Aplysia

Eric Kandel had recently set up his lab at NYU after moving from Harvard University. Kandel’s vision was to exploit the technical advantages of the marine mollusk Aplysia to elucidate mechanisms of learning and memory. Those advantages included simple stereotyped behaviors, a nervous system with only about 20,000 neurons, and neurons that were extraordinarily large compared with vertebrates. The Kandel lab consisted of an assistant professor, Irving Kupfermann; one postdoc, Harold Pinsker; and two graduate students, Daniel Gardner and Howard Wachtel. Irving was trained as a behavioral psychologist. He had worked as a postdoc with Eric at Harvard on the original description of the electrophysiological properties and synaptic connections of neurons in the abdominal ganglion of Aplysia, in a classic series of papers. He had Coke-bottle-thick eyeglasses. He looked smart, and he was. By his appearance you would mistake him for a beatnik in Greenwich Village. And then there was Harry Pinsker. If Irving was a beatnik, Harry was a hippie. Harry came as a postdoc having received his doctorate in psychology from the University of California, Berkeley. At Berkeley, he was part of the political activism of that time. But despite politics, he was highly engaged in the research and was a driving force in studying the learning capabilities of Aplysia. The lab also included a graphic artist, Kathrin Hilten, as well as a technician and a secretary. This original group was soon expanded to include Jim Blankenship, who did his thesis on synaptic potentials in cat spinal motor neurons; Vince Castellucci, who did his thesis on electrophysiological recordings from cat glial cells; and Tom Carew, who did his thesis on cortical spreading depression. Adjacent to the Kandel lab was the lab of Alden Spencer, whom Eric helped recruit to NYU. They had previously worked together at the National Institutes of Health (NIH) on the now-classic study of intracellular recordings from the hippocampus of awake animals. Alden’s lab consisted of Bob April, a neurology fellow; Bob Leibovitz, a postdoc; Esther Gardner, a graduate student; medical doctor/doctoral students Marc Dichter and Micki Selzer; and a technician.

My job was to repair equipment and design and build special equipment. Harry Pinsker in particular was always looking for new gadgets for his electrophysiology rig, so I was kept busy with projects. It was an exciting time to be in that environment. The Carew, Castellucci, Kupfermann, Pinsker, and Kandel team were doing the now-classic studies of the synaptic mechanisms of habituation and dishabituation. The idea that synaptic plasticity is a mechanism of memory had been around since Ramón y Cajal and Eugenio Tanzi. Kandel’s group went to the next level by showing that it actually occurred. They recorded decreases and increases in synaptic strength between sensory neurons and motor neurons mediating the gill-withdrawal reflex during habituation and sensitization, respectively. The intellectual environment was exciting and diverse with broad representation of cellular neurophysiologists and psychologists, and later biochemists when Jimmy Schwartz began collaborating with the group. I was exposed to the new and intriguing language of neuroscience. But it was verbal whiplash with so many new terms and each one with a worthy complement. Imagine a young man having virtually no knowledge of neuroscience, or even biology, being exposed to constant chatter about excitation, inhibition, disinhibition, feedforward inhibition and feedback inhibition, excitatory and inhibitory postsynaptic potential (EPSPs and IPSPs), homosynaptic and heterosynaptic plasticity, antidromic and orthodromic spikes, habituation and dishabituation, and associative and nonassociative learning. And there were constant references to a magical neuron called Interneuron II, which had widespread effects on numerous neurons in the abdominal ganglion, magical because the cell had not been identified despite years of searching. I had had no coursework in biology, but I began to assimilate some knowledge of neuroscience. Socially, this was a great group of very smart people excited about what they were doing. There were always great discussions at lunch in the NYU cafeteria about science, scientists, and biological and national politics. For the first time, I had a new appreciation for science and the people who do it. And unlike the stereotype of nerdy scientists, these folks led normal lives and were super friendly, open, and of good humor. One year at the holiday gift exchange, my gift was a children’s electricity project. Irv Kupfermann, who was using von Frey hairs to deliver tactile stimuli to the animal’s skin, received an envelope containing a clip of what appeared to be pubic hairs, which presumably could be used as novel tactile stimulators. We all had a big laugh.

Prominent scientists often visited the lab. A real treat was being introduced to John Eccles and John Nicholls, for me an entirely new class of celebrities. They all had interesting personalities and good humor. Alden Spencer told us after Eccles’s visit that the Nobel Laureate had said that “the problem with brain research is that the people doing it have none.” Eccles was obviously not referring to the Kandel group. The lab was making breakthrough discoveries, and the scientific world saw Aplysia as a model system to help demystify mechanisms of learning and memory. Kandel was a young superstar. Always exuberant, Vince Castellucci said Eric was god and this was the “golden age of Aplysia.” In a small way, I felt that I was part of that age.

There was another overlapping influence, the Vietnam War and the student protests that exploded across the country. I was part of it to a certain extent, attending peace rallies in Central Park and Washington, D.C. Harry Pinsker was engaged at another level. He was a committed antiwar activist and a leader of the strike at NYU Medical School. They took over the print shop and used it to print antiwar material. Harry’s extensive outside activities did not go well with Eric, however. Time away from research for any reason was unacceptable, and I sensed that serious damage was done to their relationship.

Should I Stay or Should I Go?

As a senior in college, when spring came, it was time to start looking for jobs. My attention was drawn to a posting on the Poly job board for a bio-instrumentation engineer at Grumman Aircraft Company in Bethpage, Long Island. I applied for that job, received an offer, and accepted the position. It was well paying and an opportunity to work on bio-instrumentation for the lunar lander that was being built by Grumman. So, it seemed that my brief but spectacular time at NYU was ending. But when I told Eric about the job and that I would be leaving the lab, he suggested that I should “continue working at the lab at nights and on weekends.” It may seem crazy to work two jobs, but working at NYU did not seem like work. It was a good deal for Eric to retain an experienced electronics person and a good deal for me to continue supporting a great group of scientists working on exciting projects and being part of the “golden age.” But it turned out to be more than just fixing equipment and designing devices. I had a deal with Harry Pinsker: after finishing his experiment, he would leave his isolated ganglion on the rig for me to experiment with if I agreed to clean things up at the end. (He trusted me with his rig because he knew I would fix it if I broke anything.) So, I started making microelectrodes and poking cells. It was a fantastic thrill to impale my first neuron and see real action potentials, synaptic potentials and patterns of neuronal activity in a living brain. I began to think that I could be a neuroscientist like the graduate students and postdocs in the lab. I was inching closer to a career in neuroscience.

That spring I was also notified by the student counselor at Poly that I was two credits short of graduating. Oops! How that happened is lost in time, but it was a chance to make some lemonade from a lemon. The lemonade was taking a course in biopsychology, which provided the needed two credits, but importantly, also provided an opportunity to formally begin learning about the nervous system and behavior. I am embarrassed to say, but I felt a bit superior to the other students in the class when we learned about action potentials and synaptic transmission. Those dynamic electrophysiological processes were static images in the textbook, but I had seen them and recorded them in a living neuron. So, in the fall of 1967 I was working a full-time job and traveling after work at Grumman in Bethpage to New York City to work in Kandel’s lab and take the course on biopsychology.

Graduate School at NYU

I enjoyed my time working at Grumman. I had an opportunity to work with the astronauts, outfitting them with electrocardiogram (EKG) electrodes and carbon dioxide (CO₂) and oxygen (O₂) sensors for tests of the environmental control system in a mock lunar lander. I also worked on one of the first DEC PDP-8 computers. This experience led to an assignment at Cape Canaveral working on simulated launch sequences. The task was boring, but the environment was great. One day, I drove to the launch pad and walked under a Saturn V rocket. But in the spring of 1968, we were informed that our unit at Grumman would be relocated to the Johnson Space Center in Houston. I had no interest in relocating to Houston (seems ironic because I ended up there 14 years later anyway), so I decided to pursue my growing interest in neuroscience at graduate school. I was accepted in the Bioengineering Program at NYU in 1968 and was delighted to find out that I would receive a stipend of $3,000 per year from an NIH Training Grant. The stipend was special. For the first time, I was being paid to go to school.

My master’s project was working with Alden Spencer and Esther Gardner on a project to design and build a feedback-controlled stimulator for the delivery of precise tactile stimuli to the foreleg of a cat while simultaneously recording single-unit responses in the somatosensory cortex. The project was successful, but I was increasingly attracted to the Aplysia work in Kandel’s lab. For my doctoral project I proposed to Eric that I design an improved tactile stimulator and use it to study the mechanoreceptors in Aplysia. Here, I was inspired by the work of Vernon Mountcastle and Gerhard Werner quantifying the stimulus-response properties of mechanoreceptive cutaneous afferents, and the work of John Nicholls and Denis Baylor studying the receptive field and response properties of mechanoreceptors in the leech. I found that, with a single exception, all Aplysia mechanoreceptor neurons have similar thresholds and gave similar responses to vertically applied forces. The receptive fields of the mechanoreceptor neurons could be grouped into classes according to size and location on the skin. The boundaries of at least some receptive fields seem to be invariant from animal to animal. The project went well and resulted in a paper in the Journal of Neurophysiology. In my opinion, that paper still stands as the most quantitative analysis of molluscan mechanosensory neurons.

Introduction to Neuronal Modeling

I had known about the power of computer simulations of physical systems using linear differential equations from my summer job at the Naval Training Device Center. Through my graduate courses on systems analysis and readings, I became aware of the use of those approaches to analyze and model the dynamics of biological systems. I was particularly impressed with the scope of work presented in the published proceedings of a 1969 conference organized by Carlo Terzuolo on Systems Analysis Approach to Neurophysiological Problems. That inspired me to think that I could simulate the Aplysia nervous system by applying my math and electrical engineering background. I was a bit naïve to say the least, as this is an ambitious goal even today. I started modestly with a differential-equation based model of the dynamic response of the sensory neurons using the IBM simulation language Continuous System Modeling Program (CSMP). It was then that I came up against the reality that the nervous system was nonlinear and that the linear systems approach had limited utility. (I soon took a course on nonlinear systems.) I also realized that you can’t model anything unless you have data. I had data on the sensory neuron responses, but I needed to go deeper into the system.

Lifelong Friends

During my time at NYU, I shared a rig with Vince Castellucci. He was the “dayshift” and I had the “night shift.” I started my experiments at about five in the afternoon when Vince finished and commuted back to Port Washington, Long Island, along with Tom Carew and Irv Kupfermann, who also lived there. I developed warm friendships with that crew as well as with Jim Blankenship, John Koester, and Kathy Hilten. We all had our scientific bond but, Irv, Tom, Vince, and I had a special bond because of our shared experiences on the Long Island Rail Road. Living in the same community made it easy to create a sense of extended family. All of these friends came together for Susan and my backyard wedding in Garden City, Long Island, in 1972. We were renting a house on the waterfront in Bellmore, Long Island, and had a small 15-foot motor boat. I have fond memories about digging for clams in the Great South Bay with Marcello Brunelli, Norbert Dieringer, and John Koester; water skiing with Mary Jo and Tom Carew and their family; and taking a trip to Gilgo Beach by boat with Lise and Vince Castellucci and Lise’s mother. And then there were Dan and Esther Gardner, who I would meet every year at the meetings of the Society for Neuroscience (SfN). Eric and I also established a lifelong friendship. We would meet at least once a year at the SfN or on other occasions.

From NYU to Columbia

Quantitative Analysis of the Mechanoreceptor Neurons and Their Role in the Gill-Withdrawal Reflex

After graduating in 1973, I stayed on with Kandel as a postdoc so I could do a deeper dive into the circuitry of the withdrawal reflex. That transition coincided with a move of the lab from NYU to Columbia University. I was fortunate to receive an individual F32 postdoctoral fellowship from the NIH. I continued studying the sensory neurons but moved to an analysis of the stimulus-response properties of the sensory neurons and the quantitative contribution that the sensory neurons make to the gill-withdrawal reflex. My experimental preparation consisted of the isolated abdominal ganglion with the attached siphon and gill. I used my feedback-controlled stimulator to deliver controlled force probe stimuli to the siphon skin and a photocell to monitor gill withdrawal. These studies showed that the stimulus-response properties of the sensory neurons could be fit with simple algebraic functions and that the responses were stable to repeated stimulation. Moreover, the gill contractions produced by artificially firing motor neurons were stable. These later effects were significant because they indicated that neither of these peripheral sites could explain habituation of the reflex, thus supporting the role of depression of the sensory neuron synaptic connections in the central nervous system (CNS) as a mechanism for habituation. A second important question addressed during my postdoctoral work was the quantitative contribution that the mechanoreceptor neurons make to the reflex. I found that a single sensory neuron spike contributes about 7–36 percent of the motor neuron input produced by a weak probe stimulus; that about 50 percent of the motor neuron input is monosynaptic; and that the depression of the sensory to motor neuron monosynaptic EPSP tracks the depression of the probe-evoked motor neuron synaptic input. These 1978 papers still stand as the most quantitative analysis of a molluscan reflex pathway. (These papers, and an independent one by Gordon Shepherd in 1978, were the first to introduce the term “microcircuit” into the neuroscience literature.)

One somewhat surprising observation was noted in the second of our two 1978 papers. In some cases, we observed EPSPs in the motor neurons when a probe was simply placed in the experimental chamber without touching the skin. However, we never encountered sensory neurons with such low thresholds for vibratory stimuli. We suggested that this observation may simply reflect a sampling bias, but it may also represent a previously undetected group of mechanoreceptor neurons that could also respond to water-jet and punctate tactile stimuli. Later studies by Robert Hawkins and Terry Walters provided evidence for the existence of such a low threshold population of sensory neurons, whose somata appear to be in the periphery. The take-home message was this: the interpretation of the results can be dependent on the specifics of the experimental conditions. For me, this take-home message was reinforced by the great central vs. peripheral controversy.

The Great Central vs. Peripheral Controversy

During that time, a major controversy developed between the Kandel lab and the labs of Jon Jacklet, Ken Lukowiak, and Bert Peretz on the role of the central and peripheral nervous systems in mediating the reflex. Kandel and Kupfermann in their 1969 Science paper, first characterizing the gill-withdrawal reflex, stated that the reflex is abolished when the abdominal ganglion was removed from an intact animal. Similarly, in my preparation of the isolated siphon, gill, and abdominal ganglion, the reflex was abolished when the nerves connecting the ganglion to the gill and siphon were severed. So, in our minds the critical role of the CNS in mediating the reflex was indisputable. Peretz and colleagues showed in a 1970 Science paper and several others that the reflex was intact after severing the nerves. The differences could not have been more striking! Contentious exchanges followed between the two groups at several meetings of the SfN. The neuroscience community was confused and intrigued. Who could you believe? Was the entire model of central neuron synaptic plasticity underlying habituation being torpedoed? Clearly, a resolution was needed. Eric invited Jacklet, Lukowiak, and Peretz to Columbia to try to resolve the issue. We would demonstrate our findings, and they would demonstrate theirs (although we doubted that they could). Perhaps differences in our experimental preparations might explain our different results. We monitored gill responses with a photocell, whereas, Peretz et al. used a tension transducer. We used either an 800-ms duration water jet stimulus from a Waterpik® or an 800-ms duration feedback-controlled force punctate stimulus to the skin; Peretz et al. used a 30-ms duration punctate stimulus from a “tapper,” a solenoid-driven metal rod. I suggested that we use my rig to run the two preparations simultaneously.

On the meeting day, we ran the two preparations simultaneously. Both the controlled-force stimulus and tapper stimulus produced nice responses from both the photocell and the tension transducer in the pretest. Then we cut the nerves. The controlled-force stimulus was delivered—no response, a result we expected. Next, the tapper stimulus was delivered. A response was observed, unchanged from the pretest. We were aghast. Both groups were correct! The difference seemed to be that the engagement of the central vs. peripheral nervous system was dependent, at least in part, on the nature of the stimulus. Lesson learned: When two groups have conflicting results, the differences may be explained by differences in the experimental protocols. A 1979 paper by Carew et al. summarized these and other findings related to the contributions of the central and peripheral nervous systems to the gill-withdrawal reflex.

University of Pittsburgh

One day Eric showed me a letter from Ernst “Ernie” Knobil, chair of the Department of Physiology at the University of Pittsburgh, inquiring whether Eric knew of any potential candidates for a junior faculty position in his department. (The “old-boy network” at work.) Eric encouraged me to apply knowing that Knobil was a first-rate scientist and academic leader and that the department had several distinguished faculty members, including Stanley Schultz, his former roommate during his first year at NYU Medical School. Schultz had become a leader in the field of membrane transport. Eric also knew of the work of Andre Borle who had found in 1974 that cyclic adenosine monophosphate (cAMP) could stimulate calcium efflux from mitochondria, a mechanism Eric thought might explain serotonin-induced synaptic facilitation in Aplysia. Gerhard Werner, whom I admired for his previous work on quantifying responses of cutaneous afferents, was also at Pittsburgh. So, Pittsburgh definitely had some strengths. But being a myopic New Yorker, Pittsburgh also seemed like a foreign country. My wife agreed. When I told her about the possibility of an interview, she said, “That’s just for practice, right?” I visited Pittsburgh and was impressed with Ernie Knobil, the department, the stellar faculty, and the delightful city. I also had an offer from the University of Chicago. Eric wanted me to stay on, but I felt I needed to see if I could make it on my own. So, it was on to Pittsburgh, and I started the position on January 1, 1976, with a hard-money salary of $18,000 a year and a start-up package of $30,000. Those numbers seem rather chintzy by today’s standards, but actually that package was very competitive. Also, my teaching responsibility was to be fairly light, which, in retrospect, was important for providing time to develop my research program. That first year, I just had to give one lecture on temperature regulation for the physiology course. Ultimately, I took over the lectures on resting potentials, action potentials, and synaptic transmission. I also filled in for Stan Schultz, giving his membrane transport lectures while he was on sabbatical at the University of Cambridge. (Stan’s and my lecture notes formed the basis of our book An Introduction to Membrane Transport and Bioelectricity.) I’ll say more about medical education and teaching later.

A Warning from my Chair

The first day on the job in January 1976, I had a meeting with Ernie Knobil during which time he outlined the departmental expectations of junior faculty for research, service and teaching, the “three legs” of the academic stool. It was friendly and positive and I was eager to accept the challenge. One comment was surprising as the meeting ended. Ernie warned me that I may receive some criticism from faculty members in the school because of my use of an invertebrate model system. Ernie was aware that research on invertebrate systems was not well accepted in medical schools despite the great achievements of Eric at NYU and Columbia and John Nicholls at Stanford using invertebrate models. Fortunately, I never encountered any overt bias at Pittsburgh, and Ernie and Stan were stalwart supporters of me and my Aplysia. A general bias against the use of invertebrate model systems persists in some quarters, as do biases against particular invertebrate model systems.

My First Grant

Ernie “encouraged” incoming faculty to submit grant applications before actually arriving in the department. (A departure from today’s expectations for new faculty who work for a year or more supported by their start-up funds to generate preliminary data for a proposal.) While at Columbia, I submitted a grant proposal to the National Institute of Mental Health (NIMH) to study the neuronal control of behavior. The ambitious plan was to analyze quantitatively the membrane currents of the ink motor neurons and to analyze and model all of the components of the gill-withdrawal reflex. The proposal received a good score but just missed the NIMH payline. A big break came when my proposal was noticed by Karl Frank, head of the Division of Grants and Contracts at National Institute of Neurological and Communicative Diseases and Stroke (NINCDS) and he agreed to “pick it up.” I am indebted to him for the lift that allowed me to jump start my research with R01 NS01311 “Analysis of the Neuronal Control of Behavior.” That grant included support for a technician and a state-of-the-art DEC PDP-11. The word got out that I had a new computer, prompting visits from other faculty members within and outside the department. I was the coolest guy in town even though I worked on a snail. As I write this autobiography in 2023, the PDP-11 and its 16K of memory are long gone, but I am pleased to say that the grant has been competitively renewed ever since then. I am deeply grateful to the NINDS for their enormous continuing support.

Becoming a Member of the Medical School “Academy of Educators”

Like most faculty in basic science departments in medical schools, I came to education from a background in research. Nevertheless, I turned out to be a good teacher of neuroscience, due in part to coaching from my mentors and observation of how they teach. This is the tradition of “on-the-job training” that goes back to the Middle Ages, if not earlier. Leonardo Da Vinci, famously said, “Poor is the pupil who does not surpass his or her master.” So, the bar can be set pretty high.

The Importance of Mentors

I was fortunate to have three fantastic mentors; Eric Kandel, Ernie Knobil, and Stan Schultz. Eric realized early on that progress in understanding the brain was going to require a multidisciplinary approach, and he therefore assembled a group of scientists that included psychologists, electrophysiologists, anatomists, and biochemists. It was an exciting environment, but a real challenge to the lab members, because to communicate with other lab members, you needed to be able to describe your results and ideas at a level they could understand. We were all students and teachers at the same time, and we honed our skills during our daily interactions, including lab meetings and journal clubs. From those presentations, I also discovered one of the great rewards of teaching. It’s the personal gratification that you receive from successfully explaining difficult concepts to a group of “students.”

Eric was an inspiring teacher. I had an opportunity to attend the introductory lecture that he gave in the newly established neuroscience course at NYU. He talked about the Greek philosophers and their attempts to understand the mind, Descartes, art, love, hatred, and how if you really want to understand the human condition and yourself, not to mention brain disorders, you need to understand the basic principles of the nervous system. At the end, there was an enormous applause from the class. I had some inspiring teachers in high school and college, but Eric was at another level. Miles Monroe, the character played by Woody Allen in the movie Sleeper who famously said that the brain is his second favorite organ, would certainly change his mind if he had heard Kandel’s lecture that day. Eric inspired students to learn about the brain, and he inspired future teachers to inspire their students.

Practice Is the Key to Good Communication

During my stay in the lab, I also learned one of Eric’s keys to successful communication. It was practice. Often before he would leave town to present a lecture at another university, he would present the lecture to the lab group for feedback. And sometimes he came back a second time after he had worked on it, based on the suggestions that he had received. So here was a member of the National Academy of Sciences and a future Nobel Laureate who practices lectures to his lab group. I learned that no matter how good you are, or think you are, you can probably be even better with some practice.

Then came my experience as a junior faculty member in the Department of Physiology at the University of Pittsburgh. Giving a good journal club presentation to a group of scientific colleagues was one thing, but was that scalable to giving a lecture to 150 first-year medical students? At the time, the sole responsibility of the department was to teach the course in mammalian physiology to first-year medical students. Ernie’s philosophy was crystal clear. Excellence in teaching was expected, and it was a privilege to teach in his physiology course. The department had ownership of the course, and the faculty took great pride in it. It had the tradition of always being rated by the students as the best basic science course and was known as the course whose faculty routinely received Golden Apple teaching awards. But it was not just student feedback that was solicited, which can be fickle depending on the difficulty of the exams. Every lecture was attended by Ernie and the faculty of the course, who sat in the back row and gave feedback to the lecturers, especially the new ones. The other junior faculty warned me about the intense scrutiny and that I should expect to be summoned to Ernie’s office after my first lecture. I do not think the fear factor was helpful, but it was clear that the expectations were high. But that was okay with me. I had more confidence in myself than did the other assistant professors.

That was until I found that my first teaching assignment was to give the lecture on temperature regulation; a topic that I knew virtually nothing about. (I soon learned that assignment was considered a rite of passage for new faculty.) To do it right, you needed to know multiple systems: the cardiovascular system and blood flow through the skin and muscle, sweat glands, cold and hot receptors, hypothalamic control systems, motor control of shivering, and endocrine control of cellular metabolism. To be clinically relevant, one should include hypothermia and fever. So, I had some learning to do before I could teach anything. I actually came to know and love temperature regulation. It is a great example of homeostasis and the integration of multiple systems and regulatory processes. Following the lead of Eric, I practiced that lecture—and practiced—and practiced—and practiced. To this day, my wife Susan who served as my surrogate audience, recalls the agony I put her through. Two good things did come out of those practice sessions, however. First, I got some good feedback from Susan on how to improve the lecture. Second, Susan knows more about temperature regulation than most medical students.

I gave that lecture and it seemed to be well received by the students, but my confidence was temporarily shattered when I received the dreaded call summoning me to Ernie’s office. Well, Ernie liked the lecture; he just had some constructive comments for the next time. And, before long, I was asked to do additional lectures for the next year’s course. This was not a burden, but an honor. I passed the test. I was now more than just a scientist in an academic department—I was a member of the “academy of educators.”

Swimming Is an Attempt to Stay Alive in Water

During my time at Pittsburgh, there was a lot of talk among the faculty about pedagogy, a term I had not encountered much in the past. Pedagogy was a hot topic, because we all had to lead small-group conferences on various topics in the physiology course, ranging from electrical signaling in nerve cells to the countercurrent multiplier system in the kidney. We were all trying to outdo each other to find ways to explain difficult topics, not just to the students but to each other. As in Kandel’s lab, we were again teachers and students at the same time. Of all the great teachers in the department Stan Schultz was clearly the master of pedagogy and a mentor of us all. Stan had the unique ability to explain difficult concepts to the students by using examples and humor. I remember his vivid explanations about how a pair of charged molecules move sequentially at the same speed through a membrane channel by saying it was just like a poor swimmer like him being tethered with a large rubber band to an Olympic swimmer like Mark Spitz. To emphasize that he was a poor swimmer Stan would say “To me, swimming is an attempt to stay alive in water.” So, you could envision the two “swimmers,” the graceful Spitz followed by the floundering Schultz moving through that channel together at the same speed, but with Spitz always in front! If Stan could make molecules moving through a channel interesting, I felt that I had a chance at making the brain interesting. I always think about Stan when I struggle to explain a difficult concept.

So, the extent to which I have been successful in education comes from the tremendous mentoring that I had during the early years of my career. The one problem with having Kandel, Knobil, and Schultz as mentors is the difficulty in getting a passing grade using Leonardo’s criterion, but I will keep trying. I agree with Ernie Knobil that it is a privilege to be able to teach our students. It is also a privilege to be able to inform the public about the research we do. I will discuss my efforts in scientific outreach later.

Steps to Becoming a Chair

In 1980, a strong group of sensory neuroscientists in the Department of Pharmacology was transferred to the Department of Physiology and a section on neuroscience was established in the department. A national search was initiated for a vice chair to recruit additional faculty. In the end, Ernie asked me to take the position. I saw it as a great opportunity. I became the director of the medical neuroscience course and filled four new slots. We hired Terry Crow, who worked on mechanisms of associative learning in the marine mollusk Hermissenda; Dan Simons, who worked on the rodent barrel cortex; Joe Yip, who worked on the development of chick spinal ganglia; and Ken Larsen, who worked on motor cortical circuitry. We were off to a great start, although things were about to change. But first, back to the research.

Biophysics and Behavior

The goal of my first NIH grant was to take a deep dive into the neuronal circuit for the gill-withdrawal reflex and quantitatively analyze the properties of the ink motor neurons. This project actually started when I was a postdoc collaborating with John Koester, who had been a postdoc with Eric, but who now was an assistant professor. We had become good friends during our time at NYU, when John worked on the neuronal control of the heart. During that time, we began a collaboration to study inking behavior and search for neurons that mediated spontaneous respiratory pumping, a fixed action pattern involving an all-or-nothing contraction of the gill and siphon, as well as inhibition of the heart.

Intracellular recordings from molluscan neurons in the 1960s and 1970s revealed a striking diversity in the electrophysiological properties of molluscan neurons, unlike the squid giant axon, which had become the prototypic neuron for all species. The giant axon was normally silent and then increased its firing activity proportional to the intensity of a stimulus. In contrast, some molluscan neurons showed dramatic adaptation of firing rate with a prolonged stimulus, whereas others showed delayed firing in response to a stimulus. Some neurons, such as Aplysia neuron R15, had endogenous bursting activity—cyclical bursts of spikes in the absence of a stimulus. The findings were intriguing, but we did not know if these different firing patterns had any behavioral significance. Aplysia offered a system to address the issue.

The L14 Ink Motor Neurons

Tom Carew and Eric Kandel discovered three nearly identical neurons designated L14, which were motor neurons controlling the inking reflex. Unlike the siphon-elicited gill withdrawal reflex, which is graded as a function of stimulus strength, Tom and Eric had found that the inking reflex has a high threshold and was elicited in a relatively all-or-nothing fashion. Moreover, they found that this high behavioral threshold was due to the high firing threshold of the L14 neurons, which they suggested was due to the combination of an unusually high (negative) resting potential and the activation of a voltage-dependent early outward current.

While at Columbia, I began a collaboration with John Koester and two of his postdocs, Norbert Dieringer and Eli Shapiro, to examine the inking reflex and its underlying biophysical mechanisms. We focused on the question of how behavioral responses vary as a function of stimulus duration. For example, are behavioral responses that are smoothly graded as a function of stimulus intensity also smoothly graded as a function of duration; and are behaviors that are steeply graded functions of intensity also steeply graded as a function of duration? The inking and gill withdrawal reflexes provided great systems to address these questions. We found that ink release was selectively responsive to longer duration stimuli and increased in a steeply graded fashion as duration increased. This behavioral feature was associated with a distinct delay in firing followed by an accelerating spike train in the L14 neurons during a prolonged depolarizing stimulus. In contrast, the time course of the gill-withdrawal reflex was a graded function of stimulus duration. I designed and built a voltage-clamp amplifier to analyze the underlying biophysical mechanisms of the L14 responses.

In parallel experiments at Columbia and at Pittsburgh, we first characterized a depolarization-activated fast-transient K⁺ current (I-KV-A) in L14 cells. We found that the high resting potential (−75 mV) of L14 cells ensures that the steady-state level of inactivation of the I-KV-A conductance channels will be low at rest. Thus, a train of EPSPs can activate this current maximally, reducing the initial effectiveness of the excitatory input. Therefore, cumulative inactivation of I-KV-A by a prolonged train of EPSPs is required before the input can initiate a spike train. The results suggest that a unique combination of biophysical properties of the L14 cells and the features of the synaptic input cause them to act as a low-pass filter in the reflex pathway for inking. Their high resting potential makes these cells preferentially responsive to strong stimuli, and in combination with the I-KV-A channels, to long-lasting stimuli. The delayed recruitment of a decreased conductance EPSP augments the low-pass nature of the L14 cells. We published a paper describing this work in the Journal of Neurophysiology in 1979.

The next step was to prove that the properties of the I-KV-A and decreased conductance PSPs determined the firing properties of the L14 neurons and the behavior. To address this issue, I hoped to perform an analysis parallel to what Hodgkin and Huxley did for the ionic mechanisms of the action potential of the squid giant axon. The first task, then, was to understand those classic papers. I had a superficial understanding, but needed to go much deeper. I spent weekends in Pittsburgh reading and rereading those papers until I was ready to perform a detailed voltage-clamp analysis of all the currents. I developed a conductance-based mathematical model, and, using the model, showed that the A current was indeed sufficient to account for the features of the cell firing and the behavior. This study was not only a significant technical achievement, but also it was the first time anyone had built a quantitative biophysical conductance-based model of a neuron that accounted for, and predicted, features of a behavior.

I thought it was a tour de force and submitted back-to-back papers to the Journal of Physiology, the one that published the classic Hodgkin and Huxley series in 1952. However, my bubble was soon burst when the papers were rejected, and I felt dejected. With great apprehension, I told Ernie Knobil about my failure. He was extremely supportive and encouraged me “not to take it too hard.” It was a good lesson to learn, because it prepared me for future rejections and the realization that sometimes there are disagreements about what is significant and what is not. I remember John Garcia saying that his now-classic paper on food-avoidance conditioning was rejected multiple times before it was accepted for publication. Lesson learned: You just need to move on, and that is what I did. Revised versions of the papers were soon accepted in the Journal of Neurophysiology.

Search for Interneurons That Mediate Spontaneous Respiratory Pumping: A Fixed Action Pattern Involving an All-or-Nothing Contraction of the Gill

Tactile stimulation of the siphon elicits a withdrawal of the gill and siphon, but that withdrawal, as first noted by Kupfermann and Kandel, has two components; a rapid initial graded response followed later by an all-or-nothing component. The early classic studies of habituation and dishabituation of the reflex focused on the early component and the role of the sensory neuron-to-motor neuron connection in mediating it. The late component was thought to be mediated by an unidentified neuron called Interneuron II. Interneuron II activity also occurred spontaneously and mediated the coordinated withdrawal of gill, siphon, and mantle shelf; closing of parapodia; and inhibition of heart rate accompanied by a decrease in vasomotor tone.

John Koester and I independently found that the synaptic potentials previously attributed to Interneuron II are actually produced by at least three respiratory command cells. We combined our results in a joint-authored paper in 1978. I later found that one of these neurons was one of a cluster of mutually excitatory cells (the L25 cells), which were necessary and sufficient to produce the activity of other interneurons and motor neurons activated during spontaneous respiratory pumping. The L25 neurons were also necessary and sufficient for the all-or-nothing component of the activation of gill motor neurons elicited by siphon stimulation. Discovering the L25 neurons was special for me. We had demystified the elusive Interneuron II. The finding was not earth shattering in the broader neuroscience community, but, for me, it was a homerun.

The Interneuron II story is not over, however, and the extent to which plasticity of the L25 neurons contributes to habituation, dishabituation, and sensitization of the gill-withdraw reflex has not been examined. Perhaps the degree of their engagement simply follows the decrement and enhancement of the sensory neuron connection that occurs at motor neurons. Perhaps the plasticity rules are different. There could still be an additional and major unexplored dimension to understanding the gill-withdrawal reflex and its modification by learning.

My First Book

This growing interest in the unique biophysical properties of neurons led to a 1980 Banbury Conference at Cold Spring Harbor Laboratory (CSHL) organized by Eric Kandel and Chuck Stevens. Chuck and Eric asked John Koester and me to edit a volume of the proceedings to be published by CSHL Press. Molluscan Nerve Cells: From Biophysics to Behavior was my first book, and I was excited for the opportunity to summarize the ways in which the unique membrane currents of neurons contribute to their information processing, an issue that has become of great interest and importance in the vertebrate CNS. It was also the start of a long relationship with CSHL and CSHL Press. Over the years, I have had the privilege of organizing many meetings and courses and of serving as editor-in-chief of Learning and Memory between 1996 and 2024.

Back to Synaptic Plasticity and Finding the Holy Grail for Associative Learning

Synaptic Plasticity and a Quantitative Model of Transmitter Release and Its Plasticity

A goal of my first NIH grant was to analyze quantitatively the properties of the sensory neurons in sufficient detail to construct a model of the release process. This model would be a component of the complete withdrawal circuit and the plasticity that underlies habituation and sensitization. Marc Klein and Eric Kandel had suggested that the decrement of transmitter release associated with habituation was due to cumulative inactivation of Ca²⁺ current in the sensory neurons. Sensitization was believed to be caused by a serotonin (5-HT)- and cAMP-mediated reduction of a depolarization-activated membrane current, the S-K⁺ current. Reduction of the S-current would lead to broadening of the action potential, more calcium influx and greater transmitter release (i.e., synaptic facilitation). The model of cumulative inactivation would predict that synaptic depression would be a monotonic function of stimulus interval. Other single-process assumptions such as simple depletion of transmitter would make similar predictions. Instead, I found that synaptic depression varies as a complex function of interstimulus interval and that the recovery time course of synaptic depression following a train of stimuli is variable. Shorter spike intervals produced more rapid recovery. I suggested that intracellular accumulation of Ca²⁺ at short spike intervals contributed to the rapid recovery. Clearly, things were more complex than would be predicted by a single process, and a new model was needed.

Around this time, I was fortunate to be approached by Kevin Gingrich, a first-year medical student with an undergraduate degree in electrical engineering from Cornell University who was looking for a project that involved modeling. I had just the project for him! We developed a lumped parameter model of the sensory neuron release process, which included Ca²⁺- channel inactivation, Ca²⁺-mediated neurotransmitter release and mobilization, and readily releasable and upstream feeding pools of neurotransmitter. The model not only simulated the data of synaptic depression and recovery from depression, but also qualitatively predicted other features of neurotransmitter release that it was not designed to fit. The model could not account fully for synaptic depression with only the empirically observed somatic Ca²⁺-current kinetics. Rather, the model predicted that a large component of synaptic depression was due to depletion of the pool of releasable transmitter. Kevin found time to continue the project during his four years of medical school and as a resident, when we expanded the model to include processes for associative learning.

Associative Learning and the Battle Between the Crunchies and the Squishies

In the late 1970s and early 1980s, the Kandel and Schwartz labs were making great strides in elucidating the role of cAMP in mediating the presynaptic facilitation associated with sensitization, an example of nonassociative learning. But despite the progress, some in the field were not impressed because sensitization was thought to have little relevance to vertebrate learning. The real “brass ring” was to understand mechanisms of associative learning, such as classical (Pavlovian) conditioning, and operant (instrumental) conditioning, and it looked like Aplysia was lagging behind some of the other invertebrate model systems in this aspect. Teresa Audesirk at the University of Missouri demonstrated associative conditioning of feeding behavior in Lymnaea; Jack Davis and his group at the University of California, Santa Cruz, demonstrated classical conditioning of feeding behavior in Pleurobranchaea; Alan Gelperin at Princeton demonstrated food aversion learning in Limax; and Terry Crow and Dan Alkon at the NIH demonstrated classical conditioning of Hermissenda, along with neuronal correlates of the behavioral changes. There were also examples of associative learning in arthropods, such as honeybees, Drosophila, and cockroaches. Graham Hoyle said during an SfN talk that “it was a battle between the crunchies and the squishies” for who would get that brass ring. The 1981 finding by Tom Carew, Terry Walters, and Eric Kandel that the siphon-elicited siphon-withdrawal reflex could undergo classical conditioning was the major advance that allowed Aplysia to catch up. Now the big challenge was to discover the underlying mechanism.

At that time, I was fortunate to have Terry Walters join the lab as a postdoctoral fellow. We began thinking of possible mechanisms for classical conditioning. At the most fundamental level, and neglecting the constraints on temporal order, classical conditioning is an and gate phenomenon. The conditioned response (CR) comes about after the conditioned stimulus (CS) and the unconditioned stimulus (US) are paired. Presentation of the CS alone or the US alone did not lead to conditioning. One possibility was that the mechanism of associative learning was an elaboration of mechanisms already in place that mediate sensitization. For example, the aversive US likely caused the release of 5-HT and subsequent activation of the cAMP cascade (i.e., one arm of the AND gate), but what was the CS pathway? Here we were influenced by a growing body of literature showing interactions among second-messenger cascades, in particular calcium and cAMP, as elegantly summarized in Howard Rasmussen’s 1981 book Calcium and cAMP as Synarchic Messengers. There was good evidence to suggest that the burst of spikes activated by the CS in sensory neurons would lead to an influx of calcium, which in turn could modify the adenylyl cyclase complex and potentiate cAMP levels beyond those elicited by the US alone. We tested the hypothesis using an in vitro analog of classical conditioning consisting of artificial activation of sensory neurons (CS) in the pleural ganglion paired with shock to the tail (US). We found that sensory neurons activated shortly before a sensitizing shock displayed significantly more facilitation of their monosynaptic connections to tail motor neurons than cells trained with control treatment. This associative effect was acquired rapidly and was expressed as a temporally specific amplification of heterosynaptic facilitation. We termed this mechanism activity-dependent neuromodulation.

During the course of our experiments, we learned that Tom Abrams, Tom Carew, Bob Hawkins, and Eric Kandel were pursuing similar experiments and were obtaining similar results using the sensory-to-motor neuron connections in the abdominal ganglion. We were ready to submit our paper, but Eric suggested that we hold back and allow them to finish up at which time we would submit back-to-back papers to Science. The idea was that two papers showing the same basic effect in two different reflex systems would have a greater impact than either one alone. Albeit tongue-in-cheek, Eric was fond of saying, “If one group discovers a mechanism in Aplysia it is general, but if two groups discover the same mechanism, it is universal.” We agreed to Eric’s suggestion and the papers received great reviews. One of the reviewers, who later revealed himself to be William “Chip” Quinn at MIT, said in his review that we had found the holy grail of learning.

The University of Texas Health Science Center at Houston

The University of Pittsburgh Medical Center is now one of the premier centers in the world for basic and clinical research. But in the late 1970s and early 1980s, the ship was at the point of foundering. There were cuts in the state budgets and serious problems with the organization of the various affiliated hospitals. Some good people started to explore other opportunities. One great personal and professional loss was the recruitment in 1979 of my colleague and friend Stan Shultz to chair the Department of Physiology at the University of Texas (UT) Medical School at Houston. Admittedly, it was a great opportunity for Stan, but a loss for Pittsburgh. The Texas medical school was less than 10 years old and aspired for greatness. Stan’s charge was to take the Department of Physiology to the next level by recruiting an outstanding faculty. I was flattered at a going away dinner for Stan, when Ernie wished him great success, but admonished him to “stay away from recruiting Jack Byrne.” Stan started to build the department and also quickly became an academic leader in the school. One of his new jobs was to serve as the chair for the search committee for the dean of the school. And you might have anticipated who would be the prime candidate. At a faculty meeting in 1981, Ernie dropped the bombshell that he was leaving Pitt to become dean of the UT Medical School at Houston. Ernie’s goal was to make UT Houston one of the top 10 public medical schools in the country. I felt a bit abandoned with Ernie and Stan’s departures. Leonard “Rusty” Johnson, a visiting speaker from Houston “rubbed it in” by beginning his seminar saying, “It’s good to see some people are still left in Pittsburgh.” I started to look for a new boat, and naturally Houston seemed like a good option. So, in July of 1982, I started my new lab in the newly named Department of Physiology and Cell Biology. Some 14 years earlier, I had said I would never move to Houston. Yet, here I was with a golden opportunity.

Houston also provided an opportunity to get back to the sea. I started racing sailboats on Galveston Bay and the Gulf of Mexico, first in a crew on various J boats (J/29, J/32, J/35, and J109) and eventually with my own J/22 and later J/80. Now my daughter, Kathryn, and son, Michael, were the crew members. I was not the only sailor/scientist at the Houston Yacht Club. Tom Caskey, pioneering geneticist from Baylor; and our neurologist UT Houston President M. David Low were active sailors. Soon Ernie Knobil got the bug and bought a 37-foot Westerly.

Boom Times in the 1980s and 1990s

The “oil boom” in Houston went bust soon after I arrived, but my research started to really flourish. This scientific boom was due to several outstanding colleagues who joined the lab. With graduate students Dean Buonomano, Jennifer Raymond, Ken Scholz, and John Walsh; postdoctoral fellows Len Cleary and Karen Occor; senior research associate Doug Baxter; and visiting professor Avy Susswein, I continued several lines of research started in Pittsburgh and embarked on new areas, such as the neural circuit for the tail-elicited tail withdrawal reflex, the mechanisms for long-term sensitization (LTS), nonlinear dynamics of neurons and neuronal networks, and the neuronal control of feeding behavior and its plasticity.

Back to Mechanisms of Classical Conditioning

After the back-to-back Science papers with Eric’s group, the hunt was on in both groups for the biochemical mechanism of activity-dependent neuromodulation. Both papers suggested that the mechanism for activity-dependent neuromodulation was the activity-induced influx of Ca²⁺ interacting with the serotonin-sensitive adenylyl-cyclase to potentiate cAMP levels, but we needed the evidence.

In prepandemic times, a successful career in science led to invitations to present your results to colleagues at other universities. A great benefit of these visits is meeting with students, postdocs, and faculty and learning about ongoing research, which in many cases can help inform and direct your own research. In addition, some of the students and postdocs with whom you meet are looking for future opportunities. A visit to Wesleyan University in 1981 turned out to be particularly fortuitous, because it was there that I met Karen Occor. She was finishing up her doctoral project under the supervision of Allan Berlind, working on the identification and localization of a catecholamine in the motor neurons of the lobster cardiac ganglion. She soon thereafter joined my lab as a postdoc.

Karen developed an in vitro analog of classical conditioning, consisting of isolated clusters of sensory neurons and the use of a brief application of a high K⁺ solution to mimic the CS and a brief application of 5-HT to mimic the US. Karen found a pairing-specific amplification of the cAMP content of isolated sensory neurons. The enhancement was achieved within a single trial. These results indicated that a pairing-specific enhancement of cAMP levels may be a biochemical mechanism for associative neuronal modifications. Tom Abrams and his colleagues pursued the question further and in an elegant series of experiments examined the temporal order of the pairing effects.

The Serotonin-Induced Modulation of Membrane Currents Was More Complicated Than We Thought

According to the early model of Kandel and colleagues, sensitization was believed to be caused by a serotonin (5-HT) and cAMP-mediated reduction of a specific membrane current, the S-K+ current. Reduction of the S-current would lead to broadening of the action potential, more calcium influx, and greater transmitter release (i.e., synaptic facilitation).

Doug Baxter wrote to me in 1984 about his desire to work on synaptic plasticity in Aplysia. It was an easy decision to bring him on board. He had already done excellent work on synaptic plasticity of the crayfish neuromuscular junction during his doctorate with George Bittner and postdoc with Tom Brown. Moreover, I had the necessary resources having just received new funding from the Air Force Office of Scientific Research (AFOSR). Doug turned out to be fantastic in every way; he was extremely smart and technically competent. And, he was one of the nicest and most generous scientists whom I have met. I have been extremely fortunate that our fruitful collaboration has persisted for almost 40 years. In 1985, Doug set out on an ambitious task to perform a complete voltage-clamp analysis of the membrane currents of the sensory neurons and their modulation by 5-HT. The project built on the earlier work of graduate student John Walsh, who found that 5-HT modulates a steady-state calcium-activated K⁺ current. Doug extended the analysis by examining the voltage-activated IK,Ca and the delayed outward current. He found that that 5-HT modulates not only the S- K⁺ current but also the delayed K⁺ current and a voltage and Ca²⁺- activated K⁺ current. Subsequent studies showed that the S-K⁺ current was important for changes in excitability. In contrast, the delayed K⁺ current contributed importantly to the increased duration of the action potential. Moreover, through later work by graduate student Shuzo Sugita, we found that the effects of 5-HT on the delayed K⁺ current were predominantly modulated by protein kinase C (PKC). An important conclusion from these studies is that sensitizing stimuli affect a host of processes in the sensory neurons, all of which act synergistically in a state- and time-dependent manner to enhance the release of transmitter and bring about an enhanced withdrawal response (i.e., sensitization). This engagement of multiple messenger systems and substrates elucidated in Aplysia has emerged as a general principle of synaptic plasticity. Eric and I had an opportunity to review mechanisms for short-term sensitization in our 1996 Journal of Neuroscience paper “Presynaptic Facilitation Revisited: State- and Time-Dependence.” Things have gotten a bit more complicated since then, with the involvement of additional autocrine and postsynaptic processes contributing to short-term facilitation, which Bob Hawkins and I reviewed in our 2015 paper in Cold Spring Harbor Perspectives in Biology.

Neural Circuit for the Tail-Elicited Tail Withdrawal Reflex

Len Cleary, who completed his doctorate with Jimmy Schwartz at Columbia in 1984, wrote in a letter to me that he was “most interested in starting with a physiologically interesting cell and analyzing its connections morphologically.” I invited Len to join the lab and have had the pleasure of working with him ever since. He made the outstanding discovery of a multifunctional interneuron LPl17 that was critical for mediating the tail stimulus-elicited tail withdrawal and linking sensory information from the pleural ganglion to the abdominal ganglion. That link led to activation of gill and siphon motor neurons and the Interneuron II (L25) network. It was more than a link, however. It transformed the short-lasting synaptic input it received to a slow and long-lasting response in the postsynaptic neurons. It is not generally appreciated that measures of sensitization frequently use duration as an index of the degree of behavioral change, and these changes in the duration can last many seconds. However, mechanisms of sensitization of defensive reflexes have been correlated primarily with changes in the amplitude of the monosynaptic EPSP. Neurons like LPl17 allow the changes in PSP amplitude to be transformed to changes in duration. A complementary study by postdoctoral fellow John White used a three-layer circuit model to demonstrate the sufficiency of LPl17 to mediate this transformation.

The 1985 Dahlem Conference and the Mechanisms of Long-Term Memory

My early work focused on the analyses of short-term behavioral and synaptic changes underlying habituation, sensitization, and classical conditioning, but my interest in long-term mechanisms was stimulated during a 1985 Dahlem Conference in Berlin organized by J.-P. Changeux and Mark Konishi. It was a Who’s Who of learning and memory scientists including, to name a few, Per Andersen, Mark Bear, Michel Baudry, Tim Bliss, Yadin Dudai, Hersch Gerschenfeld, Masao Ito, Mary Kennedy, Randolf Menzel, Michael Merzenich, Mort Mishkin, Roger Nicoll, Pasko Rakic, Edmund Rolls, Wolf Singer, and Richard Thompson. Invertebrates were well represented with me, Tom Carew, and Eric Kandel (Aplysia); Dan Alkon (Hermissenda); Randolf Menzel (Apis); and Yadin Dudai and Martin Heisenberg (Drosophila).

It was a wonderful conference and over those four days and nights of scientific discussions and socializing, I developed lasting friendships with many of the participants. We were divided into four discussion groups: (1) activity-dependent regulation of gene expression; (2) activity-dependent regulation of synaptic transmission and its relationship to learning; (3) activity-dependent modification of functional circuitry as a possible basis for learning; and (4) neuronal assemblies and memories. I was assigned to the group on activity-dependent regulation of synaptic transmission and its relationship to learning. We had some great discussions that were summarized in a subsequent book chapter by our rapporteur Michel Baudry. One of the great features of the format for the Dahlem conferences was the staggering of the sessions so that members of one group could “visit” other groups. I was particularly impressed with the excitement of the members and importance of the question being considered by the subgroup on activity-dependent regulation of gene expression. The idea that protein synthesis was important for long-term memory was becoming well established, but little was known about the identity of individual proteins and how they were regulated. I decided then that the tail-elicited tail and siphon-withdrawal reflex might have something to contribute.

Ken Scholz, a new graduate student who did his undergraduate work in mechanical engineering at Boston University, showed that the reflex had a memory for sensitization that persisted for at least a day, and, importantly, that LTS training led to a reduction in net outward current in the sensory neurons. The results indicated that one mechanism for the storage of LTS is the regulation of membrane currents that influence the characteristics of the action potential and the excitability of individual neurons. The results also provided insight into the relation between short-term sensitization and LTS in that the biophysical loci involved in the storage of LTS appeared to be similar to those involved in short-term sensitization. But what about the induction? Ken demonstrated that cAMP was as critical for the induction of LTS as for short-term sensitization. Injection of cAMP into individual neurons in isolated ganglia led to a reduction of outward currents similar to that produced by behavioral training. The current that is reduced over a long period of time (24 h) as a consequence of cAMP injection and behavioral training had relatively slow kinetics and mild voltage dependence and was active close to the resting potential. This result indicates that long-term reduction of this current was involved in enhancing the excitability of the sensory neurons and in the control of repetitive firing. The Kandel group was actively pursuing the role of cAMP in LTS as well. Sam Schacher, Vince Castellucci, and Eric found that bath application of a cAMP analog led to a long-term (24 h) enhancement of the EPSP in sensorimotor cocultures. Our complementary findings led to another set of back-to-back papers in Science in 1988. cAMP was doing more than inducing changes in membrane currents, however. Graduate student Fidelma O’Leary found that cAMP also produced morphological changes in the sensory neurons, including increased numbers of sensory neuron branches and varicosities. These changes required de novo protein synthesis. Thus, there is not a single expression mechanism for LTS. It is expressed both by modulation of membrane currents and by morphological changes in sensory neurons.

A constant concern of using reduced preparations such as isolated ganglia or neurons in culture (or vertebrate slice preparations) is the extent to which phenomena at reduced levels map onto changes in vivo. My strategy was to try to validate findings at these different levels. Graduate student Marcy Wainwright, working with Len Cleary, showed that LTS was associated with morphological changes in the sensory neurons, including an increased number of sensory neuron branches and varicosities. And postdoc Wai Lee, working with Len Cleary, showed in 1998 that LTS was associated with changes in synaptic strength and changes in excitability of sensory neurons. Interestingly, they also showed for the first time that the biophysical properties of the postsynaptic motor neurons were affected by LTS. An independent study by Louis-Eric Trudeau and Vince Castellucci in Montreal showed that the response in a gill motor neuron in an isolated abdominal ganglion to a glutamate agonist was enhanced 24 hours after a 60-minute treatment with 5-HT. Subsequent studies by the labs of David Glanzman at University of California, Los Angeles (UCLA) and Bob Hawkins at Columbia have greatly expanded the understanding of postsynaptic induction and expression mechanisms of LTS.

Feeding Behavior in Aplysia and Its Modification by Classical Conditioning

Although my lab had made great progress in analyzing mechanisms of classical conditioning at the sensorimotor synapse, that model system is not ideal. For example, there is a large nonassociative component to both the behavior and the synaptic facilitation, and the measure of the conditioning, the amplitude of the EPSP, is somewhat removed from the common measure of the behavior, the duration of siphon withdrawal. The duration of siphon withdrawal is difficult to measure, and the conditioned stimulus (touch to the skin) is difficult to quantify and deliver. Moreover, the conditioning used an aversive training procedure (i.e., shock). For comparison with vertebrate systems, it is desirable to use an appetitive conditioning protocol. Consequently, we were drawn to the feeding behavior in Aplysia. Avy Susswein had discovered that animals were capable of learning that food was inedible if wrapped in a plastic net, a form of associative conditioning.

A major challenge was the lack of understanding of the circuitry that controlled feeding behavior. It was not that nothing was known. Indeed, Dan Gardner, a graduate student of Eric in the early 1970s, had identified many of the neurons in the buccal ganglion and their synaptic connections. Irv Kupfermann had made major strides working with Klaude Weiss on identifying motor neurons and modulatory transmitters controlling the buccal mass. They had also identified neurons that controlled the motivational state of the animal. The major gap was the identity of neurons that initiate the buccal motor program for feeding.

Avy Susswein and I met as graduate students at NYU. Avy was with Irv Kupfermann, who had recently set up his own lab to use feeding behavior as a model system to study motivation. Avy’s thesis examined satiation of feeding behavior, which he continued when he secured a faculty position at Bar Ilan University. There he made the discovery in 1983 of associative learning of feeding behavior. Avy was a terrific behaviorist, but he lacked experience in cellular neurobiology, so he had difficulty pursuing the mechanisms underlying that form of learning. He approached me in 1985 to do a sabbatical in Houston to get that expertise. It was a great partnership. Avy brought the feeding system to my lab, and he learned intracellular recording techniques. Although we did not uncover the mechanism of associative learning, we did discover a key neuron (B31) that was necessary and sufficient for initiating the buccal motor program. That finding laid the ground work for subsequent work in my lab with Doug Baxter, as well as Avy’s lab and that of Hillel Chiel, Betsy Cropper, Mark Kirk, Irv Kupfermann, and Klaude Weiss, expanding details of the circuitry mediating buccal motor programs. That collective knowledge paved the way for examining cellular correlates of associative learning.

Avy’s associative learning paradigm was not ideal for pursuing a cellular analysis. We sought a simpler system in which a CS and a US could be paired in a traditional classical conditioning protocol. Two important developments occurred almost simultaneously. First, in 1997, Ruth Colwill at Brown showed appetitive classical conditioning of feeding behavior when a neutral chemical stimulus (CS) was repeatedly paired with food reinforcement (US). Second, Hilde Lechner joined my lab as a graduate student after doing undergraduate studies in Randolf Menzel’s lab at the Free University of Berlin. Hilde was an exceptionally gifted student who had an excellent background in learning theory. Having worked on the tiny bee brain, she was unintimidated about working with Aplysia. She was the perfect person to try classical conditioning in Houston. Hilde’s key insight was to use a mechanical stimulus rather than the chemical one used by Ruth Colwill. If conditioning was successful, the subsequent analyses would be facilitated because we knew more about the mechanoreceptor pathways than the chemoreceptors. Hilde’s protocol was successful and she went on to show that appetitive classical conditioning of feeding resulted in the pairing-specific strengthening of the polysynaptic pathway between afferent fibers and the motor pattern-initiating neuron B31, the neuron that Avy Susswein had identified 10 years earlier.

Operant Conditioning

Whereas excellent progress had been made in analyzing mechanisms of classical conditioning by us and by other groups, at that time, virtually nothing was known about the neural mechanisms of the second major form of associative learning known as operant conditioning. We made enormous strides in demystifying this form of learning. The results are also important because they allow for a comparative analysis between these two major forms of associative learning. Although they are operationally distinct, psychologists have argued for decades about the mechanistic similarities. Progress was made possible by Romuald Nargeot, an outstanding postdoc who joined my lab, and by generous support from William Berry’s program at the AFOSR. We were also inspired to examine operant conditioning of feeding behavior with the success in 1986 of Cook and Carew in demonstrating operant conditioning of head-waving behavior.

In 1994, I received a letter from Romuald asking if I would serve as a member of his thesis jury at the University of Bordeaux at Arcachon. It was a great honor to be recognized internationally as a good mentor. It was also a special treat to visit the laboratory and see the rig room where Eric did his classic experiments with Ladislav Tauc in the early 1960s. More fortune came my way when Romuald joined my lab as a postdoctoral fellow. The goal was to develop an operant conditioning paradigm using the feeding system. Rather than start with the behavior, our goal was to develop an in vitro analog. This seemed possible for two reasons. First the isolated buccal ganglion was capable of exhibiting spontaneous motor programs. Thus, we had an operant that could in principle be conditioned. Second, we knew that one of the peripheral nerves innervating the esophagus was rich in dopamine-containing fibers that signaled the presence of food in the gut. Thus, we had a potential reinforcing pathway. The idea was to activate the esophageal nerve (i.e., reward) after each fictive ingestive pattern. This sounds good, but what parameters of stimulation do we use and how many times do we deliver the reinforcements? There was no a priori answer. It was strictly trial and error, which I will say more about later. And here is where Romuald’s dogged persistence came into play. He did experiment after experiment, sometimes four in one day, exploring the “parameter space” until he found a protocol that worked. We had operant conditioning in a dish and published the result in 1997. Next Romuald explored neuronal correlates and found that changes in the excitability of neuron B51 played a major role in producing operant conditioning of the buccal motor programs.

I mentioned earlier the great benefits derived from invitations to present one’s results to colleagues at other universities. Another great benefit is attending scientific meetings, especially the small ones like the Dahlem conferences. (Regrettably, the COVID era has diminished these opportunities.) During the Fifth International Conference of Neuroethology in 1998 I had the great pleasure of meeting Bjoern Brembs. Bjoern was a student of Martin Heisenberg working on operant conditioning of Drosophila, and he thought the Aplysia system might be useful for a more mechanistic understanding of operant conditioning. I invited him to join the lab. He, like Romuald, was extremely motivated and soon showed operant conditioning in vivo. He also showed that in vivo conditioning, as in in vitro conditioning, led to changes in the excitability of neuron B51. Graduate student Fred Lorenzetti took the analysis one step further by showing that similar cellular changes in B51 were produced by contingent reinforcement of B51 with dopamine in a single-cell analog of the operant procedure. These findings allowed for the detailed analysis of the cellular and molecular processes underlying operant conditioning performed by Fred, who stayed on as a postdoctoral fellow. Fred examined second-messenger pathways engaged by activity and reward and considered how they may provide a biochemical association underlying operant learning. He found that the changes in excitability were due to the synergistic interaction of PKC and PKA (protein kinase A). Interestingly, the mechanisms of activity-dependent neuromodulation underlying this appetitive form of operant conditioning appear to be very similar to the mechanisms underlying the aversive classical conditioning of the withdrawal reflexes. In the sensory neuron, the coincidence detection involves, at least in part, a synergistic interaction between a Ca²⁺/calmodulin-sensitive adenylyl cyclase (type I) and a serotonin-activated cAMP cascade. Although the specific isoforms of adenylyl cyclase appear to differ, adenylyl cyclase appears to serve as the molecule of convergence in both forms of learning.

Our initial focus was on neuron B51, and early on, we thought changes in its excitability could account for a large part of the behavioral modifications. Not surprisingly, things turned out to be more complicated. Romuald set up an independent lab at the University of Bordeaux, and went on to find that operant conditioning led to changes in excitability of three other neurons (B30, B63, and B65), as well as changes in the electrical coupling among them. So, at least four neurons had changed. Surprisingly, all of the changes were in intrinsic properties of neurons (i.e., excitability) or electrical coupling. Where were the changes in chemical synaptic transmission that dogma says is the basis of learning and memory? Postdoctoral fellows Yuto Momohara and Curtis Neveu set out to address that issue by making an exhaustive search for additional changes. That led to the identification of yet another neuron (B4) whose excitability was altered by operant conditioning. In addition, they found a reduction in the strength of B4’s inhibitory synaptic connection to neuron B51.

Our analyses of operant conditioning revealed changes in the excitability of five neurons as well as changes in electrical and chemical synaptic transmission. But were all of these necessary for learning? To address this issue, Momohara, Neveu, and I developed and analyzed a conductance-based computational model of the central pattern generating circuit to examine the relative contributions of plasticity loci. The model indicated that the known plasticity loci showed a surprising level of synergism in mediating the behavioral changes associated with the operant conditioning. In general, this study illustrated that focus on a single locus can give a very incomplete understanding of learning, even in a relatively simple circuit. It is necessary to understand the relationship between the different loci to understand how the network is modified.

There is still much work to be done to determine the mechanisms underlying operant conditioning. Recently, in my lab, large-scale recordings using voltage-sensitive dyes (VSDs) with single-neuron resolution have begun to reveal other putative sites of plasticity. We anticipate that we will soon elucidate the complete scope of plasticity changes and the complete wiring diagram of the feeding circuit. I have great hope that the feeding system of Aplysia will ultimately provide a comprehensive understanding of the ways in which memories are encoded in a relatively simple circuit, elucidate design principles of memory encoding, and provide guidance for similar analyses in more complex systems.

Getting Molecular: The Search for Memory Proteins

You know by now that I was not trained as a biochemist or molecular biologist, but one of the great aspects of a career in science is the ability to learn and apply new techniques to address your research question. (Indeed, it might be said that a failure to do so jeopardizes your progress.) So, I had to get some expertise in molecular biology if I wanted to identify the genes and proteins for long-term memory. Harel Shouval, a colleague in my department, is fond of saying that “an airplane does not fly if it does not keep moving forward.”

I was fortunate to begin a collaboration with Arnold Eskin at the nearby University of Houston. Arnold had done outstanding work on the molecular mechanisms of circadian rhythms in Aplysia, but he was looking to expand his research into learning and memory. It was a great partnership because I had the learning background and a good model system, and he had the expertise in molecular biology. We set out to identify genes and proteins involved in long-term memory. One of our big successes was the identification of an mRNA with significantly increased expression in sensory neurons following treatments with serotonin or long-term behavioral training. Moreover, the effects of serotonin and behavioral training were mimicked by treatments that elevate cAMP. This Aplysia mRNA had a high sequence homology with a developmentally regulated gene family that includes Drosophila tolloid and human bone morphogenetic protein-1 (BMP-1).

Both tolloid and BMP-1 encode metalloproteases that can activate TGFβ (transforming growth factor β)-like molecules. That finding led to a test of the hypothesis that in addition to its role in development, TGFβ might be a key signaling molecule in LTS. And indeed, in a subsequent paper in Science, graduate student Fan Zhang found that treatment with TGFβ1 induced long-term facilitation (LTF), but not short-term or intermediate-term facilitation, and that serotonin-induced LTF was blocked by an inhibitor of TGFβ. These results and a follow-up study by graduate student Jeannie Chen indicated that activation of TGFβ may be part of the cascade of events underlying LTS. Moreover, they indicated for the first time that an extracellular biochemical feedback loop was involved in LTF. In an elegant series of experiments, Tom Carew and his colleagues have further elaborated the role of TGFβ in LTF and showed that the adult nervous system reuses developmental growth molecules to promote synaptic changes in the mature brain.

TGFβ is not the only protein to change with learning. The collective work of my lab; the labs of Carew, Kandel, and Schwartz; and more recently the lab of Irina and Robert Calin-Jageman have identified many more. The message is that there is not a single memory gene or protein. Many genes are involved, and they act together to alter the biophysical and morphological properties of the sensorimotor connection. These genes also act according to a temporal pattern. Some genes are turned on early, some at intermediate times, and some late (24 hours after training). I began to wonder what kind of control mechanisms were mediating these dynamics and whether a knowledge of the dynamics could help design better training protocols.

Chaos and Nonlinear Dynamics of Neurons and Neuronal Networks

I had a long-standing interest in neuronal dynamics going back to my earlier coursework in graduate school, but I had a great opportunity to take a deeper dive when I was approached in 1989 by Carmen Canavier, a graduate student working with John Clark in the department of electrical and computer engineering at nearby Rice University. Carmen had done her undergraduate work in electrical engineering at Vanderbilt University and was interested in the nonlinear dynamics of neurons. We came up with a project to develop an improved model of the firing pattern of the Aplysia endogenous bursting neuron R15. Carmen built a model that better fit the data, and the R15 story got more interesting when she found that with certain parameter settings the simulated neuron exhibited chaotic activity and multistability. With multistability, depending on the initial conditions, the neuron could be completely silent, exhibit continuous firing (i.e., pacemaker activity), or burst as usual. Moreover, a brief perturbation could switch the neuron from one mode to another. Here was a memory mechanism that was independent of any second messengers, kinases, or protein synthesis. During this time, we were very fortunate to receive successive grants from the Office of Naval Research’s program on Nonlinear Dynamics headed by Tom McKenna. We received interesting comments from the Aplysia community when we presented these results at an SfN meeting. Almost every Aplysiologist at one time or another has recorded from R15, just to see in real time the singular beauty of its parabolic bursting behavior. But people would observe that sometimes the bursting was not there and then it would start, or it was there, and then it went away. Was the cell dying, did the temperature change, did the electrode move? None of the above. These changes were a manifestation of multistability. The field had a bit of an “Aha” moment.

The collaboration on neuronal dynamics with John Clark continued for 10 years. Carmen continued her work in the lab as a postdoc and was joined by a succession of outstanding Rice graduate students, including Rob Butera, Semahat Demir, and Ron Dror, examining phase-sensitivity, reduced models of R15, and introduction of R15 models into ring circuits. Inserting an R15 model into a simple four-neuron ring circuit could simulate quadrupedal gate patterns, including walking, trotting, bounding, and galloping. Lesson learned: even simple neuronal circuits can produce complex behaviors when there are nonlinearities in the component neurons. I still believe that many biologists do not fully appreciate the role and importance of nonlinear dynamics in biological processes. Certainly, teaching of this topic in the graduate curriculum is insufficient.

By the late 1990s, we had made great progress understanding nonlinear dynamics of neuronal activity and mechanisms of long-term memory. It was a good time to put these different strands together.

Dynamics of Gene and Protein Networks

If there is a consistent theme throughout this autobiography, it is the great strides made when new colleagues joined the lab and brought with them new enthusiasm, expertise, and ideas; a fresh breeze to fill the sails. Unfortunately, I have not been able to tell all of their stories and enormous contributions because of space limitations. But here, I do need to note the contributions of Paul Smolen who joined the lab as a postdoc in 1996. Paul received his doctorate in 1984 working with Joel Keizer at University of California, Berkeley, followed by postdocs with John Rinzel and Erik de Schutter. Needless to say, he arrived as an extremely well-qualified computational neuroscientist.

Our first paper with Paul Smolen examined frequency selectivity, multistability, and oscillations in genetic regulatory systems. One important aspect of that paper was to look at how, in principle, competition between activating and repressing transcription factors could provide an explanation for optimal stimulus frequencies that explain the advantage of spaced vs. massed learning trials. Paul went on with me and Doug Baxter to write a wonderfully comprehensive review on mathematical modeling of gene networks for Neuron. Then, partly influenced by Arnold Eskin’s earlier work on circadian rhythms and his colleague Paul Hardin, then at the University of Houston, and with a grant from the AFOSR, we began modeling the gene and protein networks underlying circadian rhythms. We incorporated some of the newly discovered genes, and developed and published models with good predictive ability. Unfortunately, the project was terminated when the AFOSR decided, as one program officer told me, not to fund further work on any “creatures.” It was unfortunate, but the work on circadian rhythms got us “tuned up” for going full throttle into gene and protein networks for memory.

There is much more great science to come, but at this point, I think I am getting too far ahead with my story. There were some major nonscientific career developments during the 1980s and 1990s. So, let’s take a step back to 1986.

Building a Neuroscience Department and Getting Sunk by Allison and Other Misfortunes

I was doing just fine working in 1986 as a professor in Stan Schultz’s Department of Physiology and Cell Biology, but an opening for the chair of the Department of Neurobiology and Anatomy became available, and I threw my hat in the ring. It seemed like a potential opportunity to build neuroscience in the school (which was somewhat lacking), and in particular, to expand in the area of neuronal plasticity and learning and memory. I had no intent of curtailing my research program. My models were Ernie Knobil and Stan Schultz, who were great chairs and still maintained outstanding research programs. I was fortunate to be able to appoint Doug Baxter and Len Cleary as assistant professors. They handled the day-to-day lab operations, with Doug focusing on the feeding projects and Len focusing on the sensitization projects.

There were departmental faculty slots to fill and I knew from the 1985 Dahlem meeting which fields were creating the most excitement and who was active in those fields. In short time, we recruited Jocelyn Bachevalier to work on development of learning in primates, Terry Crow to work on mechanisms of learning in Hermissenda, Pramod Dash to work on gene regulation in memory, Dan Felleman to work on visual cortical plasticity, Mike Mauk to work on classical conditioning of the eyeblink response, Randy Nudo to work on motor cortical plasticity, and Neal Waxham to work on the role of calmodulin in synaptic plasticity. We were covering neuronal plasticity from molecules to networks and gaining prominence at the local and national levels. The department and the neuroscience graduate program soon went from one of the worst in the school to one of the best. We had multiple training grants and program project grants and million-dollar gifts from the Markey Trust and the W. M. Keck Foundation. That later gift established the W. M. Keck Center for the Neurobiology of Learning and Memory and allowed us to recruit Andy Bean, Ruth Heidelberger, Roger Janz, and James Knierim. In conjunction with the formation of a joint biomedical engineering department between UT Austin and Houston funded by the Whittaker Foundation, we also recruited Yin Liu and Harel Shouval. We had a fantastic group of neuroscientists, and we all shared a common goal. We were on a run. The wind was on our back, the spinnaker was up, and we were surfing the waves.

The Death of Ernst Knobil and Devastation from Tropical Storm Allison

After more than 10 years of successfully building the department, tragedy struck. In April 2000, Ernie succumbed to pancreatic cancer. Ernie was my good friend and fellow sailor, and my mentor and adviser on all things related to academic issues and biopolitics. I still feel his absence. A year later, Tropical Storm Allison came to Houston. The basement of the medical school was flooded, and we had one foot of water on the ground floor. Animals were housed in the basement. We lost all 5,000 of them, including 75 primates. The cyclotron and 3T MRI were destroyed. Emergency power was also lost, so the contents of every freezer and refrigerator in the school were destroyed. The school was devastated and so was the department. Some of the crew jumped ship, and I understood why. Jocelyn lost all of her primates, and it would be years before the primate facilities could be reestablished. She had no choice but to relocate to Emory University, which had the facilities she needed. At a time when the NIH was doubling and floating the expansion of universities, we were in dry dock and there was no growth to be had.

The Loss of Stan Schultz as Dean

All efforts were focused on returning to some semblance of normal. The university decided to never put animals back in the basement, and, as a temporary measure, animals were housed in converted lab space throughout the building. But there was no high ground to be found for a permanent fix. Here a bit of lemonade came from the disaster. The university took the Federal Emergency Management Agency (FEMA) funds, insurance money, and new state funding to construct an extension to the existing medical school building. The top two floors of the new building were devoted to animal housing, leaving the four lower floors for research expansion. Another good sign was the appointment of Stan Schultz as dean of the medical school. Stan planned to use the new space to expand the basic science departments, with each department receiving one full floor. He appointed me as assistant dean for research to provide faculty input on the design of the building. It was a major undertaking, and my responsibilities ranged from major issues, such as the extent of dry vs. wet and dedicated vs. shared lab space, to minor details, such as the selection of carpeting and paint color. After five years of planning and construction, the end result was worth the investment. Sadly, as the building was nearing completion in 2006, Stan became ill and needed to relinquish the deanship. With his departure, support for the expansion of basic science research faded. The wind had shifted and we changed from sailing on a run to sailing on a beat.

Stepping Down as Department Chair

Being a department chair is great when there are resources to grow and build, but things were never quite the same after Stan stepped down as dean. I continued on for the next 10 years making some outstanding new recruitments, such as Michael Beierlein, Valentin Dragoi, and Fabricio Do Monte. But, it was time for me to step down and let others take the helm and push the administrative frontier. I knew the writing was on the wall when, toward the end of one of my annual chair reviews, the dean said: “Jack, you know that you have more time behind you than ahead of you.” I responded that “I was just getting started.” It was a friendly encounter, but there was a message. There is an old saying in the boating community: “The happiest day of your life is when you buy your new boat. The second happiest day is when you sell it.” And as Ernie always said, and as I tell all my colleagues, “don’t worry about administrative ups and downs; concentrate on your research and everything will take care of itself.” It was time to leave the leaky ship for a different boat. Fortunately, I always keep two career boats, and the other one was still in great shape and ready to sail to new horizons.

Back to the Science

Empirical Results Were Showing Complex Dynamics of Genes and Proteins Associated with Long-Term Memory

By 2000, it was becoming increasingly clear that waves of changes in gene expression and protein synthesis occur in Aplysia and other animals as memories are acquired. When Rong-Yu Liu joined the lab in 2003, we initiated a major effort to quantify those dynamics and, importantly, to understand their functional significance. Rong-Yu received her doctorate in neuroscience from the Shanghai Institute of Brain Research, Chinese Academy of Sciences, and then received postdoctoral training at the University of North Carolina working with William Snider on the signaling pathways underlying axonal regeneration. I have been extremely fortunate that we have been able to continue working together. She is a pro at studying LTS and LTF.

Rong-Yu made the extraordinary discovery that 5-HT induced changes in mRNA and protein levels that had distinct temporal signatures. For example, immediately after 5-HT, levels of the transcriptional activator cAMP responsive element binding protein 1 (CREB1) increase, return to basal levels 1 hour later, and then rebound at 5 hours. Similar rich dynamics, albeit with a different time course, were seen with the transcriptional repressor CREB2. At the same time, it was becoming clear that there were distinct differences in the dynamics of second messengers activated by 5-HT and sensitizing stimuli. As shown originally by Lise Bernier working in Jimmy Schwartz’s lab and later extended by Tom Carew and colleagues, cAMP levels increased rapidly in response to a single stimulus, but they did not persist. In contrast, as shown by Kelsey Martin and Eric Kandel, and later extended elegantly by Gary Phillips and Tom Carew, pERK (active, phosphorylated extracellular signal-regulated kinase) is slow to activate. And importantly as Gary Phillips and Tom Carew found, once activated, pERK can be rapidly inactivated.

The Right Time to Learn

These unusual dynamics got us thinking. Perhaps they could help explain the almost universal phenomenon established in 1885 with the seminal work of Herman Ebbinghaus that spaced training with long intertrial intervals is more effective at producing memory formation than massed training with short intertrial intervals. Attempts to optimize the spacing effect generally are based on trial-and-error approaches for choosing the intervals between stimuli. Consequently most, if not all, training protocols used in animal and human studies are probably not optimal. And different protocols were being used for in vivo and in vitro studies in Aplysia. Four trials had been commonly used for LTS training by Harry Pinsker in 1973 and by Bill Frost in 1985, but Sam Schacher in his 1986 Science paper introduced a spaced training protocol for long-term synaptic facilitation (LTF) consisting of five pulses of 5-HT, with 20-minute interstimulus intervals. So LTS training used four shocks, whereas LTF training used five. When I asked Sam at an SfN meeting why he used five trials and not four, without thinking, he said, “I added one for good luck.” I am using this anecdote because it illuminates how scientists develop intervals and number of trials for behavioral training protocols. It is all trial and error and a bit of good luck. And once you find something that works, you stick with it. It does not pay to fully explore the parameter space.

Yili Zhang joined the lab in 2008 having done her graduate work in computational biology at Rutgers University where she worked with Jorge Golowash. She also had two master’s degrees—one in computer science from Virginia Polytechnic Institute, and the other in pathology from the National University of Singapore. She was well poised to tackle the challenge of determining the optimal training schedules for learning. Based on the differences in kinetics of the PKA and ERK cascades, we hypothesized that learning might be improved if the training trials were in sync with the different dynamics of these cascades. Specifically, protocols that maximize the overlap of PKA and ERK activities should induce stronger LTF. To test this hypothesis, Yili, Doug Baxter, Paul Smolen, and I built a reduced mathematical model to simulate the induction of LTF. In this reduced model, PKA and ERK converge on a phenomenological variable “inducer.” It was used to represent the product of PKA and ERK activities, and hence a reflection of downstream gene regulation necessary for the induction of LTF. The greater the peak level of inducer produced by a given protocol, the more likely that the protocol will induce a stronger LTF. We used ordinary differential equations to implement the model and simulated 10,000 different 5-HT protocols to find one that maximally activated inducer. Each protocol had five pulses of 5-minute 5-HT, but the four interstimulus intervals varied from 5 minutes to 50 minutes. We calculated the peak values of inducer in each protocol. The protocol producing the highest peak value of inducer was named the Enhanced protocol. All that was fine, but it was just a model and a simple one at that. Here is where Rong-Yu comes back in the picture. She had become very skilled in making cocultures of sensory neurons and motor neurons and measuring LTF, which could be tracked for at least five days. Rong-Yu tested the prediction using electrophysiological and behavioral techniques. The Enhanced protocol not only induced a stronger LTF than the Standard protocol at 1 day after training, it also prolonged LTF from one day to five days. It increased both the magnitude and the persistence of LTF. Moreover, at the behavioral level, the Enhanced protocol produced stronger and longer-lasting memory for LTS than the Standard protocol.

We also asked if irregularly spaced protocols could enhance normal learning, might modeling also predict protocols that restore learning impaired by a genetic mutation or by other physiological insults? One disorder that impairs learning and memory is Rubinstein-Taybi syndrome (RTS), which is commonly caused by mutations in the gene encoding CREB-binding protein, denoted CBP. This protein is a cofactor in CREB-mediated transcription. Analogs of RTS have been generated by creating a nonfunctional form of CBP in forebrain neurons of transgenic mice. We used siRNA techniques to knock down the expression of CBP and thereby mimicked the deficits in long-term synaptic plasticity found in the mouse models of RTS. Simulations predicted that a “rescue” protocol with irregularly spaced interstimulus intervals similar to the Enhanced protocol would restore LTF, a prediction that was confirmed empirically at the sensorimotor synapse.

Hitting a Home Run

It was remarkable that this simple model had such excellent predictive ability. Nevertheless, it still needs to be expanded to incorporate additional known signaling pathways and transcriptional regulators important for LTF. Moreover, before it can be applied to a mammalian system, the model and its parameters will need to be adjusted to account for the qualitative and quantitative differences in molecular species in different brain areas and different memory systems. On the positive side, tremendous progress is being made in analyzing memory systems and the underlying neuronal and molecular dynamics, which will allow for the development of better models. I have always been encouraged by the words from British statistician George Box: “Essentially, all models are wrong, but some are useful.” I believe that the strategy of computationally designed protocols based on the knowledge of the underlying kinase cascades can be extended to explore better training protocols in mammals. When I presented this work in 2012 at a scientific meeting at Scripps Florida, my colleague Paul Benjamin from the University of Sussex said, “we hit a home run.” I hope that history will agree and perhaps even call it an out-of-the park grand slam. At the very least, and as Paul Smolen, Yili Zhang, and I argued in our 2016 review in Nature Neuroscience, a consensus will emerge that a complete understanding of the spacing effect lies in understanding the dynamics of the molecular cascades involved in memory induction.

Giving Back: A Career in Neuroscience Is More Than Making Discoveries

The paragraphs that follow are among the most valuable in this autobiography because I believe that an important part of being a scientist is educating younger colleagues and sharing and explaining discoveries with the public. Such activities are particularly important for those of us who have benefited from enormous support from federal agencies, such as the NIH.

Outreach and the Dana Alliance for Brain Initiatives

At the urging of Ernie Knobil, David Low, president of the UT Health Science Center (UTHealth), established the Neuroscience Research Center in 1992. Its purpose was to serve as an “umbrella organization” to bring together neuroscience researchers within UTHealth to promote research, education, and outreach. I was appointed its director. We quickly established a monthly calendar of events, published a newsletter featuring articles from UTHealth neuroscientists, and established an annual neuroscience poster session and a Distinguished Lecture Series. In addition, and inspired by the Dana Alliance for Brain Initiatives, we initiated an annual Public Forum in conjunction with Brain Awareness Week and later Brain Night for Kids. Our local activities caught the attention of the Dana Alliance for Brain Initiatives. I was invited to become a member and participated in some of their national Brain Awareness events. We are all indebted to Barbara Gill and Barbara Best of the Alliance for their enormous support of outreach activities as well as the inspirational leadership of founder David Mahoney. These outreach events were and continue to be extremely gratifying, and they provide an opportunity to give back to the community who, through their philanthropy and taxes, make our research possible.

Summer Courses

An excellent way of interacting with the broader neuroscience community is to participate in summer courses. These events bring together students and faculty for focused efforts on concepts and techniques. I had the great pleasure of participating for many years in the course on Neural Systems and Behavior at the Marine Biological Laboratory (MBL) at Woods Hole and the course on the Biology of Memory at the Cold Spring Harbor Laboratory. Woods Hole was first, when in 1984 course directors Ron Hoy and Eduardo Macagno asked Tom Carew and me to run a two-week lab block on the neurobiology of Aplysia. We did this for two years and then another five during the time that Tom and Darcy Kelly were course directors. It was a lot of work, but we were helped out greatly by course assistants Len Cleary, Emily Marcus, and John Walsh.

I think it was a terrific experience for the students. It was also a great time for our families getting together for lunches at the MBL beach and dinners (albeit brief ones because we needed to get back for the “night shift”). The MBL experience had a lasting impact on my children who fondly remember building dams to divert spillover water from the outdoor shower at MBL beach and playing and riding bikes on Devil’s Lane and Memorial Circle. The experience was much more than the physical environment, however. They were constantly exposed to scientists and their families from throughout the United States and abroad, which I am sure influenced their pursuit of career paths in the biomedical sciences.

I also had the great privilege of being codirector for almost 20 years of the summer course on learning and memory at Cold Spring Harbor Laboratory. My involvement started when in 1985, John Koester asked me whether I was interested in taking over his role in a course that he, Eric Kandel, Fernando Nottebohm, and Keir Pearson started on the Cell and Molecular Biology of Behavior. I agreed, but thought the course should be more focused, and with everyone’s agreement, changed the name to the Cell and Molecular Biology of Learning and Memory (later changed to Biology of Memory: From Molecules to Behavior). Eric and Keir stayed on as codirectors, and we brought on board Larry Squire to cover memory systems. Later when Eric dropped out, Howard Eichenbaum and Kelsey Martin joined the team. Over the years, we had a fantastic series of lecturers, including, and to name just a few, Cristina Alberini, Tim Bliss, Allison Doupe, Leslie Griffith, Peter Holland, Mary Kennedy, Joe LeDoux, Steve Lisberger, Robert Malenka, Robert Malinow, Roger Nicoll, Chip Quinn, Cathy Rankin, Jennifer Raymond, Robert Rescorla, Christie Sahley, Jimmy Schwartz, Dick Thompson, and Scott Waddell, all leaders in their respective areas. Every summer was an intense update on the latest developments in the field. It was as great for me as it was for the students. And, we had some great students who have gone on to successful careers, including Tobias Bonhoeffer, Edward Boyden, Ruth Colwill, George Dragoi, Barbara Knowlton, Elizabeth Buffalo, and Wendy Suzuki, just to name a few.

Society for Neuroscience

I also became very active in the Society for Neuroscience, serving on numerous committees, including twice on the Government and Public Affairs Committee. It was a great opportunity and honor to represent neuroscience to the public and also to our congressional representatives through the SfN’s annual Hill Day events. I also served as treasurer of the society. I “could’a been president,” but at least I was a contender on this waterfront. In fact, a two-time contender. Perhaps there was a limit to my good fortune, as I lost these elections to David Van Essen (2006) and Eric Nestler (2015). My losses were disappointing, but as Mort Mishkin once told me “you win if you win, and you win if you lose.” And, one benefit of losing is becoming eligible to receive an invitation to join the Presidential Losers Club and attend the annual luncheon held in conjunction with the meeting of the SfN. The regulars at the luncheon, organized by club founder and three-time loser John Hildebrand, include me, Frances Jensen, Julie Kauer, Irwin Levitan, Murray Sherman, Nick Spitzer, and Leslie Tolbert.

Open-Access Neuroscience

One of my proud achievements in teaching was the development of an open-access textbook of neuroscience. The project began in 1999 with the encouragement of William Weems, a former colleague in the Department of Physiology and Cell Biology, who developed computer animations to assist in the teaching of cardiovascular physiology to medical students. He thought that neuroscience could benefit from such an approach as well. I agreed and took the concept up a notch and developed a complete online textbook of neuroscience. It was clear that computer-assisted teaching methods have great advantages over traditional methods. Animations in particular are ideal for teaching neuroscience, given the ubiquitous dynamics associated with neuronal processes, such as action potentials, synaptic transmission, and circuit activity, which in traditional textbooks can only be represented with static images. Also, an online format allows for continuous updates, avoiding the fate of traditional textbooks that become outdated soon after they are published. Bill used his position as associate vice president of academic technology to support the project by putting two graphic artists on the project. Needless to say, I was also fortunate to have the teaching faculty of the department behind the project. We essentially took the medical school neuroscience course and converted it to an electronic format. The project was completed and released as Neuroscience Online in 2009. It has been an enormous success and is used by individuals and as a core textbook for neuroscience courses around the world. In 2020, it received more than two million visits.

I have not formed any companies or tried to profit from my discoveries. The privilege of being able to do science and make discoveries is compensation enough. And what a privilege it has been to work with so many exceptional graduate students, postdoctoral fellows, and other colleagues who have inspired me and become my friends. I regret that I could not do justice in this autobiography to their enormous contributions. I also could not have wished for a better animal to work with. I am sure Aplysia has many answers to questions that have yet to be asked.

Selected Bibliography

Antzoulatos, E.G. and Byrne, J.H. Long-term sensitization training produces spike narrowing in Aplysia sensory neurons. J. Neurosci. 27:676–683, 2007. PMID: 17234599

Baxter, D.A. and Byrne, J.H. Feeding behavior of Aplysia: A model system for comparing cellular mechanisms of classical and operant conditioning. Learning and Memory 13:669–680, 2006. PMID: 17142299

Baxter, D.A. and Byrne, J.H. Serotonergic modulation of two potassium currents in the pleural sensory neurons of Aplysia. J. Neurophysiol. 62:665–679, 1989.

Baxter, D.A., Canavier, C.C., Clark, J.W. and Byrne, J.H. Computational model of the serotonergic modulation of sensory neurons in Aplysia. J. Neurophysiol. 82:2914–2935, 1999.

Brembs, B., Lorenzetti, F.D., Reyes, F.D., Baxter, D.A. and Byrne, J.H. Operant reward learning in Aplysia: Neuronal correlates and mechanisms. Science 296:1706–1709, 2002.

Buonomano, D.V. and Byrne, J.H. Long-term synaptic changes produced by a cellular analogue of classical conditioning in Aplysia. Science 249:420–423, 1990.

Butera, R.J., Clark, J.W., Canavier, C.C, Baxter, D.A. and Byrne, J.H. Analysis of the effects of modulatory agents on a modeled bursting neuron: Dynamic interactions between voltage and calcium dependent systems. J. Comput. Neuroscience 2:19–44, 1995.

Byrne, J.H. Analysis of ionic conductance mechanisms in motor cells mediating inking behavior in Aplysia. J. Neurophysiol. 43:630–650, 1980.

Byrne, J.H. Analysis of synaptic depression contributing to habituation of gill-withdrawal reflex in Aplysia californica. J. Neurophysiol. 48:431–438, 1982.

Byrne, J.H. Cellular analysis of associative learning. Physiological Reviews 67:329–439, 1987.

Byrne, J.H. Comparative aspects of neural circuits for inking behavior and gill-withdrawal in Aplysia californica. J. Neurophysiol. 45:98–106, 1981.

Byrne, J.H. Dynamic properties of mechanoreceptor neurons mediating the defensive gill-withdrawal in Aplysia. Brain Research 114:123–127, 1976.

Byrne, J.H. Identification and initial characterization of a cluster of command and pattern-generating neurons underlying respiratory pumping in Aplysia californica. J. Neurophysiol. 49:491–508, 1983.

Byrne, J.H. Ionic currents and behavior. Trends in Neurosciences 2:268–270, 1979

Byrne, J.H. Quantitative aspects of ionic conductance mechanisms contributing to firing pattern of motor cells mediating inking behavior in Aplysia californica. J. Neurophysiol. 43:651–668, 1980.

Byrne, J.H. and Hawkins, R.D. Nonassociative learning in invertebrates. Cold Spring Harbor Perspectives in Biology 7:a021675, 2015. PMCID: PMC4448621

Byrne, J.H. and Kandel, E.R. Presynaptic facilitation revisited: state- and time-dependence. J. Neurosci. 16:425–435, 1996.

Byrne, J.H. and Koester, J. Respiratory pumping: Neuronal control of a centrally commanded behavior in Aplysia. Brain Research 143:87–105, 1978.

Byrne, J.H., Castellucci, V. and Kandel, E.R. Contribution of individual mechanoreceptor sensory neurons to defensive gill-withdrawal reflex in Aplysia. J. Neurophysiol. 41:418–431, 1978.

Byrne, J.H., Castellucci, V. and Kandel, E.R. Receptive fields and response properties of mechanoreceptor neurons innervating the siphon and mantle shelf of Aplysia. J. Neurophysiol. 37:1041–1064, 1974.

Byrne, J.H., Castellucci, V.F., Carew, T.J. and Kandel, E.R. Stimulus-response relations and stability of mechanoreceptor and motor neurons mediating defensive gill-withdrawal reflex in Aplysia. J. Neurophysiol. 41:402–417, 1978.

Byrne, J.H., Shapiro, E., Dieringer, N. and Koester, J. Biophysical mechanisms contributing to inking behavior in Aplysia. J. Neurophysiol. 42:1233–1250, 1979.

Cai, Z., Neveu, C.L., Baxter, D.A., Byrne, J.H. and Aazhang, B. Inferring neuronal network functional connectivity with directed information. J. Neurophysiol. 118:1055-1069, 2017. PMCID: PMC5547257

Canavier, C.C., Baxter, D.A., Clark, J.W. and Byrne, J.H. Control of multistability in ring circuits of oscillators. Biol. Cybernet. 80:87–102, 1999.

Canavier, C.C., Baxter, D.A., Clark, J.W. and Byrne, J.H. Multiple modes of activity in a model neuron suggest a novel mechanism for the effects of neuromodulators. J. Neurophysiol. 72:872–882, 1994.

Canavier, C.C., Baxter, D.A., Clark, J.W. and Byrne, J.H. Nonlinear dynamics in a model neuron provide a novel mechanism for transient synaptic inputs to produce long-term alterations of postsynaptic activity. J. Neurophysiol. 69:2252–2257, 1993.

Canavier, C.C., Butera, R.J., Dror, R.O., Baxter, D.A., Clark, J.W. and Byrne, J.H. Phase response characteristics of model neurons determine which patterns are expressed in a ring circuit model of gait generation. Biol. Cybern. 77:367–380, 1997.

Carew, T.J., Castellucci, V.F., Byrne, J.H. and Kandel, E.R. Quantitative analysis of relative contribution of central and peripheral neurons to gill-withdrawal reflex in Aplysia californica. J. Neurophysiol. 42:497–509, 1979.

Chin, J., Liu, R.Y., Cleary, L.J., Eskin, A. and Byrne, J.H. TGF-1-induced long-term changes in neuronal excitability in Aplysia sensory neurons depend on MAPK. J. Neurophysiol. 95:3286–3290, 2006. PMID: 16617179

Cleary, L.J. and Byrne, J.H. Identification and characterization of a multifunction neuron contributing to defensive arousal in Aplysia. J. Neurophysiol. 70:1767–1776, 1993.

Cleary, L.J., Lee, W.L. and Byrne, J.H. Cellular correlates of long-term sensitization in Aplysia. J. Neurosci. 18:5988–5998, 1998.

Costa, R.M., Baxter, D.A. and Byrne, J.H. Computational model of the distributed representation of operant reward memory: Combinatoric engagement of intrinsic and synaptic plasticity mechanisms. Learning and Memory 27:236–249, 2020. PMID: 32414941

Costa, R.M., Baxter, D.A., and Byrne, J.H. Neuronal population activity dynamics reveal a low-dimensional signature of operant learning in Aplysia. Commun. Biol. 5:90, 2022. PMID: 35075264

Fioravante, D., Smolen, P.D. and Byrne, J.H. The 5-HT- and FMRFa-activated signaling pathways interact at the level of the Erk MAPK cascade: Potential inhibitory constraints on memory formation. Neuroscience Letters 396:235–240, 2006. PMID: 16356640

Fukushima, T., Liu, R.Y. and Byrne, J.H. Transforming growth factor-β2 modulates synaptic efficacy and plasticity and induces phosphorylation of CREB in hippocampal neurons. Hippocampus 17:5–9, 2007. PMID: 17094084

Gingrich, K.J. and Byrne, J.H. Simulation of synaptic depression, post-tetanic potentiation, and presynaptic facilitation of synaptic potentials from sensory neurons mediating gill-withdrawal reflex in Aplysia. J. Neurophysiol. 53:652–669, 1985.

Gingrich, K.J. and Byrne, J.H. Single-cell neuronal model for associative learning. J. Neurophysiol. 57:1705–1715, 1987.

Hawkins, R.D. and Byrne, J.H. Associative learning in invertebrates. Cold Spring Harbor Perspectives in Biology 7:a021709, 2015. PMCID: PMC4448622

Lechner, H.A., Baxter, D.A. and Byrne, J.H. Classical conditioning of feeding in Aplysia: I. Behavioral analysis. J. Neurosci. 20:3369–3376, 2000.

Lechner, H.A., Baxter, D.A. and Byrne, J.H. Classical conditioning of feeding in Aplysia: II. Neurophysiological correlates. J. Neurosci. 20:3377–3386, 2000.

Lechner, H.A., Baxter, D.A., Clark, J.W. and Byrne, J.H. Bistability and its regulation by serotonin in the endogenously bursting neuron R15 in Aplysia. J. Neurophysiol. 75:957–962, 1996.

Lechner, H.A., Squire, L.R. and Byrne, J.H. 100 years of consolidation – remembering Müller and Pilzecker. Learning and Memory 6:77–87, 1999.

Liu, Q-R., Hattar, S., Endo, S., MacPhee, K., Zhang, H., Cleary, L.J., Byrne, J.H. and Eskin, A. A developmental gene (Tolloid /BMP-1) is regulated in Aplysia neurons by treatments that induce long-term sensitization. J. Neurosci. 17:755–764, 1997.

Liu, R.Y., Cleary, L.J. and Byrne, J.H. The requirement for enhanced CREB1 expression in consolidation of long-term synaptic facilitation and long-term excitability in sensory neurons of Aplysia. J. Neurosci. 31:6871–6879, 2011. PMCID: PMC3092379

Liu, R.Y., Fioravante, D., Shah, S. and Byrne, J.H. cAMP response element-binding protein 1 feedback loop is necessary for consolidation of long-term synaptic facilitation in Aplysia. J. Neurosci. 28:1970–1976, 2008. PMID: 18287513

Liu, R.Y., Neveu, C., Smolen, P., Cleary, L.J. and Byrne, J.H. Superior long-term synaptic memory induced by combining dual pharmacological activation of PKA and ERK with an enhanced training protocol. Learning and Memory 24:289–297, 2017. PMCID: PMC5473109

Liu, R.Y., Zhang, Y., Baxter, D.A., Smolen, P., Cleary, L.J. and Byrne, J.H. Deficit in long-term synaptic plasticity is rescued by a computationally predicted stimulus protocol. J. Neurosci. 33:6944–6949, 2013. PMCID: PMC3690371

Liu, R-Y., Zhang, Y., Smolen, P., Cleary, L.J. and Byrne, J.H. Defective synaptic plasticity in a model of Coffin-Lowry syndrome is rescued by simultaneously targeting PKA and MAPK pathways. Learning and Memory 29:435–446, 2022. PMID: 36446603

Lorenzetti, F.D., Baxter, D.A. and Byrne, J.H. Molecular mechanisms underlying a cellular analogue of operant reward learning. Neuron 59: 815–828, 2008. PMCID: PMC2603610

Lorenzetti, F.D., Mozzachiodi, R., Baxter, D.A. and Byrne, J.H. Classical and operant conditioning differentially modify the intrinsic properties of an identified neuron. Nature Neurosci. 9:17–19, 2006.

Luo, C., Clark, J.W., Canavier, C.C., Baxter, D.A. and Byrne, J.H. Multimodal behavior in a four neuron ring circuit: Mode switching. IEEE Trans. Biomed. Engin. 51:205–218, 2004.

Mohamed, H.A., Yao, W., Fioravante, D., Smolen, P.D., Byrne, J.H. cAMP-response elements in Aplysia creb1, creb2, and Ap-uch promoters. J. Biol. Chem. 280:27035–27043, 2005.

Momohara, Y., Neveu, C.L., Chen, H-M., Baxter, D.A. and Byrne, J.H. Specific plasticity loci and their synergism mediate operant conditioning. J. Neurosci. 42:1211–1223, 2022. PMID: 34992131

Mozzachiodi, R. and Byrne, J.H. More than synaptic plasticity: Role of nonsynaptic plasticity in learning and memory. Trends in Neurosciences 33:17–26, 2010. PMCID: PMC2815214

Mozzachiodi, R., Lorenzetti, F.D., Baxter, D.A., and Byrne, J.H. Changes in neuronal excitability serve as a mechanism of long-term memory for operant conditioning. Nature Neurosci. 11:1146–1148, 2008. PMCID: PMC5003050

Nargeot, R., Baxter, D.A. and Byrne, J.H. In vitro analogue of operant conditioning in Aplysia. I. Contingent reinforcement modifies the functional dynamics of an identified neuron. J. Neurosci. 19:2247–2260, 1999.

Nargeot, R., Baxter, D.A. and Byrne, J.H. In vitro analogue of operant conditioning in Aplysia. II. Modifications of the functional dynamics of an identified neuron contribute to motor pattern selection. J. Neurosci. 19:2261–2272, 1999.

Nargeot, R., Baxter, D.A. and Byrne, J.H. Contingent-dependent enhancement of rhythmic motor patterns: An in vitro analog of operant conditioning. J. Neurosci. 17:8093–8105, 1997.

Nargeot, R., Baxter, D.A., Patterson, G.W. and Byrne, J.H. Dopaminergic synapses mediate neuronal changes in an analogue of operant conditioning. J. Neurophysiol. 81:1983–1987, 1999.

Nazif, F.A., Byrne, J.H. and Cleary, L.J. cAMP induces long-term morphological changes in sensory neurons of Aplysia. Brain Research 539:324–327, 1991.

O’Leary, F.A., Byrne, J.H. and Cleary, L.J. Long-term structural remodeling in Aplysia sensory neurons requires de novo protein synthesis during a critical time period. J. Neurosci. 15:3519–3525, 1995.

Ocorr, K.A., Walters, E.T. and Byrne, J.H. Associative conditioning analog selectively increases cAMP levels of tail sensory neurons in Aplysia. Proc. Natl. Acad. Sci. 82:2548–2552, 1985.

Pettigrew, D.B., Smolen, P., Baxter, D.A. and Byrne, J.H. Dynamic properties of regulatory motifs associated with induction of three temporal domains of memory in Aplysia. J. Comput. Neurosci. 18:163–181, 2005.

Raymond, J.R., Baxter, D.A., Buonomano, D.V. and Byrne, J.H. A learning rule based on empirically-derived activity-dependent neuromodulation supports operant conditioning in a small network. Neural Networks 5:789–803, 1992.

Rong-Yu, L., Zhang, Y., Smolen, P. and Byrne, J.H. MeCP2 represses the induction and maintenance of long-term synaptic plasticity. PNAS, in revision.

Scholz, K.P. and Byrne, J.H. Intracellular injection of cAMP induces a long-term reduction of neuronal K⁺ currents. Science 240:1664–1666, 1988.

Scholz, K.P. and Byrne, J.H. Long-term sensitization in Aplysia: Biophysical correlates in tail sensory neurons. Science 235:685–687, 1987.

Shapiro, E., Koester, J. and Byrne, J.H. Aplysia ink release: Central locus for selective sensitivity to long duration stimuli. J. Neurophysiol. 42:1223–1232, 1979.

Smolen, P. Baxter, D.A. and Byrne, J.H. Frequency selectivity, multistability, and oscillations emerge from models of genetic regulatory systems. Am. J. Physiol. 274:C531–C542, 1998.

Smolen, P., Baxter, D. and Byrne, J.H. Effects of macromolecular transport and stochastic fluctuations on the dynamics of genetic regulatory systems. Am. J. Physiol. 277:C777–C790, 1999.

Smolen, P., Baxter, D.A. and Byrne, J.H. A reduced model clarifies the role of feedback loops and time delays in the Drosphila circadian oscillator. Biophys. J. 83:2349–2359, 2002.

Smolen, P., Baxter, D.A. and Byrne, J.H. Mathematical modeling of gene networks. Neuron 26:567–580, 2000.

Smolen, P., Baxter, D.A. and Byrne, J.H. Modeling circadian oscillations with interlocking positive and negative feedback loops. J. Neurosci. 21:6644–6656, 2001.

Smolen, P., Baxter, D.A. and Byrne, J.H. Modeling transcriptional control in gene networks – Methods, recent results, and future directions. Bltn. of Mathematical Biol. 62:247–292, 2000.

Smolen, P., Baxter, D.A. and Byrne, J.H. How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory. Learning and Memory, 26:133–150, 2019. PMID: 30992383

Smolen, P., Hardin, P.E., Lo, B.S., Baxter, D.A. and Byrne, J.H. Simulation of Drosophila circadian oscillations, mutations, and light responses by a model with VRI, PDP-1, and CLK. Biophys. J., 86:2786–2802, 2004.

Smolen, P., Zhang, Y. and Byrne, J.H. The right time to learn: mechanisms and optimization of spaced learning. Nature Reviews Neuroscience, 17:77–88, 2016. PMCID: PMC5126970

Smolen, P.D., Baxter, D.A. and Byrne, J.H. A model of the roles of essential kinases in the induction and expression of late long-term potentiation. Biophys. J. 90:2760–2775, 2006. PMCID: PMC1414565

Song, H., Smolen, P., Av-Ron, E., Baxter, D.A. and Byrne, J.H. Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-responsive element binding proteins. Biophys. J. 92:3407–3424, 2007. PMCID: PMC2040302

Sugita, S., Baxter, D.A. and Byrne, J.H. Differential effects of 4-aminopyridine, serotonin, and phorbol esters on facilitation of sensorimotor connections in Aplysia. J. Neurophysiol. 77:177–185, 1997

Susswein, A.J. and Byrne, J.H. Identification and characterization of neurons initiating patterned neural activity in the buccal ganglia of Aplysia. J. Neurosci. 8:2049–2061, 1988.

Wainwright, M.L., Byrne, J.H., and Cleary, L.J. Dissociation of morphological and physiological changes associated with long-term memory in Aplysia. J. Neurophysiol. 92:2628–2632, 2004.

Wainwright, M.L., Zhang, H., Byrne, J.H. and Cleary, L.J. Localized neuronal outgrowth induced by long-term sensitization training in Aplysia. J. Neurosci. 22:4132–4141, 2002.

Walsh, J.P. and Byrne, J.H. Modulation of a steady-state Ca²⁺ activated, K⁺ current in tail sensory neurons of Aplysia: Role of serotonin and cAMP. J. Neurophysiol. 61:32–44, 1989.

Walters, E.T. and Byrne, J.H. Associative conditioning of single sensory neurons suggests a cellular mechanism for learning. Science 219:405–408, 1983.

White, J.A., Ziv, I., Baxter, D.A., Cleary, L.J. and Byrne, J.H. The role of interneurons in controlling the tail-withdrawal reflex in Aplysia: A network model. J. Neurophysiol. 70:1777–1786, 1993.

Young, J., Neveu, C. L., Byrne, J. H. and Aazhang, B. Inferring functional connectivity through graphical directed information. J. Neural Engineer. 18:046019. PMID: 33684898

Zhang, F., Endo, S., Cleary, L.J., Eskin, A. and Byrne, J.H. Role of transforming growth factor-ß in long-term synaptic facilitation in Aplysia. Science 275:1318–1320, 1997.

Zhang, X.O., Zhang, Y., Cho, C.E., Engelke, D.S., Smolen P., Byrne, J.H. and Do-Monte, F.H. Enhancing associative learning in rats with a computationally designed training protocol. Biol. Psychiat. Global Open Science 4:165–181.

Zhang, Y., Liu, R.Y., Heberton, G.A., Smolen, P.D., Baxter, D.A., Cleary, L.J. and Byrne, J.H. Computational design of enhanced learning protocols. Nature Neurosci. 15:294–297, 2012. PMCID: PMC3267874

Zhang, Y., Smolen, P., Alberini, C.M., Baxter, D.A. and Byrne, J.H. Computational model of a positive BDNF feedback loop in hippocampal neurons following inhibitory avoidance training. Learning and Memory 23:714–722, 2016. PMCID: PMC5110990

Zhang, Y., Smolen, P., Baxter, D.A. and Byrne, J.H. Computational analyses of synergism in small molecular network motifs. PLOS Comput. Biol. 10:e1003524.

Zhang, Y., Smolen, P.A., Cleary, L.J. and Byrne, J.H. Interactions of PKA and MAPK pathways contribute to complex dynamics of kinase activation after 5-HT treatment in Aplysia sensory neurons. Sci. Rep. 11(1):14931, 2021. PMID: 34294802

Zhang, Y., Smolen, P.D., Baxter, D.A. and Byrne, J.H. The sensitivity of memory consolidation and reconsolidation to inhibitors of protein synthesis and kinases: Computational analysis. Learning and Memory 17: 428–439, 2010. PMCID: PMC2948875

Zhang, Y., Smolen. P., Baxter. D.A. and Byrne, J.H. Biphasic regulation of p38 MAPK by serotonin contributes to the efficacy of stimulus protocols that induce long-term synaptic facilitation. eNeuro 4:e0373–16, 2017. PMCID: PMC5307297

Zhou, L., Baxter, D.A. and Byrne, J.H. Contribution of PKC to the maintenance of 5-HT-induced short-term facilitation at sensorimotor synapses of Aplysia. J. Neurophysiol. 112:1936–1949, 2014. PMCID: PMC4200012

Zhou, L., Zhang, Y., Liu, R.Y., Smolen, P., Cleary, L. and Byrne, J.H. Rescue of impaired long-term facilitation at sensorimotor synapses of Aplysia following siRNA knockdown of CREB1. J. Neurosci. 35:1617–1626, 2015. PMCID: PMC4308605

Patricia Smith Churchland

BORN:

Oliver, British Columbia, Canada

July 16, 1943

EDUCATION:

University of British Columbia, BA (1965)

University of Pittsburgh, MA (1966)

Oxford University, BPhil (1969)

APPOINTMENTS:

Assistant Professor, Philosophy, University of Manitoba (1969–1972)

Associate Professor, Philosophy, University of Manitoba (1972–1978)

Professor, Philosophy, University of Manitoba (1978–1984)

Professor, Philosophy, University of California San Diego (1984–2011)

Adjunct Professor, Salk Institute, (1994–present)

University of California President’s Professor, Philosophy (1999–present)

Chair, Philosophy Department, University of California San Diego, (2000–2007)

HONORS AND AWARDS (SELECTED):

MacArthur Foundation Research Fellow (1991–1996)

Elected, Academy of Humanism (1993)

Elected, American Academy of Arts and Sciences (2003)

Honorary Doctor of Letters, University of Victoria (1996)

Honorary Doctor of Laws, University of Alberta (2007)

Rossi Prize in Neuroscience (2008)

Prose Prize for Science Writing (2013)

Revelle Medal for distinguished service, University of California San Diego (2022)

Pat Churchland recognized that speculative philosophical approaches to questions about knowledge, consciousness, and decision-making could benefit from emerging data in the neurosciences. Her first book Neurophilosophy: Towards a Unified Science of the Mind-Brain (MIT Press, 1986) made the case for incorporating data from neuroscience, evolutionary biology, and genetics in developing theories about our mental life. Extending those ideas, she collaborated with physicist/neuroscientist Terry Sejnowski to publish The Computational Brain (MIT Press, 1992). The book’s central idea is that brains have many levels of organization from neurons to circuits to systems, and explanatory hypotheses at many levels can draw on computational principles. As one of the first comprehensive treatments of the subject, this book was widely read and republished in 2017. Her later work focused on social neuroscience especially in mammals and birds, drawing on data showing that social attachment is mediated by neuropeptides oxytocin and vasopressin. Her hypothesis was that social attachment is the neural platform for moral norms that are learned after birth. Her other publications include BrainTrust: What Neuroscience Tells Us about Morality (Princeton University Press, 2011), Touching a Nerve: The Self as Brain (Norton, 2013), and Conscience: The Origin of Moral Intuition (Norton, 2019).

Patricia Smith Churchland

Early Life

My dad left the farm when he was 12 to begin working as a “printer’s devil” for a small-town newspaper, The Brooks Bulletin, in Alberta. Further schooling was not available. As a toddler, he had suffered a bout of polio that weakened one leg so that he had a limp and could not run. Consequently, he was ill-suited for the otherwise likely jobs of wrangling cattle or logging or joining the army. Invoking a favored cliché, he would say that printer’s ink was in his veins. Indeed, he did know the printing trade well, from how to fix the temperamental linotype machine that melted the lead and dimpled out the lead type, to how to write engagingly about erecting a telephone line over the Monashee mountains. I saw his expertise because he opened a village newspaper in British Columbia’s Okanagan Valley, well before I was born. After school, I would often stop by the Oliver News office to sniff the heady smell of printer’s ink or eavesdrop as the local Mountie listed the lockups after brawls in the beer parlor.

As children do, I began to imitate my father. I thought writing was fun. While some school tasks seemed a bit tedious, it was generally fun to write. Once I reached high school age, I was permitted to use my dad’s home typewriter, a 1928 Underwood. It was a hallowed thing. As I now use a computer, his Underwood sits on a hall table, a reminder of nights of key-pounding while the Northern Lights curtained outside.

Although my mother, Katie James, had attended school until eighth grade after which no schooling was available, she trained as a registered nurse in a small far north hospital that had only two doctors. In the 1920s in Canada, a high school diploma was not required to earn the title of registered nurse (RN). Working in a remote community, the medical staff were dedicated, practical, and kindly. They treated for free many of the local Salish people, quite a few of whom had tuberculosis or smallpox. Katie’s mother was an orphan who had been shipped at age six from Scotland to work in Ontario as an indentured servant until she reached seventeen. My grandmother could barely read or write when I knew her, although she did know how to keep bees and gather honey. My mother was the first of her family to have the privilege of any schooling at all, meager though it was. Like my father, she was highly practical and taught us that you manage, no matter what turns up. Until a hospital was built in Oliver, she worked as a visiting nurse, helping people live and, sometimes, helping them as they died. Like my father, she read every chance she could and learned voraciously.

The formal education—or lack of same—of my parents is worth mentioning because one thing they excelled at, above all, is logically working things out, checking evidence when available, and discussing all manner of problems and issues from every angle. The dinner table and the cow barn were sites of extended discussions of one matter or another. Lacking “common sense” seemed to be the worst fault one could have.

When I was at home on the farm, I had chores—collecting eggs, cleaning out the hen house, weeding gardens, canning, doing laundry (wringer style), and so forth. Given the workload, for me, going to school was a pleasure—and this was true for most kids in the Okanagan Valley at that time. Being at school was vastly easier than working the farm, and besides, we had the joy of friends. As it happened, our school was exceptionally strong, because the pioneers in the Okanagan Valley keenly understood the value of education despite having little money, and they put their scanty resources into the school. After the end of World War II, the school had a windfall. Highly educated Scots and English men who were restless after their war years or who could not get jobs after the war, emigrated to Canada, and our school board wisely arranged to bring a batch to our school. They picked up teaching skills quickly, and their authoritative and clear but amusing manner of teaching elicited from us a strong desire for their approval. When I went to college, expecting to find that I was poorly trained relative to well-heeled city kids, I discovered quite the opposite. I was way ahead in every subject, including physics and math. Unlike most of them, I had been taught how to work—to work hard, efficiently, and systematically until the job was done right. Goofing off, as I saw some prosperous students do, seemed as stupid as killing a good dog just for fun.

I fell in love with chemistry in 11th grade. Its beauty and explanatory power amazed me. The mathematization of interactions was dazzling. Noticing my eagerness, my teachers warned that females did not become chemists, so I had best think of something else to do. This warning was certainly not mean-spirited but merely reflected the assumptions of their times. I did consider that a career in law might work out instead, although a little sleuthing revealed two obstacles: (1) women were rarely if ever admitted to law school, and (2) I could not possibly begin to pay for law school. I expected I could talk my way around the “woman problem,” but the second, well, the money angle really stumped me. The blokes could earn money for tuition during the summer by logging, which was not an option for women. The money issue again loomed as the major problem when I considered medical school. I ended up going to graduate school in philosophy because, as it happened, I was awarded scholarships to do that. I would like to say I followed my greatest passion, but when you are “as poor Job’s turkeys” as they intoned in Oliver, your greatest passion has to take the hindmost.

After High School

I studied philosophy as an undergraduate because I was introduced to the ancient Greeks in my freshman year. Socrates and Aristotle stood out as especially fascinating; Plato, in contrast, seemed lacking in common sense, and downright goofy at times. I was under the misapprehension that current philosophers were trying to understand how the mind works, as I took Aristotle to be. It took me a while to fathom that they actually were interested primarily in words, not things. They staged little contests in which flamboyant cleverness in wordplay counted as progress. One faculty member kindly nominated me for a Woodrow Wilson Fellowship to do graduate work in philosophy, and surprisingly, I won. With no money to do anything else, I followed that option with mixed feelings. I started a graduate program at the University of Pittsburgh, known to be a philosophy of science bastion. I did learn a lot there, and mercifully, the fashionable focus on words instead of things was regularly satirized, especially by the brilliantly witty Richie Schuldenfrei from the Bronx. Given how splendid the program was, it may seem odd that I stayed at Pittsburgh for only one year. Embarrassing to say, in that one year, I had rather foolishly stumbled into a complicated personal life. It seemed least ridiculous to just hightail it to another country, so I applied for a British Council Fellowship to go to Oxford. When the news came that the British Council would supply funds to send me to Oxford, I left Pittsburgh and the social complications behind. Needless to say, I had never traveled to Europe, and Oxford philosophy was then considered to be the fountainhead of philosophy. Highly enticing was the prospect of living in England for a while. Once settled in, I soon realized that Oxford philosophy was actually the fountainhead of wordplay and “analyzing meanings of words,” whatever that really was. The Schuldenfrei satires rang in my head, and I could not fail to realize that current Oxford philosophy should be taken with more salt than a mere pinch. Oxford being Oxford, they did not throw me out. Instead, Philippa Foot found me a supervisor who was happy to know nothing about my project (the importance of unconscious processing in decision-making) and would be obliged only to have tea with me twice. Justine Gosling, a Plato scholar at Jesus College, was perfect for me, and humored my fascination with science and the brain. I passed.

The one good thing to emerge from my early years in philosophy in British Columbia was that I met Paul Churchland, who not only was tall (nice because I was very tall for a female) but also studied philosophical questions from a knowledge of the history of science and of physics in particular. Outrageous for the time, Paul suggested that the typical common explanations we give for human behavior in terms of intentions, beliefs, and so forth might eventually be revised, perhaps quite radically, just as “element” no longer meant “earth, air, fire, and water.” His hunch was that just as medieval assumptions such as that the earth is the center of the universe turned out to be quite wrong, so too might current assumptions about the mind, such as that beliefs required language skills, be wrong. Furthermore, concepts such as” self-control” or even “reasoning” might embody false assumptions comparable the concepts of “vital spirit” or “phlogiston.” Encouraged by his Pittsburgh supervisor, Wilfrid Sellars, Paul envisaged a deeper understanding of the brain that might lead us to discover functions hitherto unknown, and that “folk psychology” might be radically modified to reflect neuroscientific discoveries (P. M. Churchland 1989). This was a commonality between us right from the beginning (see Hirstein 2004).

After he was awarded his doctorate from Pittsburgh, Paul got a job at the University of Toronto, rather a feather in his cap at the time. When I graduated from Oxford, the University of Toronto explained to Paul that they could not possibly hire me—I was a woman, and women could not really make a success of philosophy, Oxford degree notwithstanding. Yes, they already had one female philosopher on the faculty, but that was more than enough. As luck would have it, Paul and I then landed two jobs in philosophy at the University of Manitoba through the kindness of an old friend, Jack Bailey, from Pittsburgh.

From Philosophy to Neuroscience

How did the transition to neuroscience come about? First, it was sheer luck that my first job was at a university (Manitoba) that took itself seriously enough for there to be some terrific faculty, but not so seriously as to be arrogant and self-important. The story of my integration with neuroscience in Manitoba began with my exasperation in trying to learn neuroanatomy from books.

Throwing my anatomy textbook at the wall, I was forced to admit that my goal was doomed. What goal? To teach myself the organization of the thalamus, a brain structure deep under the cortex. Why the thalamus? Because in mammals, all sensory inputs (except smells) go through the thalamus and from there to cortex. It is kind of the heart and soul of all mammalian brains. In my expensive textbook, each page showed a slice of the thalamus, advancing from back to front, each two millimeters thick. The trouble was that from one page to the next the thalamus looked completely different to me. From slice to slice, I could not get any sense of continuity, of what this walnut-size thing really looked like. Visualizing a three-dimensional (3D) thalamus from two-dimensional (2D) illustrations was a dead end. Maybe going whole-hog on the real 3D object was the better way. The University of Manitoba had a medical school, and the medical school had a department of brain anatomy. Surely some neuroanatomist could show me what the thalamus looks like. Thus, my state of mind (P. S. Churchland 2021).

Cancelling my office hours with students (okay, my bad), I drove my rusty VW downtown and found the neuroanatomy department. The sign on the door read: John Baskerville-Hyde, Head. Warmly welcoming my interruption, Baskerville-Hyde listened to my tale of woe with amusement and encouragement. “Yes,” he agreed, “philosophers need to know about the brain if they want to understand the mind. Here is what we can do. Can you attend regular neuroscience lectures with the first-year medical students? For the lab component, the students will get a human brain to dissect. I will arrange for you to have your own human brain to dissect. Then you’ll begin to learn brain anatomy. In lectures, you will also learn physiology.”

Just like that, after a mere 40 minutes’ conversation, my intellectual life changed forever.

A human brain was indeed delivered to me in the anatomy lab, and holding it my hands, I felt an almost reverential humility toward this tissue that had embodied someone’s love and knowledge and skills. It looked so small relative to what a human brain can do.

The world of neuroscience was opening up to me. At the clinicians’ weekly meeting—neurology rounds—a patient with unusual or puzzling symptoms would be presented and later discussed. To my everlasting gratitude, the clinicians invited me to join their rounds. One stroke patient was a dairy farmer whose only symptoms were that he could no longer recognize faces—not those of his wife or children, or even his own face in a mirror. Particularly disappointing to him was his inability to recognize the faces of his beloved cows. Encouraged to wander the neurology ward of the hospital, I visited a stroke patient with hemineglect. She was unaware of any stimulus or event in the left-side of her space and paid no attention to the left side of her body. When I raised her left hand and brought it into her right hemispace, she said did not know who it belonged to. Another stroke patient suffered from pseudobulbar affect (brainstem lesion is the cause), which meant that when stressed, he would suddenly sob piteously for about 30 seconds or so. When the sobbing ceased, he explained that he had felt no sadness whatever, but the pseudobulbar affect was certainly a nuisance. Because Manitoba is a province spanning a vast geographic area, and because only Winnipeg had advanced medical facilities, any patient with challenging symptoms eventually came to the medical school hospital. I was fortunate to see cases that many neurologists see only rarely, if ever.

Although I prized the connection to the clinicians, it was in Larry Jordan’s local neurobiology lab that I really began to understand the challenges and the thrill of getting data from nervous systems. Larry’s lab was focused on circuitry for rhythmic behaviors—more exactly, on walking in the spinalized cat. At that time, rhythmic behaviors were usually studied in simple nonmamalian animals such as the lobster (its stomatogastric ganglion rhythmically ground up food). Rhythmic behaviors were targeted because they were an entry to the circuit level. Although no individual neuron might be producing rhythmic output, it was intriguing that the circuit generates rhythm and modifications to a basic rhythm. What drew researchers in was the prospect of understanding a circuit output in terms of the input signals, along with the physiology and the connectivity of all the neurons comprising the circuit.

Larry Jordan’s lab examined walking as controlled by the spinal cord. The experimental animal was the cat. In that lab, I came to see the wisdom of studying the rhythmic behavior as a circuit level phenomenon, not the selective business of a single rhythmic neuron or single pulsating neuron type. To isolate the circuitry in the spinal cord, the cerebrum of the animal was surgically removed under anesthesia, and a sling was used to keep the cat upright. Walking in the decerebrate cat could be sped up or slowed down by changing the speed of the treadmill its paws touched or by altering chemical balances in the spinal cord. (Jordan and Sławińska 2011) What exactly was the circuitry and how did it work, were the lab’s defining questions. Paul got very involved in the lab’s work as well, and we egged each other on as we basked in the joys of this hands-on direction. We jointly wrote a paper critical of conventional “truths” about qualia and visual experience (Churchland and Churchland 1981), sometimes drawing on data, sometimes just exposing cock-eyed logic relied upon by philosophers.

Untenured philosophy professors, as I was at the time, are typically advised to avoid risk and stay well-focused on the job they were hired to do. Providentially, my dean, Fred Stambrook, an historian with a dash of intellectual derring-do, skillfully encouraged my hands-on initiative, even while members of the Philosophy Department were faintly bewildered. In time, papers in philosophy journals were published, tenure was granted. Quietly, I thanked my lucky stars that I was not at Toronto where my unconventional shenanigans would have been seriously frowned upon.

From me, the neurologists wanted to know whether philosophers thought there was a nonphysical soul, and if so, why. For example, we discussed the split-brain results in detail. They were puzzled by those who applied the computer metaphor to the brain function, which claimed that the brain is merely the hardware on which to run the software of cognition. According to a popular philosophical assumption favored at MIT, marketed vigorously by Noam Chomsky and Jerry Fodor, was that to explain the human mind, only the software needs to be understood. Leave the hardware—the brain—out of it. Brain-phobic philosophers found that assumption reassuring and argued rather creatively in defense of it. The neurologists, however, were unmoved, compelling MIT rhetoric notwithstanding. Much later, undermined by accumulating neurobiological evidence, the misbegotten software-hardware metaphor was quietly shelved, or mostly anyhow.

To great philosophical acclaim, Jerry Fodor wrote a book, The Language of Thought (1975), supposedly showing that a language could be learned only if the child already had an innate language of thought; language learning is, according to Fodor, nothing but translation. Motivated by evolutionary biology and some knowledge of the brain, I published a paper (P. S. Churchland 1978) in the philosophy journal, Synthese, emphasizing the illogical underpinning of Fodor’s view, bemoaning the lack of data, and more generally, poking fun at the Fodor method that (only in conversation) I had rather ungraciously called “pulling science out of your ass.”

Inevitably I was drawn in to the topic of consciousness, especially because I found myself in opposition to the conviction, common among philosophers and some scientists, that only humans are conscious. More exactly, the idea was that only if you have a language can you be conscious, and of course, only we humans have language. This conviction goes back at least to Descartes and his 17th-century introspection, but perhaps even further. Still, contemporary philosophers of the “analyze-word-meanings” approach to understanding consciousness made much of an alleged “conceptual connection” between using language and being aware. “Consciousness” means, so they claimed, the ability to say what you are conscious of. Daniel Dennett, argued extensively for this view. For example, Dennett (1979) says that what we typically mean by “consciousness” requires that a conscious organism must have verbal skills, but a “what a dog has, or the right hemisphere has, is a radically different phenomenon.” I saw this as mistaking a test for consciousness (reporting verbally) with the phenomenon itself.

In my paper, “Consciousness: The Transmutation of a Concept” (1983), I marshaled evidence from many scientific sources (e.g., psychophysics, neurology, ethology, evolutionary biology) to demonstrate how feeble were Dennett’s claims. For example, Gordon Gallup had shown that chimpanzees, if given a mirror, will study themselves in the mirror, picking their teeth, and checking their behinds. If, under anesthesia, a red mark was put above their eyebrows, later they would study that mark in the mirror, gently check it with their finger and then check the finger. Lacking self-consciousness because they have no language? Surely, you jest. Undeterred by negative evidence, Dennett adheres to his speculation that acquiring language skills is necessary for consciousness. His idea is that acquiring language skills, as opposed to hiding or hunting skills, uniquely reorganize the brain. The result of such special reorganization is consciousness (see especially Ch. 14 in Dennett, 2017). In the absence of positive evidence for Dennett’s ideas here, I have found it more fruitful to look to the neurobiology of attention (Graziano, Webb, 2017) and cortical self-control of movement (Schroeder et al 2022), for example.

By the time I was dissecting human brains, I jokingly thought of myself as a neurophilosopher. The name stuck, but the risibility retreated as I began to think hard about what neuroscience teaches us about “big-question” philosophy—questions about knowledge and morality and sleep. It seemed ever more evident that I am as I am because my brain—with its genes and neurons and experiences—is as it is. Neurophilosophy as a new paradigm took hold in me because it became gloriously obvious that progress on various time-hallowed philosophical questions, such as how we learn and see and think, was beginning to be made in neuroscience, and more progress was surely in store. The way forward was unmistakable: follow the science, wallow in the science, think without fear, and ditch bad ideas without shame when you see they are duds. Still, predicting how neuroscience will proceed in the distant future is risky, to put it mildly. As our son Mark asked with six-year-old naivete, “What if the human brain is more complicated than it is smart?” Well, we may never know for sure. We can just keep working to make new tools and new discoveries until we hit the wall—but how would we know it was the wall or just a local minimum?

I should mention here that I immensely enjoyed having children, and I was particularly fortunate that giving birth and lactating were very easy for my body. Paul, too, hugely enjoyed the children, and we both found ourselves gleefully reverting to our childhood mindset in playing with our own two children, Mark and Anne. That they both went on as adults to study neuroscience was a delightful surprise, a choice shaped mostly, I think, by the fact neuroscience is now the locus of so much scientific excitement, and there is so much to be discovered, and not because we had especially prodded them in any particular direction.

We spent a year (1978–1979) at the Institute for Advanced Study in Princeton, which gave me time not only to read and think but also to visit with evolutionary biologists such as Donald Griffin, whose data on animal hunting and foraging behavior strongly indicates that they think and reason and solve problems. I also visited Charlie Gross, whose lab had discovered neurons that respond only to faces and went on to explore cognitive representations more generally. Michael Gazzaniga was at New York University, so I hopped on a train to pay a visit to him and Joe LeDoux, mostly to discuss consciousness, and especially Don Griffin’s work, showing the high probability that nonlinguistic animals can think and are conscious.

By the early 1980s, I toyed with the possibility of writing a book to illustrate the interconnections between neuroscience, psychology, and philosophy. Before long, the idea did assemble itself into an actual book, Neurophilosophy: Towards a Unified Science of the Mind-Brain, with lots of financial support from the Canada Council. The writing was not completed in Manitoba, but rather in San Diego where we had been offered jobs. Landing jobs at the University of California–San Diego (UCSD) in 1984 was an incomparable piece of luck for me and for Paul. I quickly came to appreciate this when I discovered I could walk from my office to the labs of Larry Squire and Stuart Zola, as well as to Ted Bullock’s lab at Scripps down the hill by the beach. There were, however, some uneven moments. Knocking on my office door as I was unpacking books, a rather prominent member of the UCSD Philosophy Department felt the need to explain in painful detail that he had been totally opposed to hiring women, whatever their status. Moreover, he especially opposed hiring me because he though me “mouthy.” I found myself laughing resoundingly, inadvertently confirming his “mouthy” description. I offered him a glass of sherry to share the mirth, a glass he politely refused.

In 1986, Neurophilosophy was published by MIT Press. By and large, established philosophers loathed or ignored the book. Graduate students, in contrast, snuck off to read it on their own and figured out how to collaborate with neuroscientists to do philosophy in a new way. Beth Buffalo—then a graduate student in philosophy at UCSD and now a highly distinguished neuroscientist, was an early case in point. Her work in Larry Squire’s lab on the hippocampus not only showed philosophers that neuroscience was relevant to understanding memory, but also showed neuroscientists that philosophers could be creative and skilled scientists.

Mercifully, lots of scientists, including Francis Crick and Jonas Salk, thought Neurophilosophy was a book whose time had come. Their support encouraged me to take the philosophers’ ridicule in my stride. They also arranged for me to become an adjunct professor at the Salk Institute, and I have always felt completely at home there. In the period following the publication of Neurophilosophy, I was gratified to find that science journals were ready to publish my ideas, including “From Descartes to Neural Networks” in Scientific American (1989) and “A Neurobiological Slant on Consciousness Research” in Progress in Brain Research (2005). I was also invited to give talks at many neuroscience departments who were keen to hear about why most philosophers thought that studying the brain would tell us nothing about our mental life. These visits also gave me wonderful opportunities to learn about what experiments neuroscientists were doing and why.

One of the hypotheses that Paul and I jointly developed, and which I discussed extensively in Neurophilosophy, was that brains grow high-dimensional parameter spaces (maps) and that representations, such as the layout of a house, or of things in the house, could be understood as vectors in a parameter space. On this idea, internal distances in the relationships in the maps might correspond to similarity relationships in the categories of things, such as the similarities we see between kinds of bears or between kinds of evergreen trees or kinds of footwear, and so forth. We expected that there could be integration across parameter spaces, as neurons made connections with other neurons, although how integration was achieved we had no idea. This hypothesis was sketchy, but what we wondered was whether something roughly like this, consisting of neural networks, might be a better approach to cognition than the analogy to digital computers and programs favored by Chomsky, Fodor, and Dennett (P. S. Churchland and P. M. Churchland 2002). In 2007, we were interviewed by a New Yorker journalist (Larissa MacFarquhar), who published an article about Paul and me titled “Two Heads: A Marriage Devoted to the Mind-Body Problem.”

A physicist/neuroscientist I had met at a meeting at John Hopkins, Terry Sejnowski, was persuaded to take a job at the Salk Institute in 1989, and we shared the hunch that understanding how artificial neural networks learn and represent might yield clues useful in understanding computational principles of real nervous systems. I became an informal but regular member of Terry’s computational neuroscience lab. Francis Crick, also at the Salk, adapted the Cambridge institution of afternoon tea every day at 4 P.M. in Terry’s lab. We labbies (including in those first days Read Montague, Peter Dayan, Steve Quartz, and Alex Pouget) took turns making tea and rustling up biscuits. Scientists from various other labs, such as Chuck Stevens, Leslie Orgel, and Tom Albright, often dropped in for tea, too. Teatime quickly became the daily occasion for close discussion of ideas and data, flying untried balloons, and giving the broad questions a hearing. It was a time for emerging from the comfortable burrows of safe detail into the wide-open prairie of no-holds-barred. Virtually everyone who visited the lab was coaxed or gently bullied into dilating on the philosophical (grand-scale, background, or fuzzy) questions facing computational neuroscience.

Terry and I decided to write a book, mainly for neuroscientists but also for computer scientists, to explain artificial neural net computing and learning as well as to explore ways in which brain achievements can be seen as computational. In the ensuing publication, The Computational Brain (1992), we noted that the style and principles typified by prevailing computer programs—coding, rules, exceptions to rules, and exceptions to the exceptions—were unlikely to reflect computation in nervous systems, given what is known about the basic properties of neurons and the modification of neurons through learning. Although Paul and I had thought a lot about vector-to-vector transformation in high-dimensional spaces, we had not actually built a neural network. But Terry had.

An early Sejnowski project, collaborating with graduate student Charlie Rosenberg, involved constructing an electronic neural network to translate a short piece of written text into speech. (Sejnowski and Rosenberg, 1987). The network was recurrent (loopy), so error signals would be looped back to units in the middle level, and the network would adjust the units’ weights accordingly. This error-correcting feedback to the middle layers of the network was mainly a Geoff Hinton invention, known as back propagation of error (aka backprop). The result of an error correction step was a new output sound to the same input word, generally getting a little closer to the right sound for that text, a process known as gradient descent. Left overnight to run and error-correct according to the algorithm, the artificial neural network (called NetTalk) was surprisingly accurate when tested aloud in the morning. One could easily understand its vocalizations as meaningful text. Probably, it seemed to Terry—and to me—then, that although this small network could not do very much—just map text onto speech—a greatly cranked-up colossal artificial neural network might be able to do vastly more. And that hunch turned out to be correct. In any case, error correction through negative feedback is possibly one prominent way organic brains learn, when they do learn. Error correction via backprop is how NetTalk learned.

A much harder question was whether there were going to be instructive parallels between organic brains and artificial networks concerning the mechanisms of error-correction learning. In short, does my brain use backprop? At that time (1980s) little was known about the highly complex details of brain circuits, although at the behavioral level, the importance of positive and negative feedback was well studied. The ventral tegmental area (VTA) was known to regulate reward learning, and the release of dopamine was a crucial element in how animals learned to approach or avoid a stimulus. As intense research on learning continued, it became evident that the VTA, although important, was only one part of a much larger neural system. Other important components were the hypothalamus, regions of the prefrontal cortex and the inferior parietal cortex, the amygdala, and the basal ganglia (see Averbeck and Murray 2020).

From my perspective, the algorithms by which artificial intelligence (AI) networks learn, cool though they are, appear to be much simpler than the computations used by real nervous systems as they learn. For one thing, AI machines do not have motivations or emotions: they do not run or hide or move at all; they lack diurnal cycles and do not need to forage for food or mates; they do not tend offspring. Whether these factors mean that the intelligence in AI machines is different in kind or just in degree from the intelligence of a rat or monkey is a favorite topic of discussion now in Terry’s lab. Owing to lessons learned in Larry Jordan’s lab as well as from Rodolfo Llinás, I tend to see evolution of nervous systems as ultimately serving the four Fs of motor control—feeding, fleeing, fighting, and reproducing. Fancy sensory systems and intelligence earn their keep only by serving motor control, either in the immediate future or in the longer term. Nevertheless, deep mysteries remain concerning the mechanisms for sensorimotor control.

Consequently, I wonder how much we really understand about intelligence in ourselves or in other mammals and in birds. Yes, pattern recognition as seen in AI machine output is remarkable, but living organisms have to generate adaptive movement, not just recognize patterns. In mammals, not only is the spinal cord involved, but so are the cerebellum, the basal ganglia, the motor cortex, and the contribution of sensory signals. Because sophisticated motor control is a circuit-level function and is adaptable as external conditions change, computing using only the length of an animal’s limbs, for example, is not nearly enough to approximate a cat’s movements. Thus, an AI system that learns to move from mimicking limb movements may itself move like a stick figure. Sensorimotor learning in a dog’s brain as it acquires a ball-catching skill may seem relatively easy to the casual observer, but the computations governing the feat are profoundly difficult to understand. Still, as Mark Churchland has explained to me, “many movements are executed with the same neurons without mixing them up, and one way to accomplish this is to use a different low-dimensional subspace for each task, which is learned. The arm motion you use to serve a tennis ball is different from the one you use to throw a baseball, even though the same muscles are activated. These are still early days, and not all cortex areas have been analyzed. The same dynamics may occur in the prefrontal cortex, where thoughts are dynamical trajectories in low-dimensional concept subspaces.” (See also Churchland, M.M., Shenoy, K. 2024.)

The revolution of my lifetime is that both the neurophysiology of real neural circuits and the enlargement of electronic networks have advanced in dramatic fashion, especially beginning about 2000. Experimental use of hundreds of electrodes is now common in studying neuronal circuits, while trying to dope out circuit function using a single electrode now seems quaint if heroic. Thanks to miniaturization in electronics, large language models can be not merely large but gigantic, flaunting upward of a hundred billion parameters, requiring 200 gigabytes to load. (NetTalk, the pioneer, had a measly 300 or so units.) We shall see how much we can learn about brain functions from these devices (Muller, Churchland, and Sejnowski 2024).

Although some philosophers had come to appreciate that empirical data can constrain hypotheses about the nature of the mind, the weight of opinion was that talking to and arguing with other philosophers, and perhaps dwelling on the writings of historical figures such as Immanuel Kant, is the way philosophy works. I once ventured to make a slide quoting a famous comment by economist and engineer, Edwards Deming, “Without data you are just another person with an opinion.” Although I regularly showed the slide when I give a talk, the philosophers typically dismiss it as displaying my ignorance of the way philosophy is done and should be done.

In particular, positing a nonphysical soul continued to find favor in the philosophical community. Famously, the Australian philosopher, David Chalmers, finds this idea compelling (Chalmers, 1996). His central argument consists of what he dignifies as a thought-experiment, which roughly goes as follows: I can imagine a person, like me in every way (attention, short-term memory, use of language, laughs at jokes), but completely lacking in qualia—qualitative experiences, such as feeling short of breath or seeing the colors of a rainbow fade. My brain and the Zombie’s brain are, in Chalmers’ story, exactly the same. In sum, this individual would be exactly like me, save that he would be a Zombie.

“So what if you can imagine such a thing?” you might ask. Here is the conclusion Chalmers draws: because the scenario is imaginable, it is possible; because it is possible, then whatever consciousness is, it is independent of the brain.

Does Chalmer’s conclusion follow? No, not even a little bit. Not even if you are charitable. The glaring flaw lies in relying solely on what seems possible or imaginable to establish an hypothesis about what is actual. After all, what is and is not conceivable is merely a psychological fact about us—about what we can and cannot imagine, given our capacity for imagination. It does not constitute factual evidence about the nature of things. I can imagine running faster than the speed of light, but in reality, I cannot. I can conceive of waking up some morning to find that I am a newly hatched chicken. Nothing follows about me, or chickens, except that I have a vivid imagination. (This version of my criticism was drawn from my 2023 article, “Brains and Minds.”)

Additional problems loom: if the imagined Zombie is, as the thought-experiment requires, exactly like me, then can it too imagine a world in which there are zombies without consciousness? It is not clear how to make sense of this. Incidentally, notice too that if Chalmers acknowledges that the Zombie has attentional capacities but no conscious awareness, he also runs up against the neuroscientific data showing that attention, a neurobiological trait, is typically an aspect of conscious states. So perhaps the fanciful Zombie is not exactly like me, after all. But wait: why not say the Zombie is like me and hence has conscious experiences because its brain is exactly like mine? In summary, too little thought, and not enough experiment.

I am sometimes cheered up by a casual comment by the Princeton physicist John Wheeler. He quipped that philosophers are like tin cans tied to the back of a car—they make a lot of noise, they do not move the project forward, and they are always behind.

The history of science has a rough parallel to dualism—namely, vitalism. Typical of vitalists generally, my high school biology teacher argued thus: no one can explain how living things can emerge from dead molecules. Out of bits of dead proteins, fats, and sugars, how could life itself emerge? He thought it was obvious from the sheer mysteriousness of life that the nature of life could not possibly have an explanation in biology or chemistry. His unwavering intuition about mysteriousness assured him he could just tell that life would require a nonbiological solution—that is, vital spirit. By 1953, with the discovery of the molecular structure of DNA and how its organization embodied a code for making proteins, the vitalist game folded. Done for.

Both Chalmers’s argument and the vitalist arguments are examples of the well-known argument from ignorance. Here is the general form of the fallacy: I do not know something (e.g., how the brain produces consciousness), so I do know something (e.g., that the brain does not produce consciousness). The fallacy is well named. Another common fallacy (false analogy) is to drum up this syllogism: Consciousness is a mystery, quantum phenomena are a mystery, and so they probably are the same mystery. Roger Penrose, a mathematician at Oxford, claimed that quantum gravity inside a neuron’s microtubules was the cause of consciousness—the same mystery. Although bedecked with various bits of mathematics to provide some respectability, the heart of the argument is obviously a false analogy. (The philosopher Rick Grush and I wrote a paper criticizing Penrose in detail thatappeared in Pacific Philosophical Quarterly in 1983.)

To be sure, there is much about the brain that is not understood, including the precise nature of the many mechanisms involved in timing, learning, speech, and stereo vision, or the brain configurations that cause schizophrenia or bipolar disorder, to mention only a few mysteries. Although Chalmers identifies consciousness as a uniquely hard problem, from the vantage point of ignorance, it is difficult to know which of the vast number of brain unknowns will more easily submit to progress. This tends to be the way of things in science more generally. For example, the problem of how to predict the folding pattern of a large protein from its amino acid sequence was long thought to be “a grand challenge” in biophysics, never to be automated. From the perspective of 1990, this was a genuinely hard problem. Yet by 2021, AI techniques (Alphafold2) made that very problem more tractable. When will the problem of consciousness succumb? Next decade? Next century?

How I Came to See Neuroscience as Having an Impact on the Nature of Morality

A longstanding issue discussed by philosophers concerns the origin and nature of moral convictions, and although I did not expect to have anything to say on that matter, everything changed in the 2000s.

Western philosophers have commonly seen morality as a set of rules derived either from a supernatural being, as in the Ten Commandments, or from reason. Or by combining both God and reason, as St. Thomas Aquinas proposed. In Aquinas’s view, our reason can discover—and espouse—the correct moral rules because God kindly arranges things thus. Our job is to be in a pious state of mind and deploy our God-given reason. On this approach, the aim of a moral philosopher is to unearth those rules, thus pleasing God and then to advertise the rules broadly so others will follow your lead.

As a child, I had long suspected that the supernatural explanation for the origin of moral norms lacked coherence. The Ten Commandments were ostentatiously implausible as exceptionless rules. I had known of one father of a friend whose conduct implied he deserved no honor whatever. As for keeping the sabbath, that was a luxury farmers did not have.

My callow skepticism got a refinement when, as a freshman in college, I was introduced to the Platonic dialogue, Euthyphro. Conversing outside a court of justice are the know-it-all Euthyphro and the faux-featherbrain, Socrates. Euthyphro is at the court to bring a charge of murder against his own father, who killed a mad man, albeit inadvertently. For his part, Socrates attends court to face charges of impiety—really, for asking embarrassing, if polite, questions of the high-handed theologians. As their conversation about gods and morality drifts along, Socrates, feigning innocence, asks the pious Euthyphro: is something right because the gods say it is right, or do the gods say it is right because it is right? The dilemma for a theistic approach is unavoidable. Either what is right is arbitrary (the first horn of the dilemma—merely the gods’ say-so) or the gods are irrelevant to the explanation of what makes an action right (the second horn of the dilemma—the gods merely recognize what is right). Either way, appealing to the gods does not illuminate anything about morality. What remains to be explained is what makes an action right and how we learn that. Secondarily, there is the further skeptical challenge: can we be wrong in an ethical judgment even when, like Euthyphro, we are entirely certain of our judgment?

As far as I could tell, Socrates’s dilemma had hobbled the theological approach, and it also cast doubt on the idea that human reason could find absolute rules that have no exceptions and are immune to counterexamples. Nevertheless, I was disappointed to realize that like Aquinas, many moral philosophers still assumed that reason (perhaps “God-given reason”) would reveal the deepest moral rules. Immanuel Kant, for example, held that the moral rules must be absolute and universal, and as an example, cited “always tell the truth.” Always? Always. Undergraduates, to the dismay of steadfast Kantians, found plenty of obvious counterexamples—armed Nazis questioning the doorman at Jewish hideouts and so forth—in which telling the truth would be exactly the wrong thing to do.

Jeremy Bentham and James Mill, though atheists, shared with Aquinas the assumption that reason could be relied upon to find the absolute basic rule. Additionally, according to them, they had indeed found the rule by logic and reason alone. Maximizing aggregate utility (acting so as to yield the greatest happiness for the greatest number) is the absolutely fundamental moral rule. Although the counterexample shops turned out oodles of troubling cases, the Bentham-Mill proposal, also known as utilitarianism, remains even now appealing to many contemporary moral philosophers (e.g., Peter Singer, Nick Bostrom and so-called “Effective Altruism;” for recent criticism, see L.Wenar, 2024).

A not uncommon philosophical career consists in finding ever-more subtle ways to fend off the inevitable counterexamples to utilitarianism. In graduate school, I ruefully concluded that Utilitarians and Kantians were contentedly engaged in a sterile back and forth, showing again and again how foolish the other side was, but how their side alone conforms to reason. I never expected to have anything useful to say on matters concerning morality and vowed to steer clear of morality as a topic. Neurobiology, however, changed all that.

One day in 2007, I went to hear a talk at the Salk Institute on social behavior in voles. The advertised topic was not especially compelling, but I had a couple of hours before teaching my logic class, so I found a seat in the auditorium and settled down to listen. The speaker was Larry Young from Emory University, and he began to describe the behavior of montane voles. Male and female meet, they mate, and they go their separate ways. Ho hum. Then he described the behavior of prairie voles: they meet, they mate, and then they are bonded forever. They form lifelong attachments. The male helps guard and nest and takes care of the babies. Montane voles are loners, whereas prairie voles live in large communities of voles. What, he asked, might be the differences in the brains of montane voles and prairie voles that accounts for these social differences?

Now I am on the edge of my chair. Young’s slides reveal his lab’s anatomical results. The main neurobiological contrast they found is that prairie voles have a much higher density of receptors for the neuropeptides arginine vasopressin (AVP) and oxytocin (OT) in the ventral pallidum and the nucleus accumbens, respectively, than do montane voles (Lim, Murphy, and Young 2004; Lim and Young 2006). Although all mammals have both OT and AVP centrally, it is the receptor density in specific and highly interconnected regions that marks the crucial difference in social behavior. He went on to describe the supporting evidence for the role of OT and AVP, including for example, the behavioral changes that happen after the receptors are blocked. Inspired to know more, I read everything about OT that I could find on PubMed.

Vole mating behavior is all very interesting, but whence the link to morality? The background that inspired me to think broadly about social behavior given the vole results, came from many years of attending symposia arranged by CARTA (the Center for Academic Research and Training in Anthropogeny). This institution was the brainchild of a diverse group of scientists at UCSD and Salk who in the 1990s formed a casual group called the La Jolla Group for Explaining the Origin of Humans. From different subfields, one and all they were fascinated by questions about human evolution and taught each other what they knew. They understood well that to address the differences between humans and other mammals, a very broad sweep of inquiry was needed. They wanted information from all levels of organization—from the glycobiological and genetic comparisons among mammalian species to comparisons in sensory systems and in behavior, including social behavior of many species studied by field anthropologists. This was cross-disciplinary inquiry at its fermenting best (see the CARTA website at https://carta.anthropogeny.org).

Receiving funding from like-minded donors, they formalized the group into CARTA. I was very happy to be included in CARTA from its beginning in 1998. (“Anthropogeny” is an old term, seldom used now, meaning the attempt to explore and explain the origin of humans.) In this thriving but easy-going milieu, the role of OT and AVP in prairie vole sociality raised questions about the evolution of such behavior, and what those peptides did in nonmammalian species. Drawing on the research of my CARTA colleagues, I saw a way to make progress on long-standing philosophical debates about the nature of morality. The key involved mulling the matter of sociality from an evolutionary perspective. What could be the benefits and costs of sharing food, cooperating, or showing compassion?

Despite the strong claim by Richard Dawkins (1976) that we are all born utterly selfish and must learn altruism by pressure and coercion, field studies of social behavior in many species show that the opposite holds surprisingly often. For example, at a CARTA meeting, primatologist Christophe Boesch presented data showing five distinct cases of a male chimpanzee in the wild adopting an orphan baby and raising it to maturity over an extended period of time—not an easy job. Genetic data (from carefully collected urine samples) revealed that in no case was the male chimpanzee the biological father of the adoptee. Infant adoption has also been documented in bonobos, brown howler monkeys, and Tibetan macaques. On a different note, wolves and elephants will share food and show compassion to conspecifics in the group and sometimes even to allospecifics. Black bears, though long assumed to be cranky loners, actually have rather complicated social relationships with kin across large territories, involving sharing of food and playing. (Getting this data on bears, however, took Ben Kilham some 20 years of careful observation.) The nonhuman data on altruism shows that neither a supernatural being nor language-dependent reason seems to play a crucial role in altruism (De Waal 2009, 2013).

Distinct from the Dawkins model of coerced altruism, a significant philosophical tradition, starring Aristotle, but also the Scottish geniuses Adam Smith and David Hume, sees other-regarding impulses as a deep feature of our nature. On this view, heritable social impulses form the basis for social behavior, and such impulses can be shaped and modified by the environment. Norms emerge from customs, typically making pragmatic sense and reflecting ecological conditions. Dawkins, wrong though he was about the necessity of coercion, provoked us to ask about the evolution of mammals, and in particular, to ask about the evolution of social bonding with offspring and also with others such as mates. Why did evolution select for mammalian and avian styles of sociality (De Waal 2013)?

The succinct version of the story that seems to me probable runs as follows—which I published in book form in Braintrust (2011), and in further development in Touching a Nerve (2013). The event that triggered the huge cascade of changes in the brain that eventually wired our style of sociality was homeothermy. Surprising, but probable, nonetheless. About 200 million years ago, warm-blooded animals appeared for the first time. Even in its rudimentary forms, homeothermy was highly advantageous because warm-blooded animals could forage at night, when their cold-blooded competitors had to slow down and sleep. Additionally, it allowed animals to venture into colder climates. Although homeothermy is beneficial in many respects, it has a cost. Gram for gram, homeotherms need about ten times the calories as poikilotherms. That is a huge constraint, but given the benefits of homeothermy, it favored the evolution of a new neural structures in homeotherms—structures that could learn a lot, learn very fast, and be flexible in guiding behavior, such as defense and finding food. Enter the cortex: immature at birth, it grows very quickly in response to experience, has flexibility, and enables figuring things out. Advance warning: how exactly cortical structures evolved and integrated with “subcortical” structures is not understood. Early homeotherms and premammals are no longer with us (but see Van Essen, Donahue, and Glasser 2018).

Laminar cortex is unique to mammals, though birds have been discovered to have structures anatomically comparable, with an organization more clumpy than laminar (Karten, 2012). The cortical capacity for large-scale learning makes it especially valuable, even though its additional neuronal numbers add to the energy cost that must be made up with yet more food. Benefits notwithstanding, selecting for creatures with cortex introduced yet another problem. Learning entails neuronal growth; growth is achieved by adding branches, synapses, and connections in an organized way to existing neurons. Consequently, at birth, the cortex needs plenty of room for neuronal growth to embody what is learned. How to ensure cortical space for learning and hence for neuronal growth? Immaturity of the neurons (especially those in cortex), which demands immaturity of offspring at birth.

A female turtle will lay her eggs in the sand, and then waddle off to do other things. The baby turtles upon hatching must manage on their own. But for homeotherms, if the offspring are born immature enough to make big learning advantageous enough for survival, the next problem for Mother Nature is how to rig things so that the immature offspring grow to maturity so that they too can reproduce. The solution? Well, mothers are nearby the neonates, because mothers give birth. Modify the brain so that mothers care for infants. In other words, those early mammalian mothers who tended their immature babies were more likely to have surviving offspring than those who wandered off, like mother turtles.

In mammals, vasotocin, an ancient precursor to AVP and OT, was modified and put to a new use in the mammalian brain. Jointly, OT and AVP cause strong attachment of caregivers to offspring and of offspring to caregivers. AVP on its own increases stress levels and aggression. OT on its own increases general sociality and lowers stress levels. Other neuromodulators play a role too, such

as the endocannabinoids and endogenous opioids, which make us feel good when released. (Nummenmaa et al, 2016) Along with the new neurohormones, suitable receptors evolved from vasotocin receptors. OT receptors are distributed quite widely in the mammalian brain, including in the amygdala, hypothalamus, and prefrontal cortex. Some 50 million years after the emergence of mammals, the same basic neurohormonal trick was used to ensure attachment by avian mothers and fathers to their hatchlings. Wiring homeotherms for sociality depends on a demanding style of caring, although to judge from existing species, caring seems to be a powerful force.

Apart from highly dependable mother-care, styles of sociality vary considerably among mammalian species. Monogamy is seen in only about 8% of mammalian species, including beavers, marmosets, titi monkeys, gibbons, wolves, and of course prairie voles. Attachment to various others, such as kin and friends, is seen rather more frequently. Highly social species, such as elephants, macaques, and baboons, live in groups and often show care for their kin and friends but are not monogamous. Even mice and rats seek the company of conspecifics and will become depressed when isolated. The social behavior typical of a species is related to its ecology and way of making a living. As Joan Silk (2007, p. 539) succinctly put it, “According to behavioral ecology theory, sociality evolves when the net benefits of close association with conspecifics exceed the costs. The nature and relative magnitude of the benefits and costs of sociality are expected to vary across species and habitats.” And vary, indeed they do.

Extending care and attachment beyond offspring to others, such as mates or kin or friends, probably involves relatively minor genetic changes. Small tweaks to OT and AVP receptor distribution may be all it takes to yield alterations to the social style of a particular species. An example used by Frans de Waal (2013) involves comparisons between the behavior of chimpanzees and bonobos, who now live on opposite sides of the Congo River. Initially just one species, they began to differentiate into two species once the animals were separated by an enlarged and swifter Congo River, about two million years ago. Observations show that small changes in dominance hierarchies, for example, can occur quite quickly. Bear in mind that resources are more plentiful and competitors fewer in the territory where the bonobos range, on the south side of the Congo River. Bonobos have matriarchies, whereas chimpanzees are patriarchal. Recently, bonobos have been observed cooperating not only with in-group members but also with unrelated bonobos in other groups. This too is very different from chimpanzees who typically do not tolerate chimps from other groups. Other changes such as hair density, diet, and tail tufts are also observed. Just as there is variability in cooperativeness among humans, there is variability in this trait among bonobos (Samuni and Surbeck 2023). Some variability in sociality may be related to polymorphisms in the gene for OT receptors, and some may be related to wiring differences resulting from differences in early nurturing (Carter 2017).

Cortex learns many things as the infant grows up, and among the things it learns is how to get along and manage in its social world. Basic social impulses are in play from the beginning, but learning social practices and acquiring social skills are critical to all mammalian and avian species. Their lives depend on it. The adult wiring, therefore, will reflect not only genetic endowment but also epigenetic changes resulting from interactions with the environment (Wilczyński, Siwiec, and Janas-Kozik 2019). Depending on such matters as infant cuddling or lack thereof, there may also be methylation of genes for OT and for OT receptors (Wismer Fries et al. 2005; Carter 2017).

Human societies can have rather complex sets of norms that guide the behavior of individuals, and much of moral philosophy begins by assuming that the complexities governing social behavior in, say, European countries in the 19th century, must be typical of humans generally. An evolutionary perspective, however, indicates that norms and traditions prevailing in small groups of hunter-gatherers can be rather simple and flexible, although exquisitely well suited to their specific way of life. There is no benefit to having normative complexity merely for the sake of complexity. (My 2019 book Conscience contains an extended discussion of within-species variability.)

Our hominin ancestors lived in small groups of about 25 to 100 individuals—hunting, fishing, and gathering. Some hints of their sociality can be gleaned from anthropological studies of such groups of humans in the 19th and 20th centuries, for example, the Chinook People of the Pacific Northwest by James Gilchrist Swan (The Northwest Coast 1857), and later, studies of the Inuit of the far north by Franz Boas (The Central Eskimo 1888). These studies reveal that in comparison to highly developed cultures in Europe and North America, social norms were simpler, more flexible in application, and interleaved with cherished stories of past disasters and successes. Among hunter-gatherer groups, moral norms varied somewhat and generally did not allocate a role for the supernatural in moral norms. Even when some kinds of supernatural beings were thought to exist, they might be limited to governing bear behavior or to the weather. Differing ecological conditions likely had a significant effect on customs and norms and on their modification as conditions changed. For example, customs for resolving within-group conflicts vary—for example, between the Inuit of the Arctic and the Haida of the Pacific Northwest—probably reflecting tremendous differences in ecology that affect population size and availability of food. To an unknown extent, the preferences and temperaments of persuasive individuals also may have shaped certain customs and norms (Chacon and Mendoza 2007).

The advent of agriculture about 12,000 years ago ushered in tremendous social changes wherever farming replaced hunter-gatherer ways of making a living. Among the changes are included the emergence of large-scale religions and their role as custodians and enforcers of moral norms. Known as the Neolithic Revolution, farming led to a comparative stability in food supply, settled villages, and then larger towns. It resulted in the domestication of plants and animals, the division of labor and invention of new tools and techniques, and a major expansion of the human population. Violence between large groups as they competed for resources became commonplace, with king-priest hierarchies taking the place of loose social structures organized around skills—good hunters for leading the hunt, and good storytellers or good fishers for leadership in those jobs (see North, Wallis, and Weingast 2009).

What about norms and laws as they affect us here and now? When is abortion ethically appropriate? When is war ethically appropriate? How can we settle these issues when we disagree? My provisional response: it is messy—really messy. For one thing, to come to a judgment, one must learn a lot about background matters, although admittedly, time may often be short, for example, when serving on a jury. For another, moral norms often conflict, so it is not obvious which one to prioritize. Finally, as Socrates constantly reminded us, those who proclaim themselves to be ethical experts, to whom the rest of us should defer without question, are exactly the ones we need to size up skeptically. In my Socratic moments, I tend to think it is best to be especially skeptical about the moral certainties of one religion or another. Religions and religious leaders qua religious leaders have no particular right to the moral high ground. Some, such as the Dalai Lama may come to deserve respect for their moral views, whereas others, such as Warren Jeffs of the Church of Jesus Christ of Latter Day Saints (also known as the Mormon Church), have shown themselves to be unworthy of respect.

Finally, scientists qua scientists have no special normative expertise, although of course they may have factual evidence that is especially relevant. Like anyone else, scientists qua social human beings may have acquired morally wise views about how certain norms should or should not be modified in view of the facts. As in any other profession, a scientist might be a moral cretin. So who can we turn to as a moral authority? Socrates’s counsel in my paraphrase: Mistrust any single moral authority. Seek advice widely, do your best to figure out what to do. You will not always get it right. Yes of course absolute rules we are certain we can trust would be so very handy and decision-making would be vastly easier. Alas. Life is hard.

The brain’s networks continuously face constraint satisfaction problems, both social and otherwise. In dilemmas, some considerations are not mutually satisfiable (e.g., saving one child vs. saving another). Typically, constraints are not measurable against each other—for example, how do we measure the value of training soldiers to kill against the cost to them of becoming killers? To a first approximation, the constraints will include immediate desires, but also the force of habits, reputations, the expectations of others, and the evaluation of relevant options. As the relevant constraints weigh in, the networks settle into a solution—the brain’s decision. The exact nature of the process whereby networks settle is a largely unsolved problem in computational neuroscience. But the representation of rules and their applicability to the situation at hand seems to be only one constraint among others. As I imagine a contemporary Socrates saying, “it seems that practical reasoning—what to do—mainly consists in finding a good solution to a constraint satisfaction problem. Do your best.” That response is not dramatic or flashy or rhetorically resonant. What it does have is more wisdom than the counsel of many a preacher or priest (P. S. Churchland 2008, 2019).

As I am now retired from teaching at UCSD, I have more time now to keep abreast of discoveries in neuroscience and sociality as well as developments in the legal world. Both Tom Albright (Salk Institute) and Francis Shen (Harvard Law) are working on very important problems at the interface of neuroscience and the law, concerning, for example, the courtroom rules regarding which scientific evidence is trustworthy, and the likelihood that a jury will be composed largely of nonscientists and must come to a decision (Albright 2023). This work has important practical implications, and it fascinates me.

Selected Bibliography

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Carter, C. S. (2017) The oxytocin-vasopressin pathway in the context of love and fear. Frontiers in Endocrinology 8: 356.

Chacon, R. J., Mendoza, R. G. (2007) North American Indigenous Warfare and Ritual Violence. Tucson: University of Arizona Press.

Chalmers, D. (1996) The Conscious Mind. Cambridge, MA: MIT Press.

Churchland, M. M., Shenoy, K.V. (2024) Preparatory activity and the expansive null-space. Nature Reviews Neuroscience 25(4): 213–236.

Churchland, P. M. (1989) A Neurocomputational Perspective. Cambridge, MA: MIT Press.

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Churchland, P. S. (1978) Fodor on language learning. Synthese 38: 149–159.

Churchland, P. S. (1983) Consciousness: The transmutation of a concept. Pacific Philosophical Quarterly 64: 80–95.

Churchland, P. S. (1986) Neurophilosophy: Towards a Unified Science of the Mind-Brain. Cambridge, MA: MIT Press.

Churchland, P. S. (1989) From Descartes to neural networks. Scientific American 261(1): 118.

Churchland, P. S. (2002) Brain-Wise: Studies in Neurophilosophy. Cambridge, MA: MIT Press.

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Churchland, P. S. (2011) Braintrust: What Neuroscience Tells Us About Morality. Princeton, NJ: Princeton University Press.

Churchland, P. S. (2013) Touching a Nerve: The Self as Brain. New York: Norton

Churchland, P. S. (2019) Conscience: The Origins of Moral Intuition. New York: Norton.

Churchland, P. S. (2021) Hands On. The Edge (online). https://www.edge.org/conversation/patricia_s_churchland-hands-on

Churchland, P. S. (2023). Brains and minds. In Think, ed. S. Law, 17–23. Cambridge: Cambridge University Press.

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Dennett, D. (2017) From Bacteria to Bach and Back. New York:Norton.

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Hirstein, W. (2004). On the Churchlands. Belmont, CA: Wadsworth.

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Wilczyśski, K. M., Siwiec, A., Janas-Kozik, M. (2019) Systematic review of literature on single-nucleotide polymorphisms within the oxytocin and vasopressin receptor genes in the development of social cognition dysfunctions in individuals suffering from autism spectrum disorder. Frontiers in Psychiatry 31(10): 380.

Wismer Fries, A. B., Ziegler, T. E., Kurian, J. R., Jacoris, S., Pollak, S. D. (2005) Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proceedings of the National Academy of Science USA 102: 17237–17240.

Robert Desimone

BORN:

Norristown, Pennsylvania

June 12, 1952

EDUCATION:

Macalester College, St. Paul, BA Psychology (1974)

Princeton University, Princeton, PhD Psychology and Neuroscience (1979)

APPOINTMENTS:

Staff Fellow, Laboratory of Neuropsychology, NIMH (1980–1987)

Research Psychologist (tenured), Laboratory of Neuropsychology (1987–2004)

Chief, Section on Behavioral Neurophysiology, Laboratory of Neuropsychology, NIMH (1992–2004)

Chief, Laboratory of Neuropsychology, NIMH (1997–2004)

Scientific Director and Head of Intramural Program, NIMH (1998–2004)

Director, McGovern Institute for Brain Research at MIT (2004–present)

Doris and Don Berkey Professor of Neuroscience at MIT (2004–present)

HONORS AND AWARDS (SELECTED):

Troland Prize, National Academy of Sciences (1990)

Golden Brain Award of the Minerva Foundation (1994)

Fellow, American Association for the Advancement of Science (1999)

Member, National Academy of Sciences (1999)

Member, American Academy of Arts and Sciences (2001)

Fellow, Association for Psychological Science (2007)

Helmholtz Prize of the International Neural Network Society (2010)

Patricia Goldman Rakic Prize in Cognitive Neuroscience of the BBRF (2020)

Kavli Lifetime Contribution Award of the Cognitive Neuroscience Society (2021)

Ralph E. Gerard Prize in Neuroscience, Society for Neuroscience (2021)

Robert Desimone has mapped the ventral stream for object recognition of the macaque cortex and initially established the properties of cells in many of the areas, including cells selective for the images of faces. He found that attention to a behaviorally relevant object in a cluttered field results in the filtering out of distracting information from the receptive fields of ventral stream cells. This attentional filtering results from feedback to these visual areas from cortical regions, such as the lateral prefrontal cortex, enabling people to focus on the task at hand. Attentional filtering is also accompanied by the synchronous activity of cells carrying the relevant information, increasing their impact on downstream cortical areas. He also studies the neural basis of psychiatric disorders, using nonhuman primate genetic models.

Robert Desimone

Beneath the Windmill: Family Background

I was born into a working class, Italian immigrant neighborhood in Conshohocken, Pennsylvania, in 1952. I traced my recent ancestors and their genes to Avellino Province, near Naples—a place that was also the origin of Tony Soprano, the television character, not the actor. Mom emerged from a lineage of formidable women, and she held our family together in the face of adversity. Grandma, just as steely, lived with us for a while, and I learned not to ruffle her feathers. One of my lasting memories is that when she became annoyed with my pet chicken, she lopped off its head and served it up for dinner.

Dad enlisted during World War II and returned with emotional scars. While in the army, he went through electroconvulsive therapy (ECT) after a “nervous breakdown.” I am still not sure what that meant, but back then, ECT was a hammer, and every psychiatric disorder looked like a nail. I found on eBay one of the first commercial ECT machines from the World War II era and have it in my Massachusetts Institute of Technology (MIT) office as a reminder. I believe it was the fear of future psychiatric disorders in the family that first spurred my fascination with the mind and brain. It was a prescient fear.

After returning from the army, Dad was expected to work at Desimone Motors, my grandfather’s used car business in Conshohocken, rather than attend college. My grandfather often boasted that he sold a car to the gangster Al Capone, but he was vague about the details. The lot was surprisingly small, its most distinguishing feature being the small Dutch windmill that served as the business office—a quirky marketing ploy that didn’t exactly boost sales (Figure 1). Dad thought it was hilarious; I inherited his peculiar sense of humor, as well as his practical wisdom: “when someone comes onto the lot wanting to buy a pickup truck, don’t insist on selling them a station wagon.” I’ve applied this lesson when seeking funding from private supporters at MIT.

There were three of us kids; I was the eldest, followed by my sister and brother. Although Dad worked long hours in the car business and Mom worked part-time jobs in department stores to bring in extra money, we were poor—even by our neighbors’ standards. Our house had indoor plumbing, but Mom was mortified that her family home in town had only an outhouse. My parents desired more money and education but rejected those who flaunted either. We did not have many luxuries, but I have happy memories of spending virtually every day with large numbers of other kids from the neighborhood, largely free from oversight. My father parked a shell of a junk car from the car lot at our house, and it served as a neighborhood spaceship, time machine, fort, or whatever else was needed in the moment. I often wonder if the epidemic of social media use today is not mostly a compensation for loss of the communal environment in which we humans evolved.

Figure 1. Desimone Motors.

I was sent to a Catholic parochial grade school, where I discovered that I had a more focused state of attention than most other kids. When I was reading in class, I didn’t hear any distractions, including the recess bell. Was it a coincidence that I ended up studying attention? One thing you couldn’t ignore were the frequent duck-and-cover A-bomb drills, when we all hid under our desks in case the Soviets dropped a big one on Conshohocken. At the Catholic school, I learned to question anything that seemed unreasonable, and we were taught many unreasonable things in that school. In the third grade, the nuns told us there were only two mortal sins that God could not forgive when you went to confession: murder, and cheating on a test at school. Really? God put them in the same category? I decided to do the experiment on the next test, where I cheated on a question by looking at my neighbor’s answer. I soon confessed my sin to the priest of the church attached to the school, where I expected him to sentence me to say a few additional Hail Marys, the usual punishment for my sins. You can imagine my horror when he said, “son, there are only two mortal sins that God cannot forgive—murder, and cheating on a test.” It is presumably still on my permanent record, and I never tried to replicate the experiment.

Defying his father, my dad eventually left the car business, and we moved to different cities frequently as he pursued various jobs. The frequent moving set back our education, especially for my siblings. I lied about my age to work several low-wage positions, including janitor, factory worker, waiter, substitute mailman, and taxi driver. The night shift at the taxi company in Norfolk, Virginia, was perilous at that time—tales of drivers being robbed or shot were common, and I had a few harrowing experiences myself. Everyone had a contingency plan. One older driver showed me the two guns he carried in his cab, which he justified as necessary for self-defense and for staging a believable scene should he shoot an unarmed assailant. Casual brutality was a way of life. Instead of carrying two guns, I took fighting lessons from a man who said he had been a street fighter in India. I was no John Wick, but to this day, if I ever found myself in a rough bar in a city holding an SfN convention, and you tapped me on the shoulder from behind, I would know what to do.

Beyond coping with our trying family circumstances, I was taken up with the same political-cultural issues as anyone else who was growing up in the late 1960s, in particular, the Vietnam War. Although I protested against the war, I felt guilty knowing that, unlike some of my high school classmates who would certainly be drafted, I would get a college deferment if I was accepted at a college. I decided to take my chances with the draft lottery at the time, which was based on date of birth. If you chose to go into the lottery, and the random number associated with your birthdate was lower than the cutoff that year, you were drafted regardless of college. The lottery results were reported in the newspaper, and I was profoundly relieved when my number was too high for a realistic risk of being drafted. A lucky number felt morally superior to a college deferment, and I was spared any trauma in the war.

Thinking of my father’s nervous breakdown in World War II, I wanted to go to college to become a psychotherapist. The obvious path was to work to earn enough money to attend a local state college in Norfolk, while living at home. But my parents and I dreamed that I could somehow escape Norfolk. I read fiction voraciously as a child, and for many years, I believed that reading adventure and science fiction books was an escape from my childhood conditions. Isaac Asimov was one of my favorite science fiction authors, and I built my own telescopes from scraps, hoping to catch a glimpse of alien worlds. But now I wonder whether chronic reading of other worlds might also reflect an inherited personality trait, one that is poised to escape current conditions if needed. My father engaged in several famous fantasies of this sort over the years. In researching my ancestry, I found the passenger lists of the ships that took my grandparents and great-grandparents to the United States around the turn of the last century, which revealed that they had no English, no money, and no skills. I can only imagine what personal characteristics gave them the courage to leave their homeland for an unknown world. They were probably not unlike many of the immigrants at our border today.

My own far less risky escape plan was realized when I won a National Merit Scholarship based on a standardized test that was administered in my school, and I was offered a full scholarship to Macalester College in St. Paul, Minnesota. Macalester had many attractions, one of which was its distance from Norfolk. Although standardized tests like the SAT are sometimes criticized today, the test I took served its intended purpose for me, which was to give a chance to a kid who would not have been eligible for a good college, let alone a scholarship, based on their education in schools with poor reputations. The scholarship was endowed by DeWitt Wallace, the founder of Reader’s Digest magazine, and my mother was so thankful she kept a Reader’s Digest subscription for the rest of her life.

Escape to Macalester

The early 1970s at Macalester College was an idyllic time for me, where I developed a love of psychology—or, as it might now be called, cognitive science. Macalester was located in the city of St. Paul, but the immediate surroundings felt more like a small, Midwest college town, with the broad Mississippi River just a short walk down the road. Although Macalester lacked the prestige of Stanford or Harvard, I often remind my children that what you learn and do in school matters far more than where you go. Macalester offered me incredible opportunities, but one life-altering chance slipped through my fingers: the invention of one of the first computer dating applications.

For the psychology department’s holiday party one year, I devised an app using the only available computer at the time, an IBM machine that relied on punch cards. I have always been an early adopter of technology. I asked partygoers to complete a questionnaire in advance with items borrowed from a standard test of psychopathology like, “Do you believe that people are secretly planning to harm you?” To these I added a few of my own original questions. The app’s algorithm successfully matched people for dates at the party based on their answers. The buzz after the party was so positive, I analyzed the data, including survey results, to determine which questions had the most impact. To my surprise, the most influential question was one of my own: “On a scale of 1 to 10, how likely are you to sleep with someone on the first date?” If only I’d had the foresight to launch a business. I am reminded of this whenever one of my graduating students at MIT talks about striking out on their own.

During my first year at Macalester, I participated in an eye-opening class project that required me to spend a month living on a ward at a state mental hospital. The facility housed older, chronic patients unresponsive to treatment, and the experience brought me into the realm of psychosis. Witnessing adults shuffling through the corridors, babbling incoherently, or sitting catatonic in a corner, I wondered what could have gone so terribly wrong with their brains. It started a lifelong commitment to help people like this. That state hospital was later closed, like so many others, and I wonder today what happened to those patients. I hope that they were eventually treated successfully with better medications, but I fear that they were put out on the street with other people experiencing homelessness. When I later served as a volunteer in a call-in crisis center, it became obvious to me that untreated mental illness, poverty, homelessness, drugs, and abuse were all-too-common ingredients in a stew of misery in the city.

My last encounter with mental health facilities in college came during my senior year when I squandered all of my funds for housing on a used Volkswagen (VW) Karmann Ghia, a poor man’s sports car. The body was a work of art, but the VW engine had the power of a chipmunk. Used cars ran deep in our family. Taken by its beauty and naively hoping it would attract women, I quickly found myself broke. In desperation, I took a job as a live-in, nighttime emergency worker at a halfway house for young adults recently discharged from psychiatric wards. These residents, mostly stabilized with medications, needed help rebuilding their interrupted lives. The halfway house was in financial trouble and could no longer afford professional staff overnight. Consequently, I was left in charge of a large facility with an average of one suicide attempt per night.

My responsibilities included getting out of bed, calling an ambulance, and handling the crisis—tasks for which I was wholly unprepared. Yet, the residents took pity on me, shifting their suicide attempts to daytime hours when professionals were available. I had done nothing more than show up, looking young and incompetent, but the house director was so impressed by the significant behavioral change in the residents that she offered me a daytime counseling position upon my early graduation. Until that point, I had been torn between a career in brain research or psychotherapy. My experience as a counselor at the halfway house quickly revealed that talking with people all day wasn’t my calling, and my best chance in helping people with mental disorders was through brain research. The director of the halfway house agreed. And so, a new chapter began.

Pontifical Cells at Princeton

In looking for graduate schools, I visited Charlie Gross’s (see volume 6) lab at Princeton University, and I immediately fell in love with the lab. Everything about Charlie and the lab was unconventional, from his antiwar stance to his work on the inferior temporal (IT) cortex, which was terra incognita at that time. Charlie’s lab did basic research, but acquiring fundamental knowledge about the healthy brain seemed to be an essential first step before tackling mental illness. Although the department didn’t have the money to support me as a graduate student, I was saved by another award, in this case a National Science Foundation (NSF) graduate fellowship. That award was based on a combination of grades plus performance on another standardized test, the Graduate Record Examination (GRE), which again succeeded in its purpose of providing opportunities because I did not have a conventionally strong research background in college.

I have already written some stories about Charlie and the people in his lab who had such an influence on me, including Dave Bender and Ricardo Gattass [4], and I won’t repeat those stories here. Charlie valued independence most of all, which I learned on one of my first days in the lab. While cleaning up after an experiment, I accidentally dropped a monkey’s hard contact lens down the drain of a deep sink in the housing room. I had never seen a monkey contact lens before, but it didn’t seem like something that could be bought at Lens Crafters. I panicked and dismantled the plumbing to find it, not suspecting that the trap would be filled with truly disgusting things in addition to a lens. My resourcefulness made quite an impression on Charlie, and he told everyone afterward that he thought I would make it as a grad student. I’m not sure if I adopted Charlie’s attitudes on independence in the lab or if Charlie’s attitudes happened to fit my own existing personality traits, but I left his lab valuing independence and resourcefulness for myself, my lab, and everyone around me. Plumbing skills are a plus.

Although the face cells we found in Charlie’s lab are what everyone remembers now, when I arrived in the lab the controversial discovery had been the first “hand cell” in the IT cortex—that is, a cell that responded best to the silhouette of a monkey’s hand [6]. From what we now know, this cell was probably located in what is known as a body patch in the IT cortex. We didn’t find our first convincing face cell until Charlie Bruce, a postdoc in the lab, and I were recording from the superior temporal polysensory area, or STP [1], an area adjacent to the IT that I had discovered when mapping the temporal cortex [7]. In trying to find a stimulus to drive the cell, Charlie Bruce’s head passed in front of the projection screen, and the cell went crazy. Fortunately, I had previously set up a motor-drive contraption to sweep stimuli in front of the monkey, so that the stimuli could be presented under controlled conditions. At that time, the neuronal spike trains were recorded on analog tape rather than with a computer, and the trains of action potentials were photographed from the face of an oscilloscope, using a Grass Kymograph movie camera. We quickly started drawing faces on paper or putting face photos on cardboard to put on the mechanical arm, collecting data all the time. For some reason, we had a photo of the actor Al Pacino in the lab that the cell seemed to like very much. Many people incorrectly assume that it was a picture of me. “Analyzing the data” meant developing long strips of film from the Kymograph, hanging them up to dry, and assembling them by stimulus.

STP was full of interesting cells, and the two Charlies and I had a blast studying many of them. We published a paper on the findings, including that first face cell, Al Pacino and all [1] (see Figure 2). The reactions on the grapevine started arriving like the unwanted reviews of critics after a bad Broadway play. People didn’t believe it. While we were studying face perception in IT cortex, nearly the entire rest of the field was studying early visual cortex with bars and spots. The thinking was that with enough bar and spot detectors, you could represent practically any visual stimulus. David Hubel (see volume 1) visited the lab and told us that he thought IT cells were actually selective for very long bars (David later became an enthusiastic supporter of face cell research). I was feeling discouraged when, one day, I brightened up when a visiting Japanese neuroscientist told me that the STP face cell figure was the most famous scientific figure in all Japan. I practically fell off my chair. “People in Japan believe the face cell?” I asked. Maybe Japanese scientists were more open-minded. He looked horrified by my question. “Oh, NO,” he responded emphatically. We had also bombed in Japan.

Figure 2. Adapted from [1].

There were two general criticisms of face cells. The first implied that we were just incompetent. Nearly everyone who has had the experience of recording from cells in V1 has caused a cell to respond by accidentally putting your hand or face in front of the animal. With careful study, it usually turns out that the angle of your nose just happened to be the right angle for an oriented simple cell, not that the cell was selective for faces. Needless to say, we had the same worries, so we carefully ruled out alternative explanations for the face cells. The other criticism was that face cells implied a model for object recognition that many felt just couldn’t be true. The disbelief may have arisen from Horace Barlow, who had imagined a hypothetical “grandmother cell” that would respond only to the image of your grandmother, or William James, who had earlier imagined a “pontifical cell,” that would hold the experience of seeing a specific object. How could there be enough cells in the brain to have a cell dedicated to every percept or experience? Not many people imagined neural circuits for face perception in which your grandmother or the Pope would be coded by large populations of cells selective for general face features rather than individual cells dedicated to individual people. I certainly did not imagine that years later, the face cells and face patches of IT cortex would now be in nearly every neuroscience textbook.

Many people today don’t realize how conservative the field was in the 1970s. In addition to face cells, another controversy was about whether spatial frequency analyses should be used to study early visual areas. As I mentioned earlier, at that time most of the field was firmly entrenched in the idea that the rich visual world was decomposed into bars, spots, and edges in areas, such as V1. Russ and Karen DeValois proposed, instead, that the visual cortex performed a local Fourier decomposition of visual scenes, and complex objects were reconstructed from their local spatial frequency components. No one grasped the idea that V1 cells operated as oriented, spatiotemporal filters that could be studied equally well with bars or gratings. The controversy was so heated that the SfN hosted a debate between the bar and edge advocates and the grating advocates, with Karl Pribram (see volume 2) serving as the moderator. Although I have enormous respect for Torsten Wiesel, he was one of the bar and edge leaders at that conservative time. Once, he visited Princeton, and after his inspiring talk, an assistant professor in the department tried to gently probe him about the spatial frequency approach. She asked him if he ever tried stimulating V1 cells with two bars, and Torsten was very excited to talk about how the cells treated double edges. Then she asked him if he ever tried three bars, and Torsten suddenly realized where the questions were headed. His response was that using gratings as stimuli would be like spitting in the street, something that he just couldn’t bring himself to do.

I tried to balance studying face cells with less controversial studies. Tom Albright and I discovered the axis of motion columns in MT [8], and Julia Fleming and I used horseradish peroxidase (HRP), then a new anatomical tracing technique, to map the inputs to IT cortex [9]. With Eric Schwartz and Tom Albright, we conducted the first studies showing invariance for stimulus size and position by IT neurons [10]. For that study, we were finally able to give up photographing the oscilloscope face and instead collected the data with a PDP-12 computer, the cool new technology at the time. A green-colored monster, it stood six feet tall, weighed 900 pounds, and held 4K of memory, which was less memory than taken up by an emoji on my current phone. It generated a great deal of heat, and when it became freezing in Charlie’s basement lab, someone would invariably call out to fire up the PDP-12. After searching for more than 30 years, I finally found a PDP-12 on eBay and have it on display at MIT, where it now generates more puzzlement than heat.

But with my doctorate in hand, the time in Charlie’s lab came to a close. Mort Mishkin offered me a position at the National Institute of Mental Health (NIMH) once held by Pat Goldman-Rakic before her departure to Yale, and Richard Nakamura, then a postdoc in Mort’s lab, led the recruitment. I had already been awarded an NIH postdoctoral fellowship to join Peter Schiller (see volume 7) at MIT. However, Peter generously encouraged me to accept the NIH opportunity, as it could pave the way to tenure. Charlie left me with a valuable piece of advice: focus on doing good science, not chasing tenure. The people who deserve tenure are the ones who don’t need it.

Mapping the Cortex at NIMH

Mort’s lab in the intramural program (IRP) of NIMH was in Building 9, a World War II–era building that was meant to be temporary, but it served as Mort’s lab until a new research building was built to replace it next door. The building had a long history of primate research. Some older technicians told apocryphal stories of a time when chimpanzees (long gone from the building) shared cigarettes with the animal caretakers. Pat’s former lab space had been commandeered by others in the lab, leaving only an undesirable room for me. The room contained a raised wooden floor that had collapsed with rot, a steel inner chamber for electrical shielding, and a two-foot gap that separated the inner chamber from the outer cinderblock walls. This gap was crammed with years’ worth of neglected garbage, and light fixtures dangled precariously from the suspended ceiling.

Coming from Charlie’s lab, I remained unshaken. After renovation and the removal of the rotten floor and trash, the room revealed itself to be far more spacious and pleasant than expected, with an improved aroma. Mort had secured a $25,000 “start-up package” for me, which barely covered the CPU box of a PDP-11/34 computer, a successor to the PDP-12. By the following year, I could afford the necessary disk drives (5 Mb per drive!), and I scavenged most of the rest of what I needed from government surplus, which held everything from oscilloscopes to rocket launchers.

Mort Mishkin and Bob Wurtz (see volume 7) were really ahead of their time as lab heads at the NIH. Except for Mort and Bob’s labs, most of NIH at that time operated as a kind of feudal system, with the lab heads directing all of the research, including research by several senior scientists beneath them. Although the position of a tenure-track junior scientist did not formally exist at that time at NIH, Mort treated me as one and let me do what I wanted. I initially continued to study face cells and other complex properties in IT cortex. I presented my work on face cells to the NIMH Board of Scientific Counselors (BSC), which evaluated all labs every four years, and whose recommendation was essential to keep your funding. The scientist from Harvard assigned to review me (not Hubel or Wiesel) told me privately that he didn’t believe in the face cells, and even if he did, it would be the end of my career if I continued to study them. I published one final paper on face cells in IT cortex [11], which reported the properties of larger numbers of cells and received even more attention in the field, and then I switched to mapping, anatomy, and physiology of the mostly unexplored extrastriate cortex.

Initially, I was angry to receive the advice to drop the study of face cells, and I was greatly tempted to follow Charlie’s advice to ignore tenure and concentrate on the science. But in retrospect, it was probably the right decision. At that time, finding a face cell in IT cortex was like finding a needle in a haystack. Without guidance from functional magnetic resonance imaging (fMRI), which was not available then, I could be recording for months before finding one. It was 13 years later when Nancy Kanwisher, Josh McDermott, and Marvin Chun found a face selective patch in IT cortex using fMRI in humans [12]. The definitive experiment in monkeys was then done by Doris Tsao, Winrich Freiwald, and Marge Livingstone (see volume 9), who localized a face patch in IT cortex using fMRI and then targeted it with electrodes for recordings [13]. The face patch was chock full of face-selective cells. Finally, there was a method for routinely locating them and studying their properties, but I had already moved on.

Leslie Ungerleider in Mort’s lab was the ideal collaborator for extrastriate studies. Leslie’s background was in primate behavior with Karl Pribram, but she later studied primate anatomy with Ted Jones. We mapped and/or studied the anatomy of areas MT [14–17], MST [14, 18, 19], FST [14, 19], V4t [14], TEO [20, 21], IT [22], and the posterior parietal cortex [22]. We didn’t have computer programs to flatten the convoluted cortex to display the data then, so we built models of the brains out of wires and solder, and physically flattened them. They were literally wiring diagrams. Stan Schein and I also studied the properties of cells in Area V4, showing that this key area of the ventral stream processed many types of information that was relevant for object recognition and not just color features, as others had claimed [23, 24]. By the conclusion of our studies and those of David Van Essen (see volume 9), Ricardo Gattass, Semir Zeki, John Allman, Jon Kaas (see volume 9), and others, we had at least a beginning sense of the organization and physiological properties of the dorsal and ventral streams for spatial and object vision [25, 26]. After a couple of years, Leslie and I decided to get married, and a couple of years later, we adopted a child, Matthew.

Mort’s lab was the perfect environment for primate research. Just before I went to his lab, Mort had reported the first primate model for human temporal lobe amnesia, for which the patient HM was the prime example. After I joined the lab, Mort and Leslie Ungerleider published their extremely influential account of the dorsal and ventral streams for spatial and object vision, respectively, in primates. At that time, before optogenetics, the major causal method for studying brain function was the lesion method, and Mort was the legendary master of lesions. His lab grew into an intellectual epicenter for perception and memory research in the brain, with rising stars, such as Betsy Murray, Jocelyn Bachevalier, and John Aggleton, all part of the memory brain trust. Mort knew the history of the field, partly because he had worked with some of the historical figures such as Donald Hebb. Not surprisingly, a focal point for his lab was the lab library, lined with boxes that held thousands of reprints. These were the days before electronic journals. Many discussions with Mort resulted in a trip to the library reprints, which were indexed by cards held in a tall oak chest with narrow pullout drawers, similar to the ones in any large library. The system worked well, until one summer a student was assigned the job of organizing the cards alphabetically, which they did according to the first name of the first author on the papers.

The lab library was the scene of another amusing event, but first I should say something about Mort and Charlie (Figure 3). Both were great mentors because they loved to discuss ideas with their mentees, and both had a very high regard for each other. But their styles and personalities were very different. Charlie was iconoclastic and rejected formality and many social conventions. My memories of him are in cutoff corduroy shorts, Birkenstock sandals, and long beard. Mort was very approachable, but he also dressed and acted a little “stuffy.” I don’t think I ever saw him in shorts. I would say he was easily shocked, most memorably at a birthday party held for me in the lab library. On that day, we were sitting around a table eating cake, and a woman showed up from NIH procurement, to chastise me in front of the lab for having filled out the wrong form for an order. After chewing me out, the woman reached behind her back and pulled down the long zipper of her shift dress, which fell to the floor. Anticipating his reaction, everyone turned to Mort, and the horrified look on his face was priceless. Underneath, she was dressed as Wonder Woman, and she burst into song. She worked for a service and had been paid by Leslie. That stunt worked better on Mort than it would have on Charlie, who would have been unfazed.

Figure 3. Mort Mishkin, Bob Desimone, and Charlie Gross at a Festschrift for Mort Mishkin in 2016.

Mort was a great mentor to me, but he had a troubled relationship with one of his own mentors, Karl Pribram. Karl was a prominent neurosurgeon and primate neuropsychologist, who ironically had a finger torn off by Washoe, the famous chimpanzee that spoke in sign language. It wasn’t clear what message Washoe was trying to send Karl. Karl taught Mort neurosurgery, but some of his ideas had been disproven by Mort, and he resented Mort’s success. One day, Karl visited the lab at NIMH and offered to give a talk in a seminar room. Mort asked if he had slides to show, which in those pre-PowerPoint days were actual two- by two-inch photographic slides loaded into a carousel in a Kodak projector. Karl declined, saying he would speak off the cuff. The lab members and I assembled for the talk, and after a few minutes, Karl said from the podium that he just remembered a slide he would like to show, and would Mort please take it from him and put it in the projector. Every minute or so, Karl would remember a new slide, and Mort would come up from the audience and take the slide to the projector at the back of the room. After a few slides, Mort asked Karl if he would put all of his slides together at once, so that he could load all of them into the carousel for the rest of the talk. Karl declined the offer, and for the rest of the talk utilized Mort as his personal slide boy. Washoe would have understood that message. Sometime later, Mort casually mentioned that junior scientists are not given independence by their mentor, they need to fight for it.

Paying Attention

I would love to say that I began my work on attention because I anticipated that a key architectural feature of the transformer networks (like GPT-4) of the future would be the attention layers. Unfortunately, the origin was more mundane. All of my recordings in the ventral stream in those early years were in anesthetized monkeys, and a major frustration was the variability of visual responses in areas like V4 and IT cortex. One moment there might be a strong response to the image of a face, and another moment there might be no response at all. I wondered whether this variability was due to the fact that the animal was anesthetized and not attending to the stimuli.

A puzzle with that explanation was that all of the work showing attentional modulation of cells in the monkey was in the superior colliculus or the dorsal stream cortex rather than the ventral stream. In fact, Bob Wurtz and Barry Richmond had searched for and failed to find positive attentional modulation of cells in IT cortex [27]. If attention was only relevant for the dorsal stream, its purpose might be limited to facilitating behavioral responses, such as eye and hand movements, rather than to facilitate object perception, which was more cognitive. I reasoned that understanding the mechanism of attention could be the gateway to understanding conscious awareness, which was more than a motor response. I thought an important clue to this puzzle might be that Bob and Barry had used a conventional diming task with simple spots and gratings when they failed to find positive effects of attention in IT cortex. Maybe it would be necessary to use a task and stimuli that engaged object recognition in the ventral stream.

Jeff Moran was my research assistant at the time, and he was looking for a thesis project to complete the doctorate he had started in graduate school. We therefore began to study the effects of attention in awake monkeys using a match to sample task with complex images, in V4 and IT cortex, which eventually became Jeff’s thesis project. At the time, the field was split between the majority of labs working in anesthetized animals and a small minority of labs working in awake animals. If I had been an assistant professor in a university, it would probably not have been possible to make the switch. There would not have been the money to reequip the lab, and I probably would not have received a grant without having first trained in an awake monkey lab or at least having collected preliminary data. But the IRP was supposed to be a place to take risks, and Mort and the NIMH administration gave me the funding to buy the necessary equipment. Bob and Barry were encouraging and offered helpful advice on how to record from awake, behaving animals, which turned out to be less difficult that I feared.

When we started to record from IT cortex, we immediately faced a problem. All of the attentional studies to that point had studied attention with one stimulus placed inside the receptive field (RF) of the recorded cell and one stimulus outside, with the monkey holding gaze on a fixation spot. One could then compare responses when the stimulus inside the RF was attended (the target) versus when the stimulus outside the RF was attended (distractor). The two stimuli were often identical. But the IT RFs were often so large it was difficult to place a stimulus outside the field. I was unable to do the intended experiment on the first cell recorded. To get around this problem, I decided to place inside the RF one “good” stimulus that could stimulate an IT neuron effectively on its own, and a “poor” stimulus, that elicited little or no response on its own. The good stimulus for one cell might be the image of a face and the poor stimulus might be a hand, for example. I reasoned that the poor stimulus would act like a stimulus outside the RF, since there would be little response. With two stimuli in the RF, the monkey was then cued to attend to one stimulus or the other.

I was very surprised to find that when the animal attended to the good stimulus in the RF the response was strong, but when it attended to the poor stimulus, the response was poor, even though both stimuli were located inside the RF at all times. If we reversed the locations of the stimuli in the RF, we got the same result. Thus, the effect of attention could be either to enhance or suppress the cell’s response to the pair, depending on which stimulus was attended. Listening to the cell’s response on a loudspeaker, I could hear the cell tracking the monkey’s internal focus of attention as it shifted between stimuli. I felt that I was reading the monkey’s mind. We proposed that the cells acted as though the effect of attention was to shrink the RF around the attended stimulus, excluding the unattended distractors, probably explaining why we had little awareness of unattended stimuli. This seemed a much more cognitive role for attention than how attention operated in the dorsal stream, where it seemed suited for facilitating motor responses. As I will explain later, I may have been too quick to dismiss any role for motor responses in attention in the ventral stream, but at least we had established the cognitive component.

We found similar results in V4. The paper reporting these results is my most cited empirical paper, and the results were much more readily accepted than my initial studies on face cells. The role of attention in the ventral stream eventually became a model system for studying a basic element of cognition and even conscious awareness. As a side note, the neuronal responses in awake, behaving animals were much more reliable than in anesthetized animals, so I made a permanent switch to awake animals. Jeff received his doctorate and went off to Pat Goldman-Rakic’s lab for postdoctoral work.

One conclusion that I got wrong in that first study was that in area V4, it first appeared that there was no effect of attention on the response if only one of the competing stimuli was located in the RF. In retrospect, that was likely because the task was too easy for the animal and the stimuli were very high contrast. Shortly after that first study, Hedva Spitzer in my lab did find that attention could enhance the response to the RF stimulus under those conditions, if the task was made more difficult [28]. The effects of attention were much smaller than when there were two competing stimuli in the RF, but they were nonetheless significant. John Reynolds in my lab also later showed that the magnifying effects of attention on the response to a single stimulus in the RF were stronger when that stimulus was lower in contrast, suggesting that the effects of attention were to enhance neuronal sensitivity to the attended RF stimulus and not just magnify responses [3, 29]. It wasn’t until years later when I was at MIT that Ethan Meyers, working with Tommy Poggio (see volume 8) and myself, formalized how attention solved the problem of how objects can be decoded when embedded in clutter [5].

Biased Competition

I was very fortunate to have the British psychologist John Duncan conduct his sabbatical in my lab in the early 1990s. John was well known for a dispute with Anne Triesman (see volume 8). Anne believed that the purpose of attention was to bind together all the features of a single stimulus at a time (e.g., to bind the orientation of a bar with its color), whereas John believed that attention was just a type of bias that could shift visual processing from one stimulus or feature to another. We decided that the neurophysiological work in my lab supported John’s views, and we collaborated together on a model of attention we termed biased competition, that combined psychological and neurophysiological arguments [30].

The biased competition idea received more attention, so to speak, than either of us could have imagined, and was widely cited. The basic idea was that because of the large size of RFs in the ventral stream, multiple objects in the visual field were typically located within these RFs, resulting in reduced information about any individual object. When John Reynolds was a postdoc in my lab, he had shown that, in the absence of attention, the response to two stimuli in the RF was close to the average of the response to either stimulus alone rather than the sum, which was evidence for competition [3] (see Figure 4).

Top-down feedback from structures important for attentional control, such as those in prefrontal cortex (PFC), biased that competition in favor of the most behaviorally relevant stimulus at the time. The bias was evident from the enhanced response to a single attended stimulus in the RF, and the effects on competition were evident by the effects of attention shifting the cell’s response from one stimulus to another, when there were two competing stimuli in the RF. In a collaboration with Leslie Ungerleider and Sabine Kastner, then Leslie’s postdoc, we found in human subjects results that were compatible with the animal work, including the influence of RF size [31, 32], using fMRI. Sabine then took a faculty position at Princeton, where she is one of very few people who successfully combine human and monkey work on attention.

Our biased competition account of attention offered an alternative to the idea that attention bound together objects or features—we saw feature binding as an indirect consequence of filtering distractors, and thereby possible incorrect feature pairings, out of the RF [2]. It also argued against the idea often derived from work in the dorsal stream that the role of attention is mainly to facilitate motor responses to a stimulus.

Figure 4. A quantitative account of biased competition. Left: The oval on top represents the neuron being recorded, whose firing rate is designated by the variable y. The two ovals below represent populations of “input” neurons that respond to the good and poor stimuli and that project to the upper neuron. The average responses of the input populations are designated x1 and x2. Black lines represent the excitatory projections from each input population to the measured cell, and gray lines indicate the inhibitory projections, which are assumed to depend on inhibitory interneurons (not shown in figure). The variables w1 and w2 stand for the magnitudes, or weights, of the excitatory projections from the two input populations, while w1 and w2 stand for the weights of the inhibitory projections. The equations are described in [2] and [3]. Right: Illustration of large receptive field (y) derived from inputs from smaller receptive fields (x), modeled on the left. The cone and circle represent the focus of attention on X2. This increases the weights from X2 to Y (right). With attention directed outside the receptive field, the response is close to the average of the response to each stimulus alone. The role of attention to a stimulus is to increase the weights from one input population, so that the cell responds primarily from that input. Adapted from [3].

The idea that attention biases competition between neurons, or object representations, has now been realized in computational form as a normalization model of attention, where the competition between object representations is a type of normalization, and attention is mediated by feedback to visual cortex that biases responses toward one input or another. The first quantitative model was developed by John Reynolds in my lab [33] (Figure 4). John came to the lab from a purely computational background, but he wanted to combine modeling with neurophysiology. Joined by Tania Pasternak, then taking her sabbatical in my lab, he tried to understand the finding that the effect of attention could be to either increase or decrease the response to a pair of stimuli in the RF, depending on which one was attended. The key insight was that every input to a cell derived from a stimulus must have both excitatory and inhibitory components and that the response of the cell to multiple inputs must be due to the weighted integration of all these excitatory and inhibitory inputs, or a type of normalization process. This is why, in the absence of attention, when there were two competing stimuli in the RF, the response of the cell to the pair was typically the average of the response to each stimulus alone. The role of attention was to bias the weights of the inputs from one stimulus to another. When Leonardo Chelazzi was a postdoc in the lab, he extended these findings to visual search in V4 and IT cortex [34–36]. John Reynolds developed straightforward formulas that gave a quantitative basis to the biased competition idea. Later, he and others [37] expanded on the normalization models, and they remain the most prevalent mathematical accounts for the role of attention in visual cortex today. The biological basis for those mathematical models remains unknown.

When Beth Buffalo was a postdoc in my lab, she took the attentional studies in a more causal direction, directly testing whether lesions of V4 or TEO would reduce the filtering of distractors by downstream IT neurons, as the biased competition account predicted. Richard Saunders, who learned surgery under Mort, did the lesion. In collaborative studies with Leslie, Beth, Peter DeWeerd, and Guiseppe Bertini, we found that the V4 and TEO lesions not only caused a behavioral impairment when the distracting stimuli were nearby to the target (within the range of a V4 or TEO RF) but also reduced attentional filtering by IT neurons using the same stimulus configuration, as we had predicted [38–41]. The combination of a causal manipulation coupled with both behavioral tests and neurophysiological recordings became the template for many of my future studies. I am proud to say that Beth eventually became the chair of her department at the University of Washington.

The Rhythm Method

Although I was comfortable with these accounts of attention in visual cortex based on firing rates, Wolf Singer (see volume 9) often asked me about the possible role of synchrony, or rhythmic neural interactions, in explaining the effects of attention. Wolf was well known for the idea that gamma rhythms between neurons responding to different stimuli or to features of the same stimulus might bind together these different representations. No one in my lab was willing to test this high-risk idea in the context of attention, but one day I received a note from Wolf that an extremely talented former student of his, Pascal Fries, wanted to come to my lab to do just that sort of experiment.

Pascal turned out to be one of the most efficient people to ever work in my lab. With help from John Reynolds, he set up the experiment and finished the data collection in record time. Contrary to the expectations of everyone in my lab, including me, he found a clear enhancement of gamma synchrony with attention to a stimulus in the RF of neurons in V4 [42–45]. Our thinking was that this gamma synchrony between cells would enhance their impact on downstream neurons simply due to the limited integration times of postsynaptic cells. An increase in synchrony would be the equivalent of an increase in firing rates. If you are in a room full of people talking randomly, one good way to be heard is to join a group and sing synchronously.

A puzzling later result from Beth Buffalo and Pascal Fries in the lab was that low frequency synchrony was reduced by attention, and this low frequency synchrony was prevalent in the lower layers of the cortex, whereas gamma synchrony was more prevalent in the upper layers of the cortex, suggesting that synchrony played very different roles in different layers. Yasaman Bagherzadeh trained human subjects to control their alpha with neurofeedback and found that it was negatively correlated with attention [46]. Most recently, in a collaboration with Earl Miller’s lab, Diego Mendoza-Halliday, Andre Bastos, and Alex Major found a common spectrolaminar pattern across several cortical areas in several species, from mice to humans, with gamma in the upper layers and alpha-beta in the lower layers [47]. This difference between layers may have something to do with their differential roles in feedforward and feedback connections.

Although no one denies the prevalence of synchronous interactions, because they are now found everywhere that anyone looks, I find that there is still a split in the field over their mechanistic interpretation. I find it odd that many people believe that the only important way for cells to communicate is through changes in average firing rate, as though firing rates and synchrony were mutually exclusive. I am encouraged that the field is becoming more receptive to the role of synchrony in neural computation, and I have no doubt that better tools, including high-density recordings and voltage imaging, will settle these questions.

Memory: Recordings of Things Past

The other cognitive line of research I pursued at NIMH was memory, initially with my postdoc Earl Miller, who also received his doctorate in Charlie’s lab. He was both Charlie’s scientific child and grandchild. Earl loves to tell stories of his desk in the decrepit basement of Building 9, which was located under an asbestos covered steam pipe and reached by traversing former rabbit warrens. The service elevator to the basement had an old brown stain on its wooden floor, which was rumored to have come from someone losing their leg in the iron gate that served as a door.

Earl and I published a paper in Science, in which we reported that repetition suppression served as a mechanism for working memory in IT cortex [48]. Repetition suppression was the name we gave for the phenomenon that neuronal responses to repeated presentations of the same stimulus were typically suppressed. Afterward, we added a new behavioral condition to the task, which revealed that our previous conclusion about memory was probably premature. We found a new mechanism, based on enhancement rather than suppression of IT responses to repeated stimuli, but only when the repeated stimulus was actively held in working memory. Repetition suppression was a passive mechanism, but the enhancement was active. With this new result, it seemed that repetition suppression had properties more suited for perceptual learning and a general sense of familiarity. We published a second paper in Science reporting the new results [49] in IT cortex and another one on PFC [50]. I fondly remember that my long-time friend and mentor Larry Squire (see volume 11) was incredulous that Science would publish a paper attacking a previous Science paper, by the same authors. These papers were part of Earl’s phenomenal record in the lab, which helped him land a faculty position at MIT, where he is now a distinguished professor.

Wendy Suzuki came to my lab as a postdoc after receiving her doctorate with Larry Squire. Larry and Mort had enormous respect for each other, but they pursued a friendly rivalry over the years, with different ideas about the organization of the medial temporal lobe system for memory. In my lab, Wendy found that the memory mechanisms based on response enhancement in IT cortex also extended into the entorhinal cortex, but these entorhinal responses were enhanced not only for objects that matched items held in memory but also for the locations of objects that matched locations held in memory [51]. These neuronal findings gave us a possible explanation for the behavioral studies showing the importance of entorhinal cortex for object and place memory, and we were planning to continue this work to understand how the dorsal and ventral streams might converge in the medial temporal cortex.

Cindy Erickson, another postdoc in the lab, also made the very interesting observation that cells in the perirhinal cortex of IT began to respond similarly to successively presented stimuli, based on simple temporal contiguity of the stimuli over time, a type of unsupervised learning of associations in the cortex [52]. For example, if an IT cell responded well to the image of a fork but not a spoon, repeatedly pairing the two stimuli might cause the IT cell to respond well to both. This seemed to be an essential element of an associative memory. The work on memory was picking up steam; however, I was soon faced with vastly increased administrative responsibilities, as described next, and I decided that something had to give. That something was my lab’s work on memory, which I put on ice for many years. Fortunately, Earl, Wendy, and Beth all continued to pursue memory mechanisms in their own labs. I am happy to say that Wendy eventually became a dean for the School of Arts and Sciences at New York University.

Mental Illness

Steve Hyman (see volume 10) became the NIMH institute director in the mid-1990s, one of a cadre of innovative institute directors recruited by then–NIH director Harold Varmus. The institute directors are responsible for both the intramural (IRP) and extramural programs of the institute. Steve was a psychiatrist, but he preferred to have a basic research scientist as scientific director and head of the IRP. The IRP had previously made the transition from a psychoanalytic clinical orientation to a more biological orientation, and Steve wanted an even firmer neuroscience foundation. A previous scientific director, Seymore Kety (see volume 1), was a key figure in the early transition, and he told the story of being approached by IRP psychiatrists, who said that like all previous scientific directors, he should undergo Freudian psychoanalysis. He responded that he couldn’t afford it, and that seemed to solve the problem for the moment. But the psychiatrists returned, saying that they had taken up a collection, and they would pay for his psychoanalysis. Kety responded that if they had taken up a collection to remove one of his kidneys, he wouldn’t take them up on that offer either.

Steve failed twice in recruiting a new scientific director, mostly because of some of the unattractive features of government service. Given the demoralizing failed searches, Steve offered me the position. The IRP was the largest mental health research program in the world, with more than 65 principal investigators (PIs), a budget of more than $145 million a year at that time, many staff scientists and psychiatrists, and a major clinical program that included psychiatric wards with patients spanning children to the elderly. Although the position was intimidating, I felt an obligation to support an institution that had supported me for so many years. I figured that I was being given the opportunity to shift from only taking satisfaction from the success of my own lab, to taking satisfaction from the success of the people I supported. But I also saw that this position would bring me full circle back to working on mental illness, which is why I had started in the field.

I was sent to interview with Harold Varmus, a Nobel Prize winner who was a very informal and down-to-earth NIH director. My parents would have liked him. Harold himself had little administrative experience when he became NIH director, so I didn’t think my lack of experience would faze him. When I went to see him, he had just come back from playing squash, and he asked if he could interview me from the other side of the door of the bathroom attached to his office, as he needed to take a shower. I am sure that wasn’t in the NIH human resource (HR) handbook. Harold’s lack of any pretentions served him well in his relationships on Capitol Hill, where he was well-trusted. His message to me that day from behind the bathroom door was that the public deserved much more progress than it was getting from the money invested in the IRP and that the NIH needed me to take on this challenge. It was time to revitalize the IRP.

Moving from lab chief to IRP head turned out to be more difficult that I imagined, and it was only possible because of the enormous help I received from Su Koester, my deputy director; David Rubinow, the NIMH clinical director; and Barry Kaplan, the training director. It also helped tremendously to have Story Landis occupying a parallel position as the scientific director of NINDS. Like me, although she had a doctorate, she was nonetheless responsible for a clinical program. She was also learning on the job, and I like to think that we served as role models for each other.

I knew nothing about managing a large program, and after my first couple of staff meetings, the staff bought me both a gavel and a video on how to hold a meeting, narrated by the comic actor John Cleese. The tape was funny, but the administrative problems were no joke. I eventually paid for management consultants to review the IRP and give me some administrative advice. One piece of advice I remember was to listen to the people in the program and not ride into town like a new sheriff in the old west, to clean things up. I like to think I learned to listen more, but when they finished, they said I had moved from a C to a B−. Much room for improvement.

The first big challenge in my new position came when I was brought a stack of clinical protocols and was asked to sign off on their scientific merit. As a basic scientist, I didn’t feel fully qualified to judge whether or not the clinical protocols really had merit, but I was skeptical about some of them. In one of the first reviews by the BSC of a clinical lab I attended, the PI presented the results from the use of bright lights to treat depression, compared with the placebo control of sitting in front of an “ion box.” When the clinical results turned out to be equivalent, he suggested that the results were not actually negative because they revealed that the ion box was actually a good antidepressant because of some unknown property of the ions. I called in an outside committee of top psychiatrists to evaluate all of the protocols in the IRP, so we could start with a fresh slate.

The result was depressing. The external committee recommended suspending more than half the existing protocols in the program because they just did not seem novel or important enough to proceed. What I learned was that the clinical research pipeline in the IRP, and really the country as a whole, was running dry of new ideas, which was profoundly discouraging. It was also discouraging to our IRP psychiatrists, who were dedicated to helping their patients. That dedication is probably what led to some wishful thinking about their research findings. With help and support from Steve Hyman and Dave Rubinow, I recruited Dennis Charney to head a new clinical branch, and together with Su Koester, we worked as a team to turn over more than a third of the PIs in the IRP over six years, freeing up lab space, money, and positions for new recruits. Although I tried to treat everyone with compassion and respect, and made all decisions following peer review by the BSC, reassigning so many people and encouraging them to move on was the most difficult part of my job.

Hiring new people was the best part of the job, and one of our new recruits was Carlos Zarate, a young psychiatrist. I can’t claim to have foreseen it then, but Carlos, along with Husseini Manji, Dennis Charney, and others achieved probably the greatest success in the revitalized clinical program by starting the first randomized trial of ketamine for depression, which we funded. This was the first novel mechanistic approach in psychiatry in many years, and the success of ketamine alone probably justified the cost of the new clinical program. Ketamine is also replacing ECT for some applications, so it has personal significance for me.

The profound impact of serious mental illness on patients and their families was brought home to me, when our young teenage son, Matthew, became mentally ill. He became delusional and was hoarding knives, and his psychiatrist recommended hospitalization because he was a danger to himself and others. It was devastating to be unable to help him even though I was the head of the largest mental health research program in the world. The day that Leslie and I sent him to the psychiatric hospital was the worst day of our lives, up to that time. He was later transferred to a residential treatment center for juveniles that was attached to the hospital, but after more than a year, it couldn’t help him or even control him, so they simply released him.

For the next several years, Leslie and I went through some of the turmoil that other families have gone through when handling a mentally ill child, including the crisis of the week, the numerous therapy programs, numerous medication changes, a SWAT team raid on our house, and an unwanted journey through the juvenile justice system when things got out of hand. What struck me in the group family therapy sessions was how commonly psychologists assumed that if a child was having serious problems, it must be the result of some bad behavior of the parents. Indeed, some of the parents in therapy did seem to have serious problems of their own, including depression and substance abuse. But my view was that these parents were struggling with many of the same genetic vulnerabilities as their children. The entire families seemed like victims of mental illness to me.

We were trying (unsuccessfully) to recruit Ken Kendler to the IRP at the time, and Ken was the foremost psychiatric genetic epidemiologist in the country. At the recruitment dinner, I asked Ken what he thought of The Nurture Assumption, a controversial book by Judy Harris. Judy Harris claimed that parenting, or the shared family environment, had little influence on how children turned out, including personality, talents, mental problems, academic success, and so on. She argued that both genetics and the peer group had larger influences. Ken was adamant that he had the actual heritability data from twin and adoption studies on the contribution of the family environment to the child outcome on multiple measures, and that Harris was wrong when she said that parenting had no role. “So, Ken,” I asked, “what is the number? How much of the variance in how kids turn out is due to the parenting?” He stated authoritatively that 4 percent of the variance was due to the shared family environment, not 0 percent like Harris claimed. So, there! Parenting counted for 4 percent. Judy Harris would be gratified to hear that. Ken seemed taken aback when the table erupted in laughter. It is still not settled how much parents can effectively guide their children, but new research supports the idea that polygenetic factors play an important role together with the overall environment in shaping personality and cognition. When I tell this story, I often find that parents who have highly successful children think I am deranged, but parents of children who have had serious problems often feel relieved and even grateful. I ran into Ken recently and asked him if, after 20 years, there was update on the percent variance explained by the shared family environment. He said the number was still 4 percent.

After a few years, Matthew’s life was saved for at least a time by Ray DePaulo, then chair of psychiatry at Johns Hopkins Hospital. Ray agreed to take Matthew into the Hopkins juvenile psychiatric ward, where he took him off all medications to start with a fresh baseline. That had never been done with him before, and I considered it a critical element of the scientific method, in contrast to the many physicians who seemed to pile on one medication after another chasing symptoms and side effects. When Matthew was clean, Ray prescribed lithium, the original bipolar medication which had not been tried before because valproic acid, a newer medication for bipolar disorder, had seemed ineffective. After about two to three weeks on lithium, a miracle occurred. Matthew seemed restored to the wonderful boy we knew before all of his troubles. Bipolar disorder seemed like the right diagnosis, although I no longer believe that psychiatric diagnoses have much mechanistic validity. We did not live happily ever after (both Matthew and Leslie died too young), but lithium at least brought relief to Matthew and indirectly to Leslie and me for several years. However, as frequently happens in families who have gone through trauma, Leslie and I divorced.

In one of the final chapters of that era, the NINDS director Gerry Fischbach (see volume 9), Steve Hyman, Story Landis, and I initiated a proposal to build a new neuroscience building, the Porter Building. Su Koester and I wandered around the NIH campus and found the perfect spot. Steve and Gerry convinced the NIH leadership to persuade Congress to fund the building, and we worked with the other neuroscience institutes and the brilliant architect, Rafael Vinoly, to design it. Rafael designed a stunningly beautiful building. Unfortunately, it ran over budget, and we were forced to go through what was euphemistically called “value engineering.” Value engineering meant removing from the architectural plans many things that were really nice, including many of the restrooms. Seeing the building being occupied with new people was like witnessing the birth of a baby. With the building completed, I became focused on how to fill the clinical pipeline with new ideas that could help families.

McGovern Institute at MIT

In late spring of 2004, I was approached by Bob Brown, then the provost of MIT, about the directorship of the McGovern Institute for Brain Research (MIBR). Phil Sharp was the founding director, and although he had done a brilliant job recruiting a beginning group of faculty members, he was a Nobel Prize–winning molecular biologist, not a neuroscientist, and he had only agreed to stay as director for up to five years, which was coming to an end. The mix of faculty grant funds and private donations at the McGovern Institute was really attractive, as was the fact that MIT is one of the greatest universities in the world, with academic departments such as brain and cognitive sciences and computer science, which we did not have in the IRP. Private funds could be used for risky, early-stage research, which could lead to NIH grants for the faculty if the work was successful. MIT also encouraged faculty to work with industry, and even start their own companies, which I felt would be critical for bringing lab discoveries into the clinic. It was nearly impossible for an NIH PI to start a company at the time.

I could help build basic research in neuroscience at MIT, which would then help fill the pipeline with the new ideas that clinical researchers desperately needed. It helped that my former postdoc, Earl Miller, was a professor at MIT, as mentioned earlier, so I would start with a friend and ally. The administrative burden would be far less than I had at NIMH because I would not be responsible for the scientific reviews of the PIs, and the faculty was spectacular—no turnover was needed. Conversely, one of the challenges of a scientific leadership position in academia compared with the government or the corporate world is that it rarely comes with much authority. You lead by building consensus.

I had previously met with Pat and Lore McGovern at an SfN meeting, and they shared my vision of supporting basic research while keeping an eye on practical applications in the future. Although many donors understandably contribute funds to research because of some particular family connection to disease, Pat and Lore had no such connection at the time. They simply believed in the value of brain research and that their gift would help humankind. They were also willing to put in the time to help the McGovern Institute grow and help raise additional money for research.

I also really liked Bob Brown, who was the provost at that time. About a year before Bob approached me about the position at MIT, I had been invited by Steve Hyman, then provost at Harvard, to visit Harvard to explore the possibility of a recruitment. Steve took me to see Larry Summer’s impressive office, located next to his, whose walls were adorned with the original artifacts of the Lewis and Clark expedition. I was duly impressed. Later, when I visited MIT, I met with Bob Brown in his provost office, which had a very large Monet painting on the wall. When I complemented Bob on the painting, he smiled and said it was a perfect digital reproduction. MIT seemed like the right place for me.

Days after I accepted the position at MIT in September 2004, all hell broke loose at intramural NIH, where several intramural investigators were charged with the failure to report money received from pharmaceutical companies for giving talks. It was time for another congressional investigation, and the scientific directors of the institutes would be in the hot seat. You would be damned if you knew about the problems and damned if you didn’t. At the same time, the IRP research budget became constricted. When I was called by congressional investigators, they were crestfallen when I told them I no longer worked for NIH. Many of my friends half-joked that I must have had insider information about the impending meltdown and got out in the nick of time. Actually, it was pure luck.

I had remarried when I accepted the position at MIT in late 2004, and my wife, Chen Chen, gave birth to the first of our two children before we moved to the Boston area the next spring. Having lived in a townhouse in a sprawling Washington suburban housing development near Dulles airport, we decided to go for the old Boston experience, buying a Victorian house built during the Gilded Age. It had the original box on the wall to call for servants anywhere in the house, but it seemed to be broken because no servants appeared when we pressed the buttons.

In fall of 2005, most of the neuroscientists at MIT moved into the fabulous new neuroscience building designed by Charles Correa, the iconic building with the train running through a tunnel in the middle. After we moved in, Pat and Lore McGovern funded events such as the opening celebration, and we put on one of the most sensational opening events ever held, if I do say so myself. When I was at the NIH, there had been a scandal involving a meeting of government employees someplace (not NIH) where the muffins cost $100, or something like that. After the obligatory congressional muffin hearings, it became impossible to serve coffee or cookies at any of NIH events, even if they were paid for with private funds. So, having events at the McGovern Institute, where guests were not only served dinner but also a creative artist like Nick Cave could direct a performance of dancing condoms (or so they appeared), was a welcome change.

As I described earlier, my position as NIMH scientific director was feasible only because of the key people I worked with. The same has been true at the McGovern Institute. Guoping Feng, the McGovern associate director, has been a real partner. The senior McGovern staff—including Gayle Lutchen, the administrative director; Kara Flyg, the director of development; Donna Wells, the financial officer; Jill Crittenden, the scientific adviser; Meagan Jalbert, the human resources director; and Julie Pryor, the communications director—have all been dedicated to the mission of MBIR and have made the Institute feel like a family. I think people considering whether to take scientific leadership positions should think seriously about the key staff, because they are often the people who will make the difference between whether you are a success or failure. It also helped that MIT leadership has consistently been supportive. However, even with the greatest staff and university support, I soon discovered a key difference between the leadership skills I developed at NIMH and those required at MIT. At NIMH, I was an expert at spending money, whereas at MIT, I needed to become an expert at raising money. They are nonoverlapping skill sets. Fortunately, Kara Flyg, the MVP of development at MIT, has made me look good.

I was incredibly lucky that coming to MIT coincided with major developments in science and medicine that accelerated the pace of research. The revolution in genetics not only started revealing the genetic mutations that cause vulnerability to many brain disorders but also led to the development of many genetic-based tools, ranging from optogenetics to single-cell RNA-sequencing to CRISPR methods for altering the genome. The technology for acquiring and analyzing brain imaging data from humans also improved over the years, and we are currently undergoing a revolution in artificial intelligence and machine learning, which is leading to better models of higher brain function and powerful tools for analyzing the immense quantities of data being acquired from the brain. There has never been a better time to be in neuroscience, although I must admit that rapid change can understandably make many young people in the field anxious. The key to success is flexibility.

Of course, MIT was not always a walk in the park. I hesitate to say anything about my first traumatic event at MIT, but sometimes not saying anything is more of a statement than saying something. The very public trauma not long after I arrived resulted from trying to recruit Alla Karpova to the McGovern Institute, with a faculty appointment in the Biology Department. The appointment was opposed by the head of the Picower Institute at MIT at the time. I remain grateful for all the support I received from Pat and Lore, the McGovern faculty (especially Bob Horvitz), and from Phil Sharp in the conflict. The most important thing to say about this was that Alla was the innocent victim of this conflict. She was caught in the crossfire of a battle between opposing visions of neuroscience at MIT, and mistakes were made all around. The best I can say is that I never threw her under the bus. Fortunately, Alla ended up in a position at the HHMI Janelia Research Campus, where she has been doing sensational research, and the MIT neuroscience community healed when Mark Bear and then Li-Huei Tsai later became heads of the Picower Institute. It is a fantastically collegial environment today.

Journey to the East

In 2001, while at the NIH, I made my first trip to China to attend a conference organized by my good friend Lin Chen, and I started relationships that accelerated when I moved to MIT. Pat McGovern’s company, IDG, made a great deal of money from its investments in China, and he and Lore wanted to give back something to China by helping it grow its neuroscience. They were joined by Hugo Shong, then head of IDG China investments and now the founding partner of IDG Capital. We all shared the view that brain disorders were global problems that would require global solutions, including from China. Pat and Lore decided to donate funds to start a McGovern Institute in China, organized loosely after the one at MIT. They announced a competition and invited several institutions to submit proposals for an institute, as they had done before they decided to found the McGovern Institute at MIT. My good friend Bai Lu gave us helpful advice. That all said, many people wonder how there came to be three IDG/McGovern Institutes, all in Beijing.

In 2012, after at least a year of negotiations with the competing universities, Pat, Lore, and Hugo had decided on Tsinghua University for the new institute. We dined with the Tsinghua president to finalize details and then a driver drove us back toward our hotel. As we were en route, Hugo received a call telling us that we were being diverted to Zhongnanhai in Beijing, the secretive compound near the Forbidden City that housed the innermost center of the Chinese government. None of us had ever been there before. Madame Liu Yandong, then a state key counselor and one of the most powerful leaders in China, met with us, and in a magnificent hall suitable for a state visit, she gave an eloquent speech about the importance of the McGoverns and neuroscience in China. She ended by pointedly suggesting that perhaps the McGoverns should also consider Peking University and Beijing Normal University as sites for McGovern Institutes.

As we were driven back to the hotel from the meeting, we all pondered the significance of what had transpired. Beyond the not-so-subtle pressure, it actually made sense to have three McGovern Institutes, because each of them had different strengths, with Tsinghua stronger in molecular neuroscience, Peking University stronger in systems neuroscience, and Beijing Normal University stronger in child education and development. Thus, the three IDG/McGovern Institutes were formed, and it turned out to be a much better decision than having a single institute. The IDG/McGovern donation, the IDG/McGovern Institute branding, and the occasional joint symposia with the McGovern Institute at MIT all attracted a great deal of additional funding and attention to the three institutes, including additional funding from Hugo and IDG Capital. They have grown spectacularly, each with their own directors, new neuroscience buildings, and first-rate new hires. Science is not a zero-sum game—the new faculty members at the three institutes became colleagues rather than competitors. After Pat died, his ashes were placed at the base of a tree at each of the three McGovern Institutes in China and the one at MIT. The trees are all growing beautifully.

Although the three IDG/McGovern Institutes have been very important for neuroscience in China, the most intensive research relationship I personally developed in China was my collaboration with the Shenzhen Institute for Advanced Technology in Shenzhen (SIAT), part of the Chinese Academy of Sciences. The director of SIAT, Jinping Fan; two of my neuroscience friends, Liping Wang and Zhonghua LuLu; and my former postdoc, HuiHui Zhou, had started a program dedicated to research in macaque genetic models for brain disorders. The newly constructed state-of-the art animal facility featured zoo-like group housing surrounded by trees, and it was accredited by AAALAC, the international accrediting organization that inspects and accredits animal facilities around the world, including MIT.

My colleague at MIT, Guoping Feng, and I strongly believed that primate models held the key to unlocking the next generation of therapeutic breakthroughs in brain disorders. Although mice have and always will play a crucial role in fundamental neuroscience research, treatments developed for brain disorders in mouse models have often fallen short when tested in humans. We were convinced that treatments developed in primates would stand a better chance at success in humans. Macaques with SHANK3 mutations were developed by Andy Peng at Sun Yat-Sen University and Shihua Yang at South China Agricultural University. They were developed in a breeding farm the size of a small city—I thought of it as Cambridge for monkeys. The founders were transferred to SIAT for study. SHANK3 is the gene mutated in Phelan-McDermid syndrome, which is characterized by severe intellectual disability and autism in humans. Guoping is one of the world’s experts on the SHANK3 gene, and we jumped at the chance to collaborate in studying them.

As part of the collaboration, we found that the macaques with SHANK3 mutations had alterations in social behavior, cognition, and functional connectivity measured by fMRI that were reminiscent of some of the symptoms in Phelan McDermid syndrome [53]. We were fortunate to secure grants to study the SHANK3 monkeys through the U.S.-China Cooperative Biomedical Research Program, created during a time when China and the United States cooperated in programs of joint interest. As part of the program, MIT received funds from NIH, and SIAT received funds from the Chinese National Science Foundation. Although the amount of funding was modest, we were grateful that both the NIH and the Chinese NSF had carefully reviewed and approved our collaboration on the basis that it was of mutual benefit to the two countries.

Our partnership was forged just before a time when many U.S. scientists, almost all of Chinese origin, were facing scrutiny or even persecution from the NIH, federal law enforcement, and some universities because of their collaborations with Chinese scientists and institutions. Although everyone accepts the importance of national security and the need for full disclosure of activities, this seemed more of a witch hunt. It stemmed from the “China Initiative” started during the Trump administration. These researchers were charged with violating various regulations related to foreign collaborations, but many of the charges were ridiculous, and the interpretations of these regulations changed so often that even some NIH institute directors confided in me that they could not fully comprehend them. Nearly all of the affected people were conducting basic research with results that were freely published in international journals. Furthermore, if the plan was to restrict any transfer of scientific information to China, the plan backfired because it caused many Chinese-origin scientists to return to China where they established labs.

After many lives were ruined, the rules for collaboration were eventually clarified, the China Initiative was terminated, and the witch hunt seemed to diminish. Ironically, some of the scientists caught in this dragnet had previously endured the turmoil of China’s Cultural Revolution. They never imagined that they would experience such persecution in the United States. As I reflect on my experiences in China and my collaboration with SIAT, I remain convinced that the surest path to better treatments for brain disorders is through global scientific partnerships, including the United States and China.

King of the Brain: My Unexpected Journey into China’s World of Super Brains

Among my countless adventures in China, my participation in the Super Brain television show stands out as the most unexpected and remarkable (Figure 5). This wildly successful game show showcased astonishing intellectual abilities and captivated the nation, amassing a staggering 250 million viewers who tuned in to watch achievements of the human mind. By comparison, the very popular American Idol show in the United States had an audience of less than nine million viewers.

My involvement began in 2014, during the show’s first season, when a colleague from China who was advising the show called me because of public concerns about the authenticity of the contestants’ remarkable skills. He asked me to join the panel of discussants on the stage of the show and carefully scrutinize the competition for any signs of fraud. I found that the contestants’ exceptional talents were genuine, and the show was teeming with human drama and excitement, reminiscent of an intellectual Olympics. I was hooked, and I returned every season except during the pandemic. I usually arrived at the competitions jet-lagged, once falling asleep onstage for 45 minutes. The accommodating crew simply filmed around me.

The entertainment quality of the contests was over the top. A Rubik’s Cube contest would not just require solving cubes, but solving them underwater, holding one’s breath, and blindfolded, all at the same time. A memory contest would not consist of memorizing numbers or letters, but memorizing the features of walnut halves and then finding the companion halves among hundreds of walnut halves on a wall. A comparable contest involved a wall of lips. I still have some of the walnuts and lipstick marks in my office, in a display case of mementos from the show. In later years of the show, the problems could no longer be solved with narrow talents, such as memory or perception. They required very high degrees of intelligence to solve unique puzzles, such as observing the motion of many planets and moons in an alien solar system set up on stage, and predicting their locations on a future date. Once, one of the contests was so complex I could barely understand the rules myself, and it needed to be performed at lightning speed. The host of the show asked one of the contestants if he was worried about how he would perform, and he answered that it didn’t seem so hard because it resembled in some ways the game of “Go.” Surprised, the host asked him if he was an expert at Go, and the contestant said that he had never played Go, but he had read the rules and it didn’t seem so hard. A Go champion on the panel was quite upset when this very smart novice won the contest, beating actual Go players.

Figure 5. Bob Desimone with some of the cast and contestants of the Super Brain Show in 2019. To the immediate left of Desimone is Jiang Changjian, the host, and to the right are Kunlin Wei, the leader of the Chinese team, and Yigong Shi, president of Westlake University.

The program’s popularity was further boosted by the frequent appearances of famous pop stars, comedians, and high-visibility academic leaders, such as Yigong Shi, president of Westlake University, on its panel. Yigong is one of the most accomplished scientists in China, and he is revered by many of the families with children watching the show. The very popular host of the show is Jiang Changjian, who is also a distinguished professor of political science at Fudan University. One of his talents is setting the contestants at ease and getting them to talk about their life. It was important that the audience care not only about the contests but also care about the very real people competing, always under intense pressure. The audience was introduced to obscure talents, such as Alex Cummings, the international memory champion and U.S. medical student, and Rinne Tsujikubo, a 10-year-old girl from Japan who was a calculation prodigy. The Chinese contestants ranged from children of farmers straight from the countryside to top university students and the son of a famous billionaire. The audience was live and enthusiastic, and the pace and editing were heavily influence by K-Pop.

It was the perfect mix of intellectual talents and entertainment, so it is perhaps not surprising it was so popular. One year, as I was exploring a Mayan temple in the Yucatan jungle with my family, a Chinese couple recognized me and asked about the show. My children looked at me in awe. It seemed that my participation in Super Brain had made me a recognizable figure among Chinese viewers, and it was often the first topic of conversation when I met with business and academic leaders in the country. I had to wonder whether any television show centered on intellectual talents would be so popular in the United States.

The highly entertaining contests were the brainchild of a creative team that included my friend Jia Liu, now a psychologist and AI researcher from Tsinghua University. I recruited some of the international contestants, and I persuaded other neuroscientists like Tom Sudhof, Marge Livingstone, Dora Angelaki, Tom Albright, and Mike Gazzaniga (see volume 7) to appear as guest panelists. Many people in the United States have assumed that I must speak Chinese to be on the show. I am almost ashamed to say that after more than 22 years traveling to China, I never learned to speak Chinese, although my wife and children do. On the show, I have a speaker in my ear with real-time translation of everything said. By the end of 12 hours or more of filming each day, I have the strong illusion that I actually understand Chinese.

The winner of the domestic competition phase of the show was crowned the king of the brain, and the king and many of the other contestants often became famous in China. Some became internet “influencers” and others leveraged their fame to start successful businesses. Soon, I became the international team leader for the international competition. For several years, the leader of the Chinese team was Kunlin Wei, a psychologist from Peking University. Unfortunately, the Covid pandemic interrupted my appearances on the show, but I am pleased to say that on our first post-Covid show, I led the international team to victory. It was hard to give the team much specific advice because we were informed about the exact nature of the competitions just a few days in advance, but the one piece of general advice that was always relevant was to stay calm. Often, the winner was the person who could best hold up under pressure. I think it is a relevant lesson for many of our current students and postdocs.

Throughout my career in neuroscience, my focus had been on understanding the brain to help people with disorders and disabilities. However, I soon realized that the exceptional minds on Super Brain could also hold invaluable insight into the brain. One example of this occurred during an after-show party, when Mike Gazzaniga and I questioned a Japanese calculation expert from our international team, Hiroaki Tsuchiya. We had just watched him solve complex problems with astonishing speed, such as dividing an 18-digit number by an 11-digit number, with no delay between seeing the numbers and writing the answer. Surely, Hiroaki Tsuchiya had a rare inborn talent for calculation, but it was honed by practice. He revealed that all calculation champions initially practiced with an abacus, eventually giving up the physical device in favor of manipulating an imagined one, and finally abandoning even the mental beads. Eventually, he explained, the answers simply came to him, digit by digit, as soon as he saw the problem. My guess is that the learning with the abacus engaged the motor system of his brain, which has structures, such as the basal ganglia and cerebellum, that have the capabilities to perform many calculations in parallel, which are normally needed to throw a ball or ride a bike. Even I can throw a ball without a delay to calculate the joint angles. I think Hiroaki Tsuchiya learned how to use these different parts of his brain for math calculations, and I have no doubt we have much to learn from these abilities.

Dissecting Cause and Effects in Complex Systems

I think many people who have worked in neuroscience for a long time have had the experience of publishing a few papers in a new area and suddenly finding that there are aisles of posters on the same topic at the SfN meeting. This was my experience more than 15 years ago at the SfN meeting, when I started to see many great posters reporting effects of attention on responses in many visual structures, and these posters were followed by many great papers, of course. At that point, the attention field seemed crowded with great studies, and maybe it was time to jump the shark. I decided that I should shift my own attention away from the phenomenology of attention to understanding the biological mechanisms for these attentional influences on cells. In other words, shift from correlation to causality. Given that there really were not good tools for understanding the microcircuitry of the cortex in awake macaques, the best approach seemed to be to study the interactions among the different elements of the circuits distributed across different cortical areas and subcortical structures. If you want to study the interactions between different cells in awake primates, it really helps if those cells are located in different structures.

The most important tool for studying causal interactions across brain structures in rodents has probably been optogenetics, but it had not been tried in primates. One of the many great advantages of MIT is its proximity to wonderfully creative people, such as Ed Boyden, who are likely developing whatever tool one needs. Ed and I quickly formed a collaboration to test in monkeys the opsin Arch, which can suppress neural activity when stimulated with blue light. The project was led by a joint postdoc, Xue Han, now a professor at Boston University, who succeeded in manipulating neurons using optogenetics for the first time in a primate [54]. Leah Aker, then a graduate student working with Ed and me and now an anesthesiologist and professor at Duke, later succeeded in suppressing neurons in the frontal eye fields (FEF) with the opsin Jaws, developed by Ed, which was better suited for the large primate brain because its sensitivity was shifted into the red wavelengths and was less absorbed by the blood in the brain [55, 56]. Jaws is now routinely used in primates. Ed and I have continued these collaborations in technology, now with a joint postdoc, Nava Shmoel, working on signal reporters for imaging.

Using a variety of causal methods, including optogenetics, muscimol, lesions, magnetoencephalography (MEG) recordings in humans, and analytic techniques, such as synchrony and the latency of attentional effects on cells, I sought to understand how the attentional effects on cells in visual cortex came about. For spatial attention, the FEF was already known to play a key behavioral role, and Georgia Gregoriou in my lab (now a professor in Crete) found that the effects of spatial attention on cells in FEF occurred with a very short latency—much shorter than in V4 [57]. The latencies were short enough for FEF cells to be the source of attentional feedback to cells in V4, and the cells also went into gamma frequency synchronization with V4 cells, with the phase of their activity leading that in V4 by around 10 milliseconds, around the estimated transmission time from FEF to V4. Georgia and Andrew Rossi (now a program officer at NIMH) found that lesions of PFC, including FEF, impaired the animals’ ability to attend to a target in the presence of distractors, and reduced the filtering of distractors by IT neurons [58, 59]. Leah Acker found that optogenetically suppressing FEF cells at virtually any time during a spatial attention task impaired performance in the task [55]. By contrast, when HuiHui Zhou (now a PI at the Peng Cheng Laboratory in Shenzhen) and Bob Shafer in my lab tested the role of the lateral pulvinar of the thalamus in attention, they found that deactivation of the pulvinar left the animal almost blind in the affected portion of the field, and it greatly reduced the responses of cells in V4 to sensory stimuli, whether or not the animal paid attention to them [60]. The FEF performed like an attentional control structure, whereas that part of the pulvinar seemed to have more basic visual functions. Incidentally, Bob Schafer left my lab to start his own company testing humans instead of monkeys. He later became the head of research and then CEO of Luminosity, the cognitive training company. The tech industry is increasingly an employer of some of our best postdoctoral researchers, which I think is a very good opportunity for people who are willing to consider alternative career tracks.

In another line of work in the lab, we undertook studies that questioned the very basis of many studies of spatial attention, from my own and other labs. Neurons in many brain structures play a role in oculomotor control and respond in association with saccades into their movement field or receptive field. To study spatial attention independently of these oculomotor responses, we and most other people in the field used the popular covert attention paradigm, in which animals (or people) were trained to fixate on a spot and then hold fixation on it while they attended to an object in the extrafoveal field and ignored distractors. By cuing the animal to attend to one object or another, we could test the effects of attention, independently of eye movements, or so we thought. What we didn’t know at the time was that the animals were often making small eye movements, termed microsaccades, toward the attended object and then back to fixation, two to four times per second, or roughly delta/theta frequencies. Studies in humans had shown that the direction of a microsaccade is often associated with the direction of spatial attention.

When Eric Lowet joined the lab, we decided to investigate this relationship. In many labs, the eye position signal from a typical infrared eye tracker is often too noisy to even detect small microsaccades. It is easy to ignore what you don’t measure. However, Eric had received his doctorate while working on microsaccades, so he knew how to carefully measure them. Joined by Khartik Srinivasan in the lab, Eric initially found that it didn’t make a great deal of difference whether or not a trial in a covert attention task included a microsaccade. The key insight came later, when he separated the intervals following microsaccades toward the attended stimulus from the intervals following microsaccades back to the fixation spot. As soon as that was done, it became clear that the effects of attention on the response to a stimulus in the RF were predominantly in the interval following a microsaccade toward the attended stimulus and not the opposite direction [61].

Later, Karthik, Eric, and Bruno Gomes found that cells also conveyed more information about the stimulus in an interval following a microsaccade and had sharper tuning curves [62]. It appears that attention to a stimulus is more strongly engaged when an animal makes a microsaccade toward it. Although this finding does not invalidate any of the work that has been done on spatial attention, it does put it in the context of other elements of cognition with motor associations. It brings the research on the covert attention paradigm closer to natural vision and visual search, where the eyes dart around to significant stimuli in the world, sampling them one to four times per second with saccades. In the covert attention paradigm, the same rhythmic sampling of the scene seems to occur, but with attention coupled to small saccades that often escape detection.

Focusing on Features

Feature-based attention has always seemed more intriguing to me than spatial-based attention. For spatial-based attention, it is easy to imagine that high-level areas with a visuotopic organization, such as FEF, send visuotopically organized feedback projections to areas such as V4. Cells in FEF with RFs containing a behaviorally relevant stimulus would have greater activity than cells with other RFs (the notion of a priority map in FEF), and this greater activity would be fed back to V4 to bias their responses toward the same stimulus. Synchrony between FEF and V4 could magnify these effects. But for feature-based attention, it is less clear how this feedback might work, because FEF has little or no feature selectivity, and there was no obvious map for features elsewhere in the PFC.

Imagine searching for your pen on a crowded desk. It is commonly thought that you would use your memory for what your pen looks like, and then use some or all of the stored pen features (what is known as the attentional template) to bias the neural representations of objects resembling pens on your desk so that you attend and orient toward the most likely candidates. For example, you would probably be more likely to attend first to a pencil on your desk rather than to a coffee cup. This bias in favor of searched-for features is known to operate globally across the visual field, in contrast to spatial attention, which normally operates on one or two locations at a time. Narcisse Bichot in my lab showed that during a visual search task like this, cells in V4 give enhanced responses to stimuli matching the searched-for object anywhere in the visual field. But where is the attentional template stored, and how does it bias features or object representations throughout the visual field in areas, such as V4?

It was known that during visual search, cells in FEF have greater responses to objects matching the features of a searched-for object, or the target, than to nontargets, similar to what Narcisse Bichot found in V4 [63], and HuiHui Zhou in my lab found that the latencies of these FEF cells for targets versus nontargets are earlier than in V4 [64]. Could FEF cells be the source not only of top-down feedback for spatial attention but also of top-down feedback to V4 for the features of searched-for objects? That seemed unlikely. How could FEF cells with limited receptive fields sensitize V4 cells to respond best to red targets anywhere in the visual field, to take just one example? How would FEF compute the locations of stimuli matching the attentional template when FEF cells show little or no selectivity for object features?

The answer to this puzzle was that the source of feedback for attended object features was not in FEF, but rather in an area located just anterior to FEF, which we termed the ventral prearcuate region, or VPA. Narcisse Bichot led a team in the lab to record in VPA and FEF while animals performed a visual search task, similar to finding a pen on a desk. The animal was shown a cue stimulus at the start of the trial, which varied from trial to trial. After a blank delay period, an array of stimuli appeared throughout the central visual field, and the animal was rewarded for finding and holding fixation on a stimulus that matched the cue (termed the target). The animal had free gaze and could make any number of saccades to find the target. The saccades in this case were big and easily measurable.

Narcisse found that cells in VPA often had feature or object selectivity in their responses to the cue, like in IT cortex, but also some had RFs the size of RFs in FEF [65], so the cells combined spatial and feature information, as Earl Miller had previously found in PFC. Furthermore, cells in VPA gave enhanced responses to stimuli matching the target features during visual search, like in FEF, but the latencies of these effects were even earlier than in V4. By contrast, when he computed the latency of the effects of spatial attention in VPA and FEF, the latencies were shorter in FEF. These results suggested that the locations of stimuli matching the target might be computed in VPA, with information about the location of likely targets communicated to FEF.

This idea was supported by the effects of deactivating VPA with muscimol and measuring the effects on cells in FEF. Unilateral VPA deactivation impaired search in the contralateral field, suggesting that VPA was important for search. It also eliminated the effects of feature attention on the responses of cells in FEF. For example, if there was a red stimulus in the RF of an FEF cell, following deactivation of VPA, it no longer made a difference to the cell’s response if the animal was searching for a red stimulus versus searching for a green stimulus. By contrast, following VPA deactivation, FEF cells showed normal response enhancement depending on whether or not the stimulus in the RF was the target of a saccadic eye movement. In sum, the results suggested that VPA and FEF functioned together, with VPA the source of top-down biases for feature-based attention and FEF the source of top-down bias for spatial attention and saccades.

One of the lessons I take from the work on FEF and VPA is that initial appearances (from recordings) can be deceiving. When recording from both areas during visual search, the response properties will initially seem very similar. In fact, cells throughout most of the PFC seem to have similar properties. But with careful dissection of properties coupled with causal manipulations, one can tease apart their differential roles.

What about the role of extrastriate areas, such as V4? Certainly, extrastriate areas must be the source of information about the features and locations of all the stimuli in the visual field, which is communicated to areas in PFC such as VPA and FEF at short latencies. However, our results suggested that VPA and FEF computed the locations of behaviorally relevant stimuli, with FEF then directing attention or the eyes to likely targets. If so, what was the purpose of the feedback from VPA about attended features to extrastriate cortex, if VPA and FEF could function to orient the animal to behaviorally relevant stimuli on their own?

One likely possibility is that extrastriate areas are involved in more complex, lengthy visual tasks than simply orienting to a relevant stimulus. We found a potential example of this in a study of feature-based attention in humans using MEG and fMRI [66]. Daniel Baldauf led a study in the lab in which subjects were show a sequence of faces and a sequence of houses, spatially overlapping with each other. Subjects were cued on each trial whether to attend to the faces or the houses, and to press a button if either two successive faces or two successive houses matched each other, depending on the cue. He found that the inferior frontal junction (IFJ) in PFC went into synchronized oscillations with the fusiform face area if the subjects were attending to faces and with the parahippocampal place area if the subjects were attending to houses. Furthermore, the IFJ oscillations led the ones in the temporal cortex by around 20 milliseconds, which was the expected transmission time. IFJ seemed a good candidate for the human equivalent of VPA, but in this case, the task required the sustained involvement of the face area or place area in temporal cortex to process the relevant stimulus type so it could not be solved by simply selecting a face and orienting to it. Other complex tasks probably require sustained interactions between VPA and other parts of extrastriate cortex.

How did the IFJ (humans) or VPA (monkeys) have this effect on sensory processing areas? Rui Xu and Narcisse Bichot in the lab set out to study this by measuring what we called the “connectome” of lateral PFC [67]. They used electrical stimulation of PFC applied during fMRI scanning to measure all of the brain areas activated by the stimulation, based on methods developed by Nikos Logothetis and others. By applying the stimulation to a dense grid of stimulation sites, they arrived at a very fine-scale mapping of PFC connectivity. The results showed that lateral PFC, including VPA, had connections with five of the major processing domains of the cortex, and that within each of these processing domains, the connections with PFC were topographically organized on a fine scale. If one considered an orderly progression of stimulation sites in PFC, for example, they were connected to an orderly progression of connected sites in most or all of the processing domains. Because at least some of these processing domains had a hierarchical organization, such as the ventral stream for vision, this meant that PFC was in a position to integrate information and coordinate processing at comparable hierarchical levels in nearly all major processing systems.

This method worked so well to reveal the connectome of lateral PFC in the monkey, it occurred to us that the same method might be used to map human brain neuroanatomy. Some epilepsy patients have electrodes temporarily implanted in their brains to identify the epileptic focus for later surgery. In a collaboration with the MGH neurosurgeon Mark Richardson and his colleagues, MRI physicist Atsushi Takahashi, and McGovern faculty members Ev Federenko and Nancy Kanwisher, we began a year of safety testing, and we are now ready to start the mapping the connections of these electrodes in patients with epilepsy who volunteer. This not only will give us unprecedented information about human brain connectivity but also help neurosurgeons identify components of the epileptic network in each patient, which could serve as a treatment target. It is just another example of how basic research in animals can ultimately help clinical practice.

Working Memory Revisited

I was also able to return to studying memory, which I had given up when I became NIMH scientific director. Diego Mendoza Halliday (now on the faculty at the University of Pittsburgh) in the lab used an optogenetic manipulation to dissociate the role of VPA in working memory from attention [68]. Although I had lectured in my classes for years that the neural circuits for working memory had proven impossible to dissociate from those for attention, so they were probably the same mechanism, I had never tested this idea myself. In a task requiring feature attention to direction of motion, Diego found that optogenetic deactivation of VPA impaired the animal’s performance if the deactivation occurred during the attentional selection phase of the task but not if it was deactivated during the working memory phase. Likewise, deactivation during the attentional selection phase reduced the effects of attention on cells in areas such as MST and LIP, but there was little impact on the effects of working memory on cells if the deactivation took place during the working memory phase. It looks like there is a dissociation between the circuits for attention and working memory, with VPA much more important for attentional section. I will have to change my class lectures. Although the role of prefrontal feedback in attentional selection seems well established, our study adds to a growing literature questioning what we thought we understood about the mechanisms of working memory.

We have barely scratched the surface in understanding the neural circuitry of attention, but I feel like the playbook we are following is working. Anatomy, physiology, behavior, and causal manipulations are together revealing at least the major structures involved, and the general principles of how they work together. The next major challenge will be to develop good computational models of how it works at the cellular level.

Marvelous Marmosets

My McGovern colleague, Guoping Feng, and I envisioned a two-pronged approach to developing better therapeutics for brain disorders using primate genetic models. The first approach was gene therapy to correct the genetic mutation, which Guoping had already demonstrated in mouse models of brain disorders. This might be the best solution for disorders with single gene mutations with large effects, but it wasn’t clear how gene therapy could be applied in animals with the more common polygenic forms of disorders, in which many genetic variations might each contribute a small degree to the disorder. The second approach was to try to understand the neural circuit dysfunction in a primate genetic model, and correcting it at the circuit level rather than with gene therapy. We hoped that some of the circuit dysfunctions we identified in the animals with monogenic mutations of large effect would be shared with the more common, polygenic forms of the disorder. For example, if we identified a circuit dysfunction in the striatum that led to stereotypies in one of the monogenetic models for autism spectrum disorder (ASD), a drug or some type of genetic medicine targeted to the striatum to correct the stereotypy might also be effective in other, polygenic, forms of ASD. Based on what the field has learned from the study of mouse genetic models for brain disorders, understanding circuit dysfunctions would likely require a very large effort, utilizing several neuroscience methods.

We reasoned that this need for a large neuroscience effort to understand the primate genetic models would be facilitated if we had genetically modified animals to study at MIT as well as at SIAT. The problem was that macaque studies such as these would require large groups of animals, and it would require too much space and too much money to do the studies at MIT. Although we had no experience working with marmosets, these Brazilian primates were much smaller than macaques—indeed, they were not much larger than rats and lived in multigeneration family groups. Their small size made it feasible to have a marmoset genetics program at MIT, which has limited animal space. Fortunately, we learned that the New England Primate Center was donating marmosets to a small number of national primate centers and universities. Harvard was closing the center for financial reasons, but looking back, this was a poor decision given the explosive need for primates for vaccine development during Covid. With help from then-NIMH director Tom Insel, the Primate Center gifted us a very small number of marmosets, which became the starting point for a breeding colony. The MIT Division of Comparative Medicine, first under Jim Fox and later under Kelly Pate, became our partner in developing the facilities and expertise needed for the marmosets.

We soon became desperate to obtain more marmosets to increase the genetic diversity and the rate of breeding. The only site that had available marmosets was a breeding colony in Japan, but no international carriers would transport primates from Japan to the United States at that time. Lore McGovern asked a friend who owned a fashion empire if we could fly them on their private plane, but filling a luxurious plane with rat-size marmosets posed daunting clean-up challenges, not to mention snakes-on-a-plane scenarios. Fortunately, we found a Mission Impossible–like team headed by a former Navy SEAL who seemed unfazed by transporting anything anywhere. Lore’s generous friend paid for the chartered 757 cargo plane and the Navy SEALs needed to fly the marmosets directly to a quarantine facility in the United States, and our U.S. marmosets soon had Japanese friends.

I have found the international community of marmoset researchers to be much like the marmosets themselves—highly social and cooperative. I don’t know if working with marmosets caused the researchers to develop these qualities, or whether marmosets attract people with those qualities. In either case, marmoset researchers from around the world, including Japan, England, and Brazil, as well as universities in the United States invited us to learn from them as we got started. Charles Jennings in MIBR helped us obtain a Mass Life Science Center grant to buy the key equipment for the genetic engineering platform. Guoping and his team headed by Qiangge Zhang and Martin Wienisch used CRISPR methods developed by Feng Zhang at MIBR and the Broad Institute to create the genetic mutations.

The first grant application Guoping submitted to NIH for the marmoset project was turned down because he had not already shown that we could create the genetic models. So how could we raise the money to get started? Fortunately, a private research institute and private donors committed to research on psychiatric disorders stepped in. For privacy reasons, I will not name the donors, but they gave us the critical gift funds we needed to get the program off the ground. Now, the program is supported with a mix of public and private funds. Guoping is leading a large gene therapy project in marmosets with the mutation in the SHANK3 gene found in Phelan-McDermid syndrome, and several labs at MIT, Harvard, and other cooperating universities are studying circuit function in primate genetic models to develop better therapies. Guoping’s SHANK3 mini-gene is now licensed to a company to start clinical trials. More than half my lab, including Haoran Xu, Beizhen Zhang, Florence Liang, Victoria Su, Claudia Valenzuela, Mark Fossesca, and Frederico Azevedo, is now engaged in studying social cognition in marmosets. A team led by Haoran has used ecog electrodes to map a network of areas concerned with the perception of faces, bodies, and social interactions. They work with Will Menegas, Jitendra Sharma, Erin Corbett, Ruoyang Chai, Yefei Chen, Minqing Jiang, Gina Liberti, and others in Guoping’s lab on the SHANK3 project. When new therapies for brain disorders are developed with the primate models and tested successfully in people, I will consider it a dream fulfilled.

A Thousand Flowers Bloomed

Beyond the research in my own lab, my proudest accomplishment at MIT is the role I played in developing the McGovern Institute into the research center it is today. The faculty have free will and choose their own research directions, but the McGovern funding and other major gifts allowed us to create the environment to attract the best people and to give them the support they needed to succeed, including a building (MIT committed to the new building in association with the McGovern gift), core facilities, the best administrative support, many graduate fellowships, and some significant seed funds for pilot projects, which are critical for obtaining the preliminary data needed to apply for federal funds. Pat and Lore’s commitment made more than 20 years ago made all this possible.

The formal mission of MIBR is very broad, encompassing neuroscience and many related fields, but one of the more controversial decisions of MIBR was to recruit an equally broad faculty from the very beginning. Phil Sharp recruited a faculty with interests ranging from molecular genetics, to computation, to human cognition. This beginning group included Emilio Bizzi (see volume 6), Martha Constantine-Paton, Jim DiCarlo, Michale Fee, Ann Graybiel, Alan Jasanoff, Nancy Kanwisher, Bob Horvitz, and Tommy Poggio. Martha and Emilio later retired. This diversity was criticized by some people at the time because they believed that neuroscience centers like the McGovern Institute should have a narrow focus to succeed. When I arrived at MIT, one of our distinguished board members at that time suggested that the McGovern Institute should focus on one topic, like oculomotor control, in the future. Rather than becoming the oculomotor center of the world, I felt our goal should be to have a broad impact on brain health. This would require a multidisciplinary approach, recruiting people who could communicate with each other across levels.

Facilitating such breadth required not just freedom but also a culture of collaboration. We focused on hiring people who were the best in their fields, of course, but who were also driven to work closely with others. The result was an atmosphere in which weekly faculty lunches and periodic retreats became more than social gatherings—they were idea incubators, in which conversations sparked research projects and seeded long-term collaborations.

The additional full or associate faculty members currently at MIBR include Polina Anikeeva, Ed Boyden, Ev Federenko, Guoping Feng, Ila Fiete, John Gabrieli, Mark Harnet, Hugh Herr, Mehrdad Jazayeri, Rebecca Saxe, Nidhi Seethapathi, Fan Wang, Robert Yang, and Feng Zhang, who are amazingly diverse in their interests but very interactive across levels. Most have academic appointments in the Brain and Cognitive Science Department but some have appointments in Material Science, Biology, Biological Engineering, Electrical Engineering and Computer Science, and Media Arts and Sciences. I have never worked with a more friendly and collaborative group of people. Of course, the real test of the interactive philosophy is the research progress, and in my view, it has also been outstanding. Our faculty have advanced our fundamental knowledge of the mind and brain at all levels, from gene regulation, to the biophysics of neurons, to the neural circuitry of perception and attention, to motor control, learning and memory, language, navigation, the relationship between the brain and the gut, the experience of pain and anxiety, child development, and theory of mind, with many or most advances resulting from collaborations. Being at MIT, we also have a strong interest in developing new technology, which is freely shared with the neuroscience community.

MIBR provides a very fertile field, but the faculty grow the crops, of course. For this, our faculty have benefited tremendously not only from government grants and foundation support but also from visionary private supporters, some of whom endowed research centers that are now supporting innovative research in many areas. Many of our supporters share with me and other faculty members a history of neurodevelopmental or psychiatric disorders in the family, and we all understand the desperate need for more research and better therapies. They don’t just donate money—they stay engaged with the science in many ways, including serving on one or more of our boards. Lore McGovern developed an interest in addiction and has supported a new addiction initiative. Jim and Pat Poitras funded the Poitras Center for Psychiatric Disorders Research, the first major research center established at MIBR. After hearing about my plans for translational research in psychiatry soon after I arrived at MIT, they stepped forward and asked how they could help. It has supported collaborations between John and Susan Gabrieli and several clinical groups around the Boston area, including at McLean Hospital, as well as many preclinical studies of pathophysiology in psychiatric disorders, and groundbreaking gene therapy methods. The Poitras Center was so successful that it became the prototype for five later centers. Lisa Yang and Hock Tan established an Autism Center and a Molecular Therapeutics Center, and Lisa Yang independently established the Brain-Body Center (headed by Polina Anikeeva), a Bionics Center (focused on new types of prosthetics with better neural integration, headed by Hugh Herr and Ed Boyden), and an integrative computational neuroscience center (ICoN, headed by Ila Fiete).

The centers established by Lisa Yang and Hock Tan now make up the Yang-Tan Collective, which is a research accelerator. The faculty supported by the Collective span several departments and different schools at MIT. Although the Collective covers several diverse areas of translational neuroscience, joint retreats, monthly talks by fellows, and common social gatherings have led to the creation of many bridges between projects. We also benefit from frequent interactions with the Tan-Yang Autism Center at Harvard, headed by Mike Greenberg. More than 20 postdoctoral fellows and students are supported by all of the Collective Centers, and they have all become part of a highly interactive community that has forged many new collaborations across labs. The ICoN Center of the Yang-Tan Collective only supports postdoctoral fellows who have at least two faculty mentors, for example. The Yang-Tan Collective also funds postbaccalaureate scholars who are from disadvantaged groups, giving them the research experience that they need to apply for graduate schools. All of the fellows and scholars benefit from regular personal interactions with Lisa Yang, who encourages their research. The magnitude of the gifts is extraordinary, and all of our Centers have transformed research in MIBR and MIT.

It has been a very long road since I decided as a graduate student to pursue research that I thought would ultimately help people, but I am seeing some light at the end of the tunnel. I am deeply indebted to all of the students, staff, and postdocs who did all the research in my lab over the years. I am sorry that I could not describe the work of all of them in this short autobiography. But my biggest role may turn out to be the help I have given to others to achieve this goal, not simply directing the work of my own lab. The CRISPR discoveries of Feng Zhang, many of them funded by Jim and Pat Poitras and Lisa Yang, are transforming medicine and advancing into clinical trials. The primate genetic studies headed by Guoping Feng, also supported by Lisa, Jim, and Pat, are on a solid path toward gene therapies and other therapeutics. Our faculty have cofounded numerous companies and have licensed their discoveries to an even larger number, which are developing clinical applications and starting clinical trials. I have become a cofounder of two companies myself, which are developing products for clinical use.

I believe this research progress validates the reason that I left NIMH, which was that to make clinical progress, we needed to go back to the bench and develop the foundational knowledge of the brain and behavior that would ultimately fill the clinical pipeline with new ideas. And the fundamental knowledge we have acquired is just the start—there are amazing discoveries about the mind and brain still to be made. It brings immense satisfaction to know that I have played a role in supporting so many faculty members, staff members, and students in realizing their research dreams. I feel even better when I contemplate how their work will ultimately benefit humanity. I have no doubt that Pat McGovern is also smiling someplace, happy with the seed that he planted. In a way, my broader role in helping people also serves as a token of gratitude for the aid I’ve received throughout my career—from generous scholarships and fellowships to the invaluable guidance of my mentors, Charlie Gross and Mort Mishkin.

I am also thankful for my wonderful wife and our two wonderful children, who, remarkably, are considering careers in biomedical research. This scientific autobiography is really written for them. The journey thus far has been amazing, and I see no reason to decelerate just yet. As Pat McGovern used to say, the best is yet to come.

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Charles Douglas Gilbert

BORN:

New York, New York

January 15, 1949

EDUCATION:

Amherst College, Amherst, MA, BA, Summa cum laude, Biophysics (1971)

Harvard Medical School, Boston, MA, Neurobiology, MD, PhD (1977)

APPOINTMENTS:

Teaching Fellow in Neurobiology, Harvard Medical School (1977–1979)

Principal Research Associate in Neurobiology, Harvard Medical School (1979–1981)

Assistant Professor, Department of Neurobiology, Harvard Medical School (1981–1983)

Assistant Professor, The Rockefeller University (1983–1985)

Associate Professor, The Rockefeller University (1985–1991)

Professor, The Rockefeller University (1981–present)

Arthur and Janet Ross Professor, The Rockefeller University (2004–present)

HONORS AND AWARDS:

Fellow, The Danforth Foundation (1971–1975)

Fellow, The Medical Foundation (1978–1980)

Weill-Caulier Award (1984)

Presidential Young Investigator Award (1984)

Rita Allen Foundation Award (1986)

Elected member, International Neuropsychological Symposium (1992)

Krieg Cortical Kudos, Cortical Discoverer Prize, Cajal Club (1993)

Fellow, American Association for the Advancement of Science (2000)

Elected, American Academy of Arts and Sciences (2001)

W. Alden Spencer Award (Columbia University College of Physicians & Surgeons) (2002)

Elected, National Academy of Sciences (2006)

Inaugural Fellow, American Physiological Society (2015)

Edward M. Scolnick Prize in Neuroscience (McGovern Institute, MIT) (2015)

Honorary PhD Degree, Amherst College (2022)

The objective of Charles Gilbert and his colleagues has been to understand the mechanisms of brain function at the circuit level. Gilbert has identified a component of the cortical circuit consisting of long-range lateral connections and has shown how connections between neurons operate dynamically. He has identified long-term changes in cortical connections that mediate perceptual learning and functional recovery after brain lesions, and short-term changes that enable neurons to change their function according to task demands. He has found that the functions of brain regions are under top-down influences of attention, expectation, and perceptual task. In effect, neurons are adaptive processors, capable of selecting subsets of inputs depending on the behavioral context. He has proposed a model in which this input selection, and the associated cortical dynamics, are achieved by an interaction between feedback to cortical areas and intrinsic connections within these areas. He is currently exploring how this mode of circuit interaction may account for perceptual dysfunction in neurological and behavioral disorders.

Charles Douglas Gilbert

In this memoir I hope not only to include an account of my past accomplishments but also to present a vision for a changing view of the nature of information processing in the brain. Although all of my work has focused on the modality of vision, the principles of circuit interactions we have developed in studies of visual cortical function may be more broadly applicable to all systems in the brain.

Family Life

I was born in New York City, although my parents were living in Princeton, New Jersey, at the time, where my father was a professor at Princeton University. My parents were both academics. My father was a clinical psychologist and professor of psychology and my mother was a schoolteacher. My father was fluent in German, so together with his training in psychology, he was able to apply his expertise as the psychologist during the Nuremberg war tribunals, where he interviewed all of the most senior Nazis who were being tried for war crimes. From this, he developed an interest in the psychology of dictatorship. When he sent his book Nuremberg Diary to a Princeton colleague, Albert Einstein, Einstein thanked him for the book and said, “It is truly an agonizing thought that people of such little sense of responsibility could rise to power with the consent of the people of a large and highly developed country. The greatest of political problems has made no real progress since the days of Aristotle.” Later, my father identified the same tendencies at home when he publicly called on Joseph McCarthy to submit to a psychological examination, saying “we should like to know more about the psychodynamics of the personality that delights in deliberate deception, in sensational and reckless attacks.” These thoughts remain eerily relevant. But that typified the liberal environment in which I grew up.

Our family moved several times, from Princeton to Michigan, where my father was a professor at Michigan State University, to Mexico, where he worked with psychologist Erich Fromm, to New York, where he returned to academia. I went to school on Long Island, and then went to Amherst College. At Amherst, I majored in biophysics, but perhaps following my family tradition I also had a parallel involvement in liberal politics. It was the Vietnam War era, and I chartered a fleet of buses to take me and my fellow students to a march on Washington to protest the war. Before the date of the protest we learned that the Federal Bureau of Investigation tried to induce the bus company, Peter Pan buses, to renege on our contract. We recruited the assistance of the American Civil Liberties Union, which threatened to sue on our behalf, and the bus company backed down. But I always chuckle at the idea of suing Peter Pan.

My own interest in biomedical science started at an early age. At the age of four, I declared a wish to be a medical scientist. I was the stereotypical science nerd who had many scientific adventures and misadventures in grade school and high school. At one point, convinced that the continents must have at one time fit together, I got permission from my sixth-grade teacher to take apart a globe and reassemble it into a single continent. For a physics club project, I built a particle accelerator, complete with an oil vacuum pump and a Van der Graaf generator. When I started it up, it emitted so much radiation that my science teacher shut the whole thing down. In my teen years, I was an avid reader of both fiction and nonfiction, including a number of science-related works. One book that fed my interest in biomedical research was Arrowsmith by Sinclair Lewis. It portrays an idealistic medical researcher who comes to work at a research institute in New York City. Only after I came to The Rockefeller University did I learn that Arrowsmith’s institute was modeled after the Rockefeller Institute for Medical Research, the forerunner of The Rockefeller University, where I work now. Some considerable irony that I ended up at the fictional institute that stoked my interest in medical science. I met my wife, Jennifer Jones, at Rockefeller, where she is a writer and fundraiser. We have two sons, Zachary and Jonah, both now adults and embarked on their own careers.

My family all share my passions for cooking and travel, probably because I exposed them to these from an early age. When Jennifer and I brought Zachary home from the hospital at two days old, I put him in his chair on the kitchen counter and proceeded to give him a lesson in the proper way to slice fennel. Now in a turnabout-is-fair-play, he peppers me with requests to purchase expensive cooking equipment, like a restaurant-grade vacuum sealer and a laboratory-grade water bath in order to properly sous vide a steak. And his younger brother (our son Jonah) instructs me on the proper method to slice ginger for his stir fry.

Great dining and the communal act of cooking together is an important part of our family life and life in the laboratory. Back when laboratories could have kitchens, complete with stovetops and ovens, all day (and night) experiments would be paused for a communal meal. The graduate students or postdocs would shop for ingredients (usually fresh fish), and I would prepare the meal. Jennifer and Zachary would join us, then head home while we resumed the experiment.

When Jonah came along we swapped our one-bedroom Rockefeller apartment for an old house in Brooklyn, a short commute to Rockefeller (although on some days in New York City traffic, that’s arguable). The house is a large federal-style structure, on the federal and city landmarks list, sitting on about three acres of land. It is a rather unusual place to be found in the middle of downtown Brooklyn. The only reason we could afford it was that the neighborhood at the time was in a rundown industrial area, surrounded by abandoned warehouses. Now, this part of Brooklyn has seen massive resurrection and is lively with people and even shops. But we spent many years in a largely deserted part of New York, and a house of this vintage has required a lot of attention. We are constantly designing and renovating parts of the house, if one wants to call it an extracurricular activity.

College and Medical School

While I was at Amherst College, I worked summers, and during the year, I worked at the Cold Spring Harbor Laboratory in the lab of Ray Gesteland and Robert Crouch. My project centered around the bacteriophage lambda. It was a great way to get my feet wet in experimental science, although my interests were gravitating toward studying more complex systems, and I developed an interest in studying the brain. On a fortunate day while at Amherst, I met with a visiting speaker, David Hubel, and thought his approach to studying the brain would be a good model for me to follow. I applied to, and was accepted to, the department of Neurobiology at Harvard Medical School. I wanted to pursue a combined medical and doctoral degree. Although there was no such combined formal program at Harvard at the time, I was able to put together my own program, taking the courses for the medical and doctoral programs simultaneously.

I worked in the lab of David Hubel (see volume 1) and Torsten Wiesel. Unlike much of the way labs work these days, they worked together on their own projects and let their students and postdocs (few in number at any one time) do their own thing, and they did not put their names on the papers that came from their student’s efforts. Although I was new to the field, they provided me with an empty room and a catalog and told me to think of a project.

Early Work: The Anatomy of Cortical Circuits

After some initial poking around in not so interesting projects, I ended up doing a combined anatomical and physiological project to explore the roles of the different layers of the primary visual cortex (V1). I took advantage of the then-new technique of retrograde tracing of connections with horseradish peroxidase (HRP). In papers published in 1975 with Jim Kelly, a postdoc in David and Torsten’s lab, I identified the projection targets of the different cortical layers. We showed that feedforward cortico-cortical connections originate from the superficial cortical layers, projections from layer five target the superior colliculus, and feedback cortico-cortical connections and cortico-thalamic projections originate from layer six (Gilbert and Kelly, 1975). Our findings establishing the principle that deep layers provide feedback connections and that superficial layers provide feedforward connections were subsequently used by others to map out a hierarchy of cortical areas subserving vision.

The fact that orders of magnitude more neurons project to the lateral geniculate nucleus (LGN) of the thalamus from the cortex than those originating from the retina posed the intriguing question of the role of recurrent inputs to the LGN and of the role of the LGN. Although the LGN had been characterized as a “relay” between retina and cortex, clearly much more was happening in the LGN to transform the information coming from the retina. I then did single-unit recordings from the different cortical layers, showing that the superficial layer neurons had small receptive fields, appropriate for the high-resolution function of the cortical pathway. Layer five neurons had large receptive fields selective for direction of movement, appropriate for the eye-tracking function of the superior colliculus (Gilbert, 1977). Although layer six had properties unique to that layer, it was not clear what those properties contributed to the function of the LGN. But in any event, this work led to my continued interest in mapping the circuitry of the cortex as an entry point to understanding cortical function.

At the end of my combined medical and doctoral training at Harvard, I was confronted with the decision of whether to continue with my medical training, going onto internship and residency and so on. I very much enjoyed working in the clinic, but I felt I could not do justice to either clinical work or research if I tried to do both, so I decided to continue exclusively on the research track. Still, I feel that my experience in the medical part of my training provided a valuable background for the translational possibilities of my research. It is also worth pointing out how much basic research needs to be done before its translational potential can be realized. Fortunately, we have had a glimpse of that potential, as outlined at the end of this memoir.

After completing my doctoral work on the function and efferent connections of the layers of visual cortex, I stayed on at Harvard for a period to do postdoctoral work. At that point, Torsten Wiesel and David Hubel developed research programs independent from each other, and Torsten joined my interest in doing a structure-function analysis of intrinsic cortical circuits. These experiments, which began in the mid-1970s, related the interlaminar and horizontal cortical connections to the functional properties of neurons in V1. This involved doing intracellular recording with micropipettes filled with a solution of horseradish peroxidase (HRP). After characterizing the receptive field properties of the recorded neurons, we injected the neurons with HRP, which then filled the entire soma, dendritic, and axonal arbors. This provided more complete labeling than the anatomical techniques that were available at the time—notably various silver impregnation techniques (the Golgi or Nauta stains), which provided only partial labeling, due at least in part to the lack of labeling myelinated axons. These were difficult and challenging experiments, often lasting late into the night. On occasion, Torsten would lapse into Swedish in the wee hours. From these experiments, we were able to outline a basic circuit of interlaminar connections, and further pursued the functional role of these connections by inactivating specific cortical layers, such as layer 6 (Gilbert and Wiesel, 1979; Bolz and Gilbert, 1986). We described a systematic series of connections, starting from the LGN input to layer 4 and then sequentially to the superficial layers, then layer 5, then layer 6, and finally back to layer 4. This circuit was subsequently dubbed as the “canonical circuit,” although the similarities and differences in the circuit between V1, where it has been most fully characterized, and other cortical areas remain to be further explored.

Long-Range Horizontal Connections and Contextual Influences

Our experiments (Torsten and mine) produced another result that seemed to run counter to how scientists viewed cortical circuits and receptive fields in V1. At the time, it was thought that cortical connections ran principally in the vertical direction, across the cortical layers, with little lateral extent parallel to the cortical surface, which was consistent with the columnar cortical functional architecture. Our experiments did reveal a systematic pattern of connections between the cortical layers, as outlined previously, but in addition to the interlaminar connections, we found, initially in the cat and then in the monkey, that cortical pyramidal cells formed long-range horizontal connections, extending up to about 8 millimeters parallel to the cortical surface, crossing many cycles of orientation change (Gilbert and Wiesel, 1979, 1981, 1983). The implication of this finding, if one considers the receptive field sizes and retinotopic organization of V1, is that neurons integrate input over a large area of cortex representing an area of the visual field that is much larger than their receptive fields. The resolution to this seeming contradiction is that the definition of the receptive field, and its extent, is stimulus dependent, and there are substantial nonlinearities in how neurons respond to complex stimuli. For example, although a neuron will respond to a line segment presented in the receptive field center and not at all when the segment is placed in an adjoining visual field position, the neuron can respond severalfold stronger when two line segments are presented in a collinear arrangement, with one “inside” and the other “outside” the receptive field. These interactions are sometimes referred to as “contextual influences” (see below). Of course, based on this and related observations, what is inside or outside loses its meaning. At the time the popular distinction was between the “classical” and “nonclassical” receptive field, although I found the terms unsatisfying. After all, even in his classical study of retinal ganglion cell receptive fields in the 1950s Stephen Kuffler defined the receptive field as “not only the areas from which responses can actually be set up by retinal illumination may be included in a definition of the receptive field but also all areas which show a functional connection, by an inhibitory or excitatory effect on a ganglion cell. This may well involve areas which are somewhat remote from a ganglion cell and by themselves do not set up discharges” (Kufffler, 1953, p. 45). The critical difference in our study of receptive fields in the visual cortex is in the distinction between the selectivity of neurons to a simple stimulus, such as a single oriented line segment vs. its selectivity for complex stimulus configurations, which involve many components that interact nonlinearly. The lateral interactions and contextual influences operating in V1 also can account for perceptual interactions, such as the tilt illusion. The tilt illusion involves a change in the perceived orientation of a line when it is surrounded by other lines of a slightly different orientation. Surrounding a neuron’s receptive field with a set of lines of a given orientation induces a change in its tuning to the orientation of a line placed in the receptive field center, potentially providing a cellular basis for the tilt illusion (Gilbert and Wiesel, 1990).

These contextual influences, seen in V1, are likely related to the Gestalt rules of perceptual grouping. Even in V1, neurons integrate information over large parts of the visual field, following the laws of perceptual grouping. One property of perceptual grouping, “good continuation” as described by the Gestalt psychologist Max Wertheimer, is consonant with the properties of the long-range horizontal connections, which can account for how object contours are perceptually assembled (Ts’o et al., 1986; Kapadia et al., 1995; Li and Gilbert, 2002; Stettler et al., 2002; Li et al., 2006). The responses of V1 neurons to global contours also reflect the statistical regularities of contours in natural scenes, as analyzed by then-graduate student Mariano Sigman (Sigman et al., 2001). As such, the cortex is tuned to pick out the more probable correlations in natural scenes, rather than the exceptions. As I will describe, the long-term change associated with perceptual learning is another example of how the visual cortex picks up new statistical regularities by repeated exposure to the same stimulus.

In studying the synaptic physiology of the horizontal connections, Judith Hirsch found a strong voltage dependence of inputs coming through long-range horizontal connections, potentially accounting for the nonlinearities in the responses to complex stimuli (Hirsch and Gilbert, 1991). The sort of interactions afforded by the horizontal connections have properties that underly an “association field” within V1 that mediates the Gestalt principle of good continuation. In particular, over the years with Torsten and my students and postdocs, we showed that the long-range horizontal connections connect columns of similar orientation preference. We demonstrated this in several ways as the technology for labeling the horizontal connections and visualizing the cortical functional architecture became more sophisticated. First, with Torsten, we combined labeling neurons forming horizontal connections with retrograde tracers and the orientation columns with 2-deoxyglucose autoradiography. Active neurons take up more radiolabeled deoxyglucose, but they can’t further metabolize it, so it remains stably in the neurons that have been activated during its infusion, such as with a visual stimulus consisting of a grating of a particular orientation. The active cortical regions can then be visualized with autoradiography. When the retrograde tracer was placed in a column of a given orientation, it was transported to adjoining columns preferring the same orientation. Then, with Daniel Ts’o, we measured the orientation dependency of lateral interactions by cross-correlation analysis between pairs of recorded neurons (Ts’o et al., 1986; Ts’o and Gilbert, 1988). Here again we found connectivity between similarly oriented neurons with widely separated receptive fields. With Dan Stettler and Aniruddha Das, we labeled the horizontal connections with virally mediated transfer of the GFP gene (using an adenovirus, in collaboration with Jean Bennett) and imaged the cortical architecture with intrinsic signal optical imaging (Stettler et al., 2002). This imaging technique was developed in Torsten’s lab by Amiram Grinvald (Grinvald et al., 1986), where he found that active areas of cortex have lower reflectance than inactive areas, because of changes in local blood flow and oxidative changes in local chromophores.

The continuing emergence of new experimental approaches has greatly expanded the reach of what we were able to do. The linking of cortical columns of similar orientation preference along with their lateral extent across the cortical map matched psychophysical measures of perceptual interactions mediating contour saliency, as found by Wu Li (Li and Gilbert, 2002). Wu has been a longstanding collaborator, and he skillfully helped us transition from studying neuronal function in anesthetized animals to doing experiments with awake, behaving animals. This transition was centrally important in developing our theory of the relationship between cortical circuits and function in a behavioral context. The properties of the long-range horizontal connections are reflected in the contour dependent neural responses, which are facilitated by the presence of contours that extend over large parts of the visual field (Li et al., 2004, 2006). Yet, on top of this, as I’ll discuss, these interactions are not constitutively active but rather are additionally dependent on top-down influences, with the contour-related facilitation being strongest when animals perform a contour detection task (Crist et al., 1997; Ito et al., 1998; Ito and Gilbert, 1999; Kapadia et al., 1999; Ito et al., 2000; Westheimer et al., 2001; Crist et al., 2001).

By working with awake, behaving monkeys trained to do visual discriminations tasks, we were able to link receptive field properties to perception and study the higher-order functions of early cortical areas and, critically, the role of top-down influences in mediating these properties. In this regard, I greatly benefited from my long-standing friendship and collaboration with Gerald Westheimer (see volume 5), a noted figure in the field of perceptual psychology. With his valuable input, we incorporated the tools of visual psychophysics in linking the receptive field properties of cortical neurons to visual perception. With Gerald and students and postdocs Mitesh Kapadia, Roy Crist, and Minami Ito, we made our initial findings on the interaction between contextual influences, perceptual learning, and top-down influences in early visual processing (Kapadia et al., 1994, 1995, 1999, 2000; Gilbert et al., 1997; Crist et al., 1997; Ito et al., 1998; Westheimer et al., 2001). Another fruitful collaboration was with the highly imaginative perceptual psychologist Ken Nakayama, where, with a postdoc Jonathan Bakin, we showed how neurons in areas V1 and V2 conveyed information about three-dimensional surface configurations (Bakin et al., 2000).

Adult Cortical Plasticity

Another theme of my work that emerged from our investigation of the function of the long-range horizontal connections in the cortical circuit is that of adult cortical plasticity. From the early work of Torsten Wiesel and David Hubel, it was established that experience-dependent changes in cortical circuits were limited to an early period in postnatal life, lasting a few months, known as the critical period. Their observations were based on the property of ocular dominance, how the inputs from the two eyes are brought together in V1. Monocular deprivation leads to a shrinkage of the input from deprived eye afferents and expansion of the nondeprived eye afferents. This change could be induced or reversed only within the critical period, after which the thalamocortical projections became fixed.

Although there had to be a measure of cortical plasticity throughout life to encode new memories, or perceptual learning, it was generally believed that this took place in higher-level areas of the visual cortical hierarchy, far from V1. But the work on ocular dominance plasticity during the critical period was primarily a matter of changes in thalamocortical connections, the projection from the LGN to area V1. I felt that a different component of the cortical circuit, the long-range horizontal connections, was a promising candidate for adult plasticity, even in early visual cortical areas. To test this idea, we came up with an experimental model to induce experience-dependent changes in V1—making focal binocular lesions (also referred to as scotomas) with an infrared laser at corresponding locations in the two retinas. This removed functioning visual input from a restricted area of V1, which we refer to as the lesion projection zone (LPZ). Although initially this region was silenced after binocular lesions, over a subsequent period of weeks and months, the LPZ regained functioning visual input. In effect, the cortex was remapped, with a shrinkage of the representation of the retinal scotoma and an expansion in the representation of the normal, surrounding retina (Gilbert et al., 1990; Gilbert and Wiesel, 1992). Our finding of shifting receptive fields in the LPZ was confirmed by the application of new technologies for the study of neuronal populations, cortical functional architecture, and circuitry. These included optical imaging, recording with chronically implanted electrode arrays, labeling neurons with virally mediated gene transfer, and 2-photon imaging. The receptive fields of the neurons in the LPZ had shifted from their prelesion retinal locations to sites outside the retinal scotoma, having received input from cortical neurons outside the LPZ through the long-range horizontal connections (Gilbert et al., 1990; Darian-Smith and Gilbert, 1994, 1995; Das and Gilbert, 1995; Yamahachi et al., 2009; Marik et al., 2014; Abe et al., 2015).

Although a small measure of remapping takes place in the LGN, this was insufficient to account for the more substantial reorganization occurring in the visual cortex, as I found with Corinna Darian-Smith (Darian-Smith and Gilbert, 1995). Cortical plasticity following retinal lesions was most compellingly demonstrated through the use of chronically implanted electrode arrays, which was accomplished in the lab by Hiroshi Abe (Abe et al., 2015). At each recording site, we could document the receptive field positions of single neurons before and after making the lesions. When the array was implanted in the future LPZ, we could track the changes occurring after cortical sites were initially silenced by the retinal lesion, and then we gradually recovered visually driven responses. After recovery, the receptive field positions had made large shifts to positions in intact parts of the retina, outside the retinal scotomas. This line of evidence showed that the remapping was not merely a matter of selection of neurons that were unaffected by the lesion but rather was mediated by neurons that were initially silenced and that subsequently developed new receptive fields that were substantially shifted relative to their original locations.

Another approach I applied in studying the functional recovery after retinal lesions, along with Aniruddha Das, involved the technique of intrinsic signal optical imaging, comparing the orientation maps before making the lesion and after recovery. There was a close match, supporting the idea that, because the horizontal connections linked orientation columns of similar orientation preference, they were the likely source of the reorganization (Das and Gilbert, 1995). A model, developed by a student Justin McManus in collaboration with the computational neuroscientist Shimon Ullman (see volume 13), showed how this form of reorganization could account for perceptual fill-in through the lesioned parts of the visual field and mediate a measure of recovery of function after CNS lesions (McManus et al., 2008). The model provided a mechanism for the perceptual fill-in, and perhaps more generally for how the brain can adapt to neurodegenerative disorders and stroke.

The cortical circuit responsible for this reorganization was the plexus of long-range horizontal connections. The experiments that led to this discovery benefited from my collaboration with Winfried Denk, who pioneered in developing the technique of 2-photon microscopy for deep tissue imaging in live animals. With Denk, we engineered the first 2-photon microscope for imaging in nonhuman primates. When combined with virally mediated expression of the green fluorescent protein (GFP), we were able to image, at high resolution, the somata, dendrites, and axons of neurons in V1 of Macaque monkeys. Our initial surprising finding was that, under normal circumstances, there is a continuing turnover of axonal boutons, the presynaptic sites of cortical circuits. With a student, Dan Stettler, along with Aniruddha Das and Denk, we found a rate of turnover of 7 percent per week (Stettler et al., 2006). I’ll have more to say about that later. We then examined what happened to the horizontal connections after making retinal lesions. Using the technique of longitudinal 2-photon imaging, we were able to track the changes occurring among identified axons over weeks. We found that the lesioning was followed by a period of exuberant outgrowth and pruning of the horizontal connections projecting from outside the LPZ to inside the LPZ, with the balance shifted toward a net increase (Yamahachi et al., 2009). This confirmed a result we initially obtained from postmortem studies (Darian-Smith and Gilbert, 1994) and accounted for how the LPZ neurons recovered visually driven input, shifting their receptive fields to positions overlapping with those of the neurons outside the LPZ from which they received input. Notably, the plasticity we observed occurred in adult animals, well after the end of the critical period for thalamocortical connections. Consequently, one can surmise that the limitations on cortical plasticity associated with the critical period are specific to certain cortical connections, most particularly thalamocortical connections, but other circuits, even those in V1, remain plastic throughout life.

With Sally Marik, I extended the players involved in adult plasticity from excitatory to inhibitory neurons, from the visual system to the somatosensory system, and from nonhuman primates to mice (Marik et al, 2010; Marik et al., 2014). Along with our study of the circuits engaged in cortical plasticity, we documented the expression of neurotrophins in the area undergoing topographic reorganization (Obata et al., 1999). With Marik, we revealed some of the other molecular pathways involved, notably the caspase pathway, which, rather than leading to apoptosis as it does in early development, is involved in axonal pruning in the adult (Marik et al., 2013, 2016).

Cortical Plasticity, Perceptual Learning, and Top-Down Influences

Our observations on cortical plasticity following retinal lesions may be relevant for the recovery of function after brain lesions or degenerative disease, but it seems unlikely that it evolved solely for that purpose. Instead, it was likely to be associated with experience-dependent changes in cortical function that occur throughout life under normal circumstances. Specifically, a form of implicit memory known as perceptual learning, which is broadly associated with the neocortex, seemed to us a likely candidate for neuronal plasticity in the visual cortex. Although it is established that different forms of memory are supported by different parts of the brain, with declarative memory in the medial temporal lobe and some forms of implicit memory elsewhere in the brain (including habit memory in basal ganglia and classical conditioning in the cerebellum; see Squire, volume 10), we have developed a theory of the circuit mechanisms of learning, and of systems consolidation of memory, that may be common to all forms of memory.

Clearly, it is necessary to have ongoing neuronal plasticity throughout adulthood as we continually undergo perceptual learning. One might have presumed that such plasticity would be the province of cortical areas high in the visual cortical hierarchy, with V1 being free of experience-dependent changes. In experiments with my colleague Wu Li, we found quite to the contrary that even V1 was capable of undergoing experience-dependent changes with learning, similar to what we observed following retinal lesions. Importantly, we found the neural mechanism of perceptual learning to be related to the role of top-down influences in neuronal function, which I will detail below in “The Neuron as an Adaptive Processor.” A useful tool in measuring learning-dependent changes in neuronal function is that of mutual information—that is, how much the tuning of a neuron to a stimulus attribute is dependent on the value of that attribute. We found that as animals improve on a visual discrimination task, neurons carry increasing amounts of information about task- relevant stimulus characteristics and carry less information about task-irrelevant stimulus features. The design of the experiments that show this are as follows: while recording from hundreds of neurons in multiple cortical areas, we train animals (nonhuman primates) to shift between perceptual tasks with the identical visual stimulus. Some components of the stimulus are relevant to the task, and some irrelevant. Neurons carry information about, or are tuned to the properties of, the task-relevant stimulus components and their responses are not influenced by task irrelevant components. Changing tasks switches the relationship between what is relevant and what is irrelevant, and the information conveyed by each neuron’s response changes accordingly. An example of a pair of tasks we use involves a set of five lines—a central line flanked by two parallel lines side-by-side with the central line and two colinear lines, either above or below the central line. On a trial-by-trial basis, the flanking lines are placed in different positions relative to the central line, so we can measure how each neuron’s response changes as we alter the positions of the flanking lines. We can then construct a tuning curve that represents how each neuron encodes the positional information. Animals either perform a bisection task, reporting the proximity of the central line to either of the parallel flankers, or a Vernier task, reporting the position of the central line relative to the colinear lines. We find that when animals perform the bisection task neurons become sensitive to the position of the parallel lines, which are task relevant and suppress the influence of the colinear lines, which are task irrelevant. Conversely, when the animal performs the Vernier task, the same neurons become insensitive to the position of the task irrelevant parallel lines and are highly tuned to the position of the task relevant colinear lines. Thus, as I will elaborate, neurons are adaptive processors, in which a given level of firing conveys different information under different task conditions. We have documented these changes in various visual discrimination tasks and in different visual cortical areas, including V1 and V4 (Gilbert, 1994; Sigman and Gilbert, 2000; Crist et al., 2001; Li et al., 2004, 2008, Gilbert et al., 2009; Astorga et al., 2022).

The tuning of neurons to stimulus attributes changes during the course of perceptual learning. Along with the shift in the psychometric functions, reflecting improved performance on a task, there is a shift in V1 neurometric functions, reflecting an increased sensitivity of neurons to the property involved in the task. They become more sharply tuned to the stimulus attribute that shows perceptual improvement, or put another way, neurons increase the mutual information they carry about that attribute. For example, with the bisection task, the perceptual threshold in discriminating the position of the central line relative to the parallel line improves after hundreds of trials, and the neurons in different visual cortical areas increase the information they carry about the position of these lines and further suppress the information about the task-irrelevant lines. As with the changes in cortical circuitry that we saw following retinal lesions, during periods of perceptual learning and functional changes in neurons, the horizontal connections undergo parallel processes of sprouting and pruning (van Kerkoerle et al., 2018). As we have seen with the recovery following retinal lesions, one has to make the distinction between connections that are subject to a critical period and those that undergo change throughout life. Although it may have been presumed that the functional changes associated with perceptual learning would be limited to higher-order areas in the visual cortical hierarchy, it is particularly intriguing that even the earliest stage of visual cortical processing, area V1, shows such changes. This begs the question of how perceptual learning on one task doesn’t interfere with performance on other tasks. The resolution to this problem, as I will elaborate, is that the functional properties of neurons, or their task-related tuning, are under top-down control. The underlying functional properties at the neuronal level are present only when the task is being performed, and these properties, for the same neurons, switch from task to task.

The dynamic changes in cortical circuits require a mechanism that can retain previously acquired information while encoding new information. We have seen an emerging theme: In different cortical areas, animal models and cell types, there is a high rate of synaptic turnover in the disappearance and appearance of axonal boutons. This has been seen by others in the form of dendritic spine turnover. We have documented this by longitudinal in vivo imaging of axonal boutons, the presynaptic sites. As described previously, even in the absence of experiential manipulation, such as when an animal is undergoing perceptual learning, boutons turn over at a rate of 7 percent per week. Although we were able to image for only a few weeks, there was no evidence for a privileged stable set of boutons. Even so, this amount of turnover raises the question of how information can be retained in the face of the circuit dynamics, because those circuits are the substrate of encoded information. The dynamics in connectivity may be related to the phenomenon of representational drift, whereby neurons change their tuning or optimal stimulus on a day-to-day basis. (I will discuss this further in the section on dynamic connectivity.) In addition, the changes in connectivity are associated with the constitutive sharpening in neuronal tuning that occurs during the course of perceptual learning.

The Neuron as an Adaptive Processor

Working with awake, behaving animals opened up a world of new findings and new insights into the dynamic nature of cortical function and connectivity. We further benefited from the implementation of new technologies to record from large populations of neurons while animals perform complex visual discrimination and object recognition tasks. Over a series of experiments, we studied how neuronal responses were highly dependent on contextual influences, and these influences were in turn gated by top-down influences of perceptual task and expectation. By contextual influences, I mean that our perception, as well as neurons in V1, do not simply carry information about a single, local stimulus component but rather are highly influenced by the global characteristics of scenes in which that component is embedded. And these influences of stimulus context are in turn gated by top-down influences of perceptual task and expectation, as described earlier. We showed that a given level of response by a neuron does not signal the same information under all circumstances, but it can mean entirely different things when animals switch from task to task. This shows again that a neuron is an adaptive processor, carrying different information under differing behavioral contexts. This phenomenon also requires revisiting the idea of the receptive field. Neurons do not simply reflect the presence of a given sensory stimulus in a restricted part of the visual field. Rather, they carry information in the service of a particular perceptual or behavioral goal. Even V1 shows selectivity for complex stimulus configurations, and this selectivity shifts under different perceptual tasks. This contradicts the traditional notion that V1 is a mere preprocessor, carrying only simple stimulus characteristics, such as orientation or direction of local movement. Although there may be a measure of increasing complexity as one moves anterior in the ventral visual pathway, clearly V1 represents more complex stimulus configurations than single oriented line segments. And while it had been supposed that attentional influences increase along this pathway, we have seen top-down influences operating as strongly in V1 as in higher visual areas. We have observed the effects of top-down influences involving different perceptual tasks, including brightness discrimination, contour detection, shape detection, and object recognition (Ito et al., 1998; Ito and Gilbert, 1999; Gilbert et al., 2000, Li et al., 2004, 2006; McManus et al., 2008; Ramalingam et al., 2013; Chen et al., 2014; Liang et al., 2017; Astorga et al., 2022; Altavini et al., submitted).

It might be argued that we are simply talking about attentional influences. The use of the term “attention” has been applied in various ways, most commonly spatial attention, but also object oriented and feature based attention. Although one does not wish to get embroiled in a semantic argument, we prefer to use the term “top-down influences” because the information conveyed top-down is much richer than the mere locus of attention but instead includes the discrimination task being executed at the attended location. Top-down influences also play a role in setting the stimulus selectivity of neurons by object expectation and during perceptual learning. Importantly, we found that profound top-down influences operate not just in cortical areas at the top of the visual hierarchy but as far back as V1. The effects of the top-down influences are changes in the kind of information conveyed by neurons in the areas targeted by this feedback. A given level of firing may reflect very different stimulus characteristics when subjects perform different perceptual tasks or are operating under different expectations. Effectively, this means that a neuron does not represent a fixed “labeled line,” but it represents different information on a moment-to-moment basis. Rather than compartmentalizing information for doing different tasks by different subsets of neurons, a large fraction of the entire neuronal population assumes tuning appropriate for every task. This raises the question of “read-out”—that is, how the response of a neuron is “interpreted” by the brain. The answer, presumably, is that the top-down instruction is for the target neuron to perform a particular calculation, and the area receiving the return feedforward input uses this response as the result of that instruction.

Dynamic Effective Connectivity—A Pointer Theory of Feedback

Underlying this task switching, we found that the task-dependent changes in cortical function are associated with changes in effective connectivity within the cortical network. With students Nirmala Ramalingam and Justin McManus, and my collaborator Wu Li, we studied the circuit mechanisms of top-down control using the chronically implanted electrode arrays referred to previously. With each electrode inserted into cortical sites representing different components of a complex stimulus, we were able to measure the effective connectivity between sites that were relevant to the task being performed vs. those that were task irrelevant. Effective connectivity was measured with either cross-correlation analysis of spiking activity or coherence between local field potentials (LFPs). The effective connectivity between sites switched on and off depending on the task, even though under all task conditions, all the recorded neurons were activated by the stimulus (Ramalingam et al., 2013). Although a neuron receives 10,000 inputs from other neurons, it is affected by only a small subset of these inputs at any given time. The cellular mechanism underlying this gating of specific inputs remains a mystery, although one can speculate about possibilities. Whatever the mechanism, it is likely to involve an interaction between feedback connections, which carry information about the nature of the task, and local circuits, which carry information about the stimulus context. We have proposed that in effect the feedback serves as a pointer, dynamically linking the bits of information represented in the target area. Even under a fixed anatomical framework of connections, the matrix of effective connectivity within the network is constantly changing. Our theory is further supported by simultaneous recordings in areas V4 and V1, in which we showed that the lateral interactions in V1 are dependent on V4 input (Liang et al., 2017). One can imagine that the properties of any neuron result from nested dependencies of interactions, extending widely across the brain. The pointer idea also relates to our observations about functional changes occurring over extended periods of time during perceptual learning. What is required is a heterosynaptic interaction, which involves establishing the appropriate “addressing” of the relevant intrinsic connections by the feedback inputs to an area, allowing these inputs to be gated to conduct task-relevant information. This heterosynaptic interaction is distinct from classical models of cortical plasticity that involve Hebbian changes in synaptic weights that are permanently expressed. Instead, different influences of stimulus context are not constitutively expressed but instead change from moment to moment along with a changing behavioral context.

It is worth pointing out that this view puts additional constraints on what is required of connectomics. As challenging as it has been to reconstruct all the neurons and local connections in a cortical column, a large fraction of the inputs to that column come from distant sources through long-range horizontal connections within the area, including feedforward and feedback connections from multiple other areas and from the thalamus. In a sense, each neuron, taken together with all of its inputs, is a microcosm of the brain as a whole. A full description of the anatomical circuit affecting a neuron would require a connectivity map encompassing the entire brain. Perhaps that is why most of the progress in this area comes from smaller systems like Drosophila or Caenorhabditis elegans. But the greater challenge, as I have described, is that the connectivity matrix is dynamic, with changing effective connections within a fixed anatomical framework over short timescales. And with the synaptic turnover, even the anatomical framework is undergoing constant change.

When we did combined recordings in areas V1 and V4, research associate Guadalupe Astorga and I found an intriguing sequence in the functional changes occurring during perceptual learning. At early stages of learning, the information about the attributes involved in the visual task are better represented in V4 than in V1. Another important property seen in neuronal function is the suppression of the influence of stimulus attributes that are irrelevant to the task, again better reflected initially in the characteristics of V4 neurons than V1 neurons. But over the training period, and in the following weeks, the increase in task-relevant information and suppression of task irrelevant information is seen in V1 (Astorga et al., 2022). This finding is reminiscent of an earlier study done with Mariano Sigman involving a visual search task with fMRI in humans, where a shift in cortical areas is activated by targets as they become more familiar from lateral occipital cortex to V1/V2 (Sigman et al., 2005). Continuing with the pointer idea, this reflects an engagement of pointers to V1, in addition to those previously established in V4. We have seen the phenomenon of task switching in multiple visual areas extending from V1 forward, and with different discrimination and recognition tasks. Importantly, learning in these paradigms involves not just increasing the level of mutual information for task-relevant attributes but increased suppression of task-irrelevant attributes, further supporting the idea of input gating.

With Astorga, we have made the intriguing observation that a small proportion of neurons change their task-related tuning over consecutive days, even when the animal is doing a given task. This phenomenon, known as “representational drift,” has been seen elsewhere in the brain, most notably in the hippocampus. It is tempting to relate this phenomenon to our observation of the persistent turnover of synapses that we observed with longitudinal 2-photon imaging, where at the levels of connectivity and function, the brain is in a constant state of flux. Perhaps this is the mechanism underlying experience-dependent changes, such as those we have seen during perceptual learning. By having this underlying dynamic, learning can be accomplished by a process of selection of those neurons whose tuning carries more task-related information and less task-irrelevant information. As a result, the population as a whole becomes more adaptive for the trained behavior. Of course, this idea, and the drift itself, again raises the challenging issue of readout—how a particular neuron is linked to a particular percept.

Although it has long been the goal of systems neuroscientists to find and apply the optimal stimulus set for activating neurons, some looking for a “basis set,” a fixed set of visual primitives that could be combined in various ways to represent full objects, our finding that neurons operate as adaptive processors posits a different framework. In effect, neurons take on properties that are appropriate for the current perceptual task, with their stimulus selectivity determined by top-down influences of expectation and perceptual task. Even their receptive field position shifts in accordance with that of the attended stimulus. So rather than thinking of a neuron having a fixed receptive field, it is more appropriate to think of it having a “perceptive field,” adapted to the immediate perceptual demands, than reflecting only the bottom-up inputs arising from the retina. In current work with Tiago Siebert-Altavini, we have extended the functional switching to the process of object recognition, based on natural stimuli. We have seen that when animals are cued to expect different objects, neurons switch their stimulus preferences to different objects or object components. We have seen these dynamics operating in several areas along the ventral visual pathway, including V1, which, as we have emphasized, has a more complex role in taking on task or expectation-dependent properties, not just passively encoding local stimulus features (Altavini et al., submitted). We suggest that, as we experience different environments, we are constantly operating under a set of expectations for the identity of objects in those environments, and these top-down influences interact with the incoming sensory information, leading to our ability to interpret the visual scenes we encounter.

As mentioned earlier, the pointer idea, and our findings of changes in neuronal tuning to task-relevant and task-irrelevant stimulus attributes, suggests a mechanism of synaptic plasticity different from the conventional idea of a Hebbian mechanism. Hebbian plasticity involves permanent changes in synaptic weights after concurrent activation of an input with a postsynaptic cell. Rather, what is required is a heterosynaptic mechanism, in which feedback connections develop the appropriate mapping, or “addressing” of local inputs that need to be gated during the execution of a task. Because different effective connectivities have to be set for different perceptual tasks, changing on a moment-to-moment basis, this doesn’t involve any connection strength to be established on a permanent basis. Long-term changes may also occur, as long as the strengthened or weakened inputs can be dynamically gated. By this way of thinking, memories are not encoded as a change in weight of a small number of synapses but rather as a set of potential interactions distributed across a broad cortical network.

Although I now engage in a bit of speculation, I would like to propose that the pointer idea is applicable throughout the brain. For example, the hippocampus can be considered to be a pointer that links components of memories represented in the entorhinal cortex. As observed by Brenda Milner with patient H. M., when the hippocampus is removed, older memories are retained, but only those that were acquired several years before surgery. This process, requiring an extended period for memories to become independent of hippocampal input, is known as systems consolidation. We suggest that this consolidation involves a switch in pointers originating from the hippocampus to other areas, such as the perirhinal, parahippocampal, and prefrontal cortices as well as the thalamus. We have proposed that our observation of shifting pointers from those targeting V4 to those targeting V1 during perceptual learning reflects a similar process of systems consolidation for implicit memories. We further speculate that a similar role is played by the striatum, which can activate motor primitives by targeting premotor cortex via thalamic nucleus VL. This raises a potentially important function for the thalamus as a mediator of pointers. An additional feature of the striatum pointer idea is that it may contain the dimension of time, activating the motor primitives in a particular sequence in the execution of a complex movement. Here, too, systems consolidation may play a role, with highly learned movements becoming independent of the striatum, depending on prefrontal inputs instead.

It is therefore worth considering whether this general theory of circuit interactions, involving pointers that gate neuronal inputs, expressing task-relevant inputs and suppressing task-irrelevant inputs, may be relevant to behavioral disorders that are not purely visual in character. This idea has driven my current research focus on autism. I’ve suggested that autism may be, at least in part, a perceptual disorder, in which there is a reduced ability to suppress task-irrelevant inputs. The result is a cacophony of stimulus inputs that would cause one to avoid interacting with the environment, which may be interpreted as a social deficit but is at root a perceptual one. We are currently testing this idea in animal models of autism. It is worth pointing out that other brain regions that are the source of pointers, such as the hippocampus and striatum, have also been implicated in autism, which therefore may be thought of as a disruption of a general mechanism of brain interactions that are broadly distributed, rather than a disfunction of any single brain region. In this regard, it is worth noting that hundreds of genes have been linked to autism and that these genes are ubiquitously expressed in the brain. How this pattern can account for the specific behavioral manifestations of autism is a puzzle, but perhaps the diverse set of signaling pathways linked to autism may have a common link at the level of circuits, such as those describe previously. Although we have studied some of the molecular mechanisms of experience-dependent axonal plasticity, the great challenge going forward is to understand how the diverse set of genes linked to autism and other behavioral disorders can produce the specific phenotypes of these disorders.

An emerging picture in how function is represented by the brain is one more of distributed interactive network, rather than the product of a feedforward hierarchy in which perception is represented at the top of the hierarchy after an amount of preprocessing from the lower levels. Experimentally, this requires simultaneous recording or imaging over many cortical and subcortical areas. One should consider that the function of feedback is to carry much more information than merely the locus of attention, but instead a variety of influences, including perceptual task, expectation, efference copy, and perceptual learning. Rather than thinking of perception and consciousness as being the products of the apex of a hierarchy of feedforward processing between cortical areas, they may lie in the mode of countercurrent interactions across the entire cortical network.

Cortical Dynamics

As we have pursued the themes of adaptive processing and perceptual learning, it is clear that the cortex is dynamic on a range of timescales. The information conveyed by a neuron switches from moment to moment under different behavioral contexts and changes over weeks for a given task during perceptual learning. The seemingly random changes in tuning (representational drift) and synaptic turnover may be a useful substrate for enabling the experience-dependent changes associated with perceptual learning. One may consider the changes that are adaptive for perceptual learning result from a process of selection, keeping the neurons with tunings that fit the requirements of a task. Still, one must consider how the long-term changes associated with improvement in performance on a task can keep previously learned information intact. Moreover, here again we are challenged to understand how the system can “read-out” the meaning of a given neuron’s response in the face of this constant flux in the information conveyed by each neuron under the same task conditions. This may be achieved by having cortical areas at higher levels of a hierarchy adapting to the changes at earlier levels and making the appropriate associations.

From our developing understanding of cortical circuit interactions, it is worth considering how they compare with neural network models that lack some of the key features we have unearthed. Most convolutional neural networks have a feedforward structure, lacking the lateral and feedback interactions we see in the brain. One may ask whether a neural network with enough layers can replicate cortical function without the dynamics seen experimentally, or whether certain functions are made possible by recurrent processing that are not achieved with neural network models. In other words, are current neural network models not in fact representative of real neural networks? It will be interesting to see what capabilities can be conferred to the models once true feedback and lateral interactions are incorporated.

With all this, the questions going forward proliferate. What is the mechanism, at the cellular or circuit level, of the input switching? How do feedback connections interact with intrinsic cortical circuits to enable the dynamic switching between tasks? What is the nature of the signal conveyed by feedback? What are the relative roles of different sources of feedback, for example, direct cortico-cortical connections vs. cortico-thalamo-cortical connections, or feedback to a given target cortical area from different cortical areas? In the face of synaptic turnover and shifting tuning, how is the previously learned information kept intact? Do these functional and anatomical dynamics help promote learning-dependent changes? How do circuit changes associated with learning prevent catastrophic loss of previously learned information? Even if the information is maintained, when individual neurons change their “line label,” what is the mechanism of readout to stably guide behavior? What is the value of feedback/top-down interactions that operate in the brain relative to convolutional neural network models that operate by feedforward connections alone? How can one incorporate these interactions into neural network models, and what additional capabilities would this confer?

Although I began my career as an excursion into the nature of cortical circuits and the functional roles of specific cortical connections, our findings have led me over the years to a larger exploration of the more complex properties of visual cortical neurons, the short-term dynamics and long-term experience-dependent changes in adult cortical function and connections, and their potential relevance to behavioral disorders. At present, we are left with a profusion of questions still to be resolved, ones that will lead us to an even greater understanding of the basis of human cognition.

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Daniel Johnston

BORN:

Passaic, New Jersey

December 9, 1947

EDUCATION:

University of Virginia, Charlottesville, BS, Electrical Engineering with Distinction (1970)

Duke University, Durham, NC, PhD, Biomedical Engineering and Physiology (1974)

APPOINTMENTS:

Postdoctoral Fellow and Instructor, Dept. of Neurology, University of Minnesota, Minneapolis (1973–1975)

Assistant Professor, Depts. of Neurology and Biomedical Engineering, University of Minnesota (1975–1977)

Assistant, Associate, and Full Professor, Depts. of Neurology, Neuroscience, and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (1977–2004)

Director of the Graduate Program, Division of Neuroscience, Baylor (1988–2004)

Professor of Neuroscience, University of Texas at Austin (2004–2022)

Director, Institute for Neuroscience, University of Texas at Austin (2005–2015)

Founder and Director, Center for Learning and Memory, University of Texas at Austin (2004–2020)

Chair, Department of Neuroscience, University of Texas at Austin (2011–2015)

Emeritus Professor of Neuroscience, University of Texas at Austin (2022–present)

HONORS AND AWARDS (SELECTED):

Grass Foundation Fellowship in Neurobiology, Marine Biology Laboratory, Woods Hole, MA (1976)

Michael E. DeBakey, MD, Excellence in Research Award, Baylor College of Medicine (1997)

Marc Dresden Excellence in Graduate Education Award, Baylor College of Medicine (1999)

Barbara and Corbin J. Robertson, Jr., Presidential Award for Excellence in Education, Baylor (2001)

Dart Foundation Scholar in Learning and Memory, Marine Biology Laboratory (2004–2006)

Endowed Chair, Karl Folkers Chair in Interdisciplinary Biomedical Research, University of Texas at Austin (2004–2022)

Gill Center Distinguished Neuroscience Investigator, The Gill Foundation (2009)

Elected Fellow, American Association for the Advancement of Science (2016)

Daniel Johnston’s work has focused on the use of quantitative, biophysical methods to study cortical neurons and synapses under normal and disease conditions. He made landmark discoveries on the mechanisms of intrinsic burst generation in hippocampal CA3 pyramidal neurons and on the conductance changes associated with long-term synaptic potentiation in hippocampus. Using both experimental and theoretical analyses, he laid the groundwork for the ability to voltage- and space-clamp synapses on neurons with complex dendritic trees. His group was the first to study the properties and distribution of single voltage-gated ion channels in cortical neuron dendrites. He and his team discovered that dendritic ion channels are expressed nonuniformly in dendrites, are activated by synaptic inputs, and undergo activity-dependent changes in their properties and expression patterns in parallel with synaptic plasticity, so-called plasticity of dendritic excitability. Many of the mechanisms for this plasticity of dendritic ion channels were also identified by the Johnston group. Moreover, they demonstrated how these dendritic channels contribute to the information processing and storage of the nervous system. Throughout his career, Johnston applied some of his basic research findings to a better understanding of certain neurological disorders, in particular epilepsy. His landmark findings on the synaptic nature of the electrical discharge in focal epilepsy and on the changes in dendritic ion channels or “channelopathies” that contribute to epileptogenesis have had major impacts on the field. His broad expertise in cellular neurophysiology and biophysics is embedded in the highly regarded textbook with Sam Wu entitled, Foundations of Cellular Neurophysiology.

Daniel Johnston

Prologue

As I try to recall my life from early years to the present, I’d like to use an analogy drawn from all the time I’ve spent in boats and canoes on moving water to perhaps explain how I ended up being a successful scientist. Think about watching the way things on the surface of water drift from place to place. Sometimes it seems like this drift is purely random, but of course it is not. It is influenced by the tides, winds, bottom structures, and nearby land. In some ways, my journey to becoming a scientist is analogous to this ocean drift. There were many people and events throughout my life that helped determine my ultimate career. I could have been trapped behind a rock or in an eddy, but fortunately I was not. In the sections to follow, I will highlight some of the influencers (people and places) that contributed to my “drift” toward science.

Early Years

I was born on December 9, 1947, in Passaic, New Jersey to middle-class parents. My father, Vivian Daniel Johnston Jr., was a quality control chemist for Givaudan Corp in Nutley, New Jersey (which was later purchased by Hoffman-La Roche). My mother, Elizabeth Booth Johnston was a secretary who never went to college. I have one sister, Laura, who is two years older than I am. We were very close growing up, but drifted apart over the years. The name given to me at birth was V. Daniel Johnston, III. The V. was for Vivian, but since my father didn’t want to name me Vivian, but did want me to be the “Third,” he just gave me the initial V. I dropped the V from my name as soon as I could and just used Daniel as my first name with no middle initial.

My parents met in New Jersey and married young. My mother was the youngest of four children born to immigrants from Holland. She was an amazing mother who instilled in me a deep appreciation for the importance of family. My mother’s father died when I was very young, but my grandmother, Alida, lived a long life (102 years old). She was a wonderful person whom I saw often throughout my life.

My father was born in Roanoke, Virginia, to a middle-class family. He had one older brother, Fowler. His father was his namesake, Vivian Daniel Johnston, Sr., who passed before I was born. His mother, Laura, was called Mother J, and I visited with her many times when I was young during our frequent trips to Roanoke for Thanksgiving. My father went to the University of Virginia for college and majored in organic chemistry. As a youth, he was most interested in electronics, so he thought he would major in something related to this. When my father asked his college graduate older brother for advice, Fowler told my father that there was no future in electronics! The future, he said, was in chemistry, not electronics. I suppose the latter piece of advice is still true, but certainly not the former. I still chuckle when I think about him telling me this story. Although my father didn’t major in anything related to electronics in college, it was a lifelong hobby for him. He became a ham radio operator and devoted an entire room in our house to ham radio. He also seemed to be able to fix anything electronic in our house. I’m sure his love of electronics ultimately influenced my decision to major in electrical engineering in college.

We lived in Passaic, New Jersey, until I was about five years old, and then we moved to a small town in New Jersey called Little Falls. It is nestled between the better known towns of Montclair and Paterson. The major industry in town was the Little Falls Laundry, which was situated right next to the Passaic River and a “little” falls for which the town got its name.

We had lots of pets as my father really liked animals. Our main pet was a dog named “Boots.” Boots was a mutt weighing about 40 lbs. She was brown with white paws (white boots!) and a large white spot on her head. She was a great dog, and I was very devoted to her. She was more my dog than anyone else’s. She slept at the foot of my bed until I went to sleep at night and then left my room. She also stayed with me whenever I was sick. She was my best friend, and my love of dogs has continued ever since.

We also had various and sundry other pets, including rabbits, cats, and monkeys. The rabbits were mostly for my sister, the cats for my mom, and the monkeys for my dad. The monkeys were nothing to love or hate but were simply interesting and a learning experience. They were extremely smart, but also unbelievably messy and dirty. We had two, one at a time, and they were each kept in a large cage in the basement. They threw their food and excrement all over the room. The room smelled, was hard to keep clean, and ultimately attracted bugs. I don’t think we ever realized just how wild and undomesticated they were. Ultimately, Dad had to get rid of them because one of them bit me rather severely on the thumb and hand.

Early Years: Sports

I have very fond memories of my childhood. My recollection is that I was a very quiet and shy child (and still am). I went to the cleverly named “School No. 1” in Little Falls for elementary school and then to Passaic Valley High School. There was no middle school in the town, just elementary (K–8) school and then high school. My childhood was rather uneventful, I played the trombone in the elementary school band, I got into some minor trouble during my school years (some playground fights and other mischief), and I did have one serious girlfriend, Donna, but in general I was not particularly interested in girls. I did well in school but was not exceptional. I remember my sixth-grade teacher, who got me interested in math and algebra, but mostly, I was interested in sports, primarily baseball and basketball. All of my closest friends were met through playing sports, which goes to show how important athletics were to me growing up. Actually, sports have been an important part of my entire life. In addition to baseball and basketball, I have played tennis, racquetball, squash, and many other sports. I also took up running later in life and ran in a number of marathons.

My first memories of sports revolve around baseball. I started playing organized baseball at a very early age (perhaps six?), and I think our team was called the Little Falls Laundry because of the sponsorship by the laundry. It was the farm league at that time; I wouldn’t enter Little League until around age 10. My parents were actively involved in my teams. I remember dad being the coach of most of my teams and mom being an avid rooter. Over time, I became a pretty good baseball player; eventually alternating between playing first base and pitching.

Although I remember playing basketball in the mornings and at recess in elementary school, I didn’t become serious about the game until high school. I went out for basketball in my freshman year and made the team. I had a wonderful coach whom I looked up to, Mr. Dwyer. He helped spark my love of the game. I remember playing pretty badly the first few games of the year, but Mr. Dwyer took a special liking to me and really worked with me on skills. I was tall and skinny and probably pretty uncoordinated. I remember him drilling me in shooting layups, turnaround jump shots, and rebounding. There was a rebounding drill that still sticks in my mind. A lid was put on the basket so that balls could not go through. I remember getting rebounds, putting the ball back up again, and having the ball bounce off this lid to be rebounded again over and over until my legs ached. Mr. Dwyer helped bring out in me a self-discipline and self-determination that has stayed with me ever since.

Basketball in high school was a wonderful experience for me. After Mr. Dwyer, I played for the varsity coach, Mr. Suglia. Mr. Suglia was a good coach who also seemed to have a special liking for me. I had high aspirations for a future in sports. I wanted to get a basketball scholarship to college, my father even promised me a car if I did. Passaic Valley High School was a large school, but we played in a small league because we never played against very good teams. I did well in high school but looking back I don’t think we had the competition of other big schools, and I probably wasn’t as good as I thought I was.

My experience with football deserves a special section because it had (or more accurately the coach had) a big impact on my life. I went out for football because it was the thing to do. It was totally an ego thing. To be a “real” boy you had to play football. I thought I would be considered a sissy by the girls if I didn’t play football. The truth was though that I hated football. There wasn’t anything about it that I liked. I hated being yelled at and told what to do. I didn’t like the work involved in running with pads, pushing the sleds, and hitting people. I played end because of my size and I remember catching a few passes for touchdowns. I guess I liked this, but I can’t remember anything else that I liked. The head coach was a man named Mr. Gerty. He was an intimidating bully. He was tall, about 6’4”, and weighed 250–300 pounds. He liked to scare everyone into playing football. I ultimately quit football after my freshman year, and Mr. Gerty never let me forget it and always called me a coward for doing so. This did have an impact on me for many years. It affected my self-confidence, but at the same time, it was a self-motivating force that pushed me to be the best I could at anything I tried. It also helped me to be more understanding of the feelings of others.

High School (1961–1965)

High school was fairly easy for me. My favorite subjects in high school were physics and math. I took advanced physics from Mr. Gerty, the football coach. He was actually a pretty good teacher, and the two years I took physics made me think I wanted to study theoretical physics in college. I did hang around some unsavory types of people in high school, but fortunately didn’t get too involved with them. Although my time in high school was dominated by sports, I did have some girlfriends, but I was not obsessed with girls. During high school I hung around with Doug Frey quite a bit. He went on to marry my sister and became my brother-in-law.

I worked for my Uncle Jim in the summer as an electrician’s helper during high school and into my first few years of college. I learned a great deal from working with my Uncle Jim, and it has helped me throughout my life in the various houses we’ve owned. I’ve often said that learning to be an electrician was probably the most valuable skill I ever learned. I enjoyed the work so much that I even half considered becoming a full-time electrician and not going to college. Uncle Jim was a wonderful, no-nonsense man, who died way too early from a heart attack.

One thing worth mentioning about this time is that my father had two weeks of vacation every summer in July. We spent these weeks in many places within driving distance from New Jersey, including Maine and Cape Cod. Thinking back, I don’t know how we did this, because the car we had for such trips was a VW bug. Somehow, we squeezed four people, a dog, a small outboard motor, clothes, food, and everything we needed to camp for two weeks. Sometimes we even put a sailfish sailboat on the roof! I have fond memories of many of these vacations, but the ones that stand out, and that perhaps influenced some of my future decisions, were the summers we spent at Nickerson State Park on Cape Cod. Our family continues to spend summers in Cape Cod (Woods Hole), and we now own a house there.

College (1965–1970)

The high school I attended was a fairly large regional school that was not strong academically. Although I don’t know the exact number, I can’t imagine that more than 10–20 percent out of a graduating class of approximately 450 went to college. I had my heart set on going to Princeton to major in physics. Our family doctor went to Princeton, and he tried to get me accepted. I applied to their theoretical physics program, which in retrospect was a huge mistake. Only a handful of exceptional students were accepted into this program; although I had good SAT scores, particularly in math, I was not one of them. I might have gotten accepted if I had not requested this particular program. I did visit there once and attended a basketball game. I even met with the great Bill Bradley after the game. He was a junior or senior at the time. It was a thrill of a lifetime.

I visited a number of other colleges, including the University of Virginia (UVa). UVa has a beautiful campus, and perhaps because my father went there, I applied and was accepted. Although I didn’t get a basketball scholarship to UVa, I was considered a basketball recruit. I was put in a dorm with some of the players as well as a roommate who wanted to play. He was much taller than I was and a pretty good player, but not everyone in the dorm was a basketball player. There were many others in the dorm with whom I became friends.

I remember many things about college, mostly good. Freshman year was spent as a physics major. However, I discovered that I didn’t really like the kind of physics (or math) I was learning. The concepts were too abstract and theoretical, and I was interested in more practical applications. During my freshman year, I decided I didn’t want to be a physics major. I took an introductory course in psychology, thinking I might want to be psych major, but I didn’t like that either. Toward the end of my freshman year, I took an aptitude test to see what major might fit my interests. This turned out to be incredibly helpful. Interestingly, I had the highest aptitude for being a pilot. Of course, I didn’t have the vision to be a pilot, so I turned to the second-highest-ranking aptitude, which was as an engineer. This made a lot of sense to me because applied physics and math seemed much more to my liking. I applied for the engineering school and was accepted. In retrospect, I was lucky because my grades freshman year were not that good. Because I missed all the required engineering courses during freshman year, I assumed it would take me five years to finish. I ultimately chose electrical engineering, maybe because my father was a ham radio operator, or because of the summers I had spent in high school (and later in college) working as an electrician’s helper. Whatever the reason, I really enjoyed electrical engineering.

During freshman year, I rushed different fraternities. I felt most comfortable with ATO, and so I joined. It felt good belonging to something, and I became very close to my rush class and later with some of the upper-division guys. I ended up quitting the freshman basketball team. Most everyone had a scholarship, and I felt intimidated. After I quit, I was told that I was one of the top picks to stay on the team. I should have had more self-confidence, but I still attributed this to my experience with football in high school.

My sophomore year had its ups and downs. On the upside, I enjoyed engineering and being in ATO. There were lots of road trips to girls schools (UVa at the time was all boys), and party weekends where I drank too much beer while wishing I had dates. The down part was living in an apartment. At UVa, the dorms were mostly for freshman and after that everyone was expected to live in an apartment. I ended up rooming with Doug Frey’s ex-roommate, Stoney. He came to UVa for engineering graduate school after graduating from the Citadel with Doug. We did not get along—maybe because of the differences in age or his military training, or maybe because I was too immature. In any event, it was an awful year from that standpoint. As a result, I did spend a lot of time at the fraternity house learning to play bridge and watching TV with the guys. I did very well in all my engineering courses and got mostly As. One of the important things I learned in college and being in a fraternity was how to separate work from play. My motto was to work hard and play hard, a lesson that has stayed with me throughout my life.

Junior year I roomed near the house with one of my fraternity brothers, Sam Young. Sam was a philosophy honors major and quite the talker. We got along well, so living that year was much better than the previous year. Other than my schoolwork, which was going fine, most of the rest of my college life revolved around ATO and my friends. Tom Heffron was my best friend, but he was having trouble in school. He ended up dropping out of school at some point during junior or senior year and joined the Navy. Life revolved around road trips, big weekends, and hanging around the house. I had very few serious girlfriends. I remember one woman I was smitten with from Hollins College with an unforgettable last name, Hellabush. During the summer between my junior and senior years, I worked for an aerospace company on Long Island. As a budding engineer, my job was to calculate the probability of failure for some of the electronic parts on several different space capsules. While it seemed important, I couldn’t see how it would be very accurate, but I did as I was told. I think this job, however, soured me from ever working in industry.

Senior year I figured out that I didn’t really need five years to graduate. I squeezed in all the courses I needed to graduate on time, or nearly on time. I was trying to decide on graduate school or even medical school. I considered staying at UVa and getting a doctorate in electrical engineering focusing on control theory, but ultimately I decided to pursue biomedical engineering at Duke. I did my senior thesis on eye movement recordings, and the idea of designing medical equipment was particularly appealing to me. Duke seemed to have an attractive biomedical engineering program as well as a good stipend, but that decision meant I would have to take organic chemistry. I applied and was accepted at Duke. I took organic chemistry in summer school and hated it. Way too much memorization. I had a pretty serious girlfriend my senior year, Robin, but I was incompetent with girls. Girls and relationships just scared me.

Graduate School (1969–1973)

I left for Durham and graduate school in the fall of 1969. Although I had all the credits I needed to graduate after finishing summer school, I didn’t officially graduate until the next year, 1970. I began graduate school working in Fritz Thurston’s lab. He was an expert on ultrasound transducers and became world famous for designing the transducers used for imaging babies in the womb. He was a very nice and impressive man, but I was not that interested in the topic. I took a course in physiology and got really enamored by the lectures on neurophysiology, and, in particular, those on the electrical activity of neurons. It seemed like the perfect fit for my background in electrical engineering, and so this is what I decided I wanted to do. I talked to Howard Wachtel, a neurophysiologist, about joining his lab and did so in my second year. Howard had a joint appointment in the Biomedical Engineering and Physiology Departments. Bill Wilson and Ted Carnevale were also in Howard’s lab and a few years ahead of me. There were also a few other people in Howard’s lab, and in general it was a fun lab to be in. I got friendly with John Moore (see volume 7) and some other faculty members in the physiology department, which was where Howard’s lab was located. The Physiology Department was also one of the top departments in the country at the time with some outstanding people. John Moore, of course, was one of the early designers of the voltage clamp for squid axon. Another member of the department whom I interacted with and admired greatly was Toshio Narahashi. He discovered tetrodotoxin, a blocker of sodium channels.

Most everyone in Howard’s lab worked on Aplysia, which was Howard’s main focus, being one of Eric Kandel’s first graduate students. At some point, I met with Myron Wolbarsht in ophthalmology, who worked on the eye of the Limulus. He had a woman working for him who had a technique for removing the lens and exposing the individual photoreceptors or ommatidia. She showed me this technique and after talking to Howard, I decided to work on the Limulus eye. I don’t remember how exactly I came up with the project, whether it was all or mostly my idea or whether the ideas were gleaned from Howard’s lectures and talking with Wolbarsht and his student. In any event, I decided to try and reproduce the famous Hartline experiments first describing the spread of lateral inhibition, and for which he won a Nobel Prize. Instead of using groups of photoreceptors with the lens intact as they did, I wanted to measure the spatial spread of lateral inhibition by recording from individual pairs of ommatidia. I designed extracellular electrodes in which I coated the outside with silver paint, put a fiber optic in the barrel of the pipette and filled it with saline so I could record photo-responses. I thought the whole thing was rather clever. I recorded simultaneously from two ommatidia at different distances from each other to map the strength of lateral inhibition. Each ommatidia was stimulated with light through the electrodes with presumably no light scatter between electrodes. It all seems pretty crude today, but at the time was novel. I did find some differences in the spatial spread of lateral inhibition from the original Hartline experiments. I also built a model to suggest that the strength of lateral inhibition was due to the distance of the inhibitory synapses from the photoreceptor spiking trigger zone. Although I didn’t have any direct proof of this, it was an interesting idea that made sense from a theoretical standpoint. Toward the end of my studies, I had a scare in which I feared that the light bulbs illuminating the light pipes might have reduced the total light to each bulb (the load) when they were on at the same time compared with when they were on individually. I feared that this could have contributed to the spatial spread of inhibition I measured. I did some control experiments, however, in which I separated the voltage source to each light bulb and didn’t find any evidence of such an artifact. This scare was a lesson for me that I never forgot about the importance of controls.

At the end of my thesis work, I talked to Howard about one or more papers that we could publish based on my data. Howard outlined three papers, two of which I would be first author on and one for which he would be first author, which made me really angry. I didn’t see any reason why he should be first author on any of them, just senior author. When I went to John Moore about this he was very supportive of me, partly because I was right, but also because he didn’t particularly like Howard. In retrospect, this situation probably got blown out of proportion, and in the end, I only published one paper in Journal of General Physiology. These events led to a lifetime friendship with John Moore and a deep appreciation for the sensitivities surrounding authorship.

I typed my dissertation on an IBM Selectric typewriter using lots of correct type. Howard was very critical of the content, in a good way, and I think I ended up typing some 10-plus versions of my thesis before going final. I also had to make 10–15 copies of the thesis and my future wife Jean helped me with this. I don’t remember any particular problems with my thesis defense, at least nothing like my oral qualifying exam. Although I passed my orals, I don’t think I did that well. One of the questions was about vacuum tubes! I was not prepared for that one.

For the most part, graduate school was a blast for me, one of the happiest times of my life up to that point. I loved the courses, the research, and the faculty. While in graduate school I made a strong friendship with Mike Ramsey. He was a medical doctor doing his doctoral work in biomedical engineering; his interests were in cardiology and heart monitoring. He already had a small company that he started in Tampa, which is now a much bigger company and for which he’s probably made a lot of money. Mike and I really hit it off. We both had motorcycles and although he was married (Lynn), it didn’t seem to cramp his style. We joined the Duke film society and made a silent movie, Any Old Kind of Day, based on the music of Harry Chapin. The film society (called the Freewater Film Society) had equipment and film that we could use. They paid for this from the proceeds of their Friday night film series on campus. We started another film, which involved partial nudity, but never finished it. We, mostly Mike, had fun interviewing candidates for the topless scene.

Other than my first year, I lived in a house share with four other guys, three of whom were graduate students in biomedical engineering. One of the guys was a business major whom I had lived with for part of my first year. We all got along pretty well with no major problems until the end of our time in the house when the business guy, who kept track of our shared finances, decided to try and charge us for the use of his TV the past three years. We would have none of it, but I did learn a lesson about finances from this experience.

I didn’t have many girlfriends during graduate school and met Jean as a blind date my last year. Wilkie (Bill) Wilson set it up. He knew her because she worked as a nurse for the epilepsy center at the Veterans Administration (VA) that he was involved with. She liked motorcycles! I remember our first date in which she showed up in a short dress of UVa colors. I assume she knew I went to UVa, but I thought it was pretty coincidental. We dated for the rest of my time in Durham.

While I was in graduate school, the Vietnam War was raging, and the army draft was ongoing. I got a low draft number (43), which meant I would be drafted in the army. Rather than go as an enlisted man, I joined ROTC. My first Army experience was boot camp at Fort Knox, Kentucky. It was not pleasant, but I went along as best I could. I did lose weight and get in shape, which were good things. After boot camp, I went to drills and marches on weekends during the year around once a month. The next summer, I went to what was essentially another boot camp at Fort Bragg, North Carolina. I got set up in the barracks and started drills, but early on there were a lot of medical tests and physicals. They found that I had an anal fissure, which sometimes caused bleeding during bowel movements. This condition allowed me to choose whether or not to accept a medical discharge or volunteer to stay in the Army. Needless to say, I chose to take the medical discharge, I didn’t like the Army and being told what to do. I guess I was a peacenik at the time, against the war, and essentially a liberal-leaning person. Although I don’t regret getting out of the Army, I also feel somewhat guilty about it as I know many people who went to the war and suffered because of it.

Before my defense, I had secured a postdoc in Minneapolis, Minnesota, working with Giovanni Ayala, a neurologist working on epilepsy. After defending my thesis, Jean and I drove all of my things in a U-Hall truck to Minneapolis to start my postdoc. She helped me get set up in a small apartment and then went back to Durham. She definitely wanted to get married, but I was not ready.

Postdoc (1973–1977)

I stayed in Minneapolis for a total of four years. I was a postdoc for about two of those and then I got a soft-money instructor position in the Neurology and Biomedical Engineering Departments at the University of Minnesota. Working as a postdoc and later as an instructor in Ayala’s lab was fine. We got along well, and he had a few other student’s and postdocs with whom I also got along fine. Ayala was a neurologist studying epilepsy. He had published a major paper on epilepsy some years earlier using intracellular recordings from a penicillin focus in cats. He characterized what was then called the paroxysmal depolarizing shift (PDS). I had an hypothesis that the PDS was similar in mechanisms to bursting neurons in Aplysia. I went to Ayala’s lab to explore this in Aplysia as well as to learn intracellular recordings from anesthetized cats. Bill Wilson had designed a so-called single-electrode voltage clamp (SEC), which I wanted to build and use on cat cortical neurons during the PDS. While I did build an SEC, I never got to use it in cats. Although Ayala was supposed to be the expert on in vivo cat work, it seemed that we had a hard time keeping the cats alive. He was a great guy, but not much of an experimentalist. As a result, most of my work in Ayala’s lab was with Aplysia. In fact, my first paper from Ayala’s lab was in Science, in which we tested the actions of Dilantin on Aplysia bursting neurons. I published a total of nine papers and three book chapters during my four years with Ayala.

At some point during my time in Minneapolis, I visited Eric Kandel’s lab in New York. Ayala knew Kandel fairly well, and at the time, Kandel was on the board of the Klingenstein Foundation, which was originally set up to fund epilepsy research. Arnold Kriegstein, a postdoc in Kandel’s lab, was involved in a project trying to raise Aplysia in the lab. I think it was partly set up at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, but somehow it was also ongoing in Kandel’s lab at Columbia. To get money from the foundation, Kandel needed to have some tie-in with epilepsy. So, after my first paper was published on the effects of Dilantin in Aplysia, the idea was born that I would go to Columbia and test the effects of Dilantin on developing Aplysia. Anyway, I went there for several weeks, but the project never went too far. There were some very nice people in the lab, including John Koester, Tom Carew, and Vince Castellucci, to name a few. It was an intense environment where I never felt quite comfortable. Eric and I, however, remained cordial over the years whenever we would occasionally meet at meetings.

A pivotal experience I had while working with Ayala came when he encouraged me to apply for the Grass Summer Fellowship Program at the MBL in Woods Hole. I did apply, was accepted, and credit this with completely changing my career. I had proposed to use the SEC I had built to clamp the squid giant synapse to test the effects of anticonvulsant drugs (mostly Dilantin). When I arrived in Woods Hole and set up my rig in the Grass lab, I had no idea how to even dissect the squid synapse. I went to Rodolfo Llinás’s lab to see if I could watch his dissection. The first time I went, I was told by his student, Kari Walton, to come back the next day after she discussed my request with Llinas. I came back the next day, and she told me that “Professor Llinas told me to show you nothing.” This was quite a shock to me as the MBL seemed a very open and collegial environment. What I didn’t know at the time was that there was an intense competition (rivalry) going on between Llinas’s lab and another lab, consisting of a collaboration among Milton Charlton, George Augustine, Steve Smith, and Bob Zucker, to be the first to voltage clamp the squid presynaptic terminal and measure calcium currents. I ended up meeting Milton, and he showed me everything and was extremely helpful and supportive. This was an incredible summer. I met many amazing people, both other Grass Fellows as well as all the scientists who gave informal talks to the Grass Fellows. It was also an eye-opening experience, and although I didn’t make any great breakthroughs on the experimental side, the networking with other people was invaluable. It literally changed my life and career. I fell in love with Woods Hole and was determined to return at some point. Although I did return to Woods Hole, it would not be for another 13 years in the summer of 1989.

The last year of my time in Minneapolis was very stressful, but some positives came from it. I had several trainees. One was a medical doctor, Gerald Slater, who got me interested in a different anticonvulsant, Valproate, or Valproic acid. We published one paper and a review on the topic. I also worked with another faculty member, J. Sheppard, on reaggregate cultures along with a student, Carl Stafstrom. Carl was a great guy who went on to have a very successful career as a medical doctor/doctor in the field of epilepsy.

During my time with Ayala, he was recruited by Stan Appel, who had recently moved from Duke to Baylor College of Medicine (BCM), to establish a new department of neurology. Ayala asked me to come with him, and so Appel offered me a position as an assistant professor of neurology, which I accepted, starting at BCM in 1977.

Jean and I ended up getting married in December 1973 only months after I had moved to Minneapolis. I had taken her to meet my parents and my sister Laura, and they liked her. We got married in the chapel at UVa by a minister of Jean’s choosing on December 21. Only immediate family members were invited to the wedding and reception. We held a small reception and spent our wedding night at the Bohr’s Head Inn near Charlottesville. I refused to wear anything formal, just a camel hair sport’s jacket and brown turtleneck. We also played the Moody Blues for wedding music. I was quite the nonconformist.

Jean moved to Minneapolis to live with me shortly after getting married. We rented another U-Haul truck, this time filled with all of Jean’s things, and drove it from Durham to Minneapolis. It was in the middle of winter, so it was not a pleasant experience. We had rented a house on the south side of Minneapolis; however, we only stayed there a bit less than a year. We bought a house across from Lake Hiawatha on East 43rd Street and 26th Avenue. It was a small house, but it was all we needed. We met a neighbor’s golden retriever named Rufus while living at the rental house. We loved him and decided to get a golden retriever puppy of our own. We found someone with a new litter either in or on the way to Wisconsin and went to visit. The mom had around 10–12 puppies. We played with them and chose the one who kept wanting to play with us and chew my sock. The puppies were so cute! I think it was the first night that we had the puppy that he chewed an extension cord and got shocked in the mouth. He was lifeless, and we didn’t think he would live. We drove him to the vet who looked at him and thought he might survive. On the way home Jean was crying and saying that he didn’t even have a name. I suggested Coulomb. She asked, “What the hell is a coulomb?” I explained that it was a unit of electrical charge, so she said okay, at least it was appropriate. I slept with Coulomb on the floor of the bathroom during the night hoping that he would live, and he eventually came to. Although he had a serious scar on his tongue and lips, he seemed fine. He was a great dog. We fell in love with Golden Retrievers, and up to now have had five (two females and three males). They are great pets.

There were lots of things I remember about Minneapolis: walking to basketball games in 30-below temperatures and getting ice cream on the way, Leonard Slatkin and rug concerts by the symphony in the summers, cross-country skiing with Coulomb, and of course, our friends Wendy and Muff. They both were great friends whom Jean met at a bridge class. We played bridge with them often, especially in the winter. We also went on a few canoe/camping trips with them. We have mostly lost touch with Wendy, but Muff, now calling herself Meg, has remained close. She got married and moved to Oregon some years after we left Minneapolis. She has come to visit us in Woods Hole and has come to both our girls’ weddings in Texas.

While I was a Grass Fellow at the MBL in Woods Hole, Jean stayed in Minneapolis most of the summer, but came to visit a few times. Our dog, Coulomb, however, was shipped several times and stayed in a kennel so I could see him more frequently. He, of course, had a great time and I was glad to see him more than I otherwise would have if he had stayed with Jean at home for the entire summer. In retrospect, our separation for most of that summer was not a good thing for our marriage, but I was ignorant to this at the time.

Jean had been working with Bob Gumnit, a neurologist, as an epilepsy nurse in his epilepsy center. She had a similar job at Duke working for Tony Escueda in his epilepsy clinic at the VA. There were a number of epilepsy conferences during the year that she had gone to while at Duke, and she attended one, I think, in the fall of 1976. When she came back from the conference, she didn’t want anything to do with me, and we separated shortly thereafter. It looked like we were headed for a divorce. However, we ultimately both agreed to have individual counseling. While separated, I decided to do what I had always wanted to do, get a pilot’s license! (I flew quite often after getting my license, and even later bought an old Cessna 182, but in 1980, I had a crash with six people on board. Fortunately, no one was injured.) I don’t actually remember how long we were separated, but it was at least several months. We later had some joint counseling sessions and decided to get back together. We have now been married for 50 years. In retrospect, I had paid too much attention to my career and not enough to my marriage. My take-home message from this experience is that the stresses of two careers can be significant, but one should not give up on a marriage too easily. The later rewards from being with someone and ultimately having a family together are enormous and far outweigh any difficulties along the way.

I was recruited to BCM in February, and we moved in August. February in Houston seemed like heaven coming from Minnesota, but August was a wake-up call. Clearly, this was a different climate than we had been used to for the past four years in Minnesota.

First Real Academic Job: Baylor College of Medicine in Houston

I have lots of memories, mostly good, about my first job in Houston. At Baylor, my electrophysiology rig was in Ayala’s lab, which was set up in the new Neurosensory Center, a building Peter Kellaway helped establish. Peter was an electroencephalogram (EEG) expert. In fact, he was the first one to bring the EEG technique to the Houston area. He was an impressive man who was head of the Epilepsy Research Center (ERC) at the Methodist Hospital. Peter welcomed me into the ERC, and I was part of the center throughout my time at Baylor. Peter was a doctor, but he knew how to function in the medical world. I think he recognized my ability as a scientist right away and how I was essentially most of what was good in the Ayala lab. Others in the ERC I interacted with were Jim Frost, an EEG expert more on the technology side, and of course, John Hablitz. Hablitz and I hit it off right away, and we started collaborating as soon as my lab was set up. John and I wanted to use the SEC to record from neurons in brain slices. Bob Thalmann, a neuroscientist in the Cell Biology Department, had done a short sabbatical with Carl Cotman and Gary Lynch, who were early adopters of the brain slice technique. Bob showed John and I how to do brain slices. John had more experience with animal dissections than I did, so he did most of the surgeries while we were experimenting with the technique. I don’t remember it taking us very long before we had live healthy slices and were recording from neurons. These were fun and exciting times. Although Ayala was not really that involved in the experiments per se, he was in the lab often enough to kibitz about experiments. He was very supportive and never tried to tell us what to do. Although technically I had an independent (assistant professor) position, Ayala was the head of the lab. He never dictated anything, however, and often had some good ideas. He and Bob Thalmann also did some projects together in the early days.

The switch from Aplysia to brain slices was a natural outgrowth of the feedback I had received from one of my first National Institutes of Health (NIH) grant applications that I submitted while in Minneapolis in which one of the reviewers suggested that until Aplysia have seizures he/she could not support an application with Aplysia being used as a model system to study epilepsy. That review really hit home for me. My first grant at BCM was a project associated with the ERC and was indeed on brain slices. John Hablitz and I published a paper in Nature using the SEC on CA3 neurons in slices. I think it was one of the first, if not the first, papers in which neurons in a brain slice had been voltage clamped. That paper was a springboard for me that led to many papers and projects, some epilepsy related and others just basic research. Funding was not really a problem as I had both ERC-related project grants and independent NIH and foundation grants. We had a number of trainees in the lab, mostly postdocs at first until my first graduate student, Bill Hopkins, joined the lab. Frank Lebeda was one of my first postdocs along with Doug Baxter. I also worked and published with Warren Strittmatter and Nick Bryan. Warren was a neurologist interested in protease inhibitors, and Nick was a neuroradiologist interested in contrast agents. It was a productive time for me.

During the course of the voltage clamp study of CA3 neurons that I did with John Hablitz, I became interested in the question of how well one could voltage clamp a neuron with a complex dendritic tree. The seeds for this interest were planted in me thanks to the influence of John Moore while I was a graduate student at Duke. He, of course, was a stickler for the requirement of having an adequate space clamp based on his and others’ work on the squid axon. I read many, if not all, of the works of the great Wilfred Rall. Cable theory was right up my alley given my background in electrical engineering. I also used cable theory as a part of my doctoral thesis. Based on Rall’s work and a bit of novelty on my part, I built a theoretical model of a CA3 neuron. I presented this work at a Winter Conference on Brain Research (WCBR) meeting at a ski resort in Colorado. It was an annual meeting I tried to attend each year, not only because it was an interesting meeting but also because I liked to ski. After my presentation at the meeting, a man named Tom Brown came up to me and said he was building similar cable models and seemed quite excited by my presentation. We really hit it off, and we spent much of the rest of the meeting talking science and skiing. We ultimately arranged to meet again both in Houston and at the City of Hope where he had just taken a position and agreed to maybe even collaborate on some projects.

I later published my paper on the cable properties of CA3 neurons in what was then a new journal. In retrospect, that was a big mistake. It should have gone into a more established journal where it would have been more widely read. I thought I had some novel math in this study that I wanted more people to appreciate. In addition to this paper, I began collaborating with Ted Carnevale. I knew Ted from graduate student days at Duke, and we continued to interact in the subsequent years. We put together what I thought then (and still do) was one of my most important and innovative papers on the theory of current and voltage flow to and from the soma and a remote synapse on a dendritic tree. In some ways, it was a bit ahead of its time, but it laid down some fairly simple and straightforward principles, such as the asymmetry in the spread of voltage and current between dendrites and soma, the effect that a voltage clamp applied to the soma has on voltage and current distribution, and the charge transfer between dendrites and soma. These were extremely important ideas and principles, especially because the voltage clamp was being more widely applied to complex neurons.

The cable properties paper and the paper with Carnevale helped lay the ground work for the collaboration I had with Tom Brown. Although I did visit him at the City of Hope several times, all of our active collaborations took place in Houston. Tom was brilliant, with a different but complementary background to mine, and we really meshed scientifically. We were incredibly productive. Tom would come for weeks at a time, and we would do intense daily experiments. Most of our work was directed toward understanding synaptic transmission using the mossy fiber synapse as a model synapse. We focused on this synapse because of its proximity to the cell body where we thought we would have the best chance for an adequate space clamp. This was probably the first voltage clamp study of a mammalian synapse in a brain slice. We also built a model to determine the degree of error because of the lack of a space clamp. I remember while writing one of the papers that Tom came up with the phrase “electrotonically compact” to describe a CA3 neuron and our ability to adequately describe the biophysical properties of mossy fiber synaptic transmission. Tom was very clever with words, and I really liked this description. We both later regretted this phrase, however, because it ended up being used by everyone to justify their use of the voltage clamp to analyze all synapses on hippocampal pyramidal neurons, although that was never our intent. In fact, our results showed that the mossy fiber synapse was probably the only excitatory synapse on a pyramidal neuron for which a reasonable space clamp was possible. Tom and I published a number of other papers and reviews, but I believe that our voltage clamp studies of the mossy fiber synapse were one of the two major contributions from our collaboration. After Tom moved from City of Hope to Yale, our interactions declined considerably. (As an aside, the Brown and Johnston, 1983, paper was my first and only peer-reviewed paper sent to a major journal in which the reviews came back without a single suggestion for revision! Nothing but over the top compliments. One of the reviewers turned out to be Chuck Stevens.)

In addition to our work on synaptic transmission, we made what was considered by many in the epilepsy field another major contribution. At the time, there was a raging controversy surrounding the PDS in focal epilepsy. This had been recorded intracellularly, extracellularly, and with EEG recordings. Some believed that the PDS was due to intrinsic burst mechanisms in a single pyramidal neuron, and I had favored this idea based on my previous work with Aplysia bursting neurons and CA3 neuron intrinsic bursts. Others, however, thought that the PDS was the result of a hyperexcitable network of interconnected neurons. These were competing camps, but the tide was shifting toward the former idea favored by David Prince and his collaborators who described the PDS as a single cell or voltage-dependent burst. Again, using the voltage clamp technique, Tom and I unequivocally showed that the PDS was due instead to a large, network-driven synaptic input. We did this by clamping a neuron to different potentials in a slice made “epileptic” with a convulsant drug and then showing that the frequency of the PDS discharge did not change with membrane potential. Then, most convincingly, we showed that the PDS could be reversed in amplitude when sufficiently depolarized beyond the synaptic reversal potential. We published these findings in Science, and the results completely changed the focus of the field from single neurons to network behavior. Because I had initially favored the idea of the PDS being an intrinsic burst, I ended up being completely wrong. I have said throughout my career that nothing makes me happier or more excited by science than to be the one to disprove my own hypothesis! Tom was much more interested in synaptic plasticity so this was more of a side project for him, but I remain very proud of that work.

I ultimately did become more interested in synaptic transmission and plasticity thanks to Tom’s influence. I remember one day while doing experiments Tom asking me if I had ever heard of Hebb’s postulate. Not having had much psychology training, I had not. He, of course, went on to test Hebb’s postulate in one of his more seminal papers using some of the techniques we had developed together. I also remember us being among the first to use internal cesium in our intracellular pipettes and remarking about what we called “hyperspace” when we tried to hyperpolarize cells. This, of course, turned out to be due to a block of HCN channels, which I ended up studying intensely later in my career. We continued to collaborate more independently on a few projects related to mossy fiber synaptic transmission, but eventually we went our separate ways.

Personal Life in Houston

I never really wanted to have children. I thought it would ruin my career, but of course Jean did. She became pregnant in 1978. I remember vividly when she told me. We were lying in bed one night watching TV. She snuggled up to me and whispered in my ear, “I have a surprise, I’m pregnant.” At that moment the TV at the foot of our bed simply died. It was an old picture tube TV in which the screen shrinks to a small circle of light until it goes black. I looked at that TV and thought that I was looking at my career. It was over! Getting used to the idea of becoming a father took some time, and this was not an easy pregnancy for Jean. She ended up in the hospital with preeclampsia and delivered by C-section several weeks early in May 1979. I remember seeing my daughter for the first time. She weighted 4 pounds, 5 ounces and fit in the palm of my hand. I had never really seen a newborn before and was amazed by how, even being so small, she had all the correct wrinkles on the knuckles of her fingers. It took a while for me to connect with my new daughter, Lisa Danielle, but by six months, I was completely overcome with the joy of having this new person in my life. For someone not wanting children at all, I was now ready to have a dozen!

Our second child, a daughter named Lauren, was born in 1982. She was quite a handful from the beginning and required much of our time. Thinking back years later, we always regretted not having spent more time with Danielle. Fortunately, however, both daughters have turned out to be wonderful adults with their own children, so maybe we did something right. Our third child, David, was unexpected. When we found out we were pregnant, I was hoping for another girl. I had gotten so attached to Danielle and Lauren that I couldn’t image having a boy. David, however, was delightful and such an easy child to raise. He was born in 1984 and now has two of his own children. We are now blessed with seven grandchildren, with maybe more on the way.

Raising three children was so much fun, but also quite challenging. Jean was a nurse who worked full time until David was two years old. At that point, we decided that we were paying so much in childcare that it almost wasn’t worth it financially for Jean to work. Thankfully, Jean was willing to become a full-time mom, and she was good at it! Although I still spent as much time as I could with all three children, this change did allow me to devote more time to my work. I thoroughly enjoyed all the family time together both in Houston and on vacations. As important as my career had been to me, I would have traded it for my family in a heartbeat if I had had to. I have so many wonderful memories of swim meets, soccer games, daddy-daughter dances, and of course our summers in Woods Hole beginning in 1989. The one dark spot, and it’s a big one, from our time in Woods Hole is David’s bike accident and head injury at Nickerson State Park. It is painful to even think about, so I’ll instead end this personal-life section on an upbeat note with the fact that David recovered and now has a wonderful family and career of his own.

New Division of Neuroscience (1989)

I continued working in the Neurology Department at Baylor, rising through the ranks from assistant to associate and then to full professor during the years from 1977 to 1986. These were happy and productive times, but neuroscience at Baylor and throughout the country was growing, and many independent departments of neuroscience were being created. In 1989, Baylor recruited Jim Patrick from the Salk Institute to be head of a new Division of Neuroscience at Baylor. It was an independent academic department in everything but its name. For some complicated political reasons, it had to be called a division rather than a department, but it really made no difference to anyone what it was called. I had been the director of the Graduate Program in Neuroscience for several years, and while it was to remain interdepartmental, the graduate program was now to be based within the new department. Jim offered me the first academic appointment in the division, so I moved my primary appointment (and lab) from the Neurology Department to the new department and to a new building. Although I did receive a bit of startup money for this move, it was still mostly a soft-money position. The joke at Baylor was that tenure meant that you had a guaranteed job, just not a salary. I remained as director of the Graduate Program. I loved working with graduate students and helping to develop a rigorous training environment for them. This remained a joy of mine throughout the rest of my career. As part of Jim’s recruitment package, he had many positions to fill, and much of my time was spent helping in these recruitment efforts. We hired many outstanding faculty, including David Sweatt, Peter Saggau, Paul Pfaffinger, Michael Crair, John Dani, Fabrizio Gabbiani, Rob Gereau, Nikos Logothetis, David Sparks, John Maunsell, Read Montague, Mark Perin, Sarah Pallas, and Dan Ts’o. Many of these people have become household names in the field of neuroscience. I learned a great deal in working with Jim to help develop this new department. Jim had very high standards and was uncompromising in hiring only the very best people. He also was honest, open, and interacted well with all the faculty in the department. These were lessons I took with me for later in my career.

I had many outstanding graduate students during this time, one of whom was Nelson Spruston. After graduating from Baylor, Nelson went to Germany to do a postdoc with Bert Sakmann at the Max Planck in Heidelberg. After being there for a few years, Nelson invited me for a visit to give a talk and to see some of the techniques in the Sakmann lab for recording from dendrites. I was extremely impressed with not only the methods but also the people in the lab who were using them (e.g., Greg Stuart, Michael Hausser, Jackie Schiller, among others). Everyone, including Bert, was extremely open and collegial. I learned as much as I could, and when I returned to Houston, I set up several rigs using the methods from the Sakmann lab. Jeff Magee had already been in the lab for a short time and was struggling to record mossy fiber synaptic responses, but he immediately appreciated the power of these new methods. Also, given our more channel-oriented interests, we decided to begin studying ion channels in dendrites. Some of this interest in ion channels was inspired by the work I had done during several summers at the MBL in Woods Hole with John Lisman and Bill Ross. I will take a brief detour here to reminisce about my MBL/Woods Hole experiences.

The Marine Biological Laboratory

It would be hard for me to write a scientific autobiography of my career without including some description of my many summers at the MBL. As I mentioned earlier, being a Grass Fellow in 1976 was a career-changing experience for me. I vowed then to somehow try and get back to the MBL for more summer research. Because at the time, there was no way to use rodents for experiments at the MBL and all my work was with brain slices, my hopes for doing research at the MBL were slim. I had met John Lisman during the summer of my Grass Fellowship, and we remained cordial whenever we saw each other at various scientific conferences. In 1988, he told me that the MBL was going to establish a small vivarium above the old Marine Resources Center. He had become interested in the neurophysiology of brain slices and wondered if I would be interested in collaborating with him at the MBL and whether I would teach him brain slice recording techniques. I, of course, jumped at the chance. He was a regular each summer at the MBL so he made all the arrangements for the lab, whereas David Jaffe, a graduate student of mine at the time, and I packed up our equipment and shipped it to Woods Hole for the summer of 1989. We actually shared a lab that summer with Bill Ross and Ann Stuart who were doing a calcium imaging project together on barnacle photoreceptors. Everything was going fine, but at some point during the summer, John, Bill, and I decided to try to image calcium in the dendrites of CA1 pyramidal neurons from brain slices. This turned out to be incredibly successful and led to several summers of collaborations, as well as several landmark papers on both calcium and sodium signaling in dendrites. Bill was the imaging expert, John was the idea man, and I guess I was more of the experimentalist. Anyway, we all meshed extremely well.

I continued to spend each summer at the MBL in either collaborative projects with John, Bill, and others or with the small group of people I brought with me from Texas. I cannot imagine what my career would have been if not for the summer research at the MBL. Not only were the collaborations fruitful, but just interacting with all the amazing scientists who came to the MBL each summer either to do research or to teach in one of the courses was quite inspiring for me. I am always amazed at how many neuroscientists have had some MBL experience. It is truly a special place.

On a more personal level, all three of my children essentially grew up in Woods Hole, spending each summer there well into college. We drove to Woods Hole from Texas each year in a minivan packed with dogs, rabbits, birds, food, and clothes. I guess the summer trips to Cape Cod in a VW bug when I was a kid prepared me for this! All of my children took classes at The Children’s School of Science when they were young, had summer jobs in and around Woods Hole when they got a bit older, and looked forward to spending each summer in Woods Hole. They still have many friends from Woods Hole with whom they have remained close throughout the years. Our oldest, Danielle, learned to scuba dive near Woods Hole, and I went diving with her many times at different locations on the Cape. Actually, all of my children learned to dive, and a number of my business trips were combined with family scuba diving excursions. Unfortunately, I had a diving accident on Curacao in 2018 at one of the many Winter Conferences on Neural Plasticity I attended and ended up spending eight days in a hyperbaric chamber. I haven’t dived since.

After spending many years living in the MBL cabins, my wife and I eventually bought a house on Wilson Road, which we later sold to Bill and Nechama Ross, and then we bought another house on Fern Lane. We continue to spend part of each summer in Woods Hole. Some of the things we are “famous” for are the backyard Texas barbeques we had for many summers. We invited as many people as we could, which sometimes numbered as many as 150. The other “event” we had one summer, which attracted some attention by the MBL community, was a litter of golden retriever puppies. It seemed as if almost everyone in Woods Hole at some point came to play with them in our backyard.

Another, nonscientific but life-changing experience for me that I attribute to (or blame on!) MBL and Woods Hole is my love for fishing. All the labs I worked in at the MBL were in the Whitman (now called Rowe) building. Although most of our work at the MBL was using imaging methods requiring blacking out the windows, occasionally I’d look out the window to see all the boats in Woods Hole harbor with people fishing. It was so mesmerizing that I decided I had to give it a try. During the winter of 2000, I got on the internet and found a used boat in Martha’s Vineyard that I had surveyed and ultimately purchased. It was waiting for me at a marina in Falmouth Harbor when we got to Woods Hole in the summer of 2001. I didn’t know much about handling a boat so it was all very new to me. I bought some fishing gear from Eastman’s tackle shop and Andreas Frick, a postdoc of mine who had come with me to the MBL, and I took the boat out into Vineyard Sound, dropped our lines into the water, and just waited for the fish to bite. Needless to say, we came up empty-handed. I decided I needed some help. There was a flyer in Eastman’s for a charter captain who would take you out on your boat. This seemed ideal for me because I also wanted to learn how to run my boat. His name was Eric Stapelfeld, who was one of the best striped bass fishermen on the Cape. During the next 10 years or so, I did a lot of fishing with Eric, many times as his deckhand. I learned a great deal from Eric and became a pretty good fisherman in the lower Cape area. Our downfall came when we went into the charter fishing business together with a used lobster boat that Eric refurbished as a fishing boat. The business never really went anywhere, so after a few years, I sold the boat. Unfortunately, Eric and I hardly speak anymore, but I do give Eric a great deal of credit for teaching me how to fish in the area and generally for feeding what became quite an addiction for me.

I often think about how fishing is like doing electrophysiology experiments. You are constantly making adjustments in real time, trying different things, and of course being superstitious when one of them might actually work! In psychology, it’s called intermittent reinforcement. Two of my good friends, Steve Redman and Bill Spain, both electrophysiologists and avid fishermen, would agree with me on this. They came to fish with me in Woods Hole for some 15 straight years until Covid hit. When the fish weren’t biting, we would always talk science. I ended up buying five different boats in the Falmouth/Woods Hole area. I now regret having sold some of them, but the old saying that “a boat is a hole in the water that you pour money into” is quite appropriate for my fishing/boating experiences.

Dendrites

Now back to science. The 10-plus years from around 1992 until I left Baylor for the University of Texas in 2004 were quite magical for me scientifically. I had some truly outstanding postdocs and graduate students whose work became focused on neuronal dendrites. In particular, we were interested in the voltage-gated ion channels expressed in dendrites, their plasticity, and how they contributed to the information processing and storage of the nervous system. Jeff Magee started these studies with cell-attached patch clamp recordings of single sodium and calcium channels. Then there was Dax Hoffman with recordings of single potassium channels and, of course, Costa Colbert with both experiments and modeling. There were many talented people in the lab at the time studying various aspects of dendritic function, including outstanding biophysicists, experimentalists, theorists, and disease translationalists. The lab space was designed with a conference table in the center with many small rig rooms around the periphery. People would go into their rig rooms to do experiments and then come out into the conference table area to talk with whomever was around. The discussions at that table were intense and groundbreaking. I don’t think my lab ever experienced such an exciting and productive period. We were truly at the forefront of an emerging field. We had mostly left behind the field of synaptic plasticity, and basically started our own field. There were many groundbreaking and highly cited publications during this period, and most of the people in the group ultimately took independent positions at leading institutions. When we would subsequently get together at neuroscience meetings, everyone acknowledged that this period of time in my lab was indeed magical and was never really duplicated again in my or in anyone else’s lab.

The “Book”: Foundations of Cellular Neurophysiology

As part of the Graduate Program in Neuroscience, I taught a course in cellular neurophysiology with Sam Wu. Sam was a faculty member in the Department of Ophthalmology. He was a wonderful electrophysiologist studying retinal neurons from salamanders. Sam and I became very close while I was still in the Neurology Department. Our labs were on adjacent floors in the Neurosensory Center, and we would get together and talk science all the time. We both had engineering backgrounds and felt that neurophysiology should be taught at a fundamental and mathematical level. So, we decided we would teach a rigorous course to first-year graduate students and provide everyone with some background in the functional properties of neurons. Sam wanted to teach the more biophysical parts—for example, the statistics of ion channel opening and closing, theories of ion channel permeability, and Hodgkin Huxley equations—while I would teach cable theory, synaptic transmission, including quantal analysis of transmitter release, and synaptic plasticity. The course began in the late 1980s and continued until I left Baylor in 2004. It was a required course, so all the graduate students at Baylor during that time were “subjected” to the course. Many did not want to take it, but most said they were glad they did and learned a great deal. We had extensive notes that we made for the course and, after a few years, we decided to see if it would be possible to convert our notes into a textbook. We contacted several publishers, but it was Fiona Stevens from the MIT Press who landed the contract. Of course, we discovered that converting course notes into a textbook was much more difficult than we thought it would be, and it ended up being a multiyear project. Rick Gray, a special person in my lab who I will discuss in some detail at the end, was instrumental in the process, in part because MIT wanted the book to be typeset using LaTex. Although I was somewhat familiar with LaTex, Sam was not. Fortunately, Rick was an expert. Also, all the figures had to be put into a form suitable for LaTex. Rick did all of this. Overall, it was a monumental project. If we had known ahead of time how much work it would be, I don’t think any of us would have considered it.

One of the unique aspects of the book was the inclusion of extensive homework problems at the end of each chapter along with the answers to these problems in appendices. One appendix had short answers to each problem, while another appendix had the complete solutions. This way the student could check to see if they were on the right track by looking only at the short answer before looking at the complete solution. Including so many homework problems presented an editing challenge in and of itself because it was time-consuming to ensure that all the problems and answers were correct and typeset properly. The first printing of the book, unfortunately, had numerous errors, but many of these were corrected by the second printing. Sam, Rick, and I are extremely proud of the book. It has been through tens of printings and has sold nearly 10,000 copies. It is a unique book and has been used mostly as a reference but also as a textbook. We always intended to come out with a second edition, but we could never overcome the effort involved in doing so.

The Move to the University of Texas at Austin (2004–2022)

The Division of Neuroscience at Baylor was a fun and exciting place to be during the 1990s. We had a great department with many wonderful faculty and staff. The science was outstanding, the faculty was collegial, and everyone was focused on what was most important: research and education. Although I never actively sought positions elsewhere, occasionally I would be contacted by other institutions to see if I might be interested in moving as either a full professor or as a department chair. Some opportunities sounded more interesting than others, but I usually accepted the offer to visit and evaluate the possibilities. I recall visiting University of Alabama–Birmingham, University of Pennsylvania, University of Wisconsin, University of Washington, Yale, University of Chicago, Tufts, Brown, MIT, Duke, University of North Carolina, and the Medical College of Georgia. There may have even been a few others that I don’t remember. Some of these institutions were just looking at me for a professor position, while others were interested in me as department chair. It was flattering to even be considered by some of these institutions, and in all cases the visits were educational. I got to see both the positives and negatives of other places and usually came away with the conclusion that there was no perfect academic institution, and I was happy to stay where I was.

I don’t remember the exact year, but at some point between 2000 and 2002, Jim Patrick became a dean at Baylor. I’m sure that this was a good move for Jim, but unfortunately, it was not good for the division because he also remained as the chair. During the next few years, the environment in the division changed considerably for the worse. It was difficult for Jim to advocate for the division as a chair should do because he was also dean with an obvious conflict of interest. As a result, the support and status for the division went downhill considerably. It became clear that the faculty were not happy with this situation, and it was only a matter of time before people started leaving. I think Rob Gereau was the first to leave, but over about a five-year period, the division lost eight senior faculty members, Rob, David Sparks, me, David Sweatt, Nikos Logothetis, John Maunsell, Mike Crair, John Dani, and perhaps a few others whom I don’t remember. In my opinion, this was a major downfall of the division. Because I left in 2004, I won’t dwell on what happened at Baylor because most of what I know is second- or third-hand information. Suffice it to say that Jim’s decision to remain chair after becoming dean was a huge mistake for the division.

Harold Zakon from the Section of Neurobiology at the University of Texas at Austin (UT) invited me to give a seminar in the fall of 2001. It is a beautiful campus, and I met some of the faculty and learned a bit about neurobiology at UT. About six months later, Harold contacted me and asked whether I might consider a leadership position at UT. I said sure, but didn’t really think much would come of it. At the time, they were considering someone else for the position, and I figured he would take it. During the next two years, I took many trips to Austin and met with many people, including members of both the faculty and the administration. The more I learned about the possibilities at UT and the resources that the administration was willing to devote to building neuroscience, the more interested I became. The dean of natural sciences at the time, Mary Ann Rankin, was a joy to work with. She and the provost, Sheldon Eckland-Olson, seemed committed to increasing the number of neuroscience faculty members, expanding the infrastructure, and making UT competitive in neuroscience with other similar institutions. Our negotiations continued for almost two years, until I finally signed a contract in early 2004. I was to become director of the Institute for Neuroscience (INS) as well as the director of the new Center for Learning and Memory (CLM).

The INS was an interdepartmental graduate program that had been established some years earlier but was in need of strong leadership. There were three main departments, all in different colleges, that were the core of the INS. Each had different views about graduate education, and they didn’t agree on much. I thought that my experience as head of an interdepartmental graduate program at Baylor for so many years would serve me well in this position. There was also no real department of neuroscience at UT but there was a Section of Neurobiology within the School of Biological Sciences. Harold was chair of that section, and, although it was offered to me, I didn’t really want his job. One of the main tasks of the section was teaching neuroscience to the large number of undergraduate students at UT. I had little experience with undergraduate education, and I wanted to focus my efforts on enhancing neuroscience research at UT. I felt I could do this by establishing the CLM. I thought that CLM could provide a research focus and identity that would help to attract and recruit new faculty members. As part of the agreement, CLM was given 10 new faculty lines at any level and space in a new building. Although there was a core group of excellent neuroscientists at UT, the group was small and UT did not have a national reputation for neuroscience. My idea was to first try to recruit a few senior faculty who could provide some name recognition for CLM. I also thought that it would be easier to recruit into the new center (CLM) rather than to the faculty at large. I began contacting people I knew right away, well before I actually moved to UT. I also wanted to recruit outstanding senior women who would then help me recruit junior women so we could have a gender-balanced center. Although I wanted a diverse center both in terms of gender, race, and area of research (from molecular to humans), my motto was always to “hire the best athlete.”

My first recruit was Rick Aldrich from Stanford. Rick of course was a great scientist, who later was elected into the National Academy of Sciences, but it was also an opportune time to recruit him. He had just lost his Howard Hughes Medical Institute funding, his brother lived in College Station, and he grew up in the southwest (New Mexico and Arizona). Mary Ann offered him a great package, which included being chair of Neurobiology and two faculty lines. My second recruit was Kristen Harris. I met her many years earlier at a meeting at the MBL and had followed her and her work for many years. She had been at Harvard and Boston University but recently had moved to the Medical College of Georgia. She actually tried to recruit me to Georgia but that fell through rather quickly. Kristen was also a great scientist, as well as a great role model for women in science, and her research was a perfect fit for CLM. After these two senior hires, we focused our efforts on recruiting junior faculty members. We formed a search committee, advertised in all the usual places, and contacted as many people as we could at other universities to let them know about our recruiting efforts. I applied successfully for a big state grant, which helped with Kristen’s recruitment (electron microscopes are expensive!), and an NIH stimulus grant, which helped me leverage an 11th faculty line for CLM from the college. Although there were a few people we tried to recruit who decided to go elsewhere, we were very successful in our recruiting efforts and assembled an amazing group of faculty for the CLM. In addition to Rick and Kristen, we hired Ali Preston, Michael Drew, Kim Raab-Graham, Helmut Koester, Ila Fiete, Hiroshi Nishiyama, Laura Colgin, and Boris Zemmelman. Michael Mauk from UT Houston had written me a letter asking to be considered for a position at UT Austin. He was not that happy where he was, and he thought that his research would be a good fit for CLM. Although Mary Ann was not that enthusiastic about another senior hire, especially one from another Texas institution, Mike also brought with him his wife, Susan Cushman. I had known Susan from the time she was a doctoral student with Paul Pfaffinger at Baylor. I thought that she would be an ideal person to help with development efforts for CLM. As a team, they seemed attractive enough to convince Mary Ann to make offers. Mike came in as a full professor and Susan as a senior administrator in charge of development and community relations.

Laura Colgin and Boris Zemmelman were our last recruits, bringing the total number of faculty members in CLM to the 11 we were promised, with me making it an even dozen. We were also balanced in terms of research areas, which spanned levels of analysis from molecular to human, and in terms of gender (5 of the 11 hires were women). I also tried hard to recruit another outstanding scientist (a women of color), but the university at that time was not as committed as they should have been in applying the resources necessary to attract minorities. Other than this and a few other failed searches, faculty recruitment turned out to be much easier than I had anticipated. Once we had an identity with Rick, Kristen, and me, it was more attractive for the outstanding junior scientists on the market to consider UT. Also, we could make a pretty attractive offer compared with many other places with nine month’s salary for only teaching one course, new and generous lab space, and some other perks that stood out above other competing places. People also liked the idea of joining something new (CLM). Susan had many great ideas, such as establishing a yearly (later changed to biannual) community outreach program called Memory Matters; a yearly CLM retreat; and a biannual symposium, which we called the Austin Conference on Learning and Memory (ACL&M, which was a takeoff from the name of the famous Austin City Limits). CLM was on its way to becoming a nationally and internationally recognized center of excellence. I also resisted the notion of having CLM encompass everyone on campus whose research was remotely related to learning and memory. I thought that this would be a mistake; there were other, less successful, all-encompassing centers on campus that helped convince me of this. I wanted to keep CLM small and collegial, including only those interested and willing to contribute toward the goals of CLM. Nicholas Priebe, Jonathan Pierce (two recruits while Rick Aldrich was chair of Neurobiology), and Nace Golding later joined CLM and were great members and contributors. One of the things we did to help keep CLM collegial and collaborative was to have weekly faculty meetings over lunch, with different people giving informal 30-minute talks about their research each week. We also used this time for people working on their grants to get critiqued by the rest of CLM. This could only happen if it was a relatively small and friendly group. I think the grant critiques helped a great deal in everyone’s success in grant funding. Overall, I think CLM was a winner, with many of the things we did perhaps serving as a model for other centers. I need to acknowledge that none of this would have been possible without the help and support of outstanding staff members: Kathleen Pantalion, Cindy Thompson, and Jason Goltz.

While developing CLM was relatively easy, being director of the INS was challenging, to say the least. There were serious structural problems that I was never able to fully overcome. The most difficult problem was the financing of the INS by the three main colleges that had a significant number of faculty as members of INS. The three colleges were Natural Sciences, Liberal Arts, and Pharmacy. As part of my contract, each college was supposed to contribute a yearly amount to the INS roughly based on the number of their faculty in the INS. For many reasons, this was a struggle to make happen every year. The second problem was in teaching. To develop a strong educational program for graduate students, we had to have faculty willing and able to teach graduate courses. The INS had no teaching budget to pay part of the salaries of the faculty teaching graduate courses. The teaching load in each of the three colleges was quite different, and faculty received teaching credit only for teaching undergraduate courses in their respective colleges. We had to get the approval from the different department chairs each year to allow faculty to get credit toward their required teaching load for teaching a graduate course. This made it difficult to establish a graduate curriculum in neuroscience. The third problem was in the standards for graduate students. Each college and department felt differently about graduate students. Before I came to UT, graduate students were directly admitted to a particular lab with the graduate stipend being paid by having the graduate student work as a teaching assistant (TA) in that department each semester. This meant that research progress by students was slow, and many students took seven or more years to finish their doctorates.

I did have some success with these and other core issues. With the help of Kristen Harris and some of the other new faculty members in CLM, we established a new set of bylaws for the INS. This included higher standards for admission of applicants, which was mediated by a general admission committee. There were no direct admits allowed into particular labs. We required research rotations during the first year with the stipends being paid by the INS and established new courses. There were some growing pains, however. For example, the INS was used to admitting some 20 students per year. I think in the first year of implementing the new admissions standards, we admitted only a handful of students. Also, while it was typical for students in the old system to take seven years to complete their degree, we implemented a number of financial incentives to shorten this to five years. This meant that there were fewer TAs to help with teaching the many undergraduate courses. After a few years, however, the quality of the graduate students increased significantly, and we had a large number of outstanding applicants every year. The curriculum was improved somewhat, although I had to endure a lawsuit brought against me by one of the faculty members who I had removed from teaching. The problems I was never able to solve, however, mostly related to the financial and teaching issues.

After about eight years at UT, I was asked to become chair of the Section of Neurobiology. Rick Aldrich had completed his five-year term as chair and was ready to devote more of his time to research. My goal for being chair was to help bring the section together and to convince the administration that we should become an independent department rather than a section in the School of Biological Sciences. Unfortunately, Mary Ann Rankin had stepped down as dean of the College of Natural Sciences and moved to the University of Maryland. Linda Hicke from Northwestern University was hired to replace her as dean. Dean Hicke was not supportive of neurobiology/neuroscience and terminated much of the money that had been going to the Section of Neurobiology and INS. Also, she changed the status of the CLM from an independent research unit to being a part of the Section of Neurobiology. Needless to say, we did not get along. I felt that she had violated many of the provisions of my contract, but there was little I could do about it other than bring a lawsuit, which I was not about to do. The one good thing she did, however, was to abolish the School of Biological Sciences and establish three independent departments: Integrative Biology, Molecular Biosciences, and Neuroscience. We finally had our own department, but my struggles with the dean were never ending. After four years as chair, I stepped down and Mike Mauk took over. I thought that the department was in good shape when it was handed over to Mike and that most of the faculty thought I had done a reasonable job (you can’t please everyone). My guiding principles were to be honest and transparent with the faculty and to advocate for them (and not yourself) whenever possible. Around that time, I also stepped down as director of INS. I did remain as director of CLM, however. That was my baby!

Research at University of Texas

Thus far, I have devoted most of this section to my administrative successes and failures at the University of Texas, but I would be remiss if I did not also discuss some of our advances in research during my years at UT. Because more of my time was now being spent on administrative duties than it was at Baylor, research in my lab was very much dependent on Rick Gray. I had secured a partially funded research professor position for him as part of my recruitment package, and he earned it! I also received a similar kind of position for Randy Chitwood, who also helped considerably to keep the lab functioning. Both Rick and Randy were instrumental in whatever successes we had at UT. Rick especially was a unique individual to whom I devote a section at the end of this biography.

Shortly after leaving my lab, Jeff Magee made a fundamental discovery about the gradient of HCN or h-channels in dendrites of CA1 hippocampal neurons. This turned out to be a similar, or even steeper, gradient than what we had shown previously for A-type potassium channels. Although I tried hard not to infringe on Jeff’s findings, it seemed like everything we did related to dendrites turned out to depend on h-channels. Fortunately, after several landmark papers, Jeff pursued other things and did not dwell on h-channels. I certainly did not want to compete with Jeff. Some of the unexpected findings we made that ended up being due at least in part to h-channels were the so-called E-S potentiation described many years earlier with long-term potentiation (LTP), intrinsic plasticity, dopamine regulation of excitability, mGluR-dependent changes in excitability, excitability gradients, epilepsy, depression, actions of ketamine, and oscillations.

I had some outstanding students and postdocs during my years at UT. One in particular was Rishi Narayanan. I met him one summer at the MBL. He was taking the Methods in Computational Neuroscience course in which students had to do a project supervised by a summer scientist. He came to me and asked if I could help him, which I was delighted to do. I don’t remember what his summer project was, but we certainly hit it off, and he later asked to do a postdoc in my lab. Rishi had an engineering background, but very little experience doing wet lab experiments. I had previously accepted other computationally oriented people with no experimental training for postdocs who didn’t turn out very well. Rishi, however, was so smart and engaging that I was glad to accept him into my lab. Rishi was amazing and had great success transitioning from purely computational work to hard-core electrophysiology. He took the lab in many new directions and published several seminal papers. Another postdoc was Darrin Brager. He joined my lab while I was still at Baylor and actually stayed at Baylor for a few years after I left because his wife was finishing up her pediatric residency at Baylor. Darrin commuted between Houston and Austin on a weekly basis for almost two years so he could do experiments in the lab. Darrin was very successful and produced many great papers. After his wife moved to Austin, she joined a medical practice in San Marcos. With his family now in Austin, Darrin decided to stay at UT with a promotion to an independent research faculty position. In retrospect, he probably should have transitioned to a faculty position at another institution, but he was happy where he was. Darrin’s work was outstanding, he received his own federal funding, and had many excellent trainees, but UT was never willing to put him in a tenure track position. I always regretted this, but there was little I could do.

The Transition Period toward Retirement

Although I tried to be active in the lab again after so many years as directors of the two centers and chair of what was now a department, it was clear that I was unable to be as engaged in research as I once was. I still had NIH funding, with some 40 years of continuous NIH funding, including what might still be a record at National Institute of Mental Health (NIMH) of a grant with a perfect score of 100! However, there was one experience with the NIH that still grates on me. I put together what I thought was a very interesting grant related to possible cellular mechanisms for the known comorbidity between epilepsy and depression. I contacted a program officer at the NIMH and asked if she would look at the aims of this grant and advise me on what study section would be best to send it to. She said she would be happy to do so. I sent them to her, and after several days, I called her again to see what advice she might have. She was someone with a doctorate, but she had little or no research experience beyond her graduate work. She told me that NIMH would not be interested in this grant and then proceeded to tell me what types of experiments I should be doing. I found it incredible that someone with her level of experience would have the chutzpah to tell a senior scientist with some 40 years of NIH funding what types of experiments I should be doing. She further told me that NIMH really didn’t abide by priority scores anymore and that they just funded what they want to regardless of peer review. I related this experience to a number of other colleagues who had dealt with NIMH, and no one was surprised and many had similar experiences. NIMH seemed to be doing more top-down micromanaging of grant funding than they used to. Although I previously had funding from other institutes, such as National Institute of Neurological Disorders and Stroke (NINDS), and could have pursued funding there, this experience really soured me on the NIH and funding in general. I had always thought that peer review was the foundation and principle that led to the highest quality and most innovative research possible and was the essence of what made the NIH and research in the United States so special.

In addition to not being as focused on research as I used to be, the atmosphere in the department had changed considerably, which made me uncomfortable at best. Divisions clearly had formed between different groups in the department, with some getting favorable treatment by the chair at the expense of others. Many of the faculty would come to me to complain, but there was little I could do about it. The department was just not the happy place that it used to be. These and other things made me begin to think about my eventual retirement, but I didn’t know when to pull the trigger. When Covid hit in 2020, the labs were closed, and I had to work from home. Fortunately, most of the trainees in my lab had left for other jobs before Covid, so ongoing research was not that affected by the lab closures. However, I was in the middle of teaching my yearly neurophysiology course at the time, so all of the lectures from then on were done remotely. I definitely did not like remote teaching. I always enjoyed the close interaction and engagement with students, which was just not possible over Zoom. This teaching experience also made me think about retirement. A few years before Covid, my wife and I had purchased a house on North Padre Island just southeast of Corpus Christi. We loved the beach and fishing, so we basically moved there during Covid. We really loved it there, making me think more seriously about retirement. The final straw, so to speak, was the untimely and tragic death of my long-time friend and colleague Rick Gray (see “Memorial to Rick Gray”). With Rick’s passing, I had little motivation to reinvigorate my lab and research, so I decided to finally retire in January 2022. Laura Colgin had already taken over as director of the CLM; Darrin Brager was moving to University of Nevada, Las Vegas; and the one research assistant I had in the lab, Brandy Routh, had been accepted into graduate school and began working in another lab. It seemed like the right time to retire, but other than fishing, I really had no plans for doing anything in retirement. I would have been happy to contribute in some way to the department, but the new chair who had taken over from Mike Mauk never really asked me to do anything, so we just sold our house in Austin and moved completely to North Padre Island.

Conclusion

Although I may have had a few regrets along the way, I am satisfied that I did my best during my career to advance my area of neuroscience. I also tried to be a leader and help others achieve their own successes. From my time in college, the motto of working hard and separating work from play (including family life) has helped guide me through the years. I’ve had a wonderful career. If I could return briefly to my drifting ocean water analogy at the beginning, the “influencers” for my drift to science were many, and I am forever grateful. My wife and family may not have directly influenced my drift toward science, but they had an enormous impact on whatever success in science I may have had. Although my career has been immensely satisfying, nothing comes close to the joy of being with family and friends.

Memorial to Rick Gray

Richard Gray was born on a family farm near Miles, Iowa. He did his undergraduate work at the University of Illinois, Urbana, and came to BCM as a research assistant with Mike Merickel. He later joined the graduate program, and my lab, where he completed his doctoral work. He did a brief postdoc with John Connor at the Roche Institute of Molecular Biology in New Jersey and then rejoined my lab as a research associate. He was later promoted to assistant professor at Baylor and as a research scientist at the University of Texas. Rick was an amazing individual both due to his technical skills and his personal interactions with everyone in my lab. He could fix anything, probably from his experience in growing up on a farm. Rick became highly skilled in electronics, computer programming, and all types of experimental electrophysiology. His real love was in channel biophysics, and that is where most of his experimental work was focused. He helped and mentored virtually everyone who came through my lab. Especially during my time in Austin, he was simply indispensable for whatever successes we had in research. Everyone who came in contact with Rick adored him. He had a bad heart and always thought he would die of a heart attack, but in the end, it was cancer that took him at the early age of 68. He is sorely missed by everyone who knew him. I do not know what my scientific career would have been like if I had not had Rick Gray by my side.

Acknowledgment

Special thanks go to Dr. Greg Ordemann for helping me edit the final version of this autobiography.

Trainees

In addition to Rick Gray, I had many simply outstanding students, postdocs and collaborators throughout my career. I would like to thank all of them for their important contributions to both my research and to my personal development as a scientist and academician.

Graduate Students

John W. Whisler, MS UofMN; Warren Watson, MS, UofMN; Carl E. Stafstrom, MD/PhD, UofMN; William F. Hopkins, PhD, Baylor; Richard Gray, PhD, Baylor; Ronald Fisher, MD/PhD, Baylor; Nelson Spruston, PhD, Baylor; David Jaffe, PhD, Baylor; Erik Cook, PhD, Baylor; Craig Powell, MD/PhD, Baylor; Robert Avery, MD/PhD, Baylor; Lalania Schexnayder, MD/PhD, Baylor; Dax Hoffman, PhD, Baylor; Xixi Chen, PhD, Baylor; Yuan Fan, PhD, Baylor; Yul Young Park, PhD, UT; Chung Sub Kim, PhD, UT; Ann Clemens, PhD, UT; Sachin Vaidya, PhD, UT; Andrea Haessly, MS, UT; Elizabeth Arnold, PhD, UT; Brandy Zrubek Routh, student researcher, UT.

Postdoctoral Fellows

Gerald E. Slater, MD, UofMN; Howard Wood, PhD, Baylor; Frank J. Lebeda, PhD, Baylor; Douglas A. Baxter, PhD, Baylor; Richard Gray, PhD, Baylor, William H. Griffith, PhD, Baylor; Paul A. Rutecki, MD, Baylor; Richard J. Hallworth, PhD, Baylor; Flavio Villani, MD, Baylor; Stephen Williams, PhD, Baylor; Paul E. Schulz, MD, Baylor; Lise Eliot, PhD, Baylor; Jeff Magee, PhD, Baylor; Costa Colbert, PhD, Baylor; Brian Christie, PhD, Baylor; Ajay Kapur, PhD, Baylor; Mark F. Yeckel, PhD, Baylor; Nicholas Poolos, MD/PhD, Baylor; Li-Lian Yuan, PhD, Baylor; Shigeo Watanabe, PhD, Baylor; Andreas Frick, PhD, Baylor; Yong Liang, PhD, Baylor; Randy Chitwood, PhD, Baylor; Desdemona Fricker, M.D./PhD, Baylor; Helmut Koester, PhD, Baylor; Mala Shah, PhD, Baylor; Andreas Jeromin, PhD, Baylor; Amiel Rosenkranz, PhD, Baylor; Darrin Brager, PhD, Baylor; Laurea Diaz, PhD, UT; Rishikesh Narayanan, PhD, UT; Clifton Rumsey, PhD, UT; Payne Chang, PhD, UT; Stephanie Carlson, PhD, UT; Yul Young Park, PhD, UT; Chung Sub Kim, PhD, UT; Nikolai Dembrow, PhD, UT; Seena Mathew, PhD, UT; Kelly Dougherty, PhD, UT; Brian Kalmbach, PhD, UT; Ruchi Malik, PhD, UT; Chung Sub Kim, PhD, UT; Niraj Desai, PhD, UT; Rahul Kumar Rathour, PhD, UT.

Visiting Scientists

John J. Hablitz, PhD; Claudio Frank, MD; Thomas H. Brown, PhD; Nicholas, T. Carnevale, MD/PhD; Massimo Avoli, MD; Henri Conde, PhD; Michele Migliore, PhD; Geri Christofi, PhD; Christophe Bernard, PhD; Darrin Brager, PhD; Richard Gray, PhD.

Chronological Bibliography of Selected Peer-Reviewed Publications

Johnston, D., and Ayala, G.F. Diphenylhydantoin: The action of a common anticonvulsant on bursting pacemaker cells in Aplysia. Science 189:1009–1011, 1975.

Johnston, D., and Wachtel, H. The electrophysiological basis for the spatial dependence of the inhibitory coupling in the Limulus retina. J. Gen. Physiol. 67:1–25, 1976.

Johnston, D. Voltage clamp reveals basis for calcium regulation of bursting pacemaker potentials in Aplysia neurons. Brain Res. 197:418–423, 1976.

Ayala, G.F., Lin, S., and Johnston, D. The mechanism of action of diphenylhydantoin on invertebrate neurons. I. Effects on basic membrane properties. Brain Res. 121:245–258, 1977.

Ayala, G.F., Johnston, D., Lin, S., and Dichter, H. Mechanisms of action of diphenylhydantoin on invertebrate neurons. II. Effects on excitatory and inhibitory synaptic mechanisms. Brain Res. 121:259–270, 1977.

Ayala, G.F., and Johnston, D. The influences of phenytoin on the fundamental properties of simple neural systems. Epilepsia 18:299–307, 1977.

Whisler, J.W., and Johnston, D. Epileptogenesis: A model for the involvement of slow membrane events and extracellular potassium. J. Theor. Biol. 75:271–288, 1978.

Slater, G.E., and Johnston, D. Sodium valproate increases potassium conductance in Aplysia neurons. Epilepsia 19:379–384, 1978.

Johnston, D. Phenobarbital: Concentration dependent biphasic effect on Aplysia burst firing neurons. Neurosci. Lett. 10:175–180, 1978.

Johnston, D. Voltage, temperature and ionic dependence of the slow outward current in Aplysia burst firing neurons. J. Physiol. (London) 298:145–157, 1980.

Johnston, D., Hablitz, J.J., and Wilson, W.A. Voltage clamp discloses slow inward current in hippocampal burst firing neurons. Nature (London) 286:391–393, 1980.

Stafstrom, C.E., Johnston, D., Wehner, J.M., and Sheppard, J.R. Spontaneous neural activity in fetal brain reaggregate cultures. Neurosci. 5:1681–1689, 1980.

Johnston, D. Passive cable properties of hippocampal CA3 pyramidal neurons. Cell. Mol. Neurobiol. 1:41–55, 1981.

Johnston, D., and Brown, T.H. The giant synaptic potential hypothesis for epileptiform activity. Science 211:294–297, 1981.

Johnston, D., and Lam, D.M.-K. Regenerative and passive membrane properties of isolated horizontal cells from a teleost retina. Nature (London) 292:451–454, 1981.

Hablitz, J.J., and Johnston, D. Endogenous nature of spontaneous bursts in hippocampal neurons. Cell. Mol. Neurobiol. 1:325–334, 1981.

Carnevale, N.T., and Johnston, D. Electrophysiological characterization of remote chemical synapses. J. Neurophysiol. 47:606–621, 1982.

Bryan, R.N., and Johnston, D. Epileptogenic effects of radiographic contrast agents: An experimental study. J. Neuroradiol. 3:117–120, 1982.

Lebeda, F.J., Hablitz, J.J., and Johnston, D. Antagonism of GABA-mediated responses by d-tubocurarine in hippocampal neurons. J. Neurophysiol. 48:622–632, 1982.

Baxter, D.A., Johnston, D., and Strittmatter, W.J. Protease inhibitors implicate metalloendoprotease in synaptic transmission at the mammalian neuromuscular junction. Proc. Nat. Acad. Sci. (USA) 80:4174–4178, 1983.

Brown, T.H., and Johnston, D. Voltage-clamp analysis of the mossy fiber synaptic input to hippocampal pyramidal neurons. J. Neurophysiol. 50:487–507, 1983.

Johnston, D., and Brown, T.H. Interpretation of voltage-clamp measurements in hippocampal neurons. J. Neurophysiol. 50:464–486, 1983.

Johnston, D. Valproic acid: Update on its mechanisms of action. Epilepsia 25:1–4, 1984.

Johnston, D., and Brown, T.H. The synaptic nature of the paroxysmal depolarizing shift in hippocampal neurons. Ann. Neurol. 16:S65–S72, 1984.

Hopkins, W.F., and Johnston, D. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science 226:350–352, 1984.

Gray, R. A., and Johnston, D. Rectification of single GABA-gated chloride channels in adult hippocampal neurons. J. Neurophysiol. 54:134–142, 1985.

Rutecki, P. A., Lebeda, F. J., and Johnston, D. Epileptiform activity induced by changes in extracellular potassium in hippocampus. J. Neurophysiol. 54:1363–1374, 1985.

Barrionuevo, G., Kelso, S.R., Johnston, D., and Brown, T.H. Conductance mechanism responsible for long-term potentiation in monosynaptic and isolated excitatory synaptic inputs to hippocampus. J. Neurophysiol. 55:540–550, 1986.

Griffith, W.H., Brown, T.H., and Johnston, D. Voltage-clamp analysis of synaptic inhibition during long-term potentiation in hippocampus. J. Neurophysiol. 55:767–775, 1986.

Gray, R., and Johnston, D. Noradrenaline and beta-adrenoceptor agonists increase the activity of voltage-dependent calcium channels in hippocampal neurones. Nature (London) 327:620–622, 1987.

Rutecki, P.A., Lebeda, F.J., and Johnston, D. 4–Aminopyridine produces epileptiform activity in hippocampus and enhances synaptic excitation and inhibition. J. Neurophysiol. 57:1911–1924, 1987.

Hopkins, W.F., and Johnston, D. Noradrenergic enhancement of long-term potentiation at mossy fiber synapses in the hippocampus. J. Neurophysiol. 59:667–687, 1988.

Terrian, D.M., Johnston, D., Claiborne, B.J., Ansah-Yiadom, R., Strittmatter, W.J., and Rea, M.A. Glutamate and dynorphin release from a subcellular fraction enriched in hippocampal mossy fiber synaptosomes. Brain Res. Bull. 21:343–351, 1988.

Williams, S.H., and Johnston, D. Muscarinic depression of long-term potentiation in CA3 hippocampal neurons. Science 242:84–87, 1988.

Williams, S., and Johnston, D. Long-term potentiation of hippocampal mossy fiber synapses is blocked by postsynaptic injection of calcium chelators. Neuron 3:583–588, 1989.

Fisher, R., Gray, R., and Johnston, D. Properties and distribution of single voltage-gated calcium channels in adult hippocampal neurons. J. Neurophysiol. 64:91–104, 1990.

Fisher, R., and Johnston, D. Differential modulation of single voltage-gated calcium channels by cholinergic and adrenergic agonists in adult hippocampal neurons. J. Neurophysiol. 64:1291–1302, 1990.

Jaffe, D., and Johnston, D. The induction of long-term potentiation at hippocampal mossy fiber synapses follows a Hebbian rule. J. Neurophysiol. 64:948–960, 1990.

Rutecki, P.A., Lebeda, F.J., and Johnston, D. Epileptiform activity in the hippocampus produced by tetraethylammonium. J. Neurophysiol. 64:1077–1088, 1990.

Williams, S., and Johnston, D. Muscarinic depression of synaptic transmission at the hippocampal mossy fiber synapse. J. Neurophysiol. 64:1089–1097, 1990.

Chetkovich, D.M., Gray, R., Johnston, D., and Sweatt, J.D. NMDA-receptor activation increases cAMP levels and voltage-gated Ca2+ -channel activity in area CA1 of hippocampus. Proc. Natl. Acad. Sci. USA 88:6467–6471, 1991.

Williams, S., and Johnston, D. Kinetic properties of two anatomically distinct excitatory synapses in hippocampal CA3 pyramidal neurons. J. Neurophysiol. 66:1010–1020, 1991.

Jaffe, D.B., Johnston, D., Lasser-Ross, N., Lisman, J.E., Miyakawa, H., Ross, W.N. The spread of Na+ spikes determines the pattern of dendritic Ca2+ entry into hippocampal neurons. Nature (London) 357:244–246, 1992.

Miyakawa, H. Ross, W.N., Jaffe, D., Callaway, J.C., Lasser-Ross, N., Lisman, J.E., and Johnston, D. Synaptically activated increases in Ca2+ concentration of hippocampal CA1 pyramidal cells are primarily due to voltage-gated Ca2+ channels. Neuron 9:1163–1173, 1992.

Spruston, N., and Johnston, D. Perforated patch-clamp analysis of the passive membrane properties of three classes of hippocampal neurons. J. Neurophysiol. 67:508–529, 1992.

Spruston, N., Jaffe, D.B., Williams, S.H., and Johnston, D. Voltage- and space-clamp errors associated with the measurement of electrotonically remote synaptic events. J. Neurophysiol. 70:781–802, 1993.

Villani, F., and Johnston, D. Serotonin inhibits induction of long-term potentiation at commissural synapses in hippocampus. Brain Res. 606:304–308, 1993.

Eliot, L.S., and Johnston, D. Multiple components of calcium current in acutely-dissociated dentate gyrus granule neurons. J. Neurophysiol. 72:762–777, 1994.

Jaffe, D.B., Ross, W.N., Lisman, J.E., Lasser-Ross, N., Miyakawa, H., and Johnston, D. A model for dendritic Ca2+ accumulation in hippocampal pyramidal neurons based on fluorescence imaging measurements. J. Neurophysiol. 71:1065–1077, 1994.

Powell, C.M., Johnston, D., and Sweatt, J.D. Increase in autonomously active protein kinase C in the maintenance of NMDA-receptor-independent LTP. J. Biol. Chem. 269:27958–27963, 1994.

Schulz, P.E., Cook, E., and Johnston, D. Changes in paired-pulse facilitation suggest presynaptic involvement in long-term potentiation. J. Neurosci. 14:5325–5337, 1994.

Christie, B.R, Eliot, L.S., Ito, K.-I., Miyakawa, H., and Johnston, D. Different Ca2+ channels in soma and dendrites of hippocampal pyramidal neurons mediate spike-induced Ca2+ influx. J. Neurophysiol. 73:2553–2557, 1995.

Magee, J.C., Christofi, G., Miyakawa, H. Christie, B., Lasser-Ross, N., and Johnston, D. Subthreshold synaptic activation of voltage-gated Ca2+ channels mediates a localized Ca2+ influx into the dendrites of hippocampal pyramidal neurons. J. Neurophysiol. 74:1335–1342, 1995.

Magee, J.C., and Johnston, D. Characterization of single voltage-gated Na+ and Ca2+ channels in dendrites of rat CA1 hippocampal neurons. J. Physiol. (London) 487.1:67–90, 1995.

Magee, J.C., and Johnston, D. Synaptic activation of voltage-gated channels in dendrites of hippocampal pyramidal neurons. Science 268:301–304, 1995.

Migliore, M., Cook, E.P., Jaffe, D.B., and Johnston, D. Computer simulations of morphologically reconstructed CA3 hippocampal neurons. J. Neurophysiol. 73:1157–1168, 1995.

Schulz, P.E., Cook, E., and Johnston, D. Using paired-pulse facilitation to probe the mechanism of LTP. J. Physiol. (Paris) 89:3–9, 1995.

Avery, R.B., and Johnston, D. Multiple channel types contribute to the low-voltage activated calcium current in hippocampal CA3 pyramidal neurons. J. Neurosci. 16:5567–5582, 1996.

Christie, B.R, Magee, J.C., and Johnston, D. Dendritic calcium channels and hippocampal long-term depression. Hippocampus 6:17–23, 1996.

Christie, B.R, Magee, J.C., and Johnston, D. The role of dendritic action potentials and Ca2+ influx in the induction of homosynaptic long-term depression in hippocampal CA1 pyramidal neurons. Learn. & Mem. 3:160–169, 1996.

Colbert, C.M., and Johnston, D. Axonal action-potential initiation and Na+ channel densities in the soma and axon initial segment of subicular pyramidal neurons. J. Neurosci. 16:6676–6686, 1996.

Magee, J.C., Avery, R.B., Christie, B.R., and Johnston, D. Dihydropyridine-sensitive, voltage-gated Ca2+ channels contribute to the resting intracellular Ca2+ concentration of hippocampal CA1 pyramidal neurons. J. Neurophysiol. 76:3460–3470, 1996.

Williams, S., and Johnston, D. Actions of endogenous opioids on NMDA receptor-independent long-term potentiation in area CA3 of the hippocampus. J. Neurosci. 16:3652–3660, 1996.

Avery, R.B., and Johnston, D. Ca2+ channel antagonist U-92032 inhibits both T-type Ca2+ channels and Na+ channels in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 77:1023–1029, 1997.

Christie, B.R., Schexnayder, L.K., and Johnston, D. Contribution of voltage-gated Ca2+ channels to homosynaptic long-term depression (LTD) in the CA1 region in vitro. J. Neurophysiol. 77:1651–1655, 1997.

Colbert, C.M., Magee, J.C., Hoffman, D., and Johnston, D. Slow recovery from inactivation of Na+ channels underlies the activity-dependent attenuation of dendritic action potentials in hippocampal CA1 pyramidal neurons. J. Neurosci. 17:6512–6521, 1997.

Cook, E.P., and Johnston, D. Active dendrites reduce location-dependent variability of synaptic input trains. J. Neurophysiol. 78:2116–2128, 1997.

Hoffman, D., Magee, J.C., Colbert, C.M., and Johnston, D. Potassium channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons. Nature 387:869–875, 1997.

Magee, J.C., and Johnston, D. A synaptically-controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275:209–213, 1997.

Colbert, C.M., and Johnston, D. Protein kinase C activation decreases activity-dependent attenuation of dendritic Na+ current in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 79:491–495, 1998.

Hoffman, D.A., and Johnston, D. Down-regulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC. J. Neurosci. 18:3521–3528, 1998.

Kapur, A., Yeckel, M.F., Gray, R., and Johnston, D. L-type calcium channels are required for one form of hippocampal mossy fiber LTP. J. Neurophysiol. 79:2181–2190, 1998.

Cook, E.P., and Johnston, D. Voltage-dependent properties of dendrites that eliminate location-dependent variability of synaptic input. J. Neurophysiol. 81:535–543, 1999.

Hoffman, D.A., and Johnston, D. Neuromodulation of dendritic action potentials. J. Neurophysiol. 81:408–411, 1999.

Migliore, M., Hoffman, D.A., Magee, J.C., and Johnston, D. Role of an A-type K+ conductance in the back-propagation of action potentials in the dendrites of hippocampal pyramidal neurons. J. Computational Neurosci. 7:2–15, 1999.

Poolos, N.P., and Johnston, D. Calcium-activated potassium conductances contribute to action potential repolarization in the soma but not the dendrites of hippocampal CA1 pyramidal neurons. J. Neurosci. 19:5205–5212, 1999.

Yeckel, M.F., Kapur, A., and Johnston, D. Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. Nature Neurosci. 2:625–633, 1999.

Johnston, D., Hoffman, D.A., Magee, J.C., Poolos, N.P., Watanabe, S., Colbert, C.M., and Migliore, M. Dendritic potassium channels in hippocampal pyramidal neurons. J. Physiol. 525:75–81, 2000.

Kapur, A., Yeckel, M.F., and Johnston, D. Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway. Neuroscience 107:59–69, 2001.

Liang, Y., Yuan, L.-L., Johnston, D., and Gray, R. Calcium signaling at single mossy fiber presynatpic terminals in the rat hippocampus. J. Neurophysiol. 87: 1132–1137, 2002.

Nakazawa, K., Quirk, M.C., Yeckel, M.F., Watanabe, M., Chitwood, R.A., Sun, L.D., Kato, A., Carr, C.A., Johnston, D., Wilson, M.A., and Tonegawa, S. Evidence for a crucial role of hippocampal CA3 NMDA receptors in associative memory recall. Science 297:211–218, 2002.

Poolos, N.P., Migliore, M., and Johnston, D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nature Neurosci. 5:767–774, 2002.

Watanabe, S., Hoffman, D.A., Migliore, M., and Johnston, D. Dendritic K+ channels contribute to spike-timing induced long-term potentiation in hippocampal pyramidal neurons. Proc. Natl. Acad. Sci. USA 99: 8366–8371, 2002.

Yuan, L.-L., Adams, J.P., Swank, M., Sweatt, J.D., and Johnston, D. Protein kinase modulation of dendritic K+ channels in hippocampus involves a MAPK pathway. J. Neurosci. 22:4860–4868, 2002.

Bernard, C., and Johnston, D. Back-propagation in dendrites is controlled by a distance-dependent modifiable threshold. J. Neurophysiol. 90:1807–1816, 2003.

Frick, A., Magee, J.C., Koester, H., and Johnston, D. Normalization of Ca2+ signals by small oblique dendrites of CA1 pyramidal neurons. J. Neurosci. 23:3243–3250, 2003.

Jeromin, A., Yuan, L.-L., Frick, A., Pfaffinger, P., and Johnston, D. A modified Sindbis vector for prolonged gene expression in neurons. J. Neurophysiol. 90:2741–2745, 2003.

Bernard, C., Anderson, A.E. Poolos, N.P., and Johnston, D. Acquired dendritic channelopathy in temporal lobe epilepsy. Science 305:532–535, 2004.

Chen, X., and Johnston, D. Properties of single voltage-dependent K+ channels in dendrites of CA1 pyramidal neurons of rat hippocampus. J. Physiol. 559:187–203, 2004.

Frick, A., Magee, J.C., and Johnston, D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites. Nature Neurosci. 7:126–135, 2004.

Shah, M.M., Anderson, A.E., Leung, V., and Johnston, D. Seizure-induced plasticity of h-channels in entorhinal cortical layer III neurons. Neuron 44:495–508, 2004.

Varga, A.W., Yuan, L.-L., Anderson, A.E., Schrader, A., Wu, G.-Y., Gatchel, J.R., Johnston, D., and Sweatt, J.D. CaMKII modulated Kv4.2 channel expression and upregulates dendritic A-type K+ currents. J. Neurosci. 24:3643–3654, 2004.

Wang, J., Yeckel, M.F., Johnston, D., and Zucker, R.S. Photolysis of postsynaptic caged Ca2+ can potentiate and depress mossy fiber synaptic responses in rat hippocampal CA3 pyramidal neurons. J. Neurophysiol. 91:1596–1607, 2004.

Chen, X., and Johnston, D. Constitutively active GIRK channels in dendrites of hippocampal CA1 pyramidal neurons. J. Neurosci. 25:3787–3792, 2005.

Fan, Y, Fricker, D., Brager, D., Chen, X, Lu, H.C, Chitwood, R, and Johnston, D. Activity-dependent decrease of excitability in hippocampal neurons through increases in Ih. Nature Neurosci. 8:1542–1551, 2005.

Koester, H.J., and Johnston, D. Target-cell dependent normalization of transmitter release at neocortical synapses. Science 308:863–866, 2005.

Chen, X., and Johnston, D. Voltage-gated ion channels in dendrites of hippocampal neurons. Pflugers Arch. 453:397–401, 2006.

Chen, X., Yuan, L.-L., Zhao, C., Birnbaum, S.G., Frick, A., Jung, W.E., Schwarz, T.L., Sweatt, J.D., and Johnston, D. Deletion of Kv4.2 gene eliminates dendritic A-type K⁺ current and enhances induction of long-term potentiation in hippocampal CA1 pyramidal neurons. J. Neurosci. 26:12143–12151, 2006.

Rosenkranz, J.A., and Johnston, D. Voltage-dependent dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex. J. Neurosci. 26:3229–3244, 2006.

Yuan, L.-L., Chen, X., Kunjilwar, K., Pfaffinger, P., and Johnston, D. Acceleration of K+ channel inactivation by the MEK inhibitor U0126. Amer. J. Physiol. 290:C165–C171, 2006.

Brager, D.H., and Johnston, D. Plasticity of intrinsic excitability during long-term depression is mediated through mGluR-dependent changes in Ih in hippocampal CA1 pyramidal neurons. J. Neurosci. 27:13926–13937, 2007.

Gasparini, S., Losonczy, A., Chen, X., Johnston, D., and Magee, J.C. Associative pairing enhances action potential back-propagation in radial oblique branches of CA1 pyramidal neurons. J. Physiol. 580 (Pt.3):787–800, 2007.

Narayanan, R., and Johnston, D. Long-term potentiation in rat hippocampal neurons is accompanied by spatially widespread changes in intrinsic oscillatory dynamics and excitability. Neuron 56:1061–1075, 2007.

Rosenkranz, J.A., and Johnston, D. State-dependent modulation of amygdala inputs by dopamine-induced enhancement of sodium currents in Layer V entorhinal cortex. J. Neurosci. 27:7054–7069, 2007.

Andrsfalvy, B.K., Makara, J.K., Johnston, D., Magee, J.C. Altered synaptic and non-synaptic properties of CA1 pyramidal neurons in Kv4.2 KO mice. J. Physiol. 586(16):3881–3892, 2008.

Narayanan, R., and Johnston, D. The h channel mediates location-dependence and plasticity of intrinsic phase response in rat hippocampal pyramidal neurons. J. Neurosci. 28:5846–5860, 2008.

Shin, M., Brager, D.H., Jaramillo, T.C., Johnston, D., and Chetkovich, D.M. Mislocalization of h channel subunits underlies h channelopathy in temporal lobe epilepsy. Neurobiol. Dis. 32:26–36, 2008.

Rosenkranz, J.A., Frick, A., and Johnston, D. Kinase-dependent modification of dendritic excitability after LTP. J. Physiol. 587:115–125, 2009.

Routh, B. Johnston, D., Harris, K.M., and Chitwood, R. Anatomical and electrophysiological comparison of CA1 pyramidal neurons of the rat and mouse. J. Neurophysiol. 102:2288–2302, 2009.

Dembrow, N.C., Chitwood, R.A., and Johnston, D. Projection-specific neuromodulation of medial prefrontal cortex neurons. J. Neurosci. 30:16922–16937, 2010.

Narayanan, R., Dougherty, K., and Johnston, D. Calcium store depletion induces persistent perisomatic increases in the functional density of h channels in hippocampal pyramidal neurons. Neuron 68:921–935, 2010.

Narayanan, R., and Johnston, D. The h current is a candidate mechanism for regulating the sliding modification threshold in a BCM-like synaptic learning rule. J. Neurophysiol. 104:1020–1033, 2010.

Lewis, A.S., Vaidya, S., Blaiss, C.A., Liu, Z., Stroub, T., Brager, D.H., Chen, X., Bender, R.A., Estep, C.M., Popov, A.B., Kang, C., Van Veldhoven, P.P., Bayliss, D.A., Nicholson, D.A., Powell, C.M., Johnston, D., and Chetkovich, D.M. Deletion of the HCN channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J. Neurosci. 31:7424–7440, 2011.

Brager, D.H., Akhavan, A.R., and Johnston, D. Impaired dendritic expression and plasticity of h-channels in the fmr1–/y mouse model of fragile X syndrome. Cell Reports 1:225–233, 2012.

Dougherty, K.A., Islam, T., and Johnston, D. Intrinsic excitability of CA1 pyramidal neurons from the rat dorsal and ventral hippocampus. J. Physiol. 509:5707–5722, 2012.

Kim, C.S., Chang, P.Y., and Johnston, D. Knockdown of HCN1 channels in dorsal hippocampus enhances network activity and leads to anxiolytic- and antidepressant-like effects. Neuron 75:503–516, 2012.

Brager, D.H., Lewis, A.S., Chetkovich, D.M., and Johnston, D. Short-term potentiation and heterosynaptic plasticity in CA1 neurons from mice lacking the h-channel auxiliary subunit TRIP8b. J. Neurophysiol. 110:2350–2357, 2013.

Dougherty, K.A., Nicholson, D.A., Diaz, L., Buss, E.W., Neuman, K.M., Chetkovich, D.M., and Johnston, D. Differential expression of HCN1 and HCN2 subunits alters voltage-dependent gating of h-channels in CA1 pyramidal neurons from the dorsal and ventral hippocampus. J. Neurophysiol. 109:1940–1953, 2013.

Kalmbach, B.E., Chitwood, R., Dembrow, N., and Johnston, D. Dendritic generation of mGluR mediated slow afterdepolarization in layer 5 neurons of prefrontal cortex. J. Neurosci. 33:13518–13532, 2013.

Park, Y.Y, Johnston, D., and Gray, R. Persistent Na+ current mediates neuronal excitability in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 109:1378–1390. 2013.

Routh, B., Johnston, D., and Brager, D.H. Loss of functional A-type potassium channels in the dendrites of CA1 pyramidal neurons from a mouse model of fragile X syndrome. J. Neurosci. 33:19442–19450, 2013.

Vaidya, S.P., and Johnston, D. Temporal synchrony and gamma to theta power conversion in the dendrites of CA1 pyramidal neurons. Nature Neurosci. 16:1812–1820, 2013.

Clemens, A.M., and Johnston, D. Age- and location-dependent differences in store depletion induced h-channel plasticity in hippocampal pyramidal neurons J. Neurophysiol. 111:1368–1382, 2014.

Edwards, J., Daniel, E., Kinney, J., Bartol, T., Sejnowski, T., Johnston, D., Harris, K.M., and Bajaj, C. VolumeRover: Enhancing surface and volumetric reconstruction for realistic dynamical simulation of cellular and subcellular function. Neuroinformatics 12:277289, 2014.

Moya, M.V., Siegel, J.J., McCord, E.D., Kalmbach, B.E., Dembrow, N., Johnston, and Chitwood, R.A.. Species-specific differences in medial prefrontal projections to the pons between rat and rabbit. J. Comp. Neurol. 13:3052–3074, 2014.

Ashhad, S., Johnston, D., and Narayanan, R. Activation of inositol trisphosphate receptors is sufficient for inducing graded intrinsic plasticity in rat hippocampal pyramidal neurons. J. Neurophysiol. 113:2002–2013, 2015.

Dembrow, N.C., Zemelman, B.V., and Johnston, D. Temporal dynamics of L5 dendrites in medial prefrontal cortex regulate integration versus coincidence detection of afferent inputs. J. Neurosci. 35: 4501–4514, 2015.

Desai, N.S., Siegel, J.J., Taylor, W., Chitwood, R.A., and Johnston, D. Matlab-based automated patch clamp system for awake behaving mice. J. Neurophysiol. 114:1331–1345, 2015.

Kalmbach, B., Johnston, D., and Brager, D.H. Cell-type specific channelopathies in the prefrontal cortex of the fmr1-/y mouse model of fragile X syndrome. eNeuro 2(6):1–21, 2015.

Kim, C.S., and Johnston, D. A1 adenosine receptor-mediated GIRK channels contributes to the resting conductance of CA1 neurons in the dorsal hippocampus. J. Neurophysiol. 113:2511–2523, 2015.

Siegel, J.J., Taylor, W., Gray, R., Kalmbach, B., Zemelman, B.V., Desai, N.S., Johnston, D., and Chitwood, R.A. Trace eyeblink conditioning in mice is dependent upon the cerebellum, amygdala, and dorsal medial prefrontal cortex: Behavioral characterization and functional circuitry. eNeuro 2(4):1–29, 2015.

Malik, R., Dougherty K.A., Parikh, K., Byrne, C., and Johnston, D. Mapping the electrophysiological and morphological properties of CA1 pyramidal neurons along the longitudinal hippocampal axis. Hippocampus 26:341–361, 2016.

Desai, N.S., Gray, R., and Johnston, D. A dynamic clamp on every rig. eNeuro 4:1–17, 2017. https://doi.org/10.1523/ENEURO.0250-17.2017

Kalmbach, B.E., Gray, R., Johnston, D., and Cook, E.P. A systems-based analysis of dendritic nonlinearities reveals temporal feature extraction in mouse L5 cortical neurons. J. Neurophysiol. 117:2188–2208, 2017.

Malik, R., and Johnston, D. Dendritic GIRK channels gate the integration window, plateau potentials and induction of synaptic plasticity in dorsal but not ventral CA1 neurons. J. Neurosci. 37:3940–3955, 2017.

Routh, B.M., Rathour, R.K., Baumgardner, M.E., Kalmbach, B.E., Johnston, D., Brager, D.H. Increased transient sodium conductance and action potential output in layer 2/3 prefrontal cortex neurons of the fmr1-/y mouse. J. Physiol. 595:4431–4448, 2017.

Siegel, J.J., Chitwood, R.A., Ding, J.M., Payne, C., Taylor, W., Gray, R., Zemelman, B.V., and Johnston, D. Prefrontal cortex dysfunction in Fragile X mice depends on the continued absence of Fragile X Mental Retardation Protein in the adult brain. J. Neurosci. 37:7305–7317, 2017.

Kim, C.S., Brager, D.H., and Johnston, D. Perisomatic h-channels regulate depressive behaviors following chronic unpredictable stress. Molec. Psych. 23:892–903, 2018.

Arnold, E.C., McMurray, C., Gray, R., and Johnston, D. Epilepsy-induced reduction in HCN channel expression contributes to an increased excitability in dorsal, but not ventral, hippocampal CA1 neurons. eNeuro 6:1–22, 2019.

Baowang, L., Routh, B.N., Johnston, D., Seidemann, E., and Priebe, N.J. Voltage-gated intrinsic conductances shape the input-output relationship of cortical neurons in behaving primate V1. Neuron 107:185–196, 2020.

Brandalise, F., Kalmbach, B.E., Mehta, P., Thornton, O., Johnston, D., Zemelman, B.V., and Brager, D.H. Fragile X mental retardation protein bidirectionally controls dendritic Ih in a cell-type specific manner between mouse hippocampus and prefrontal cortex. J. Neurosci. 40:5327–5340, 2020.

Kim, C.S., and Johnston, D. Antidepressant effects of (S)-ketamine through a reduction of hyperpolarization-activated current Ih. iScience, 2020. https://doi.org/10.1016/j.isci.2020.101239

Gray, R., and Johnston, D. Sodium sensitivity of KNa channels in mouse CA1 neurons. J. Neurophysiol. 125:1690–1697, 2021. https://jneurophysiol.podbean.com/e/sodium-sensitivity-of-kna-channels-in-mouse-ca1-neurons

Routh, B., Brager, D.H., and Johnston, D. Ionic and morphological contributions to the variable gain of membrane responses in layer 2/3 pyramidal neurons of mouse primary visual cortex. J. Neurophysiol. 128:1040–1050, 2022.

Mu-ming Poo

BORN:

Nanjing, China

October 31, 1948

EDUCATION:

Tsinghua University, Taiwan, Physics (1970)

Johns Hopkins University, PhD, Biophysics (1974)

APPOINTMENTS:

Postdoctoral Fellow, Purdue University (1974–1976)

Assistant, Associate, Full Professor, University of California, Irvine (1976–1985)

Professor of Research, Yale University School of Medicine (1985–1988)

Professor of Biological Sciences, Columbia University (1988–1995)

Stephen Kuffler Professor of Neurobiology, University of California, San Diego (1996–2000)

Professor of Neurobiology and Paul Licht Distinguished Professor in Biology, University of California, Berkeley (2000–2014)

Professor in Biology Emeritus, University of California, Berkeley (2015–present)

Founding Director (1999–2019) and Scientific Director (2020–present), Institute of Neuroscience, Chinese Academy of Sciences, Shanghai

Director, Shanghai Center for Brain Science and Brain-Inspired Technology (2019–present)

HONORS AND AWARDS:

Member, Academia Sinica. Taiwan (2000)

Fellow, American Association for Advancement of Science (2001)

Ameritec Prize for Paralysis Research (2002)

Docteur Honoris Causa, Ecole Normale Supérieure, Paris (2003)

P.R. China International Science and Technology Cooperation Award (2005)

U.S. National Academy of Sciences, member (2009) and international member (2018)

Qiu-shi Distinguished Scientist Award, Hong Kong (2010)

Chinese Academy of Sciences, foreign member (2011) and regular member (2018)

Docteur Honoris Causa, Hong Kong University of Science and Technology (2014)

Founding Member, Hong Kong Academy of Science (2014)

Gruber Neuroscience Prize recipient (2016)

Inaugural Sherrington Lecture, Oxford University (2018)

Stephen Kuffler Lectures, University of California at San Diego (2018)

Docteur Honoris Causa, Claude Bernard University of Lyon (2019)

Mu-ming Poo began his research as a biophysicist studying protein mobility in cell membranes and receptor localization mechanisms during synaptogenesis. He later developed a method for assaying axon growth in response to guidance factors in vitro and showed that the attractive vs. repulsive growth cone turning induced by a guidance factor depends on the internal cyclic nucleotide concentrations. He also studied the role of neurotrophins and electrical activity in synaptic plasticity and characterized the time window for spike timing-dependent plasticity. His recent interest is to use nonhuman primates to study cognitive functions and brain disorders.

Mu-ming Poo

My Family

My family belongs to a subgroup of Han Chinese known as “Hakka,” or guest families, who migrated in ancient times from the Yellow River basin to Southern China as a result of wars and famines. The ancestors of the Poo family settled in a village known as Sanheba (three-river village) in eastern Guangdong providence. The Mei-jiang River flows south from Sanheba to the South China Sea through the port city of Shantou, where many Chinese immigrants embarked on their journeys to Southeast Asia. My grandfather was a boatman on a barge used to transport goods along the Mei-jiang River. He lost his life during a typhoon season, leaving my grandmother and five children. Grandmother made a meager living by selling vegetables grown in the family farm, and with the help of relatives, managed to send the kids one-by-one to attend schools in Shantou. Remarkably, all five children eventually received a college education. My father was the third child, and he was helped throughout his school years by his big brother, a self-made man who worked his way to become a high-ranking official in the provincial government.

My father Liang-shao Poo attended an elite Zhongshan High School in Guangzhou and graduated from Jiaotong University in Shanghai in 1938, with a degree in aeronautical engineering. He joined the Chinese Air Force, along with many of his classmates, at the outbreak of the Sino-Japanese war. My uncle Liang-lou Poo graduated from the Chinese Air Force Academy and became a fighter plane pilot. During a social gathering, my uncle Poo introduced my father to a pilot friend’s sister Shou-yu Li, who later became my mother. In 1943, my father was sent by the Chinese government to the United States for advanced studies in aeronautical engineering. He spent two years in the Brooklyn Polytechnic Institute in New York, obtained a master’s degree, and received two more years of practical training in the U.S. aero-industry before returning to Nanjing in 1947 to take a job in an Air Force factory producing propeller engines. Under the order of the Nationalists government, he left with the factory to Taiwan before I was born on October 31, 1948, in Nanjing’s Air Force Hospital, under candlelight during a power outage. The light came back soon after I was delivered. The doctor suggested that I should be named “light” (ming). I was thus named Mu-ming, with “mu” (meaning “admire”) the family middle name. Two months later, as Mao’s People’s Liberation Army was approaching Nanjing, my mother carried me in her arms and, together with my sister and grandmother, boarded an overcrowded boat from Nanjing up the Yangtze River to Wuhan, where they managed to get train tickets to Guangzhou and then a ship to Taiwan.

The family settled in a small coast town Qingshui in central Taiwan, where my father was appointed as the head of an airplane engine factory. He was a diligent and austere manager at work and a strict father at home. I was greatly influenced by his strong self-discipline and work ethic. I recall that he was always working at the desk in the evenings, correcting proofs of Chinese translations of engineering manuals for his factory workers. He once taught me how to use a slide rule he had kept since his student days, but I never found a chance to use the skill. My mother had a college-level education but did not have her own job. She kept the family in good order. I excelled in a local primary school and was later accepted into the Taichung City’s First Middle School for six years of middle school education. The school had an excellent library, with a large collection of ancient and modern Chinese books, from which I developed a strong interest in literature and history. To borrow books from the library, we searched for books in a catalog in the library hall and sent in a slip with the priority list to the staff for fetching the books from the storage room. I still have vivid memories of the face of a female staff, with her smiling and sometimes suspicious looks at me, a kid with a head barely reaching the check-out counter in the beginning, who grew into a tall young man in six years.

I had two siblings, an elder sister Mu-rong (Alice P. Lin) born in Chengdu during wartime, and a younger brother Mu-chou born in Taiwan. Mu-rong had a strong influence on my intellectual development; she had a literary bend and bought most of the books in the family. She later received a doctoral degree in social work from University of Michigan, had a distinguished career in public health, and once served as the deputy mental health commissioner for New York State during Mario Cuomo’s administration. She died in 2014 of ovarian cancer. My brother Mu-chou received his doctorate in Near Eastern Studies from Johns Hopkins University. He excelled as an Asian scholar specializing in Egyptology and comparative ancient history. He is still teaching in the History Department of the Chinese University of Hong Kong. I was married in 1974 to Wen-jen Hwu, a chemist-turned-oncologist specializing in melanoma treatment who worked for many years at the MD Anderson Cancer Center. We divorced in 1994. Wen-jen and I have two daughters, both born in the United States. Ai-jen graduated from Columbia University with a major in women’s studies, and she became an accomplished labor organizer. She is now the president of the National Domestic Workers Alliance and director of Caring Across Generations. Ting graduated from Barnard College majoring in film studies and has a successful career as an editor and director of documentary films, with an Oscar-winning record. I remarried in 2003 to Yang Dan, a former student at Columbia who became a distinguished neurobiologist in systems neuroscience and sleep research. Yang has been a close partner in my scientific journey over the past two decades.

Studying Physics at Tsinghua University

When the time came for my college education, I followed my father’s advice and entered the Department of Nuclear Engineering at Taiwan’s Tsinghua University in 1966. This was my top choice at the time, because nuclear energy appeared to be a thing of the future, and Taiwan was planning to build its first nuclear power plant. However, I realized during my freshman year that I should learn more basic physics for my college education, so I applied to be transferred to the Physics Department. Unsatisfied with the way physics was taught by young instructors who mostly read their lecture notes, my fellow student Wu (Alex) Chao and I decided to learn physics ourselves by studying Richard Feynman’s Lectures on Physics. Alex was much better at understanding the material, and catching up to his pace was my daily goal. Alex later became a distinguished accelerator physicist at Stanford and once headed the theory division for the ill-fated superconducting supercollider. Overall, my best physics education at Tsinghua was studying the three volumes of the Feynman Lectures with Alex Chao.

One late winter night in 1968, while passing through the library hall, I noticed James Watson’s Double Helix in the new book exhibition window. Having heard of Watson and Crick’s Nobel Prize work on DNA structure, I was the first to check out that book. It was the first science book that struck my fancy. I learned how great science was done and how it could be such an exciting adventure. In the early summer of 1968, a physics professor Yi-yan Lee called me into his office. He had received an invitation from the Hsu Foundation in Hong Kong to help launch a publishing project in Taiwan—translation of popular science books from English into Chinese. The first book he selected was George Gamow’s Mr. Tompkins in Wonderland, a book on discoveries in modern physics that Mr. Tompkins learned in his dreams. Lee said that since I had learned some physics and seemed to be good in English, I should translate the book into Chinese, with the condition that it had to done by the end of summer. I took the job with trepidation. It was quite difficult for a 19-year-old kid to miss all the summer vacation fun with friends and spend 10 hours a day at the desk for three months. I did finish the job by the end of the summer, with some help from my friends Alex Chao and Ning Hsieh. When the next summer came, Lee handed me two volumes of a book on Interesting Experiments to translate, a manual for middle-school kids to do physics and chemistry experiments at home, using readily available household materials. All three books were published by the Hsu Foundation during 1968–1969. Gamow’s book was reprinted many times in Taiwan and was on the recommended summer reading list for high-school students for many years. When Gamow’s book was ready for publication, I wrote to Professor Gamow, who lived in Colorado then, requesting a preface for the Chinese version of his famed book. Sadly, I received a reply from Mrs. Gamow saying that he had passed away earlier that year. My translation work had earned me a handsome fee that allowed me to buy a good-quality used violin made in Czechoslovakia. The real benefit, as I realized later, was the cultivation of self-discipline. I had no problem later in life to work at the lab bench for long hours. By translating Interesting Experiments, I probably also developed a knack for doing experiments with simple means and making usable gadgets from junk materials in the lab, a skill that facilitated the pace of my doctoral research.

Graduate Studies at Johns Hopkins

After one year of compulsory military service as an instructor in the Taiwanese Army, I arrived in Baltimore in late August of 1971 for graduate studies in physics at Johns Hopkins University. I was greatly impressed by the beautiful Homewood campus and the high-quality physics faculty, but was immediately stressed by the duties of being a teaching assistant for Physics 101. With an English proficiency barely sufficient for conducting a conversation, I had to stand in front of a group of students to answer questions about lecture materials and course assignments. The first-year graduate courses in quantum mechanics, classical electrodynamics, and linear algebra were no less demanding. When the spring term arrived, I applied to take the doctoral qualifying examination. This was quite unusual at the time, because most students took the qualifying exam after a few years into their doctoral thesis work. Nevertheless, my request was granted. The exam consisted of a series of meetings with individual faculty members, answering questions in various areas in physics, and ended with a general oral exam in front of a group of professors. Many questions were quite unexpected. For example, would a large ball and a small ball fall to the ground at the same time if the Pisa Tower were filled with oil? How do you calculate the true position of a star, given light refraction by the atmosphere? What is the chance of hitting a tree if you fire a bullet into the forest? I soon found out that the examiners just want to know how I thought through the problems rather than the answers, because I was often stopped half-way into my calculations.

The Hopkins’ Physics Department had a nice tradition of allowing graduate students to do their thesis work with any faculty member on campus. After passing the qualifying exam, I began to think about potential thesis projects. Having read Watson’s story of DNA structure, I thought X-ray crystallography may be a good choice. On an early spring day in 1972, I ventured into the office of Warner Love, then chair of the Jenkins Department of Biophysics and a crystallographer, and asked for his advice. He pulled out a reprint from his drawer, a paper by Francis Crick on the solution of helical structure using X-ray diffraction data, and asked me to read it and come back to talk afterward. I read the paper loaded with Bessel functions and found it rather boring. Instead of going back to Professor Love, I began sitting in on a course on General Physiology given by a biophysicist Richard Cone. I found the lectures fascinating—how complex physiological processes could be understood with simple physics and mathematics. After the course was over, I asked Richard whether I could work in his laboratory during the summer, and he kindly agreed. When the summer ended, my lab work was satisfactory enough for Richard to take me on as a graduate student.

Richard was a brilliant physicist-turned-biophysicist. He gained an early fame for dissecting the cellular origin of early receptor potentials in the electroretinogram. When I joined his laboratory in the fall of 1972, he was working on two problems. First, to find evidence for the “calcium hypothesis of phototransduction”—light activation of rhodopsin in the disk membrane of photoreceptors causes calcium release from the discs, which in turn induces a photoceptor potential by blocking sodium channels in the plasma membrane. Although I did not participate in the phototransduction work, I was exposed to the exciting atmosphere and intense competition among the labs of Richard Cone, Bill Hagins, and others. Several years later, the “internal transmitter” turned out to be cyclic guanosine monophosphate (cGMP), a rather unlikely candidate at the time. The second area Richard worked on—rhodopsin mobility within the disk membrane—brought him the greatest glory. It was a time when membrane biology was undergoing a mini-revolution as people realized the fluidity of cell membranes. In an elegant experiment, Richard showed that rhodopsin undergoes rapid rotational diffusion in the photoreceptor disc membrane, suggesting a local membrane viscosity of about 1 poise (Cone, 1972).

After joining Richard’s lab, I was assigned the job of finding out whether rhodopsin could diffuse laterally in the disc membrane and, if so, whether the bulk membrane viscosity experienced by rhodopsin’s lateral movement is the same as that reported by its local rotational motion. Richard suggested a conceptually very simple experiment: bleach isolated a rod photoreceptor outer segment on one side to create a gradient of unbleached rhodopsin molecules in the plane of disc membranes, which were all aligned perpendicularly to the rod axis. Then, by measuring the rate of redistribution of rhodopsin absorbances between the bleached and unbleached sides, I could determine rhodopsin’s translational diffusion coefficient. It took me a few weeks to build a small motor-driven gadget that could be fitted into the cavity of a microspectrophotometer. The 1- to 2-μm slit for the bleaching and measuring light was formed by the edges of two razor blades and focused through an objective lens onto the photoreceptor outer segment. Alternating absorbance measurements on two sides of the outer segment was made simply by motor-driven movements of a tilted glass slide in and out of the light beam. Within a few months, I obtained convincing evidence for rapid lateral redistribution of bleached and unbleached rhodopsin molecules in the disc membrane.

To deduce the diffusion coefficient of rhodopsin molecules from the rate of their redistribution was not straightforward, because the disc membranes have many deep fissures that impose complex boundary conditions for rhodopsin diffusion. My math friend told me that an analytical solution of a diffusion equation for such complex geometry would be a nightmare, and this was a time before one could perform Monte Carlo simulations of diffusion processes using a desktop computer. Eventually, I got around this problem by performing an “analog” computation—assessing the effect of similar fissures on the rate of heat diffusion in metal discs, after one side of the disc was dipped quickly into hot water. Because heat diffusion and molecular diffusion follow the same equation, I could directly measure the effect of disc geometries on the rate of heat diffusionas compared with the rate in a disc with analytically solvable geometry. I thus deduced the lateral diffusion coefficient of rhodopsin in the frog photoreceptor disc membrane to be 3.5 ± 1.5 cm²/s. Based on the Stokes–Einstein equation, the bulk viscosity of the cell membrane experienced by rhodopsin was about 1 poise (Poo and Cone, 1974), the same as that found by Richard for its rotational diffusion. This diffusion coefficient for rhodopsin later became the benchmark value for “free” lateral diffusion of membrane proteins, because there is no apparent cytoplasmic constraint on rhodopsin’s motion. In the absence of a bleachable chromophore like that in rhodopsin, the photobleaching method was later used for measuring diffusion of membrane proteins with fluorescent ligands attached. Fluorescence recovery after photobleaching (FRAP) is now a standard method used to study protein diffusion in cells.

I gave my doctoral thesis defense in December 1973 to a committee assembled by the Physics Department, with some biologists as members. This was about two and half years since I began my graduate study at Hopkins. A clear downside of such a short duration was the lack of extensive graduate training in either physics or biology, and I had no idea about what to do after receiving my degree. Nevertheless, despite my short stay in his lab, Richard Cone had a profound influence on the taste and style of my later research—to ask important questions and use the simplest experimental approach to answer them. Quick and simple approaches often yield insight upon which more sophisticated experiments and analysis can be developed later.

Searching for Exciting Biology at the Marine Biological Laboratory

When the summer of 1974 came, Richard suggested that I should go to the Marine Biological Laboratory (MBL) in Woods Hole to get a better feeling about what’s exciting in biology before deciding what to do for my postdoc. Alan Fain kindly accommodated me in his newly established lab in MBL, and Ann Stuart from Harvard also offered me an opportunity to learn electrophysiology in her summer MBL lab. For three intense months at MBL, I spent most mornings sitting in the lectures of summer courses in neurobiology and physiology. I attended a memorable, and probably last, lecture by Kenneth Cole on his invention of voltage clamp and John Dowling’s lively physiology lectures, in which he drew the entire gut system on the board in seconds with chalk in both hands. Most afternoons I worked in Ann’s laboratory, learning how to pull glass microelectrodes, make intracellular recordings from the axon of barnacle ventral eye photoreceptors, and measure their membrane properties that might account for the spread of photoreceptor potentials along the long axon. One late evening, while I was concentrating on the complicated barnacle dissection under dim red light, an old man came to the lab. He looked over my shoulder and asked a few questions, to which I did not reply with much attention. Sensing my unresponsiveness, he soon left. The next morning, I asked Ann about this old man, and Ann said “Oh, that must be Steve.” This was the only time in my life that I could have talked with the great Stephen Kuffler, and I missed it!

Lab work was only a small part of life at MBL. In the evenings, there were always seminars and lectures in all fields, accompanied by lively exchanges. Thursday night seminars were mostly neurobiology related, often on unpublished results fresh out of the laboratory. Friday Evening Lectures were my favorite, because they were grand summaries of the scientists’ lifelong work presented in a way understandable by an audience from diverse backgrounds. All these wonderful talks left me with the impression that biology is full of fascinating topics for young budding scientists to work on, but I still did not get a clear sense about what I should pursue. One afternoon near the end of the summer, I wandered through a new book exhibition in Lilly Hall and spotted a book On Development by J. T. Bonner, just published by Harvard University Press. I bought the book and read it in a few days. Bonner described the problem of development in two perspectives: an evolutionary view of development (later known as “evo-devo”) and a molecular view on how newly synthesized materials could be localized in the developing system. I was greatly attracted to a section on localization mechanisms, in which he cited extensively the work of Lionel Jaffe, who showed that physical forces—light, gravity, pH gradient, and electric field—could polarize rhizoid outgrowth from a fertilized fucus egg, leading to polarized root/stem development of this brown alga. I was particularly fascinated by many of Jaffe’s simple and elegant experiments. For example, to demonstrate the appearance of endogenous electric fields associated with polarized development, he piled a string of fertilized fucus eggs in a thin capillary tube, applied light from one end to polarize their development, and detected an emerging potential difference between two capillary ends with a voltmeter. Studying the role of physical forces in development sounded like an interesting area to work on. I soon applied to Lionel Jaffe for a postdoc position at Purdue University and was quickly accepted. Two decades later, when I reflected on how accidental reading of his book had started my research in developmental neurobiology, I wrote a letter to Professor Bonner, then retired from Princeton, thanking him for writing the book. He kindly replied with his characteristic modesty.

Postdoctoral Research at Purdue University

Lionel Jaffe was the most focused and dedicated researcher I have ever met. Trained at Caltech in the early 1950s, he spent his entire scientific career trying to figure out the mechanism that polarizes a fertilized fucus egg. Most interestingly, he found that an endogenous transcellular current appears during the polarization process—positive ions flow into the budding rhizoid and out of the other end of the egg. He thought that this current was responsible for driving the polarized movements of cytoplasmic substances. A relatively steady extracellular field around the polarizing egg due to the transcellular current was detectable with a vibrating platinum electrode. After arriving at West Lafayette, I began to use the “vibrating probe” to search for the existence of endogenous currents associated with neurite outgrowth in cultured neurons. The neurite’s growth cone, however, is one hundred times smaller than a fucus egg, and the electrode became too noisy when its size was greatly reduced. After many months of technical work without avail, Lionel suggested that I reinvestigate whether applied electric fields could polarize neurite outgrowth—along the line of research on “galvanotropism” in the 1920s. The early findings of nerve galvanotropism were later discredited by Paul Weiss, who argued that the effect was indirectly induced by mechanical guidance of the plasma clots in the culture substrate that became oriented by the applied field. My new task was to see whether the electric field could orient nerve growth in a liquid culture medium. I soon found that extracellular electric field could indeed accelerate neurite growth and bend them toward the cathodal pole of the field.

Given my interest on membrane protein mobility, I thought that an electric field could polarize the distribution of growth-relevant membrane proteins by “electrophoresis.” However, growth cones of the chick neurons I was using were too small for mapping protein distribution. I then noticed a paper published by Nick Spitzer on cultured Xenopus spinal neurons and myocytes (Spitzer and Lamborghini, 1976), which are much bigger than chick neurons. I wrote to Nick for help, and he graciously invited me to visit his lab in La Jolla to learn the culturing method. It was late spring of 1976. Young faculty members Nick Spitzer and Darwin Berg, fresh out of Steve Kuffler’s neurobiology department, were setting up a vibrant neurobiology community on the Pacific Coast. I spent three days in Nick’s lab, watching him making cultures on a simple lab bench, recording from single neurons in culture and in Xenopus larvae, and shouting with excitement whenever he got a cell. The lab atmosphere was drastically different from what I had experienced in the east. There was more fun and less inhibition. This impression must have influenced my decision to move to La Jolla two decades later.

After returning to West Lafayette, I began to study the effect of electric fields on membrane protein distribution in large cultured myocytes, together with Ken Robinson, another postdoctoral fellow in the Jaffe lab. We decided to focus on a heterogenous group of membrane glycoproteins that bind to the lectin concanavalin A (Con A), which could be covalently labeled with a fluorescent ligand. We soon obtained convincing evidence of electric field-induced redistribution of Con A receptors in the myocyte membrane. We found marked accumulation of Con A receptors on the side of the myocyte facing the cathode within 30 min after applying a field of about 10 mV across a 10-μ-wide cell. We reported the results in an experimental paper (Poo and Robinson, 1977), with an accompanying paper on the theory of electrophoresis in membranes by Jaffe (1977). In the meantime, I also found that a steady electric field could strongly bias the direction of growth cone extension of Xenopus spinal neurons toward the cathode. The latter phenomenon was thoroughly examined by my graduate student Nilesh Patel a few years later (Patel and Poo, 1984).

University of California at Irvine

After two years of postdoctoral work in the Jaffe lab, I was expected to leave and find a faculty position. I applied for positions in a few universities and eventually received an offer of assistant professorship from the University of California–Irvine (UC Irvine) Physiology Department. Arriving in Irvine in the fall of 1976, I was given a small lab of about 200 square feet and $20,000 of start-up funds, which allowed me to buy a used Zeiss microscope, a Getting preamplifier, and a pair of micromanipulators.

Synaptic Clustering of ACh Receptors

With a humble beginning and diligent work by my first graduate student Normal Orida, we showed that steady extracellular electric fields could induce electrophoretic accumulation of surface nicotinic acetylcholine receptors (AChRs) on cultured myocytes and that accumulated receptors formed stable clusters without post-field back diffusion (Orida and Poo, 1978), suggesting an intrinsic propensity of AChRs for self-aggregation. We also made quantitative studies on electrophoretic and diffusion processes of other membrane proteins and lipids (Poo, 1981). By this time, I began to realize that a more biologically relevant problem was not how mobile membrane components are, but rather how they become localized in the membrane to perform their biological functions. Synaptic physiologists had long been interested in understanding how AChRs become clustered at postsynaptic muscle membrane during the formation of neuromuscular junctions. Two possibilities were then proposed: newly synthesized receptors in the cytoplasm are locally inserted into the postsynaptic membrane, or alternatively, initially randomly inserted receptors redistribute themselves through lateral diffusion and become trapped at the synaptic site by binding to some aggregation-inducing locally secreted factors (named “agrin” or ARIA). Monroe Cohen and Christian Anderson at McGill University found that AChRs tagged with fluorescent α-bungarotoxin are initially dispersed in cultured Xenopus myocyte membrane, but became clustered to the site of neurite contact within an hour after the contact. Measurements with FRAP on α-bungarotoxin-labeled AChRs yielded a diffusion rate too slow to account for the neurite-induced AChR clustering, possibly because of the impediment by the bulky fluorescent tag on AChRs. How could one measure the diffusion of native AChRs without a fluorescent tag? This problem puzzled me for some time. During one sleepless night lying in bed, a simple idea jumped to mind—just locally inactivate some surface AChRs with α-bungarotoxin and monitor the recovery of local ACh sensitivity by iontopheretic application of ACh pulses, as native functional AChRs diffuse into the inactivated area. I did the experiment next morning, and it worked beautifully. Within a few weeks, enough data were collected to show that the diffusion rate of native AChRs is much faster than that based on FRAP measurements, and it is sufficient to account for AChR clustering through lateral redistribution (Poo, 1982). In later years I always hoped that sleepless nights would bring some useful thoughts, but that rarely happened!

Transmitters Secretion from Growth Cones

In the early 1980s, the appearance of gigaohm-seal patch clamp method allowed measurements of single-ion channel currents in membrane patches excised from cells. At the time, a talented physiologist, Steve Young, joined my lab for postdoctoral research, and he built a patch clamp amplifier by following the circuit diagram and specifications described in the paper published in Pflugers Archiv by Hamill et al. (1981). Using this patch clamp, Steve did two interesting experiments. First, by on-cell patch recording from cultured myocytes, he showed that AChRs in the electrophoresis-induced clusters in the myocyte membrane had a longer mean channel opening time than those dispersed in the same membrane (Young and Poo, 1983a), indicating that ion channel properties depend on their state of clustering and probably the local lipid environment. The second experiment was more novel. Using an outside-out patch of myocyte membrane as a “sniffer” for ACh, which activates single ACh channels in the patch, Steve found that the growth cone of Xenopus spinal neurons spontaneously secretes pulses of ACh. A few weeks later, we heard from people returning from the Society for Neuroscience Annual Meeting that Gerald Fischbach announced in a lecture during the meeting that his lab had discovered ACh secretion from the growth cone of cultured sympathetic neurons, using the same approach. I immediately called Gerald about our finding, and we agreed to coordinate the publication of the results, which appeared in two back-to-back papers in Nature a few months later (Hume et al., 1983; Young and Poo, 1983b). The significance of growth cone secretion of transmitter before synaptogenesis, however, remains unclear. It could be a signal broadcast by the growth cone to its environment for some purpose, or just a by-product of exocytotic insertion of new membrane materials during nerve growth. Nevertheless, it indicates that the growth cone is ready to serve presynaptic functions, because firing the neuron could evoke Ca²⁺-dependent ACh secretion from the growth cone (Sun and Poo, 1987).

Visits to Pasadena

Some of most memorable events during my Irvine period were associated with my trips to Pasadena, mostly to visit Chun-fang Wu, then a postdoc fellow in Seymore Benzer’s lab at Caltech, whom I befriended during my Purdue days. Chun-fang and I met often during weekends in either Irvine or Pasadena to do fun experiments together. In one weekend, we devised a trick to dissociate and culture embryonic ganglionic neurons from third-instar Drosophila larvae with minimal damage to these small fragile cells (Wu et al., 1983), a method that became useful later for single-channel recording from Drosophila neurons. When I first met Seymore Benzer in his Caltech lab, our in situ electrophoresis papers had just appeared. The first thing Benzer said when he saw me was to point to these two articles and ask, “Is this real? Did you check Jaffe’s math?” Seymore did not take for granted any published results, and he himself published very little. I learned from Chun-fang later that every paper from Benzer’s lab was meticulously written and scrutinized before submission—people in the lab had to sit around a table for hours to go through every sentence of the paper, including those who were not coauthors. My last encounter with Seymore was in the 2004 Society for Neuroscience dinner reception honoring him as the first Gruber Prize recipient. During my brief talk as a member of the Prize Committee, he was visibly pleased by my comment that his paper-writing ritual was in active practice in my Institute of Neuroscience (ION) in Shanghai. Unfortunately, this writing ritual did not persist at ION. Fast publication without much concern about the quality of writing has become an overwhelming trend.

In his later years at Caltech, Max Delbruck became interested in membrane protein mobility. Together with a mathematician Philip Saffman, he published a modeling paper in which the membrane protein is depicted as a cylinder spanning the lipid bilayer and diffuses in an isotropic medium of a defined viscosity. This model nicely predicted the relationships between the rates of rotational and translational diffusion of rhodopsin that Richard and I had measured. The Saffman-Delbruck (1975) model later became the basis of many theoretical studies of protein mobility in cell membranes and lipid bilayers. When our work on in situ electrophoresis of membrane proteins appeared in 1977, he invited me to give a talk in his biophysics seminar series. His enthusiasm in talking about science remained high, despite his deteriorating health. I talked with him in his office before the seminar and was quite moved when he started making calls to remind people about the seminar. The talk did not go smoothly because of Max’s frequent interruptions. Nevertheless, I was congratulated afterward by Lily Jan, then a postdoc fellow in the Benzer lab, for being able to finish the talk. Max’s interest in Brownian motion in cell membrane was probably related to his thinking on the reduction of dimensionality in biological diffusion processes. In an article published several years earlier (Adam and Delbruck, 1968), he put forth the idea that for a soluble substrate to reach its membrane-bound enzyme, it could first bind nonspecifically to the membrane surface and then diffuse on the surface until it found its target. He proposed that three-dimensional (3D) diffusion in solution coupled with two-dimensional (2D) diffusion on the membrane could make the target searching more efficient than the direct search by 3D diffusion alone. Back in Irvine, Mike McClosky and I were intrigued by this idea, began to gather the relevant data, and tried to determine whether the two-step process could be advantageous in various membrane-associated reactions. Unfortunately, we found that available data on lateral diffusion rates in membranes, membrane-substrate affinities, and the endogenous concentrations of enzymes and their aqueous substrates did not support the hypothesis (McCloskey and Poo, 1986).

Teaching in Postcultural Revolution China

I flew to Beijing on a cold December night in 1981, 33 years after I was carried by my mother to Taiwan. Through deserted and dimly lit streets, I was taken to the guesthouse of Beijing Medical College. Over the following month, I gave an intensive course for medical school instructors on cellular neurophysiology and membrane biology. This was part of an exchange program between Beijing Medical College and UC Irvine. The Chinese Ministry of Health had selected 40 basic science instructors from various medical schools for a month-long course. Most students in the course were older than me and had apparently suffered from a lack of academic activity due to the Cultural Revolution. Each day, I gave two to three hours of lectures in the morning and a research seminar in the afternoon on my own research or topics close to my interest. The students were eager to learn and very attentive in taking notes, but asked very few questions. My teaching activity in China continued in the following two summers, including a three-week membrane biophysics course in 1983 at Tsinghua University in Beijing for more than 200 students from many universities, and a two-week biophysics workshop in 1984 for 20 students at Nankai University. The Nanki workshop included laboratory sessions, in which the participants assembled a patch clamp amplifier and made the first single-channel recording in China, using cultured Xenopus myocytes.

The normalization of U.S.-China diplomatic relationship in 1979 was followed by active academic exchanges. Among the first group of scholars visiting the United States was a physicist, Nan-ming Zhao, from Tsinghua University, who spent a year at my Irvine lab in 1979 to learn membrane biophysics. Nan-ming often chatted with me about his self-appointed mission of restoring the Biology Department in Tsinghua. In the early 1950s, there was a massive reorganization of Chinese universities following the Soviet model. All of Tsinghua’s science and humanity departments were moved to Peking University, making Tsinghua a pure engineering school. In June 1983, Tsinghua decided to restore the School of Science and approved Nan-ming’s plan of establishing a new biology department, together with his proposal that I serve as the chair. I agreed to serve on a part-time basis, leaving daily administrative work to Nan-ming. With the first class entering in the fall of 1985, the immediate task was to establish the curriculum, recruit teaching faculty, and set up teaching laboratories. However, it was nearly impossible to begin any research program, because the funding could barely cover the staff salary and teaching expenses. Feeling powerless to make useful contributions, I resigned from the position after two years, but have kept my Tsinghua connection since then. A brilliant student in the first class of 1985, Yi-gong Shi later became a distinguished structural biologist at Princeton. He returned to Tsinghua in 2005 to lead Tsinghua’s School of Life Science, which is now ranked among the top few in China.

Yale Medical School

While the research in my Irvine lab was making good progress, I had the unsettling feeling that I had not landed on an important problem. Sometime in 1984, Chuck Stevens came to Irvine to review the campus programs and mentioned his plan of setting up a Molecular Neurobiology Section at Yale, focusing on structure-function studies of ion channels that incorporate the latest molecular cloning and single-channel recording technologies. I thought more about this exciting area and called Chuck a few days later to ask about the possibility of joining his section. Chuck was enthusiastic about the idea but mentioned that he only had a nontenured research professorship to offer. Because I was already a tenured professor at Irvine, going to Yale would mean giving up a safe and comfortable job. Against the advice of some of my friends, I took the risky route to the east in the spring of 1985. The Molecular Neurobiology Section of Yale Medical School occupied a wing of the Tompkins Memorial Pavilion of Yale Hospital. The space given to the section was extremely small, with each laboratory occupying no more than a few hundred square feet. Chuck joked about the benefit of working in tight space—people are forced to get along with each other and to interact frequently. Indeed, during my three years at Yale, I had collaborated with Susan Amara, Michael Lerner, Steven Smith, and JoAnn Buchanan. Although not all work reached fruition, these collaborations greatly expanded my research interests.

Early Events of Synaptogenesis

Our finding of spontaneous ACh secretion from growth cones suggests that they are quite ready to serve presynaptic functions, and synaptogenesis could be a rapid event. After arriving in New Haven, we made intracellular recordings from cultured myocyte and waited for their contact of spinal neurons by growth cones to determine the time course of synaptogenesis. Later, we moved the loosely attached myocyte (“myoball”) with the whole-cell recording pipette (the “chopstick-meatball” experiment) into contact with a growth cone. With the precise control of the timing of nerve-muscle contact, we found the immediate appearance of both spontaneous and evoked synaptic currents, with synaptic efficacy increasing gradually over the first few minutes after contact (Xie and Poo, 1986). JoAnn Buchanan from Stephen Smith’s lab worked side by side with Yian Sun to prepare electron microscopic samples for the same nerve-muscle synapse that Yian had just recorded. They found that the early contacts capable of functional transmission were morphologically undifferentiated. It took a few hours before the emergence of anatomically recognizable synaptic structure, for example, active zone-like presynaptic specializations with vesicle clustering and postsynaptic membrane thickening associated with clusters of AChRs (Buchanan et al., 1989). Thus, anatomically undifferentiated contacts could be functionally active, and functional network activity in the developing brain could be more complex than that implied by morphologically identifiable synaptic connections.

Cell-Cell Recognition and Specificity of Synaptogenesis

Ever since Roger Sperry proposed the chemoaffinity hypothesis, synaptogenesis has been regarded as a specific process requiring matching of cell surface “recognition” molecules between pre- and postsynaptic neurons. Our results on neuromuscular synaptogenesis, however, suggest that functional synapses could be established between two cells if one could secrete transmitters and the other has transmitter receptors on the surface to respond. In fact, the hypothesized specific cell-cell recognition molecules for synaptogenesis have long been elusive, although many heterogenous surface adhesion proteins could impose some selectivity in the formation of stable contact between cells. Because transmitter receptors, transporters, and ion channels are a relatively cell type-specific group of membrane proteins for each neuron, all of them have large ectodomains for interactions with membrane proteins in the opposing cell surface. Thus, I proposed that these proteins could serve for selective adhesion and contact stabilization by interacting across the contact, and they themselves could also become trapped at the contact site for their intended functions (Poo, 1985). We made several attempts to test this hypothesis over the years, such as generating transmitter receptor ectodomain peptides to blocking selective neuronal adhesion, but we failed to obtain any convincing results.

Columbia University

My time at Yale ended abruptly in 1988, when Chuck Stevens decided to move to the Salk Institute, and the Section of Molecular Neurobiology was to be dissolved. I soon accepted a professorship offer from Columbia’s Biology Department, where Darcey Kelley, Marty Chalfie, Eduardo Macagno, and Cyrus Levinthal had established an exciting neurobiology group. Added to the attraction of Columbia was the exciting atmosphere of the Morningside campus, New York Upper Westside, and a high-rise Riverside apartment overlooking the Hudson River.

Vesicular Transmitter Secretion from Non-neuronal Cells

The advent of molecular cloning had led to the identification of many proteins associated with synaptic vesicles and presynaptic membranes. One approach to understand how these proteins work together to achieve rapid calcium-dependent vesicular secretion is to reconstitute the synaptic vesicle secretion machinery in a non-neuronal cell through step-by-step introduction of neuron-specific presynaptic proteins and assay the functional contribution of each protein. Lacking any molecular expertise, I asked Paul Greengard at Rockefeller University to collaborate on reconstituting vesicular secretion in Xenopus oocytes, which was the standard expression system for testing the function of cloned ion channels. One of my first graduate students at Columbia, Janet Alder, spearheaded the collaboration. Janet’s first experiment was to purify synaptic vesicles from the torpedo electric organ, inject them into Xenopus oocytes, and examine whether calcium-dependent secretion of acetylcholine could be detected. By expressing nicotinic AChRs in the plasma membrane of these oocytes, we could detect vesicular secretion by the appearance of events resembling miniature synaptic currents (minis). Indeed, Janet found that oocytes could show secretion of torpedo synaptic vesicles and the secretion depended on the expression of vesicle protein synaptophysin (Alder et al., 1992). Unexpectedly, another graduate student, Yang Dan, came to my office one day and showed me recordings of minis from isolated myocytes, when she loaded the whole-cell recording pipette with 1 mM ACh. Because the events were rather rare, my immediate reaction was that there must be some residual nerve terminals hidden underneath the myocyte. Yang soon came back with more recordings showing lots of minis, when ACh concentration in the pipette was elevated to 10 mM, and ACh secretion could be evoked by depolarizing the myocyte (Dan and Poo, 1992b). It appeared that cytoplasmic ACh had somehow hijacked the vesicle exocytosis pathway in the myocyte and that calcium-dependent vesicular exocytosis actually occurs in non-neuronal cells. Reconstitution of synaptic vesicle secretion could thus be accomplished in any cell type by expressing a few neuron-specific synaptic vesicle proteins that elevate the efficacy of excitation-secretion coupling. Indeed, fibroblasts loaded with ACh exhibited more efficiently evoked ACh secretion by expressing a neuron-specific isoform of synaptotagmin (Morimoto et al., 1995).

Activity-Dependent Synaptic Competition

Our studies of synaptogenesis in nerve-muscle cultures led us to the activity-dependent synaptic competition during synapse development, a problem thoroughly reviewed by Jeff Lichtman and Dale Purves in their textbook Principles of Neural Development published in 1985. They also proposed a trophic factor hypothesis—synapses compete for trophic factors secreted at the synapse in an activity-dependent manner, with active synapses taking up more factors and surviving, whereas inactive synapses are deprived of the factors and eliminated. We began the study of synaptic competition by examining cultured Xenopus myocytes that were coinnervated by axons from multiple neurons. A graduate student, Yi-juan Lo, found that repetitively stimulation of one of the coinnervating neurons resulted in the suppression of synapses made by unstimulated ones, without affecting the efficacy of the stimulated synapse (Lo and Poo, 1991). This activity-induced hetero-synaptic depression of “inactive” synapses could represent a form of synaptic competition. Yang Dan later showed that such competition was mediated by cellular processes in the postsynaptic myocyte, because iontophoretic application of ACh pulses could substitute for the active nerve terminal to suppress inactive synapses. Coactivating the presynaptic neuron could also protect the synapse from the suppression by ACh pulses, but only when the neuronal activation occurred within 10 msec of ACh pulses (Dan and Poo, 1992a). This was a clear indication of the importance of spike timing in synaptic plasticity, a theme we later studied systematically at central glutamatergic synapses.

Neurotrophins as Synaptic Modulators

For many years, the distinguished neurophysiologist Ladislav Tauc organized a yearly meeting known as “Gif Lectures in Neurobiology” at Gif-sur-Yvette in suburban Paris, a wonderful place to meet neuroscientists from diverse fields. At a dinner party during the 1991 meeting, I met for the first time Nancy Ip, then a group leader in the newly founded company Regeneron in New York. Nancy was working on the cloning and physiological studies of various neurotrophic factors and their receptors. At the end of the dinner, Nancy and I decided to collaborate on studying the potential synaptic function of neurotrophins. A graduate student, Ann Lohof, performed the experiment and found that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 indeed could markedly potentiate spontaneous and evoked synaptic currents at cultured Xenopus nerve-muscle synapses (Lohof et al., 1993). Other laboratories soon demonstrated the rapid potentiation effect of BDNF at glutamatergic synapses in cell cultures and brain slices and the requirement of endogenously released BDNF for LTP induction at hippocampal CA1 synapses. In the subsequent decade, neurotrophins and their receptors, BDNF and TrkB in particular, were shown to be involved in a variety of brain disorders. Although originally identified as factors promoting neuronal survival and growth, neurotrophins are now regarded as neuromodulators for regulating neural circuit development and plasticity (Poo, 2001; Park and Poo, 2012).

Joining the “Synapse Club”

Our findings in nerve-muscle cultures had often prompted the question of their in vivo relevance and whether the neuromuscular synapse is a good model for central synapses. The turning point was perhaps a symposium on synaptic transmission held in Sweden in 1992. I gave a talk in front of a large group of intimidating synaptic physiologists, with Paul Greengard as the session chair. At some point during my talk, I proposed that the mature neuromuscular junction represents the ultimate synapse; it has attained the most reliable and potentiated state for synaptic transmission without the need for long-term potentiation (LTP), whereas all central synapses are immature synapses trying to climb up the ladder. Thus, the neuromuscular synapse should be given an honorary membership in the exclusive synapse club. The audience responded enthusiastically, and I talked beyond the allotted time. Paul later claimed that he had to pull me away from the platform, but that was an exaggeration. Per Andersen, the grandfather of LTP, was sitting in the second row. He stood up and stretched his arm to shake my hand as I stepped down from the podium, presumably a gesture of accepting the neuromuscular junction into the synapse club.

University of California at San Diego

My introduction to neurobiology was the textbook From Neuron to Brain (1976) by Stephen Kuffler and John Nichols. Kuffler was a scientist of great vision and broad interests, and the Harvard Neurobiology Department he created was the cradle for many leading neuroscientists of our generation. His character and impact were vividly portraited in a memorial volume “Steve,” written collectively by his colleagues and students. In memory of Steve, an anonymous donor, presumably one of his Harvard progenies, established the Stephen Kuffler Chair of Neurobiology at the University of California–San Diego (UCSD). I was greatly honored to receive an offer from Nick Spitzer and colleagues to be the inaugural Kuffler Chair. I arrived in La Jolla at the end of 1995, along with a large group of graduate students and postdoctoral fellows.

Growth Cone Guidance

An initial focus of my UCSD lab was to study the chemotaxis hypothesis of growth cone guidance, proposed by Ramón y Cajal nearly a century ago. Using the growth cone turning assay developed at Columbia (Lohof et al., 1992), two of my students, Hong-jun Song and Guo-li Ming, demonstrated that a gradient of BDNF was effective in causing chemotropic turning of Xenopus spinal neuron growth cones. By further studying second messengers that could be involved in the turning response, they made a remarkable discovery—the same BDNF gradient caused repulsive rather than attractive growth cone turning, when a competitive membrane-permeable analogue of cAMP or a protein kinase A inhibitor was present in the culture medium (Song et al., 1997). Thus, the growth cone’s turning response depends on the level of cytoplasmic cAMP activity, and the attractive vs. repulsive effect of BDNF is not due to the intrinsic property of BDNF but rather is determined by the internal state of the neuron.

This was the time when the netrin and semaphorin (collapsin) families of guidance factors were identified as attractants and repellents for various types of neurons, respectively. Over a period of a few years, in collaboration with Marc Tessier-Lavigne, Christine Holt, Corey Goodman, and Lisa McKerracher, we showed that nearly all putative guidance factors could cause either attractive or repulsive turning of the growth cone, depending on the overall cytoplasmic level of either cAMP or cGMP (Song et al., 1998; Song and Poo, 2001). The magnitude of cytoplasmic Ca²⁺ gradients was also found to be critical in setting the direction of growth cone turning (Hong et al., 2000; Henley et al., 2004). These cytoplasmic second messengers are known to be downstream mediators and integrators for the effects of many extrinsic factors (e.g., cytokines, transmitters, neuromodulators, growth factors, adhesion molecules) and intrinsic factors (e.g., electrical activity) converging on the neuron. The growth cone thus integrates multiple signals received by a neuron, before its decision on attractive vs. repulsive turning in the gradient of a particular guidance factor.

There were nearly two decades of intense activity in the axon guidance field, stimulated largely by the discoveries of guidance factor families in the 1990s and findings of abnormal development of nerve connections resulting from genetic deletion or mutation of these factors. Although in vitro experiments had shown the attractive and repulsive actions of these factors when they were applied in a diffusive gradient, whether or not axon pathfinding in vivo depends on long-range gradients of secreted guidance factors remained unclear. Gradients of BDNF or netrin-1 bound to the culture substrate were shown to be equally effective as the diffusive gradient in causing growth cone turning (Mai et al., 2009), but secreted factors are unlikely to diffuse far from the secreted site because of their binding to the extracellular matrix. It is thus unclear how the spatiotemporal distribution of guidance factors within the tissue could be tightly regulated for guiding axons through the torturous terrain of the developing brain. Advances in spatial and temporal transcriptomic analysis may facilitate future studies of axon guidance in vivo, within the context of tissue morphogenesis.

Spike Timing-Dependent Plasticity

After moving to La Jolla, our study of synaptic competition was extended from cultured nerve-muscle synapses to retinotectal synapses in vivo. This transition was inspired by the work of Bill Harris and Christine Holt on the developing retinotectal system. With their help, two of my graduate students, Li Zhang and Huizhong Tao, were able to perform in vivo whole-cell recording from tectal neurons in unanesthetized Xenopus larvae and examine how retinal ganglion cell (RGC) axons coinnervating the same tectal neuron compete with one another during activity-dependent refinement of retinotectal connections. We initially had in mind the popular version of Hebb’s hypothesis that correlated firing of neurons strengthens their synaptic connections. By varying the time intervals between the spiking of RGCs and tectal cells, we hoped to quantitatively assess the extent of correlation in pre- and postsynaptic spiking required for strengthening and weakening of the retinotectal synapse. Surprisingly, our results showed that correlation is not the only factor involved. The order of spiking was critical—repetitive spiking of the RGC within ∼20 ms before the tectal cell spiking led to synaptic potentiation, but RGC spiking after the tectal cell spiking within a similar ∼20 ms interval caused synapse depression (Zhang et al., 1998). Both potentiation and depression were N-methyl-D-aspartate (NMDA) receptor-dependent, in line with an earlier finding on the induction of LTP and long-term depression (LTD) in cortical slices (Markram et al., 1997). Within the context of synaptic competition in vivo, we characterized the complete time window of spike timing-dependent plasticity (STDP). In parallel experiments, Guo-qiang Bi also found similar STDP time windows at synapses between cultured hippocampal neurons (Bi and Poo, 1998). Within a few years, STDP was found by many labs in various types of excitatory and inhibitory synapses, with some variations in the time window and amplitude of LTP/LTD (Dan and Poo, 2006; Lu et al., 2007).

Backpropagation of LTP and LTD

Perhaps the most novel finding from my laboratory at La Jolla was the backpropagation of LTP and LTD from the output synapses of a neuron to input synapses on its dendrites and to other output synapses made by its axon collaterals. This discovery began in 1997 when two unrelated threads converged in my UCSD lab. The first was my memory of Crick’s comment that the powerful “backpropagation” algorithm for training artificial neural networks is biologically implausible (Crick, 1989)—signals in real neurons propagate from dendrites to the axon, but not the other way around. The other thread was the development of the method for simultaneous whole-cell recordings from three or more interconnected neurons in hippocampal cell cultures. While searching for an interesting problem for using the multipatch recording method, it occurred to me that we could test whether synaptic modifications induced between a pair of neurons could spread to other synapses in the network. Reiko Fitzsimonds and Hong-jun Song soon discovered an extensive retrograde spread of activity-induced LTD to other synapses onto or made by the presynaptic neuron (Fitzsimonds et al., 1997). Hui-zhong Tao and Li Zhang later showed that LTP could also backpropagate, and there was no forward propagation of LTD or LTP to the output synapses of the postsynaptic neuron (Tao et al., 2000). In retrospect, there was a prelude to these findings in nerve-muscle cultures, when Sydney Cash found that presynaptic depression caused by Ca²⁺ elevation in the postsynaptic myocyte could spread to other synapses made by the same presynaptic neuron on other myocytes (Cash et al., 1996).

Our findings on the presynaptic spread of LTP/LTD did not raise much interest in the plasticity field, probably because they were found in cell cultures. It took a few years before I realized that the best place to demonstrate this phenomenon in vivo is in the retinotectal system, where backpropagation of synaptic modifications from the tectum to retina could be attributed only to the spread of signals within the presynaptic neuron rather than feedback connections. A few years later, a postdoc fellow, Julin Du, was able to show that BDNF-induced potentiation and activity-induced LTP or LTD at retinotectal synapses could indeed backpropagate through the optic nerve to cause corresponding potentiation and depression of bipolar cell synapses on retinal ganglion cells (Du and Poo, 2004; Du et al., 2009). Nevertheless, the physiological significance of this phenomenon remains unclear. Having corresponding modifications of input synapses in accordance with those occurring at output synapses of a neuron may help to achieve more efficient activity-dependent refinement of neural circuits.

Kuffler Lectures

In 1998, I initiated the annual Kuffler lectures series at UCSD, using the endowment fund associated with the Kuffler Chair. Each year, a distinguished neuroscientist was invited to UCSD for a week, during which the lecturer gave a set of three lectures to summarize his or her life’s work and interacted with neuroscience faculty and students via lab visits, luncheons, and dinners. The visit ended with a grand dinner with La Jolla neuroscience community in the Birch Aquarium at Scripps overlooking the Pacific Ocean. David Hubel, Francis Crick, and Sydney Brenner were the first three lecturers before I left La Jolla, and the Kuffler lectures continue to this day. The three lectures by Crick in 1999 were entitled: “Neuroscience: The Impact of Molecular Biology,” “Consciousness: The Nature of the Problem,” and “Consciousness: Recent Ideas and Experiments.” I made a poster for his lectures using the M. C. Escher’s lithograph Bond of Union (1956), in which two heads face each other, linked by two helical ribbons, with molecule-like spheres floating through them. I thought it symbolizes well Crick’s transition from molecular biology into the nature of consciousness. Crick must have liked the choice because he quickly accepted the poster design.

University of California at Berkeley

In 2000, I was persuaded to move my laboratory to Berkeley, where my close friend Yang Dan had set up her laboratory a few years earlier, and weekend travel became too difficult. A big attraction of the Berkeley community was the strong developmental neurobiology group consisting of David Bentley, Corey Goodman, Carla Shatz, John Ngai, Gunther Stent, and David Weisblat, and also the towering eucalyptus forest facing my office window. Joining the Berkeley faculty was also a belated consolation to my failure to get into Berkeley’s biophysics graduate program 30 years earlier.

Functional Consequence of STDP

In the Berkeley lab, we continued to study the functional implications of STDP, which could potentially encode temporal sequence information. Florian Engert, Huizhong Tao, and Li Zhang showed that after conditioning with repetitive unidirectional moving stimuli, Xenopus optic tectum neurons developed long-lasting direction-selective responses to the same stimulus used in training (Engart et al., 2002), and this was due to STDP of retinotectal synapses induced by sequential firing of RGC inputs (Mu and Poo, 2006). Moving stimuli also induced sequence firing of rat V1 neurons, and repetitive training with a moving stimulus led to the storage of the memory of sequential firing that could be retrieved by activating only neurons that fired early in the sequence during training (Xu et al., 2012). Besides temporal sequence, STDP mechanism could also help to store interval information. Guo-qiang Bi showed that a network formed by cultured hippocampal neurons could store the memory of the time interval (up to 100 ms) between two sequential stimuli repetitively applied to a neuron in the circuit. This was achieved by STDP at various synaptic sites within polysynaptic pathways, based on differential delays in polysynaptic spike propagation to specific pre- and postsynaptic cells (Bi and Poo, 1999). Mechanisms for storing temporal information over seconds and minutes remains rather elusive. Reverberative neural activity within the network could serve to store temporal information over a period of seconds, as shown by German Sumbre in zebrafish larvae. Following repetitive visual stimuli at a regular interval (up to 10 s), the optic tectum exhibited reverberating activity waves at the same interval for a brief period (up to 30 s) (Sumbre et al., 2008).

Spaced vs. Mass Learning

The Xenopus retinotectal system also allowed us to address the role of spontaneous activity in the brain. In 2003, a postdoc fellow Qiang Zhou made a serendipitous discovery. He normally used whole-cell voltage clamp recording of the tectal neuron to monitor the stability of LTP or LTD induced at retinotectal synapses by one episode of repetitive visual stimuli or by a train of theta-burst stimulation. One day somehow he switched the whole-cell recording mode from voltage-clamp to current-clamp, allowing the recorded neuron to undergo spontaneous spiking. To his surprise, normally very stable LTP and LTD found in continuous voltage-clamp mode decayed gradually within 30–60 minutes. This erasure of LTP/LTD by spontaneous activity depended on the activation of NMDA receptors, similar to that for LTP/LTD induction. However, this effect of spontaneous activity could be prevented if the single episode of repetitive stimuli was split into three episodes that were spaced a few minutes apart (while keeping the same total number of stimuli). Most interestingly, there was an optimal interval for the spaced stimulation (∼5 min in this case); spacing either too short or too long was ineffective in stabilizing LTP/LTD (Zhou et al., 2003). The advantage of spaced over mass learning is well known in memory research. This finding offers a synaptic basis for determining the optimal interval for spaced learning; it also points to a potential function of spontaneous activity—clearance of memories that are not worth keeping in the brain.

Development and Plasticity of GABAergic Transmission

A group of free-spirited students and postdocs in my lab in La Jolla and Berkeley had ventured into many problems associated with early cortical development. On some occasions, I became aware of their work only after they came to talk to me about their findings. In a memorable day in La Jolla, Karunesh Ganguly and Alejandro Schinder surprised me with the result of a very simple experiment, in which they found that GABA added to the culture of cortical neurons could speed up the developmental switch of GABA’s action from excitation to inhibition. They soon found that GABA-induced Ca²⁺ elevation in developing neurons could upregulate the expression of a K⁺/Cl⁻ co-transporter KCC2, which reduces the excitatory action of GABA by extrusion of cytoplasmic Cl⁻ (Ganguly et al., 2001).

After developmental maturation, inhibitory GABA synapses are susceptible to further activity-dependent modifications. Two postdoctoral fellows, Hubert Fiumelli and Laura Cancedda, found that repetitive postsynaptic spiking could induce LTD of GABAergic synapses, due to a Ca²⁺-dependent downregulation of KCC2 function (Fiumelli et al., 2005). High-frequency correlated pre- and postsynaptic spiking also induced LTP of inhibitory synapses, through GABAB receptor-mediated local upregulation of Na⁺/K⁺/2Cl⁻ cotransporter (NKCC1) activity that increases cytoplasmic Cl⁻ (Xu et al., 2008). Unlike local mechanisms underlying plasticity of glutamatergic synapses that involve mostly modifications of presynaptic transmitter secretion and/or postsynaptic transmitter receptors, transporter modulation will affect cytoplasmic Cl⁻ concentration over the dendritic domain beyond individual synapses. Thus, LTP/LTD induced at an inhibitory synapse could spread substantially to other inhibitory synapses along the dendrite.

Development and Maintenance of Neuronal Polarity

My interest in polarity formation in developing neurons was revived in 2008 when Maya Shelly arrived in Berkeley for her postdoctoral research. Maya proposed to study the molecular basis of axon/dendrite polarization in developing neurons, particularly the function of LKB1/STRAD complex that plays a crucial role in epithelia polarization, a subject of her doctoral studies. Using Gary Banker’s model system of isolated hippocampal neurons in culture (Banker and Cowan, 1977), Maya showed that LKB1 phosphorylation at the tip of a neurite represents a molecular determinant for axon initiation (Shelly et al., 2007). Such an event could be initiated by local exposure of the neurite to extracellular BDNF, which activates PKA by local elevation of the cAMP level in the neuron.

The mechanism of axon/dendrite differentiation must account for the Gary Banker’s observation that each cultured hippocampal neuron initially develops multiple neurites, but only one differentiates into the axon and the rest become dendrites. In 1951, Alan Turing proposed a molecular mechanism of morphogenesis in which polarized biological structure could emerge through a slow-diffusing local autocatalytic activator coupled with the generation of a fast-diffusing global inhibitor. This proposal has inspired many biological studies on the molecular mechanism underlying the polarization of cells and tissues. Our venture into the Turing mechanism began with the discovery that cAMP and cGMP, two second messenger molecules known to exert reciprocal antagonistic regulation, are involved in neuronal polarization. Sarah Heilshorn, who joined the lab to learn neurobiology before taking her faculty position at Stanford, devised a neat culture substrate with bound stripes of chemicals. Together with Maya Shelly and Byungkoon Lim, she found that locally elevated cAMP and cGMP activities in the hippocampal neurite promote its preferential differentiation into axon and dendrite, respectively (Shelly et al., 2010). Further experiments suggest that the local autocatalytic process at the growing axon could begin with a stochastic fluctuation of local cAMP or localized presence of extracellular factors (such as BDNF) that elevates cytoplasmic cAMP. This cAMP elevation could induce localized BDNF secretion that caused local TrkB activation through autocrine action of BDNF, and TrkB activation in turn further elevated local cAMP level, promoting more local BDNF secretion (Cheng et al., 2011). Such autocatalytic process eventually leads to stable cAMP accumulation locally and axon differentiation via activation of LKB1 and other axon determinants. Conversely, because of reciprocal suppression between cAMP and cGMP, cGMP elevation gradually develops at distant neurites, promoting their differentiation into dendrites (Cheng and Poo, 2012).

After axon/dendrite differentiation, the maintenance of the polarity becomes the issue—how cytoplasmic and membrane components are shipped and maintained in the axon vs. dendrite compartments. While at my Columbia lab, Bettina Winckler first began to study the existence of a diffusion barrier for membrane components at the axon hillock (Winckler and Poo, 1996). She found no apparent barrier for lipids, but her later work in Ira Mellman’s laboratory at Yale showed a clear diffusion barrier for membrane proteins (Winckler et al., 1999). In the cytoplasm, there is also the need for some cellular structure that regulates the molecular traffic in and out of the axon. Ai-hong Song in my Shanghai lab later found the emergence of a cytoplasmic “filter” at the hillock after axon differentiation—an actin-based meshwork that impedes free diffusion of large macromolecules, but permits the passage of specific kinesin-driven transport of axon-destined cellular cargos (Song et al., 2009). This line of work on axon/dendrite polarization and maintenance in my lab ended as the lab members involved began to set up their own laboratories to continue the work.

An Infamous E-mail Letter

In 2001, my Berkeley lab had grown to a size that was becoming difficult to supervise. While being disturbed by the lack of progress and frequent absence of some people in the lab, I wrote an e-mail to all lab members, suggesting that they should spend sufficient time in the lab (at least eight hours a day and six days a week) and inform me of their absences from the lab for one day or more. I made a strong argument that continuous concentration in lab work was necessary to achieve significant progress, and I asked those who disagreed with my “rules” to leave the lab. One student (out of more than 20 people) indeed left. This e-mail was later widely circulated on the web, and I was accused by some of being a “dictator” Interestingly, I was told that my e-email was found on the wall of many labs, but whether it was to endorse or condemn my rules was unclear. Some Chinese websites posted versions of my letter with added rules (presumably by some supervisors), such as no after-lunch nap in the lab, a habit of many Chinese students. In a report on my work in China (Cyranoski, 2011), I was quizzed on this letter and on my “dictatorial” style in the lab. The best answers were in fact provided by some of my formal lab members (now exceeding more than 150), who have since established laboratories in five continents.

Institute of Neuroscience, Shanghai

The Chinese Academy of Sciences (CAS) went through a revitalization process in the late 1990s, through the effort of its then President Yong-Xiang Lu, who secured a substantial amount of government funding for CAS institutes. In the spring of 1998, I met President Lu in a café at the San Francisco Airport, the first stop of a CAS delegation to the United States. Lu convinced me that the time was ripe for CAS to revamp its neuroscience program, and he invited me to visit several CAS institutes and make recommendations. In the summer of 1998, I visited Shanghai Institute of Brain Research (SIBR), the Institute of Physiology in Shanghai, and the Institute of Biophysics in Beijing. I found that the conditions for research were quite depressing. For more than a decade, China’s open-door policy had led to a massive exodus of scientists to institutions overseas, leaving these CAS institutes with very few active investigators. There were only three labs left in SIBR, which was founded by Hsiang-Tong Chang, the “grandfather” of modern Chinese brain research. While struggling through my report to CAS, I decided that the best approach to uplift Chinese neuroscience was to establish a new institute, with new infrastructure and an attractive environment for recruitment. I asked the then-SIBR director Chien-Ping Wu and three colleagues in the United States (Bai Lu, Lin Mei, and Yi Rao, who were then running a joint lab at SIBR) to cosponsor the proposal for founding the Institute of Neuroscience (ION). The proposal was quickly approved by President Lu, with the condition that I serve as its director. During the first decade of my directorship, I made regular bimonthly trips to Shanghai, each lasting one to two weeks. Because I was still a full-time faculty and running an active lab in Berkeley, the ION directorship was considered to be part of my uncompensated academic activity, reported annually to the Berkeley administration. By early 2012, however, frequent trips became too exhausting, and I began to phase out my Berkeley lab, and formally retired from Berkeley in 2014. My ION directorship ended by 2019, but I continued to serve an advisory role as the scientific director and run a laboratory on neural plasticity. Over the two decades of my directorship, I was fortunate to have had the help of a most dedicated and trustworthy manager, Yan Wang, who was able to deal with most administrative affairs, allowing me to focus mainly on academic matters.

At the beginning of ION, six lab heads were recruited from within China. To justify the salary and research support at a level much higher than that in other Chinese institutions, each laboratory was required to publish at least one paper every four years in the “top seven” international neuroscience journals. Many Chinese colleagues thought that was impossible because there had not been a single paper published in those journals over the previous decade based on work done in China. However, it turned out that every lab met the requirement. By 2005, it was estimated that ION investigators were publishing about one-third of all high-profile papers in biological sciences from China. With this publication record, the lab head recruitment became much easier, and ION grew rapidly. New to the CAS system, I introduced in 2002 biennial lab reviews by an international scientific advisory board, which provided critical comments on research programs and conducted tenure reviews for ION investigators. No one was exempted from this review. This requirement created a crisis in 2005, when one senior ION member refused to be reviewed because he was already elected as a CAS academician. I stood firm on this issue. CAS leadership had to intervene and resolve the crisis by offering him a very nice position elsewhere within the CAS system. Another difficult event was the case of scientific misconduct in 2009. An investigation committee consisting of both external and internal scientists found clear evidence of data falsification by a lab head. I therefore decided to terminate the ION appointment of this individual. This was a step rarely taken by a Chinese institution, and it created quite a commotion in the neuroscience community.

Setting up a rigorous graduate training program was one of my top priorities at ION. Many standard practices in U.S. universities were adopted, such as laboratory rotations before the selection of thesis adviser, annual thesis progress reports to a committee, and interaction with seminar speakers at lunch meetings. Perhaps the most notable practice, enforced through my personal participation in more than 100 thesis committee meetings over the years, was the uninhibited critique of the students’ research projects in the presence of their thesis advisers. This practice allowed the student to truly benefit from the input of multiple faculty members. The annual meetings of ION, where students and postdocs from each lab make oral presentations, also involved active and provocative exchanges. This was quite a cultural change for a Chinese institution where face-saving is very important. I gave a director’s address in each annual meeting, on various aspects of scientific research and graduate training, and transcripts of my talks were widely circulated on the Chinese internet.

Over the past two decades, 23 lab heads left the ION for other institutions in China, many of them taking leadership positions. Among them were five CAS academicians who were elected based on their research achievements in ION. These scientists left with their graduate students, postdoctoral fellows, external funding, and equipment. I made very little effort to retain them or to set barriers to prevent their move, and I was blamed by the CAS administration for being unable to keep excellent scientists and maintain the “stability” of ION. My own experience taught me that mobility is a good thing for an institution and the scientific community. Indeed, most of the people who left ION excelled in their careers and introduced many good ION practices to their new institutions. In any case, ION has accomplished its goal of being an institute that nurtures young neuroscientists in China.

I also run a laboratory of neural plasticity in ION with a cosupervisor, Shumin Duan (1999–2005) and Xiaohui Zhang (2006–2012). Under this arrangement, the laboratory was very productive and many graduate students carried out doctoral research on a variety of subjects in axon guidance, neuronal polarization and migration, synaptic plasticity, neuron-glia interactions, and cognitive functions. Most students went abroad for postdoctoral training afterward, and many are now running their own labs in China or abroad.

STDP beyond Synapses

The neural plasticity field is mostly concerned with plasticity of the synapse. In 2000, a MS/Ph.D student, Karunesh Ganguly, in my UCSD lab found that LTP induced at the synapse between cultured hippocampal neurons was accompanied by increased intrinsic excitability of the presynaptic neuron, because of a PKC-dependent modification of presynaptic Na⁺ channels (Ganguly et al., 2000). Four years later, Chengyu Li and Jiang-teng Lu in my Shanghai lab showed that the excitability of presynaptic neurons was also reduced after LTD induction in both hippocampal cultures and slices, an effect requiring presynaptic PKA- and PKC-dependent modification of slow-inactivating K⁺ channels (Li et al., 2004). The presynaptic effects on intrinsic neuronal excitability were observed at the soma, indicating global backpropagation of signals from the presynaptic nerve terminals to the entire presynaptic neuron. Using hippocampal slices, Zhiru Wang and Ninglong Xu measured the spatial summation of synaptic inputs at the dendrites of CA1 neurons and found that LTP and LTD induction also results in a persistent increase and decrease, respectively, in the linearity of dendritic summation of synaptic potentials. These changes of summation properties were specific to the modified inputs and reflect localized dendritic changes involving Ih channels and NMDA receptors (Wang et al., 2003). Thus, STDP involves not only local LTP/LTD of synaptic efficacy but also substantial changes beyond synapses in both pre- and postsynaptic neurons. Notably, postsynaptic spread of the dendritic changes associated with LTP/LTD is much more restricted than the presynaptic effects, consistent with our previous observation that there is extensive backpropagation but no forward propagation of LTP/LTD.

Nonhuman Primate Research.

Ten years after founding ION, I became increasingly aware of the need for using nonhuman primates (NHPs) to study higher cognitive functions and brain disorders. Using a director’s discretionary fund provided by CAS, I established facilities for rearing macaque and marmoset monkeys in 2009 and began to recruit investigators interested in studying NHPs. As of 2023, about one-third of ION’s 55 labs were doing NHP-related research. In 2018, Nikos Logothetis visited Shanghai, and we discussed the possibility of setting up an International Center for Primate Brain Research (ICPBR) in Shanghai, with the goal of establishing NHP facilities with high international standards and open to investigators around the world to conduct NHP research. With a special fund from the Shanghai government, ICPBR became a reality in 2020, when Nikos and four other laboratory heads moved from Tubingen to Shanghai. Beginning in 2018, ION also began a collaboration with the International Brain Research Organization (IBRO) to sponsor a regular Summer School in Primate Neurobiology, with the goal of promoting an interest among young researchers in studying NHPs.

A strong justification for the use of NHPs is the potential development of animal models of brain diseases, given the obvious inadequacy of mouse models of brain disorders, especially psychiatry diseases. In 2016, a graduate student, Zhen Liu, in Zilong Qiu’s ION laboratory, working with the macaque platform director, Qiang Sun, overexpressed the human MECP2 gene in 1-cell monkey zygotes obtained via in vitro fertilization, implanted the embryos in surrogate female monkeys, and generated monkey offspring. These monkeys showed Rett syndrome–like phenotypes, such as repetitive movements and deficits in social interactions (Liu et al., 2016). A few years later, Hong-jun Chang and Qiang Sun generated macaque monkeys with the deletion of a circadian core gene BMAL1 using CRISPR-Cas9 editing in 1-cell zygotes. The monkeys exhibited sleep disorders, dampened circadian oscillations of circulating hormones, and a variety of psychotic phenotypes, including anxiety and depression-like behaviors and defective social interactions (Qiu et al., 2019). A variety of macaque models for brain disorders with strong genetic contributions, including Parkinson’s disease, fragile-X syndromes, and Angelman’s syndrome, are now being constructed with this gene-editing approach at the ION facility.

Cloning of Macaque Monkeys

The gene-editing approach has generated monkeys with varying degrees of disease phenotypes, because of variations in the genetic background of edited embryos. Mouse models with homogenous genetic background had been produced by inbreeding over many generations, but this is not practical for the macaque, which has a long generation time of five to six years. Cloning of animals by the somatic cell nucleus transfer (SCNT) method appears to be a solution. Since the birth of Dolly the Sheep in 1996, cloning by SCNT has been achieved for more than a dozen mammalian species, but not in NHPs. In November 2012, I called a small meeting among ION researchers in the suburban town of Wuzhen, and put forward the cloning of macaque monkeys as a major goal of ION’s NHP platform. By improving the SCNT protocol and screening epigenetic modulators that could reactivate development-relevant genes in the transplanted somatic nucleus, Zhen Liu (by then a postdoctoral fellow in my lab) and Qiang Sun succeeded in cloning macaque monkeys by SCNT in late 2017, using cultured fibroblasts derived from an aborted female fetus (Liu et al., 2018). I named these two macaque sisters Zhong-zhong and Hua-hua (with “Zhong hua” meaning Chinese). They now live well among a group of monkeys in our facility. The SCNT method was soon used to generate a group of five cloned monkeys from the skin fibroblasts of a donor BMAL1-deleted monkey that exhibited the most severe psychotic phenotypes (Liu et al., 2019). The cloned monkeys showed similar anxiety and depression-like phenotypes as the donor monkey. Hong-Jun Chang and his colleagues are now using these BMAL1-deleted monkeys for preclinical efficacy tests of new candidate drugs for anxiety and depression.

Studying Higher Cognitive Functions in NHPs

A well-recognized use of NHPs is to study higher cognitive functions that are unique to primates. For many years, primatologists have shown that some great apes, but not macaque monkeys, exhibit self-consciousness by passing the mirror self-recognition test—touching a dye mark on the face when seeing his or her own face in a mirror. In 2014, Neng Gong and I decided to train monkeys to perform the mirror self-recognition task. We projected a laser light spot on a board behind the head of a head-fixed monkey, and the monkey needed to touch the spot seen in the mirror to receive a reward. By this training, the monkey learned the association between the mirror image of the arm and hand with his own proprioceptive sensation. After a few weeks, all five trained monkeys realized that the mirror image represented their own body and were able to pass the face mark test of mirror self-recognition (Chang et al., 2017). Thus, mirror self-recognition represents the animal’s ability to associate the mirror image with his own body. The loss of mirror self-recognition ability found in severe cases of mental disorders, such as Alzheimer disease, schizophrenia, and autism, probably reflects defective multisensory association and recall, and our training protocol for monkeys may prove to be useful as a therapeutic tool. In another study using NHPs, Huan-huan Zeng in my lab used two-photon Ca²⁺ imaging to monitor the activity of a large population of neurons in the primary auditory cortex of awake marmosets, which have a complex repertoire of calls. He discovered many types of neurons that responded selectively to different calls in the primary auditory cortex, and these cell-selective cells were largely distinct from the well-known frequency-tuned cells in the primary auditory cortex (Zeng et al., 2022). This is a first step in studying neural processing of call sequences in the marmoset brain.

China Brain Project

When the global wave of big brain projects began in 2013, I was asked by the China’s Ministry of Science and Technology to organize a series of meetings to discuss and plan a national brain project. When it formally began in 2021, China Brain Project (CBP) represented a 10-year program of basic research on the neural basis of brain functions and on applied neuroscience that includes diagnosis and intervention of major brain diseases and brain-machine intelligence technology, such as brain-computer interface, neuromodulation methods, and brain-inspired machine learning and computing devices (Poo et al., 2016). The basic neuroscience program includes a component of mesoscopic brain mapping—to identify all cell types in the mouse, monkey, and human brains, and to map the input/output connectivity of each neuron type in all brain areas of mice and monkeys. Since the U.S. BRAIN Initiative has made much progress in mapping cell types and connectivity in the mouse brain, I thought CBP could make more substantial contributions by focusing on the macaque brain (Poo, 2022), which is much more complex and requires large-scale collaborative efforts around the globe. This is exemplified by the recent mapping of spatial transcriptomes of the entire macaque cortex at the single-cell resolution (Chen et al., 2023). It identifies layer- and region-specific putative cell subtypes and paves the way for mapping cell type-specific connectomes of the monkey brain. Single-cell spatial transcriptomes also provide information on the neighborhood composition of various cell types in the brain. With further information on the temporal changes and cross-species differences in gene expression, one can now explore the molecular and cellular mechanisms underlying morphogenesis and evolution of the brain.

Brain-Inspired Machine Learning

Our discovery that LTP/LTD could backpropagate in the presynaptic neuron was inspired by the backpropagation algorithm of artificial neural networks (ANNs). I had deliberately termed the phenomenon “backpropagation,” but it failed to attract the attention of ANN community. Nearly two decades later, I convinced Bo Xu and his colleagues at the Institute of Automation of Chinese Academy of Sciences in Beijing to incorporate this natural backpropagation as part of a learning algorithm for spiking neural network (SNN). They used STDP-based LTP/LTD to induce modification of synapses on output-layer neurons of a three-layer SNN, based on the timing between network-induced spiking of the output neuron and expected spiking, which serves as the supervising signal. The resultant potentiation/depression of output-layer synapses was allowed to backpropagate to a subset of synapses on the hidden-layer neurons. This learning rule enabled the SNN to outperform other conventional backpropagation-based algorithms in learning several benchmark tasks in both accuracy and computational cost (Zhang et al., 2021). Furthermore, inspired by the finding on neuromodulator-induced STDP rules, they implemented a metaplasticity mechanism in the SNN learning algorithm, resulting in a greatly reduced catastrophic erasure of previous memories in several standard continuous learning tasks as well as a reduced computational cost (Zhang et al., 2023). Brain-inspired machine learning methods are likely to contribute to the future development of energy-efficient artificial intelligence.

Retrospective and Prospective Research

For students and postdoctoral fellows who joined my laboratory with a limited biology background, I often suggest that they read a good textbook, identify a hypothesis of interest, repeat the experiments that had laid the foundation for the hypothesis by using newly developed methodologies. A good example was Sergei Popov, a physicist from Moscow, who reexamined the “tip growth hypothesis” of growth cone extension as described in the first edition of Molecular Biology of the Cell by Alberts and colleagues. The hypothesis states that new membrane materials for axon growth are transported in the cytoplasm to the growth cone, followed by local membrane insertion. The main evidence is that carbon particles attached to the membrane of growing neurites did not move forward. Instead of using carbon particles, Popov loaded a small amount of fluorescent lipids locally into the axon of cultured neurons and monitored the profile of fluorescent lipids with time. He found that, as the fluorescent lipid patch spread laterally in the membrane, the center of mass of the fluorescent patch moved forward in the growth cone. This approach suggested that new membrane is inserted at the base of the axon, pushing a bulk membrane flow toward the tip (Popov et al., 1993). However, Popov later showed in his own lab that forward membrane flow occurs only in fast-growing axons, whereas tip insertion is favored when the growth rate is low. The new problem is to find out the cytoplasmic mechanism that regulates the site of new membrane insertion. In any case, the tip growth hypothesis was removed in later editions of the textbook by Alberts and colleagues.

Our experiments on the developing retinotectal system also aimed initially at reexamining the textbook version of Hebb’s hypothesis on synaptic modification by correlated activity. Using a newly developed in vivo whole-cell recording, we found results that led to the discovery of time windows for STDP and the revision of Hebb’s hypothesis (Bi and Poo, 2001). I call this way of doing science the “retrospective” approach, and its outcome is always useful—either confirmation and strengthening of a textbook hypothesis or, more rewardingly, its refutation or revision. This is distinct from the normal “prospective” approach—designing new experiments to test an existing hypothesis, and revising the hypothesis when sufficient refuting evidence has been accumulated. Although both approaches could achieve the same goal of revising existing hypotheses, the retrospective approach seems more effective, given that it aims directly at its experimental foundation.

Epilogue

I was invited back to La Jolla to give the 20th Kuffler lectures in 2019. I chose the title of “Pathfinding in Neurobiology” to describe my scientific ventures in three areas: neuronal polarization and axon guidance, synapse formation and plasticity, and memory and cognition. This title appeared more purposeful than the one I used for my 2016 Gruber Prize lecture: “Random Walks in Neurobiology.” I felt that my scientific career was a pathfinding process largely driven by circumstances and serendipity. In writing this autobiography, I noted the apparent haphazardness of many choices along my career path and research problems, and I reflected on the fact that many research problems were not pursued in sufficient depth before I moved onto others. I could attribute this to the lack of formal training in a specific area of biology that could have consolidated a long-term goal of solving a specific biological problem. It may also have been my lack of patience in pursuing the nuances of a particular subject. Many of my research ventures were also initiated by students and postdocs who happened to join my lab; some of them have made substantial progress in pursuing the subject later in their own labs.

In retrospect, the most enjoyable period of my scientific life was the time I had weekly individual meetings with each lab member in my office, when I learned from what they had learned and figured out with them the most interesting experiment to do. Arriving at a good plan for experiments was as exciting and rewarding to me as seeing experimental results. For this, extensive conversational discourse is essential. Gunther Stent once asked over the dinner table, “If you had unlimited resource[s] to pursue your interest alone on a desolate island and are forbidden from talking with anyone, would you do it?” Indeed, my scientific pathfinding was accompanied and largely driven by people I had the fortune to interact closely with. To them, I owe an enormous gratitude. Some unusual circumstances I encountered and took advantages of, as someone with cultural background in both the East and West, have led to many ventures beyond the confines of my own laboratory. Besides being a researcher, I have also enjoyed my life as a teacher and administrator and, as such, I probably have left more lasting footprints.

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Joseph S. Takahashi

BORN:

Tokyo, Japan

December 16, 1951

EDUCATION:

Swarthmore College, BS, Biology (1974)

University of Texas Austin, Zoology (1975–1979)

University of Oregon Eugene, PhD, Neuroscience (1981)

APPOINTMENTS:

Fellow, Pharmacology Research Associate Training Program, NIH/NIMH (1981–1983)

Assistant Professor (1983–1987), Associate Professor and Associate Chair (1987–1991), Professor and Associate Chair (1991–1996), Department of Neurobiology and Physiology, Northwestern University

Walter and Mary E. Glass Professor in the Life Sciences, Northwestern University (1996–2009)

Investigator, Howard Hughes Medical Institute, Northwestern University (1997–2009)

Director, Center for Functional Genomics, Northwestern University (2001–2009)

Walter and Mary Elizabeth Glass Professor Emeritus, Northwestern University (2009–present)

Investigator, Howard Hughes Medical Institute, UT Southwestern (2009–2023)

Loyd B. Sands Distinguished Chair in Neuroscience, UT Southwestern (2009–present)

Professor and Chair, Department of Neuroscience, UT Southwestern (2009–present)

Investigator Emeritus, Howard Hughes Medical Institute (2023–present)

HONORS AND AWARDS (SELECTED):

Honma Prize in Biological Rhythms Research (1986)

Sixth C.U. Ariëns Kappers Award, Netherlands Society for the Advancement of Natural Sciences, Medicine and Surgery (1995)

Fellow, American Academy of Arts and Sciences (2000)

Fellow, American Association for the Advancement of Science (2001)

W. Alden Spencer Award in Neural Science, College of Physicians and Surgeons, Columbia University (2001)

Eduard Buchner Prize, German Society for Biochemistry and Molecular Biology (2003)

Member, National Academy of Sciences, USA (2003)

Member, Academy of Medicine, Engineering and Science of Texas (2009)

Outstanding Scientific Achievement Award, Sleep Research Society (2012)

Member, National Academy of Medicine, USA (2014)

Peter C. Farrell Prize in Sleep Medicine, Harvard Medical School, Division of Sleep Medicine (2016)

Gruber Neuroscience Prize, Gruber Foundation, Society for Neuroscience (2019)

Joseph Takahashi is a pioneer in elucidating the genetic and molecular mechanisms of the mammalian circadian clock system. His lab discovered the first circadian clock gene in mice and humans, named “Clock.” The CLOCK protein and its heterodimeric partner, BMAL1, act as the primary transcriptional activators of the circadian gene network in animals. He used mutagenesis and behavioral screening in mice to isolate the Clock mutant mouse, which then opened the way to find the underlying gene by positional cloning and transgenic rescue of circadian rhythms at the behavioral level. Many years later, his lab was able to solve the crystal structure of the CLOCK:BMAL1 complex; thus, going from a genetic screen for a mutant mouse to the underlying gene and protein, and the solution of its atomic structure. Before the discovery of clock genes in mammals, the significance of circadian rhythms to essential cellular functions was unclear. With the discovery of the clock gene network and the finding that CLOCK:BMAL1 are upstream regulators of thousands of genes in cells, molecular interactions have revealed that the circadian clock system directly regulates metabolism, immune function, cell growth and cancer, sleep, neurological diseases, aging, and longevity.

Joseph S. Takahashi

My Family

I was born on December 16, 1951, in Tokyo, Japan. My parents met in Tokyo as a consequence of the postwar occupation of Japan by the U.S. government following the end of World War II (WWII). My father, Shigeharu Takahashi (1921–2000), worked as a civilian agricultural economist in General Douglas MacArthur’s staff in Tokyo. He obtained that position by virtue of being in the U.S. Army, being a Japanese-American who could speak both English and Japanese, and having graduate training in agricultural economics. My paternal grandfather, Shigetaro Takahashi (1877–1955), immigrated to the United States in 1896. He was the second eldest son of a rice-farming family in Wakayama prefecture in Japan. Because the eldest son inherits the rice farm, my grandfather had to find something else. He decided to go to San Francisco and there he established a successful “Oriental” import business named the Kisen Company Silk House on 157–159 Geary Street about a half block away from Union Square. During the 1906 earthquake and fire in San Francisco, the Kisen Company store sustained damage but survived and continued until about 1920. My paternal grandmother, Hana Morikawa (1884–1957), married my grandfather in 1910. They had four children: Kiyo (1913–2015), Shigeharu, Tomiko (1918–2011), and Edwin (1929–2009). They lived on Pine Street in San Francisco, and for most of their lives, their home was a safe harbor for Japanese immigrants trying to find their way in the United States. During the Depression, my grandfather was able to take over a store that had gone out of business and opened the second Kisen Company store on 456 Grant Avenue from about 1930 to 1942, when they had to vacate it and sell off the inventory at a huge loss.

After the attack on Pearl Harbor, about 120,000 people of Japanese ancestry were forcibly relocated and incarcerated in concentration camps in the western United States under Roosevelt’s Executive Order No. 9066. My father was the only member of our extended family who was not interned (with the exception of an aunt and two cousins who were visiting relatives in Japan when the war broke out). As described by my cousin, Ruth Sasaki,¹ our family in San Francisco was taken to the Tanforan “Assembly Center” in San Bruno (a barely repurposed race track) for about six months; and, then they were transferred to the Topaz Relocation Center in Utah in September 1942 until around September/October 1945, when the camp closed. They lost most of their property (real estate) and possessions and had to sell them for less than 10 cents on the dollar.² My aunt Kiyo worked in medical records at the Topaz Hospital before she resettled in Chicago in 1944, and my aunt Tomi was the Supervisor of Topaz preschools. After release from the “camps” in 1944–1945, Japanese Americans continued to face discrimination in housing, violence, vandalism, and defacing of Japanese graves. Only many decades later was it acknowledged in 1976 by President Gerald Ford’s Proclamation 4417 that the internment was “wrong” and “that this kind of action shall never again be repeated”³ and by a Congressional report in 1983 that “Executive Order 1066 was not justified by military necessity, and the decisions that followed from it—exclusion, detention, … were not founded upon military considerations. The broad historical causes that shaped these decisions were race prejudice, war hysteria and a failure of political leadership.”⁴

In 1942, my father was a student at the University of California Berkeley. When the internment began in San Francisco, professors at Berkeley tried to get many of the nearly 700 Japanese American students transferred to the east so that they did not have to be interned in the relocation camps. My father and another student were transferred to Ohio University in Athens, Ohio. When they arrived at Ohio University, the administration reversed its decision and said sorry you cannot transfer. Then the most amazing thing happened: the student council and students protested the administration’s reversal and eventually the administration backed down and admitted my father and the other student. Thus, my father was the only member of his extended family who was not interned during WWII. Eventually my father graduated from Ohio University and entered graduate school in economics at the University of Chicago from 1944 to 1945. Ironically, after a year and a half in graduate school, he was drafted into the U.S. Army. He was stationed at the Defense Language Institute Foreign Language Center in Monterey, CA, where he taught Japanese to U.S. troops, and he rose through the ranks to master sergeant. When the war ended, he was recruited to serve in the postwar occupation of Japan led by MacArthur.

My mother, Hiroko Hara (1920–1984), was born in Kobe, Japan. My maternal grandfather, Kumetaro Hara, and grandmother, Hisako Nakamura Hara, came from privileged families in Japan (descendants of the Seiwa Genji clan). My first cousin once removed, June Grandwells, was told the following family legend by her grandmother, Masa (who was Kumetaro’s daughter-in-law):

One of our ancestors in the Hara family was the Head Retainer of the Kish House (Kish is actually a name of the place, present Wakayama), one of the three branches of Tokugawa clan, established by Ieyasu to provide successors to the Tokugawa shogunate in case the main line should become extinct. As the fifth head of Kish House became the eighth Shogun Yoshimune (Tokugawa), it is possible that the Head Retainer accompanied him to Edo (present Tokyo) Castle, the center of the shogunate, although I have absolutely no proof of our Head Retainer serving in the Yoshimune’s era.… Under the Peerage Act of July 7, 1884, the Meiji government expanded the hereditary peerage with the award of Kazoku (aristocrat) status to persons regarded as having performed outstanding services to the nation. The former 15th shogun, Tokugawa Yoshinobu, became a prince (or a duke), the heads of primary Tokugawa branch (shinpan Daimyo) became marquises, and the heads of the secondary branches became counts. I was told that one of the members of the Hara family was offered to be awarded Kazoku status (possibly the count, the highest honor for anyone from a non-Kuge or non-Daimyo house) for his achievement from the Meiji Emperor in person. The person in question was most likely your grandfather or possibly great-grandfather, who unbelievably turned the offer down.

As a consequence of his family’s standing, my maternal grandfather went to college at the University of Pennsylvania in 1903. Then he obtained his doctorate in engineering in Berlin and worked as a senior engineer at Kawasaki Marine Engineering. Because of his experience in Europe, he loved classical music and wore western clothing in Japan. They had six children, the youngest of whom were my aunt, Chieko Hara (1914–2001), and my mother. Both Chieko and my mother went to Sacred Heart School in Tokyo (Seishin Joshi Gakuin) and were raised as Catholics. There they both learned to speak English. They also were trained in piano, and my aunt was sent to Paris at the age of thirteen, where she studied with Henri Gil-Marchex (1894–1970) and Lazare Levy (1882–1964). In 1932, Chieko won the Premier Prix at the Conservatoire de Paris becoming the first Japanese pianist to enter and win this prize. She then had to return to Japan, but subsequently returned to Paris to study with Alfred Cortot (1877–1962). In 1937, Chieko went on to win a special prize at the Third International Chopin Piano Competition in Warsaw, Poland, and became an acclaimed concert pianist in Europe. The story about my aunt is too involved to describe here, but Rie Ando wrote a wonderful doctoral thesis (2010)⁵ chronicling her artistic and tumultuous life.

Japan, Burma, and Pakistan

Although my mother’s family was well off before WWII, they lost everything during the war. During the postwar occupation, MacArthur’s rebuilding of Japan’s economy involved many large contracts with Japanese companies. My mother by virtue of having gone to Sacred Heart School could speak English almost fluently and was able to get a job as a bill collector for one of these companies doing business with the U.S. occupation forces. My father’s boss in MacArthur’s staff was John Cooper, and he had met my aunt Chieko at one of her concerts in Tokyo and found out that she had an unmarried sister. He told my dad that he should meet her and made the introduction. This is how my father and mother met each other in Tokyo. Initially, American occupation forces were not allowed to marry Japanese “aliens,” but eventually this prohibition was lifted, and my parents were married in November 1950. The following year, I was born in a U.S. Army hospital in Tokyo. The occupation of Japan formally ended on April 28, 1952, and at that time, my dad found a new job as an agricultural economist with the Robert Nathan Associates firm in Washington, D.C. We made our way to Washington when I was a baby, and then my father was put on foreign assignment in Burma (Myanmar). We moved to Burma in 1952 and lived in Rangoon, Burma, until 1958 when I was seven years old. This was the beginning of the military control of Burma when General Ne Win was invited by Prime Minister U Nu to take over the country and later a series of military coup d’états led to the complete control of the Burmese government by the military for the next 60-plus years.

Burma was a lush tropical paradise and was the beginning of my experience and love of nature. My mother loved animals, and we had many pets (beloved Siamese cats and a Lhasa Apso dog). In addition, there were chickens, ducks, and more dogs owned by our house staff known as “domestic servants” in the day. This was a remnant of the British colonies in India of which Burma was a part before their independence in 1947. I had a nanny who was Karen, an ethnic group in southeastern Burma, and through her I learned to speak both Burmese and Karen fluently as a child. Sadly, after leaving Burma, I never spoke Burmese again, and I cannot remember a word. I always wonder whether those languages might still be lurking somewhere in my brain.

My father loved to fish, and we went on many fishing trips in Burma. There was a lake down the street from our house where we caught carp, catfish, and snakehead fish (called nga yant in Burmese). My father also took me on field trips up the Irrawady River into the jungle. We would have armed guards on board the boat because of the bandits further up the river. In these outings into the jungle, we would see many exotic birds, monkeys, snakes, and turtles, and of course, we caught many different types of fish. Green peacocks are the national symbol of Burma, and we would see these often. Elephants and water buffalos were the workhorses in Burma. Timber elephants were used for lumbering of teak and carrying heavy loads. Each elephant had a mahout (rider and trainer), and you could see the special bond between each pair. Water buffalo were used for plowing rice fields and their milk was used for many dairy products. I also remember all the unusual insects there: giant millipedes the size of a cigar, large black scorpions, huge grasshoppers, and crickets (that were fried and sold at markets). It was like living in a zoo!

Because of the military takeover of Burma in October 1958, we had to leave the country and my father had to find a new job and was engaged in consulting work with USAID in South America. Meanwhile, my mother was pregnant with my sister, Nancy (1959–2012), and so my mother and I moved to Rome, Italy. My mother chose Rome for two reasons: she wanted to be close to her sister, Chieko, who now lived in Florence, Italy, and she wanted to deliver Nancy at the Seventh-Day Adventist Hospital in Rome. On May 9, 1959, my aunt Chieko married the Spanish cellist, Gaspar Cassado (1897–1966),⁶ in Siena, Italy. The wedding took place in Count Chigi’s (Guido Chigi Saracini, 1880–1965)⁷ palace in Siena (Palazzo Chigi-Saracini) around the time of the Palio of Siena festival. Typical of Catholic weddings, it was a very long affair. I was a ring bearer in the wedding party, and there was great fanfare around the wedding (my first time in newsprint and TV). Count Chigi was a patron of the musical arts, and he founded the Academia Musicale Chigiana in 1932 and the Siena Musical Week Festival in 1939. Both Alfred Cortot⁸ (Chieko Hara’s teacher) and Pablo Casals⁹ (Gaspar Cassado’s teacher) attended the wedding. In Italy, it was customary for children to drink both coffee and wine at a young age by watering down the drinks to reduce their punch. So, coffee drinking began at the age of eight for me, and at the wedding, I was able to partake in champagne. I have photos of my mother looking at me from across the room with her mouth agape because I was happily quaffing champagne.

In Rome, our apartment on Via Veneto overlooked what was to become the Olympic grounds in 1960. Because my father was overseas, my mother had a wonderful chauffeur named Vincenzo. He would take my mother and me on an outing every weekend to museums, Roman ruins, gardens, and drives in the countryside. It was truly a cultural experience for a young child. Sadly, we only lived in Rome for one year. My father secured a job at the World Bank in Washington, D.C., and shortly afterward, we moved to the D.C. suburbs in Bethesda, Maryland. We lived about one mile away from the National Institutes of Health (NIH) campus. I went to Alta Vista elementary school from the second to fourth grade. Then my father was assigned to Karachi, Pakistan, in 1962. We lived in Karachi for two years during which I went to Karachi American School for fifth and sixth grades. Similar to my experience in Burma, Pakistan was a beautiful place, but instead of a jungle, it was an arid desert. Again, the animal life was exotic: camels were the primary beast of burden. I also had friends whose fathers took us hunting for deer and wild boar as well as ducks and doves. But, most memorable for me was fishing with my dad almost every weekend on the Arabian Sea. The Arabian Sea is like most tropical oceans and had abundant schools of crevalle jack, blue crevalle, king mackerel, mahi-mahi, bonito, barracuda, cobia, grouper, and red snapper. Schools of dolphins and porpoises were frequently seen, and many would surf on the bow wave of the fishing boat as we trolled along. We also had a friend of the family who had a cottage on the beach with a two-mile stretch of sand flanked by rocky reefs. There, we found all sorts of intertidal wildlife among the seaweed and rocky pools. I also remember vividly being able to see giant sea turtles laying their eggs on the beach at night. All of these experiences forged my love of the ocean and aquatic organisms.

Perhaps most influential for me in sparking my interest in biology in Pakistan was the hobby of keeping pigeons as pets. I started with a pair of pigeons that we bought at the bazaar in Karachi. We built a coop on the roof of our house, which had a flat cement roof. When first bringing home a pigeon, they plucked the distal wing feathers so that the bird could not fly well until the feathers grew back after a few weeks. Then you gave the pigeons a nice home with food and water, and magically after that they stayed even though they could fly free. Gradually, I would go to the market and buy more pigeons. There were all kinds of “sport” pigeons in the market, including different coloring, fantails, and “tumblers,” which were pigeons that did backflips when they were flying. Once you had a flock of pigeons, they would attract other pigeons that might fly by. Or if you saw a stray pigeon flying around, you would go to the roof and send your flock to fly in the air. The flock of pigeons typically would fly in circles around the rooftop before landing back home after a while. Most of the time, the stray pigeon would join the flock in flight and then eventually land on the roof. I would then leave a trail of bird seed from the roof into the pigeon coop. When the stray pigeon entered the coop, I would close the door and go into the coop and catch the pigeon. We then plucked its flight feathers, and it would stay on the roof until it could fly again, and by that time, it had found a new home. One of the most interesting things that the pigeons did was to court and form pair bonds. Then they would build nests in their nest boxes, lay eggs, and take turns incubating them (about 18 days), and pretty soon there would be hatchlings. The parents fed the hatchlings and squabs by regurgitation of crop milk. After about four to six weeks, the pigeons become independent and looked like adults. I was fascinated by the entire life cycle of pigeons and also by the progeny from the various mated pairs since many pairs had different coloring, tails, or behavior (tumblers). These were my first lessons in animal breeding and genetics. The inheritance of different colors of feathers was interesting, but perhaps most interesting was the inheritance of tumbling behavior, which appeared to be genetic rather than learned.¹⁰

In addition to the natural world in Pakistan, I was also exposed to the stark realities of the developing world. Not far from our home in Pakistan, there was a refugee camp behind a tall chain-link fence enclosure. The residents, I was told, were from India and made a living producing cow dung cakes that were used for fuel, resulting in an income of less than $200 per year in the 1960s. We frequently were accosted by beggars on the streets. Sadly, many of these individuals had been maimed on purpose to promote their life of begging—for example, by cutting off their tongue so that they could not speak. Others were blind or were lame and could not do normal tasks. In the bazaars, one would be constantly pursued by young children begging for money. I had to learn at an early age to steel myself from these sad souls and try to ignore their calls. Such poverty and dire living situations were very eye-opening for me and made me greatly appreciate life in the United States.

President John F. Kennedy was assassinated while we lived in Pakistan, and I remember that day vividly. My friend whose father was in the military called me to tell me about Kennedy. I was a great fan of JFK and had a large poster photo of him in my bedroom. We were all devastated by his senseless loss.

Bethesda and Rockville

In 1964, we moved back to Bethesda, Maryland, and I went to North Bethesda Junior High School for seventh and eighth grades. I took up playing the guitar and took classical guitar lessons and also was a rhythm guitarist in a rock and roll band. We played a lot of gigs and one of the cadre of musician friends back then was Nils Lofgren.¹¹ Nils was amazing. He picked up the guitar and in months he was already professional! My friend Tom Miller was in a band with Nils, and one time, our band was in a battle of the bands at the junior high with Tom and Nils’s band. They beat us handily.

One of my hobbies during junior high was raising tropical fish. I was especially fascinated with cichlids, angel fish, and discus. These fish had elaborate mating rituals and would lay eggs and care for them. To provide conditions under which the fish would breed, I had to learn about their native habitats and create appropriate conditions for them. For example, discus were the most difficult to breed, and the water had to be extremely soft and treated with peat to mimic the acidic water of the Amazon. My other hobby at the time was tinkering with engines and go-karts, which I loved to drive at the Korvettes shopping center parking lot in Rockville on Sundays when the stores were closed. I loved taking apart the engines and putting them back together (without too many parts leftover).

During this time, my parents bought a property in Potomac Highlands, which is between Rockville and Potomac, Maryland. They designed and built a new house on the property and after eighth grade, we moved to Rockville. I went to Julius West Junior High School for nineth grade, and then Richard Montgomery High School in Rockville. At the time, Richard Montgomery was 50 percent college prep and 50 percent vocational. (Today Richard Montgomery is a magnet school.) Because it had a vocational school, there were many practical courses that I could take as electives. So, I was able to take mechanical drawing, industrial arts (shop), and my favorite, auto mechanics every year. For our senior year independent project, my best friend, Walter Gardiner, and I rebuilt the V8 engine in his 1959 Ford Thunderbird. These vocational courses turned out to be extremely helpful many years later. Mechanical drawing made it easy for me to read and understand architectural plans for lab renovations and new buildings; shop honed my woodworking and machine shop skills; and auto mechanics taught me much about how things worked and how to repair them. All useful skills in life and in science. I found academics relatively easy in high school, and as a consequence, I did not have to study very hard or develop good study habits. Despite this, I graduated third in my class. I was also vice president of the Student Council and Mike McCord was president. We had meetings at his home in Rockville, and I met his father, James W. McCord Jr., who would become infamous as one of the Watergate burglars a few years later in 1972.

As soon as my friends and I turned sixteen, we were able to get jobs and work during the summers. We mostly started with jobs at the local country club nearby. We began as dishwashers and then could be elevated to busboys. In my case, I was promoted to an assistant cook in the main kitchen (for reasons that I don’t remember or fathom). There was the executive chef of the kitchen and a second chef, and the assistant cooks. It was a very interesting learning experience for me to prepare meals on a large scale and to use all of the elaborate kitchen equipment. As the summer progressed, I was given more responsibility and autonomy, and I learned to plan and execute meals to be prepared at specific times. My mother taught me how to cook and, as a child, I had learned to prepare my own breakfasts before school, so she prepared me for my summer job as a cook. Another funny episode at the country club was an annual event called the Hawaiian Luau. My additional task as assistant cook was to dress up in a Hawaiian costume and turn the roasted pig on the patio, likely because I was the only Asian working there (but I didn’t mind because I love Hawaii). The next summer, I was promoted again to become the cook for the Men’s Grill (very sexist back then!). This was a small kitchen and bar that was open for breakfast and lunch. There were only two of us: Larry the bartender, my boss, and me. Every morning I would stock the kitchen in preparation for the day’s menu. This was very good training for me in planning and logistics. There was always a big rush at lunchtime. Larry would bark out the orders to me from the order window, and I would plan how to have all of the items in each order come out simultaneously. After about an hour, the intense rush would be over and then Larry and I could recover and finish out the day. I did the Men’s Grill job for two summers before going off to college. I learned many skills from these summer jobs that would serve me well in the future, including planning, logistics, and scale.

Swarthmore College

For college, I went to Swarthmore College, a small liberal arts college on the Main Line suburbs south of Philadelphia, Pennsylvania. Compared to my high school, Swarthmore was tiny—only about 300 students per class year (my high school had 660 students per class). Because of its small size, you knew almost everyone at Swarthmore. In some ways, it was too small because the familiarity could become stifling. Also, it was a big change from high school—half of the students were valedictorians, and I could no longer coast by. Looking back, Swarthmore was also a very good place for me. Initially, I was interested in both biology and engineering, and so I began as a bioengineering major. After the first year, I realized that I was more interested in biology than engineering, and so I switched my major to biology. Every science course at Swarthmore had a laboratory session attached. From my experience as a faculty member, I now know that this is very rare in universities. In addition, because Swarthmore was small, there wasn’t a huge selection of courses for me to take in biology. As a result, I took all of the upper-level core courses at the time: genetics, molecular and cell biology, physiology, invertebrate zoology, and the biology of animal communities (BOAC). Ironically, I really did not enjoy molecular and cell biology or genetics. But this training became important for me many years later. I was especially attracted to the study of animal behavior and ethology because of an influential professor, Kenneth Rawson, who also worked on circadian rhythms.¹² He taught the BOAC course, which was actually an ethology course (the study of natural animal behavior as opposed to psychology, which at the time was dominated by the school of B. F. Skinner and operant conditioning¹³). He had the most amazing laboratory exercises in this course. We did field studies to observe and record the mating behavior of ducks in the spring—repeating the work of Niko Tinbergen (1907–1988),¹⁴ who described fixed action patterns. We studied the work of Konrad Lorenz (1903–1989),¹⁵ who described the phenomenon of imprinting. And, perhaps most compelling, we repeated the experiments of Karl von Frisch (1886–1982),¹⁶ who described the dance language of bees. Dr. Rawson had set up a bee hive encased in plexiglass in the lab with an exit out of the window to the lawn in front of the biology building. We set up feeding stations that had sugar-water feeding stations in different locations in the field. Eventually, foragers bees would come to the feeders and then we would mark the bees using different colored paint spots. Then back at the bee hive, we could observe the forager bees that we had marked at the feeding stations. In the hive, the forager bees would perform their waggle dance, which encoded both the direction of the food source relative to the angle of the sun as well as the distance from the hive. Direction was encoded by the orientation of the waggle dance relative to vertical, which represented the position of the sun. The frequency of the waggles during the waggle dance encoded the distance of the food source from the hive. Amazingly, we could completely replicate these classic experiments done by von Frisch. This experience was eye-opening for me. I had never known the beauty of scientific experiments and the profound insight that could be obtained from studying model organisms such as the honey bee.

The tipping point for me was a lab in the BOAC course on electric fish. As I described, I was an avid tropical fish hobbyist. I had never seen electric fish before and was fascinated by them. These were weakly electric fish, and there were gymnotids from the Amazon as well as mormyrids from Africa. The lab exercise was to put electrodes into the fish tanks and then visualize the electrical discharges on an oscilloscope. We would then catalog the various electrical discharge patterns of the different species of electric fish. There were about a dozen different species to describe. Some of the fish discharged very high-frequency continuous sine wave signals (Eigenmania sp.). Others had low-frequency sporadic discharges (Gymnotus sp., Hypopomus sp., Elephant nose fish). I asked Dr. Rawson how long the fish would discharge like this and whether they might rest given that it seemed that continuous electrical discharge might be energy intensive. He said, “why don’t we do an experiment and see what they do.” So, we set up a chart recorder to the pre-amp and oscilloscope and monitored the frequency of the electrical discharge over time. The first fish that we recorded was a Hypopomus electric fish. What we observed was that when left undisturbed, the fish would hide in a tube during the daytime and go completely silent, and then at night it would become active and would have elevated discharge levels. We then put the fish tank in a dark box, and incredibly, a circadian rhythm of electrical discharge was expressed by the fish. I was hooked! How did this happen and did the other species of electric fish also display circadian rhythms?

This experiment occurred during my junior year. Until that point, since I was a biology major, I became a default premed student. My closest friends at Swarthmore, David Mallot and Brooks Martin, were both hardcore premed students and went on to become physicians. So, not really knowing what my options were, I took the premed curriculum. In the fall of my junior year when one would apply to medical school, I learned for the first time that you could go to graduate school in biology. Out of about 40 biology majors in my class, only a couple of us went to graduate school instead of medical school. I told my parents that I had decided not to apply to medical school and instead would pursue research. Of course, my mother was a little disappointed because it was the tradition in the Hara family to become doctors or lawyers, but my parents nevertheless were very supportive of my decision. For my senior year, I did an independent research thesis project on circadian rhythms in electric fish. I went on to measure the electrical discharge patterns of about a half-dozen species of electric fish and wrote a thesis on my findings. At Swarthmore, independent thesis projects were evaluated by an outside faculty examiner at the end of the senior year. My external examiner was Dr. Patricia DeCoursey (1932–2022) from the University of South Carolina.¹⁷ Pat knew Ken Rawson from the University of Wisconsin, where they both had worked with John T. Emlen (1908–1997; father of Stephen T. Emlen at Cornell). Pat was the first person in the field of circadian rhythms to publish a phase response curve to the resetting effects of light pulses in a mammal in 1960.¹⁸ She had left academics to raise a family, but sadly her husband, George,¹⁹ died prematurely of cancer in his 40s, and Pat had to go back to work. At the University of South Carolina, she was friends with F. John and Winona Vernberg²⁰ who directed the Belle W. Baruch Institute for Marine Biology and Coastal Research at the University. The Vernbergs arranged a faculty position in the Baruch Institute for Pat, and she then had to find a project relevant to marine biology. Pat needed a research technician and through our interaction at my thesis examination, we connected, and Pat offered me the job. After graduation from Swarthmore, I moved to Columbia, South Carolina, to work with Pat in the Baruch Marine Institute. The year that I spent with Pat was truly wonderful. She became my mentor, and I became her circadian rhythms enthusiast. Although we could not work on circadian rhythms directly, we decided to work on a project to study the daily vertical migration of zooplankton in the water column in the estuary at the Baruch Institute field station. It was a fun project. We built a pontoon boat to conduct the water sampling. Then we designed and built an apparatus to lower into the water and collect water samples at different depths. We then collected samples at different times of day and the tidal cycle. The zooplankton samples were then counted and assessed for vertical migration. When we were back in Columbia on the main campus, Pat and I had countless discussions on circadian rhythms. I also had to apply to graduate school in the fall. At that time, I was interested in three fields: marine biology, orientation and navigation in pigeons, and circadian rhythms. In addition, to working at the Baruch Marine Institute, I had also worked on a National Science Foundation (NSF) summer fellowship at the Chesapeake Biological Laboratory (University of Maryland) in Annapolis, Maryland. The life of a marine biologist was nice: working on the water, being outside, catching fish, and playing volleyball, but I did not find the core work of collecting samples and doing field studies very interesting. It was more observational than experimental. So marine biology ranked third. In the BOAC course taught by Rawson, we studied bird migration and pigeon homing behavior. This led me to visit my Swarthmore friend, John Phillips,²¹ who worked in the lab of Kraig Adler at Cornell University in Ithaca and introduced me to the Department of Neurobiology and Behavior, where William T. Keeton (1933–1980)²² and Stephen Emlen²³ were renown experts studying pigeon homing behavior and celestial navigation in birds. With my love of pigeons as a child in Pakistan, I was very interested in working with Keeton.

For graduate school, I applied to the Scripps Institute of Oceanography at University of California–San Diego (UCSD) where James T. Enright (1932–2004)²⁴ and Walter Heiligenberg (1938–1994)²⁵ were faculty; Cornell University in Ithaca where Keeton and Emlen were faculty; Stanford University where Colin S. Pittendrigh (1918–1996),²⁶ the founder of the field of circadian biology, was in biological sciences; and the University of Texas at Austin (UT Austin) where Michael Menaker (1934–2021)²⁷ was in zoology. It was an incredibly hard decision for me to choose which of the three directions to go: oceanography, orientation and navigation, or circadian rhythms. But in the end, I became most interested in circadian rhythms.

University of Texas at Austin and the University of Oregon at Eugene

After applying to work with Michael Menaker, he wrote a letter to Pat DeCoursey saying, “that Takahashi looks pretty good, but can he speak English? … because we would like to support him as a teaching assistant.” Pat resolved that question easily. Later that spring, Menaker invited me to Austin for an interview and visit to the lab. I flew to Austin and Menaker picked me up at the airport in his 1954 MG TD roadster. The moment we first met, I knew that Mike was special and that we had much in common. We both went to Swarthmore College, loved nature, and loved sports cars (I had a 1970 Austin Healey Sprite). I knew that Mike was the right person to work with and joined his lab late that summer. Mike’s lab was an exciting place in which to work. The lab was engaged in photoperiodism in hamsters led by Jeff Elliot, Milt Stetson, and Fred Turek.²⁸,²⁹ Till Zimmerman was conducting the pineal transplant experiments that demonstrated the pineal was a circadian pacemaker.³⁰ The initial work showing the pineal was a circadian oscillator in vitro was being done by Chuck Kasal.³¹ Heidi Hamm was working the biochemistry of the melatonin biosynthetic enzyme, N-acetyltransferase.³² Fred Davis was studying the development of circadian rhythms in mice and hamsters.³³ Faculty who were especially influential for me at UT Austin were George Bittner, Frank Bronson, James Larimer, and George Pollak.

At the time, Menaker was best known for his discovery of extraretinal photoreceptors that mediated entrainment of circadian rhythms in birds.³⁴ This led to the discovery that the avian pineal gland was essential for the expression of circadian activity rhythms in sparrows,³⁵ which was the first anatomical locus to be shown to be critical for circadian rhythms in a vertebrate (predating the discovery of a similar role for the mammalian suprachiasmatic nucleus [SCN] in 1972). The lab was also the first to clearly demonstrate that photoperiodic time measurement of reproduction used a circadian clock to measure daylength in a mammal.²⁸

I decided initially to explore whether the SCN of birds also played a role in the regulation of circadian rhythms of birds. This would involve surgically lesioning the SCN of birds using house sparrows as the model system because they had robust circadian activity rhythms in constant darkness and because the role of the pineal had been established. At the time, no one in the Menaker lab was experienced in making brain lesions, especially in birds in cases in which the SCN had not been well-described anatomically. In talking to Colin Pittendrigh (Pitt) at Stanford, Mike learned that Pitt had a new postdoc, Rod van Buskirk,³⁶ who had been a student at the University of California–Irvine (UC Irvine) in the lab of James McGaugh (see volume 4)³⁷ and was an expert at making lesions and doing histology. He offered to train me in brain lesioning techniques and histology at Stanford. I was able to spend three weeks with Rod in Pitt’s lab learning how to do SCN lesions in mice, perfusing and fixing brains, cutting sections on a freezing microtome, mounting them on slides, and staining them with Nissl. Pittendrigh’s lab was also an exciting place. Gene D. Block and Terry L. Page were postdocs in the lab,³⁸ and Serge Daan (1940–2018)³⁹ and Pittendrigh had just completed writing the classic five-paper series on the properties of circadian activity rhythms in nocturnal rodents.⁴⁰,⁴¹ Next door, H. Craig Heller⁴² was studying hibernation, and in the same building, was Donald Kennedy’s lab,⁴³ where Gene Block was also a postdoc. Upon my return to the lab, I was able to determine the anatomical location and stereotaxic coordinates of the SCN in house sparrows and to make an extensive set of lesions in the SCN region and study the effects of these lesions on circadian locomotor rhythms.⁴⁴ SCN lesions indeed disrupted circadian activity rhythms in sparrows and therefore both the pineal gland and the SCN were essential for the generation of circadian behavioral rhythms in passerine birds.

Mike’s lab was the perfect environment for independent and motivated individuals. Mike had many resources that included the main lab on the UT Austin campus in Patterson Laboratories, and he had a “field” lab on the outskirts of town named Balcones Research Center, which was an abandoned magnesium plant built by the federal government during WWII and was acquired and owned by UT Austin. There we had our aviaries for birds and our very large-scale facilities for locomotor activity recording in house sparrows. At the time, Menaker had many hundreds of recording channels with automated computer collection of the data. This technology was led by Ed Kluth, a PhD in physics, who masterminded the data collection system. This was in the late 1970s and computers were only beginning to become available to labs. We used 8-bit programmed data processor (PDP) computers that communicated by punch tape. Despite these ancient relics, we were able to view our computer-generated actograms every week at lab meeting. We then transitioned the activity data collection system from birds to rodents, and many innovations for large-scale recording of circadian activity rhythms were developed by the Menaker lab back then. This system was influential to my career: those of us in the field have spent the past 50 years optimizing and scaling our ability to collect circadian data in an automated fashion ever since.⁴⁵

After I had spent about three and half years in the Menaker lab, Mike was recruited to become the inaugural director of the Institute of Neuroscience at the University of Oregon in Eugene. Mike had been on the faculty at UT Austin since 1962 so you can imagine how much equipment had accumulated and had to be moved and set up in Oregon. Upon making his decision, Mike hired Sue Williams, a former technician in the lab, to organize and facilitate the move and to set up the new lab in Eugene. The disassembly, packing, and transport of the hundreds of circadian activity chambers was truly a monumental task. The lab equipment filled up two tractor trailer moving vans. In Eugene, Oregon, we also had a “field station” annex to our main lab on campus called the Bio-Social Research Center. The facility was originally built for Dr. John Fentress (1939–2015) to study the behavior of wolves. Slightly off campus, it had a central building that was ideal for housing our circadian chambers, animal colony rooms, and aviaries. Outside were the enclosures designed for wolves, some of which the Menaker lab used for aviaries and others used to house crab-eating macaques from another lab.

After we moved the lab to the University of Oregon at Eugene, Pat DeCoursey spent a sabbatical in the lab, and we conducted action spectrum experiments for phase shifting the clock in hamsters.⁴⁶ Although I had attended UT Austin for my first four years of graduate school, I decided to transfer to the University of Oregon and obtained my doctorate in neuroscience in 1981. Oregon was an exciting place. Graham Hoyle, Russell Fernald, Frank Stahl, George Streisinger, Edward Herbert, Chuck Kimmel, Michael Posner, and Monte Westerfield were there. In addition, Jim Simmons, James Weston, Frederick Dahlquist, and Ross Lane were on my doctoral committee in Eugene. For my doctoral thesis, as I’ve described, I worked on the role of the SCN in the regulation of circadian activity rhythms in house sparrows to test whether the SCN in birds played a role similar to that seen in rodents. In separate work, I also developed a flow-through explant culture system for avian (chick) pineal glands that recently had been shown to express autonomous circadian rhythms of N-acetyltransferase activity.³¹,⁴⁷ To achieve higher time resolution and sampling from individual pineal glands over time series and to determine whether chick pineal glands could express persistent (more than two days) circadian oscillations, we collected culture medium samples continuously for four to seven days with a fraction collector and used melatonin release as the rhythmic output. In Eugene, we were able to expand the flow-through system from 4 channels to 16 channels and expand our melatonin radioimmunoassay capacity to 1,000 samples per week with the able assistance of Sherry Wisner, a research technician in the Menaker lab. At the time, this seemed to be relatively large scale, but we had to use radioimmunoassay of melatonin as our rhythmic output which was tedious and time-consuming. Despite these limitations, we were able to demonstrate that chick pineal glands expressed circadian oscillations of melatonin for at least four cycles in continuous darkness.⁴⁸ In addition, the chick pineal gland was responsive to light in vitro and this could be seen both as an acute inhibition of melatonin release as well as the enhancement of melatonin rhythms when maintained in LD12:12 light-dark cycles in culture. Thus, the chick pineal contained an entire circadian system: (1) a photic input pathway; (2) a circadian oscillator; and (3) an output pathway for melatonin synthesis.

I completed and defended my doctoral thesis in 1981, and I believe that I was the first doctoral student to graduate from the Institute of Neuroscience at the University of Oregon, Eugene, which began in 1979.

Mike was a big thinker and was always interested in evolution and “why” things in life were the way they were. He gave us great latitude in the lab and was not detail oriented. Indeed, we all knew that Mike was not a hands-on mentor and was happy to admit that he was not very good with his hands. Instead, Mike trained our minds. He was a critical thinker and our lab discussions about every subject were sharply focused on logic and evolutionary biology, which of course is not always logical. Many great ideas were discussed at length and then each of us would try to design and organize the best experiments to test our ideas. If you could make a good case for an experiment, then Mike would give you the green light and you were off to the races. It was a wonderful environment to conduct research and to learn the ways of the scientific world. Mike let us all in on the inner workings of the faculty and department politics. Thus, Mike trained us not only in how to do good science but also in how to survive and maneuver the world of publishing, grant writing, and university politics. Finally, Mike was an exceptional writer, and he took great pride in writing and tried to transfer these skills to us. In retrospect, I can see clearly how rare this was and how fortunate we as trainees of Mike have been.

Sadly, for the field of circadian biology, Michael Menaker passed away on February 14, 2021.²⁷ One profound regret that I have (despite continuous nominations since 2004) is that Mike was not elected into the National Academy of Sciences, which was a distinction that he clearly deserved. Since 2003, more than a dozen individuals working in the field of circadian rhythms were elected to the NAS, including Jeff Hall (2003), Michael Rosbash (2003), Joe Takahashi (2003), Woody Hastings (2003), Anthony Cashmore (2003), Aziz Sancar (2005), Mike Young (2007), Steve Kay (2008), Jay Dunlap (2009), Susan Golden (2010), Louis Ptacek (2012), Xinnian Dong (2012), Amita Sehgal (2016), Mitch Lazar (2017), Ying-Hui Fu (2018) and Ueli Schibler (2022). The most obvious and prominent omission from the NAS in our field is Michael Menaker.

NIH and NIMH

During my final year at the University of Oregon, I was awarded a Pharmacology Research Associate Training Program (PRAT) fellowship for two years from the National Institute of General Medical Sciences at the NIH. I decided to work with Martin (Marty) Zatz who was a member of Julius (Julie) Axelrod’s (see volume 1)⁴⁹ Section on Pharmacology in the Laboratory of Clinical Science in the National Institute of Mental Health (NIMH). Marty worked on the beta-adrenergic regulation of adenylate cyclase and N-acetyltransferase in the rat pineal gland with Julie,⁵⁰ and we decided to apply his expertise on adrenergic receptors and cyclic nucleotides to the chick pineal circadian oscillator. I was Marty’s first postdoc, and the lab was made up of the two of us. The lab was a single room with a lab bench and two desks at each end at which Marty and I sat. This was embedded within Julie’s Section on Pharmacology, which was in turn embedded within the much larger Laboratory of Clinical Science led by Irwin Kopin.⁵¹ We focused on photic and circadian regulation of cyclic nucleotides in the chick pineal gland in vitro.⁵² In addition, I collaborated with Arnold Eskin at the University of Houston on the serotonergic and cyclic nucleotide regulation of circadian rhythms in the Aplysia eye, which at the time was the best in vitro preparation for studying circadian oscillations.⁵³,⁵⁴

Marty was a character to say the least. We initially got along very well, but after a while, things became more tense. I was used to having a great deal of independence in the Menaker lab, which was a large freewheeling intellectual and physical space. The contrast with Marty’s lab was stark. Unlike Mike Menaker, Marty was very hands on and was involved in everything that I did. After about a year or so, this became stifling for me and led to some disagreements that distanced us until we resolved them many years later.

During my second year at NIMH, Julie’s section became part of Michael Brownstein’s Laboratory of Cell Biology, and Marty and I became members of the Brownstein lab. There I learned critical skills from Tomas Hökfelt,⁵⁵ a renowned scientist visiting from the Karolinska Institute, and Miklós Palkovits, the famous Hungarian anatomist. From Hökfelt’s technician, Gun Norell, I learned immunohistochemistry, and from Palkovits,⁵⁶ I learned rapid freehand dissections of rodent brains that would later be important for me to apply to the SCN.

Because I had a two-year fellowship at NIH, and I did not want to continue working there, I was exploring postdoctoral opportunities with Denis Baylor at Stanford. From my work with Pat DeCoursey and Menaker at Oregon where we measured the first action spectrum for phase shifting the circadian clock in a mammal,⁴⁶ I had become extremely interested in phototransduction mechanisms. King-Wai Yau and Denis Baylor (1940–2022) had just published classic papers on the biophysics of phototransduction in isolated rod photoreceptors.⁵⁷,⁵⁸ I vividly remember visiting Baylor’s lab at Stanford and was very fortunate to meet Lubert Stryer who had recently discovered the mechanism of photoactivation of the G-protein transducin.⁵⁹ Stanford was an amazing place. In addition, my sister, Nancy Takahashi, was an undergraduate at Stanford from 1977 to 1981, where she studied architecture and urban design and was on the Council of Presidents from 1980 to 1981. I visited Nancy on campus many times and came to love the Stanford campus.

Northwestern University

At the same time, however, Fred Turek at Northwestern University recruited me to apply for a faculty position in the Department of Neurobiology and Physiology on the Evanston campus. Fred was a former postdoc with Menaker, and he and I overlapped in the Menaker lab for about a week. I remember going to Fred’s going-away celebration at Scholz Beer Garden in Austin, Texas. Fred likes to say that we were a tag team. He took care of Menaker’s lab when he was a postdoc and then handed it over to me when I began in 1975. I applied for the job at Northwestern and was interviewed and then was offered a tenure-track position as an assistant professor. This event changed my original plan to go to Stanford, and I accepted the position at Northwestern and began in July 1983. My lab was next door to Fred’s lab in an “interesting” building known as Hogan Hall. The architect’s concept of the building for scientists was a monastery. He designed the building in a manner that reduced interactions because he believed that scientists would want to work in isolation without distractions. What could be further from the truth for those of us in science? In any case, Fred’s lab and mine shared a hallway entrance so thankfully we were not isolated from each other. Ironically, our two labs occupied the space that had previously been Frank Brown Jr.’s laboratory. This was ironic because Frank Brown did not believe in endogenous circadian oscillators and hypothesized that the 24-hour daily rhythms in living systems were driven in response to subtle geophysical cues from the earth’s rotation.⁶⁰ He and his disciples argued strongly against the existence of endogenous circadian clocks and believed all 24-hour rhythms were exogenously controlled. Although Brown’s hypothesis was the antithesis of the work from the founders of our field, Colin Pittendrigh and Jürgen Aschoff (1913–1998),⁶¹ Frank Brown was a true gentleman on the few occasions that I was able to meet him. After Frank Brown’s retirement, the exogenous hypothesis of circadian rhythms gradually faded away and today is buried under a mountain of evidence that circadian clocks are endogenous and are genetically determined.

When I started my new lab at Northwestern, I was interested in two areas of focus: (1) the sensitivity and integration of photic stimuli that entrain circadian rhythms in rodents; and (2) the cellular and molecular basis of circadian oscillations using the chick pineal as a model system. To study the photic entrainment of rodents, we used golden hamsters because of their extremely precise circadian rhythms of wheel-running activity. My first graduate student, Dwight Nelson, took on this project, and we focused on the threshold and integration of light stimuli that induced phase shifts in the circadian rhythm in constant darkness. Dwight performed beautifully quantitative experiments on the integration of intensity and duration for light pulses that reset the hamster clock.⁶² He showed clearly that hamsters could integrate light information for tens of minutes and that the optimal integration time was 300 seconds. Pulses either shorter or longer in duration were less effective in phase shifting and required more photons to achieve comparable phase shifts to that seen with 300-second pulses. The integration time of this photoreceptive system was 100 times longer than the known integration time of rod (1 second) or cone (100 milliseconds) photoreceptors, raising the question “at what stage in the photic pathway is the long integration time achieved?” The long integration time, high threshold, and spectral sensitivity curve for phase shifting was not consistent with the known photoreceptors in the hamster at the time. Indeed, in retinal degenerate mice, Russell Foster and colleagues showed that circadian phase-shifting responses to light were intact in the absence of rods and most cones,⁶³ strongly indicating that there must be additional photoreceptors in the retina. In 1998–2000, Ignacio Provencio discovered the novel photopigment, melanopsin, which was expressed in a subset of retinal ganglion cells in the retina.⁶⁴ In 2022, David Berson and Samer Hattar provided compelling evidence that melanopsin-containing retinal ganglion cells were intrinsically photosensitive,⁶⁵,⁶⁶ and subsequent work from many labs has firmly established that the mammalian retina has three classes of photoreceptors: rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs).⁶⁷,⁶⁸ Interestingly, the long integration time for the photoresponse for phase shifting can be seen in the spike output of ipRGCs and the Ca²⁺ responses of SCN neurons (Michael Tri Do, pers. comm.).

To study the cellular and molecular basis of circadian clocks in vertebrates, I chose to use the chick pineal gland as a model system because it contains all three elements of a circadian system (an input pathway, a circadian oscillator, and an output pathway) that could be studied in vitro. Upon setting up my lab, we focused on using primary dissociated cell cultures from the chick pineal. Cultured pineal cells were much more robust than pineal explants and allowed us to scale up these experiments using 96-well plates. Barbara Pratt, a talented postdoc, was able to study alpha-2 adrenergic and vasoactive intestinal polypeptide (VIP) regulation of melatonin and cyclic AMP in pineal cells.⁶⁹,⁷⁰ My graduate students, Linda Robertson and Selene Nikaido, were able to use perfused pineal cells grown on microcarrier beads to study circadian photic entrainment by light and circadian regulation of cyclic AMP synthesis and release.⁷¹⁻⁷³ We could study many aspects of the circadian clock in pineal cells, including the role of macromolecular synthesis and cyclic nucleotide and Ca²⁺ regulation.⁷⁴ Unlike the Aplysia eye circadian clock,⁵³ however, cyclic nucleotides did not reset the oscillator as an input but instead regulated melatonin synthesis in the output pathway. Protein synthesis inhibitors, however, were potent resetting agents and their phase-shifting action mimicked the effects of dark pulses (the opposite of light pulses).⁷⁴ We explored the role of protein synthesis in both rodents and chick pineal cells and found that protein synthesis inhibitors also mimicked dark pulses in hamsters.⁷⁵ The locus of action was the SCN, as demonstrated by microinfusion of anisomycin into the SCN region.⁷⁶ In 1990, the labs of Benjamin Rusak and William Schwartz reported that light exposure induced c-FOS expression in the SCN.⁷⁷,⁷⁸ Jon Kornhauser, a graduate student who worked with Kelly Mayo and me, rapidly followed up on the c-FOS experiments, and we showed that c-fos induction in the SCN was quantitatively correlated with the magnitude of phase shift induced by light in hamsters.⁷⁹ We also found that the induction of c-fos was dependent on the circadian phase and was only induced during the subjective night. Jon went on to show that jun-B was co-induced with c-fos in the SCN and that AP-1 DNA-binding activity was light induced in the SCN.⁸⁰ Soon after, we were contacted by Mike Greenberg and David Ginty about using the light response in the SCN to study Ser¹³⁵ phosphorylation of CREB using a phosphospecific antibody that David had recently created.⁸¹ The three of us (David, Jon, and I) performed the experiments together and found a rapid phosphorylation of CREB in cells of the SCN following light exposure of animals to light. Like the c-fos and AP-1 response, CREB phosphorylation was also “gated” by the circadian clock in the SCN. This work led to a long-term friendship with both David Ginty and Mike Greenberg.

In addition, to these two lines of inquiry, I also delved into identifying melatonin receptors. Margarita Dubocovich and I developed a high-affinity binding assay for melatonin receptors using 2-iodomelatonin as a ligand. I had used iodinated melatonin analogs for radioimmunoassays for our chick pineal melatonin flow-through experiments, and we had to radioiodinate the melatonin analog for the radioimmunoassay ourselves. Thus, it was easy for me to radioiodinate 2-iodomelatonin as a ligand for receptor binding assays. I synthesized and purified the 2-[¹²⁷I]iodomelatonin ligand, and Margarita did the binding assays. It worked like a charm. We were able to define high-affinity melatonin receptors using this ligand and published a two-author paper in 1987.⁸² Subsequently, this created a cottage industry for melatonin receptors and the ligand could be used to identify melatonin receptors in the brain using autoradiography.⁸³

During this time, I met my first wife, Barbara Snook, who was a nurse at Evanston Hospital and who was going back to finish her bachelor’s degree at Northwestern. Barbara graduated from Northwestern and then went to medical school at Tufts University in Boston. Barbara was from Northampton, Massachusetts, and came from a line of physicians. Her grandmother was a medical doctor and was the first female medical examiner in the state of Massachusetts. Her father, George A. Snook (1925–2017),⁸⁴ was an accomplished orthopedic surgeon and team physician at the University of Massachusetts in Amherst. After one year at Tufts, we decided to get married in 1985 and Barbara transferred to Northwestern Medical School and graduated in 1988. We lived in a university house very near to campus in Evanston. Barbara decided to do a residency in pathology at Evanston Hospital. She was interested in clinical pathology, but Evanston was stronger in surgical pathology, so the first year was pretty brutal with constant autopsies to be performed. Once Barbara became pregnant with our first child, Erika, who was born in 1991, she decided to take time away from medicine and devoted herself to raising Erika. In 1994, our son, Matthew was born, and Barbara then became a full-time mother to our two children. At that time, we finally were able to buy our own house and we moved to Wilmette, Illinois, into a very nice neighborhood on the North Shore. Once the kids were in school, Barbara then pursued one of her interests and went to the University of Illinois Chicago to get a master’s degree in public health. Erika and Matthew continued to be the center of her attention; therefore, Barbara did not pursue her career in medicine. She used her expertise in medicine and public health to volunteer for Congresswoman Jan Schakowsky (Ninth District, Illinois).

Once the children had grown enough, I introduced them to my two athletic passions, tennis and skiing. I was in my 40s at this time and having to focus intensely on the lab meant that staying in shape went by the wayside. After playing tennis, I noticed that my knees were sore, and the first signs of age were creeping in. This was an important wake-up call for me because I realized that I needed to pay more attention to my health and fitness. So along with tennis, my tennis pro, Jill Bachochin, who was very intense, became my personal trainer. She completely whipped me into shape, and magically, my knee pain went away. After Jill transferred to another tennis club, I had the good fortune to have Michelle Casati as my tennis pro. Michelle was on the pro tour for 10 years (ranked as high as 18th in the world) and was the best coach I have ever had. Since that time, I have always stayed in shape, and 30 years later my knees are still fine. Skiing has been more of a challenge both in having opportunities to be able to ski and remembering that I am no longer that teenager who could blast down the black diamond slopes with moguls willy-nilly. Now the blue runs are more my speed.

Search for Circadian Proteins and the Turning Point

Returning to circadian biology, based on the resetting effects of protein synthesis inhibitors in every circadian system that had been studied, the photic induction of immediate-early genes in the SCN, and the discovery of the period gene in Drosophila,⁸⁵ I was convinced that we had to find “circadian” genes and proteins. An extremely talented MD/PhD student, Jose C. Florez, joined my lab, and Jose decided to use two-dimensional (2D) gel electrophoresis to find oscillating proteins in chick pineal cells. We adopted the quantitative 2D-gel electrophoresis method developed by Jim Garrels at Cold Spring Harbor Laboratory,⁸⁶ and obtained a system from Protein Database Inc., which at the time was the state-of-the-art system. Jose conducted beautiful 2D-gel experiments and was able to quantitate 700 radiolabeled proteins from chick pineal cells.⁸⁷ A number of proteins changed significantly during the circadian cycle, but two (p56 and p22) in particular were most striking. Jose was able to use preparative 2D gels and isolate the p56 protein for peptide sequencing. The identity of p56 was tryptophan hydroxylase, which was confirmed by immunoblotting. Although we had achieved our goal of finding newly synthesized circadian cycling proteins, the result was disappointing because tryptophan hydroxylase is on the output pathway for the synthesis of melatonin. We did not know previously that it oscillated, but unfortunately, it was not a component of the circadian oscillator mechanism. Parenthetically, Jose Florez went on to have an incredible career on the genetics of type 2 diabetes and is now the chair of Medicine at Massachusetts General Hospital.

The 2D-gel experiments of Jose Florez were a turning point for me. Here we had used the most sophisticated biochemical method for detecting circadian rhythms in newly synthesized proteins. Jose could analyze more than 700 proteins, yet we could identify only a handful of them by peptide sequencing. Furthermore, a cell expresses more than 10,000 proteins and we could “see” only the top 700. That left the majority of the proteome invisible to us. There had to be another way to find circadian clock proteins. I came to realize that the only way that you could find a gene or protein without any preexisting information is genetics. You need a clear phenotype that you understand, but you do not need any mechanistic understanding of the phenotype as long as it is genetically transmitted (heritable). From following the discovery of the period locus in Drosophila by Ron Konopka and Seymour Benzer,⁸⁸ it was clear that single genes could control circadian rhythmicity. In addition, the discovery of a spontaneous mutant in the golden hamster that had a 20-hour period length clock demonstrated that, like Drosophila, rodents could also carry single-gene mutations with strong circadian clock phenotypes.⁸⁹

Genetics, My Second Career

Lawrence (Larry) H. Pinto in my department at Northwestern was using mouse mutants to study the visual system. Larry knew William (Bill) F. Dove and Alexandra (Alex) Shedlovsky (1933–2023) in the McCardle Center at the University of Wisconsin, Madison, who were conducting N-ethyl-N-nitrosourea (ENU) mutagenesis screens for an enzyme, phenylalanine hydroxylase. Larry, Fred Turek, and I decided to meet with Bill Dove and Alex, and we set up a collaboration to perform an ENU screen for circadian activity rhythms in mice. J. David McDonald in Bill and Alex’s lab performed the ENU mutagenesis and conducted a dominant screen for phenylalanine hydroxylase mutants using a C57BL/6J genetic background. After screening the mice in Madison, they shipped the mice to Evanston, and Martha Vitaterna, a talented postdoc in my lab, screened the mice for circadian phenotypes using our standard wheel-running activity assay. At the time in about 1990–1991, I decided to “invest” up to 100 wheel-running cages to this screen. This was a modest investment because we had many hundreds of wheel-running cages at our disposal. Our thinking at the time was that the ENU mutation rate was about 1 in 700 per locus per gamete and that if we screened 2,100 mice, we might achieve 3× coverage of the genome at this mutation rate. With 100 cages and a four-week phenotyping time for each mouse, we could screen 1,200 mice per year and achieve our goal of screening 2,100 mice in less than two years.

Despite the work of Konopka and Benzer (1971)⁸⁵ showing that mutations in a single locus could either abolish, shorten, or lengthen circadian rhythms in Drosophila, there was great skepticism that ENU mutagenesis could be used to isolate behavioral mutants in mice. ENU mutagenesis had been used only to identify lethal and overt mutations in mice. There were a few prevailing notions that led to this skepticism. First, behavior was thought to be a complex trait that was polygenic and unlikely to be driven by single genes. Second, most behavioral assays in rodents were devised for ease and convenience in the laboratory rather than for more ethological or naturalistic considerations. Thus, many behavioral tests for locomotion, anxiety, and learning and memory employ tasks and arenas that are contrived and artificial. As I have written elsewhere,⁹⁰ the variance in quantitative assessments of many behavioral assays is significant and therefore many behaviors are too noisy for screens. For example, a gold standard assay for learning and memory is context-dependent fear conditioning. In later work,⁹¹ screening many thousands of mice for defects in context-dependent fear conditioning, we found that the standard deviation for the percent freezing score was about 20 percent, with a floor of 0 percent and a ceiling of 100 percent freezing. With a mean level of 50 percent freezing, the greatest deviation possible would be 2.5 standard deviations from the mean or a Z-score of 2.5, equivalent to a coefficient of variation of 40 percent. Despite these general concerns, we were fortified with the knowledge that our circadian phenotype was orders of magnitude less variable (0.17 hour standard deviation divided by a mean of 23.7 hour = 0.00717 or a coefficient of variation of 0.7 percent). In addition, as I have discussed elsewhere,⁹² the key circadian phenotype is period length. This phenotypic measure is much less prone to artifacts because the overt periodicity that we measure at the behavioral level is determined by the periodicity (timing) of the underlying oscillator, even though the output pathway may be complex or many steps away from the oscillator. Other circadian parameters, such as the level or amplitude, can be affected independently of the oscillator and thus are less reliable phenotypes. Finally, the coefficient of variation of phenotypes, such as level or amplitude, are much larger than that seen for circadian period.⁹⁰

Armed with this knowledge, we undertook the circadian ENU screen, and Martha tested about 40 mice in the first batch. Mouse #25 in this batch expressed a circadian period of 24.8 hours in constant darkness. This was 1 hour longer than wild-type (WT) mice and was 6 standard deviations away from the mean circadian period of the screening population (23.7±0.17 standard deviation).⁹³ Because we found this mouse very early in the screen, we only screened 304 mutagenized mice. Test crossing this male mouse by conducting a backcross to WT females revealed that about half of the offspring carried the 1-hour-long phenotype confirming that the mutant phenotype was heritable and consistent with a dominant mutation. Intercrossing two presumptive heterozygous carrier mice then produced litters that might carry homozygous mutations. Indeed, in the very first F2 litter, there were four mice born, and upon circadian phenotyping, there were (phenotypically) one WT, two heterozygotes, and one homozygous mutant—a perfect 1:2:1 ratio for a semidominant Mendelian trait. This was the first homozygous mutant that we observed, and its phenotype was spectacular. The mouse could entrain almost normally on LD12:12, but upon release into constant darkness, it had a 28-hour circadian period, waking up 4 hours later each day. After about two weeks in constant darkness, the 28-hour circadian rhythm damped out and became arrhythmic. Thus, the mutation was semidominant for circadian period length with heterozygotes having a 1-hour-longer period and homozygotes having a 4-hour-longer period length. Light pulses could transiently restore the rhythm in constant darkness and reexposure to LD12:12 could restore a diurnal rhythm. We went on to map the mutant genetically to mouse chromosome 5 using the simple sequence length polymorphism (SSLP) map that had just been created in Eric Lander’s mouse genome center.⁹⁴ We named this mutant “Clock,” which ultimately was an acronym because one of the reviewers of our paper said it was too early to know whether the mutant was directly related to the circadian clock. The name of the gene then became “Circadian locomotor output cycles kaput” or Clock based on the phenotype of the mutant, which we published in 1994.⁹³

Discovery of the Clock Gene

Once we had isolated the Clock mutant mouse, which had a long circadian period phenotype that was comparable to the longest period mutants seen in Drosophila, we knew we were on to something. I began to change the focus of the lab to mouse genetics. We had already made the transition to molecular biology in the early 1990s, and now with the Clock mutant in hand, we could use this mutant to find the underlying gene using positional cloning. In the mid-1990s, positional cloning of mouse and human genes was nontrivial.⁹⁵ High-resolution genetic maps were only completed for the mouse in 1996,⁹⁶ physical maps of the mouse genome in 1999,⁹⁷ and the genome sequence of the mouse was not completed until 2002.⁹⁸

The first step in positional cloning was to map the Clock mutation with high enough genetic resolution (less than 1 centimorgan) to identify the genomic region of the mutant locus so that the genomic DNA could be cloned physically. David King, a talented graduate student in the lab, led this effort with Martha Vitaterna who made mapping crosses to two other inbred strains of mice to allow genotyping of the crosses. Bill Dietrich in Eric Lander’s lab was very generous in sharing his SSLP genetic mapping information and advising us along the way as he was creating the high-resolution genetic map of the mouse genome.⁹⁶ In the end, we collected about 2,600 meiotic events to fine map the Clock mutant to a 0.3-centimorgan interval in the middle of mouse chromosome 5. During this mapping process, it was clear that the task of positional cloning would require a team effort. There were too many different aspects of the project to do and too many different skill sets required for success. Thus, about a dozen members of my lab worked together as a team over a three-year period (1994–1997) to perform all the various steps required to find and clone the Clock gene (fine mapping, physical mapping, transcription unit identification, gene structure, cDNA identification, identification of the causative mutation, and transgenic mouse methods to confirm the identity of candidate genes as causal). I described the cloning of the Clock gene to the lab as a restriction point that we had to go through. On the other side, everything would open up, and each of the lab members could run with the fruits of the discovery.

I was fortunate to be introduced to Jeff Friedman at Rockefeller by Michael Young during a seminar visit there. Jeff had just cloned the mouse obese (ob) mutant using positional cloning and was in the process of publishing their landmark paper in Nature.⁹⁹ We were completing our high-resolution genetic mapping of Clock and transitioning to physical mapping of the region. Once we had fine mapped Clock to the midpoint of chromosome 5, we found that no one had been there before, and the region had not been cloned or physically mapped. In addition, very few of the genes in the region had been annotated. A large deletion mutant (W19H) in the region contained the Kit locus that was 0.7 cM proximal to Clock.¹⁰⁰ Complementation crosses of Clock with W19H showed that Clock was located within the W19H deletion; however, we estimated that W19H was about 2.8 cM in size, which did not narrow the critical region containing Clock sufficiently. Importantly, the deletion mapping of Clock allowed us to determine that the Clock mutant allele behaved as an antimorph.¹⁰⁰ The W19H deletion allowed us to observe the effect of a single copy of the Clock mutant allele in the absence of a WT allele. This Clock/deletion phenotype was more severe than the phenotype of Clock/+ heterozygotes, but it was less severe than the phenotype of Clock/Clock homozygotes. In addition, the +/deletion hemizygous phenotype was indistinguishable from the homozygous WT phenotype. Thus, the null allele was recessive to the WT allele. The relative severity and order of these mutant phenotypes is the defining characteristic of an antimorphic allele.¹⁰¹ This knowledge would be important for us later when we needed to rescue the Clock mutant to prove its gene identity.

Armed with this high-resolution genetic map, the next step was to map the genomic region physically. Yeast artificial chromosome (YAC) libraries of the mouse genome were available, and we were able to isolate a 1-megabase-long YAC clone that spanned the genetic interval containing Clock (assuming that we had not made any mistakes in genotyping recombinants that closely flanked the Clock locus). In talking to Jeff Friedman, he had just used bacterial artificial chromosome (BAC) clones to physically map the mouse ob region and encouraged me to use BACs to physically map our region. Although we did have a YAC clone spanning the region, YACs were very difficult to purify and manipulate (requiring pulse-field gel electrophoresis) and were unstable. In addition, many YAC clones were known to be chimeric (containing inserts from different parts of the genome) and therefore might be unreliable. We were able to screen a mouse BAC library using our genetic SSLP markers as sequence tagged sites (STS) and created a BAC contig physical map of most of the nonrecombinant genetic interval containing Clock. BAC clones were very stable and bacterial expression facilitated the recovery of significant amounts of DNA.

To find transcription units (genes within the region), two methods were used at the time: exon-trapping and cDNA selection. We decided to focus on cDNA selection because Jon Kornhauser and I had made cDNA libraries from the mouse SCN in order to find genes that differed between dark and light exposure of mice. We assumed that circadian clock genes should be highly expressed in the SCN because this was the anatomical locus of the circadian clock in mammals.¹⁰² Yaliang Zhao, a graduate student in the lab, performed the cDNA selection experiments. She used BAC clones as probes to screen the SCN libraries directly. In a second method, we developed a cDNA selection method based on the DNA subtraction method, representational difference analysis (RDA), to isolate cDNA fragments that hybridized with BAC DNA from the contig. Phil Lowrey in my lab was using genetically directed RDA to clone the hamster tau mutation, which we achieved a few years later in 2000.¹⁰³ In the end, cDNA selection worked and was extremely valuable in reconstructing the genomic structure of the Clock gene; however, it was not a comprehensive method and required the gene to be expressed in order to identify it. Therefore, we undertook a third method, which was to shotgun sequence BAC clones in the critical region. Lisa Wilsbacher and Ashvin Sangoram, two talented MD/PhD students, took on this aspect of the project. They purified BAC clones from the contig and made M13 shotgun libraries for single-stranded sequencing. This method turned out to be the best and most robust method for identifying genes in the contig. In addition, we used this genomic sequence to determine the gene structure of all the genes in the contig. A few years later, Lisa published the complete sequence and comparative analysis (mouse and human) of a 204 Kb interval containing the Clock locus.¹⁰⁴ Ironically, when we deposited this genomic sequence in GenBank, we were in the top 10 of groups depositing mouse genomic sequence—the rest of the list were all genome centers.

As we steadily created our genetic and physical map of the genomic region containing the Clock gene, we knew that we would need independent evidence that a specific candidate gene was the causative gene. For positional cloning in human genetics, independent evidence was satisfied by identifying two independent causative (with a phenotype) mutations in the same gene. In our case, we only had one mutation; therefore, we would need another way to confirm that the gene was causative. The best approach was to try to rescue the mutant using a WT version of the candidate gene. I had learned in conversations with Eddy Ruben at Lawrence Berkeley Labs and Nat Heintz at Rockefeller that one could make BAC transgenic mice reliably that contained very large inserts of 100–200 Kb. Doug Engel at Northwestern had also successfully made transgenic mice with YAC clones that were about 300 Kb in size. I was fortunate that I had two extremely talented research technicians, Eun-Joo Song and Weimin Song (later), who could make transgenic mice by pronuclear injection, and my lab had already set up a microinjection facility because our core facility was not efficient in creating transgenic or ES-cell derived mice at that time. We selected BAC clones that covered a 200 Kb critical region that should contain the Clock gene to make BAC transgenic mice using in vivo complementation as a functional assay for the Clock gene. Because previous work had shown that the mutant Clock allele was antimorphic (a “competitive” type of dominant-negative mutation),¹⁰⁰ we reasoned that it should be possible to rescue the Clock mutant phenotype by overexpression of the WT gene. Initially, we made three different BAC transgenic mouse lines. One of these lines containing a 140 Kb BAC transgene (BAC 54) completely rescued the Clock mutant phenotype. I remember the lab meeting in August 1996 vividly. Marina Antoch presented the results of crossing the BAC transgenic mice to Clock mutant mice. Of the three transgenic lines, only BAC 54 rescued the Clock mutant phenotype. This was a watershed moment because the rescue experiment showed beyond a shadow of doubt that the Clock gene was located within a 140 Kb interval. Until this point in time, we had hoped that our genetic and physical mapping was correct, but there was always the possibility that one or more recombinant mice had been mistyped and our genetic map of the critical region could be off. The rescue of the Clock mutant phenotype with a 140 Kb physical piece of DNA proved the gene was there. Subsequent shotgun sequencing of BAC 54 by Lisa Wilsbacher and Ash Sangoram revealed that there was only one gene located in the BAC. The gene turned out to be large, covering about 100 Kb genomically. Together the team, using cDNAs from the region and the genomic sequence of BAC 54, found that the Clock gene contained 24 exons (I joked later: one exon for every hour of the day) and encoded a basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) domain protein. The predicted amino acid sequence of the Clock gene strongly suggested that it was a transcriptional activator. Looking back, this was clearly the highlight of my career. Despite the naysayers, we had conducted a forward genetics phenotypic screen for a circadian mutant mouse to isolate the Clock mutant mouse, and we had used this mouse to find the causative gene using positional cloning and in vivo complementation using transgenic BAC mice.

We prepared two manuscripts of this work: one on the positional cloning and a second on the in vivo complementation of the Clock mutant. We submitted the manuscripts to Science magazine, where Katrina Kelner was the editor handling our submission. Shortly afterward, I made our first public announcement of the cloning of the Clock gene at a Neuroscience Symposium at the NIH organized by Zach Hall in March 1997. I spoke in a session in which I was preceded by Eric Kandel. I presented our work, and the response was overwhelmingly positive. Interestingly, within 24 hours of my talk, Ben Lewin of Cell Press contacted me stating that he had heard that we had cloned the Clock gene and that he would be very interested in having us submit our work to Cell. Of course, this was a dilemma because we had already submitted an editorial inquiry to Katrina Kelner at Science. I called a lab meeting, and we discussed this exciting invitation to submit our papers to Cell. The team unanimously thought that publishing in Cell would be preferable to Science. Therefore, I withdrew our submission to Science, and we submitted to Cell. Lewin reviewed our manuscripts in less than two weeks and accepted them pending minor revisions and offered us the cover. Thus, on May 16, 1997, our two papers were published in Cell.¹⁰⁵,¹⁰⁶ In retrospect this was a very good decision because our two papers spanned 26 pages in Cell. Had we published in Science, I am fairly certain that they would not have given us 26 pages to publish our papers.

As I mentioned before, there was always great skepticism that our approach to finding circadian clock genes in mice would work. First, there was the bias that single genes would not strongly affect circadian behavior because it was “complex.” Second, once we had isolated the Clock mutant mouse, there were two forms of skepticism: (1) we would not be able to clone the gene because positional cloning was too difficult (and we had better ask Eric Lander to help us clone the gene!); and (2) even if we succeeded in cloning the gene, it would not be very informative—it might be Calmodulin Kinase II. Well, we proved the skeptics wrong. The moment our paper appeared in Cell, the entire attitude to our work changed. Everyone now applauded it, and the skepticism and naysayers disappeared. This was truly one of the most enjoyable times of my career.

Howard Hughes Medical Institute

May of 1997 was also a signal moment for me because I was chosen to be a Howard Hughes Medical Institute (HHMI) Investigator with my appointment beginning on July 1, 1997. I considered it a high privilege to be able to work within such an august organization. My appointment to HHMI was not my first interaction with the institute. Donald Harter who was the HHMI scientific officer for Northwestern University was surprised that I had not been nominated in the 1994 HHMI competition. At that time, HHMI had just switched from institutional appointments to competitions for HHMI appointments. The competitions were limited to a set of universities, however, and each entity was allowed to nominate a finite number of candidates. In the case of Northwestern, only two candidates could be nominated and, in 1994, I was in line for nomination but two individuals were ahead of me. Meanwhile in 1996, I was recruited to Duke University and Baylor College of Medicine. There were four remaining institutional HHMI appointments in the country in 1996, and I was offered HHMI positions at both Duke and Baylor. My first wife, Barbara, was a New Englander and was not inclined to move to the south, so I eventually declined both positions, which was incredibly difficult for me because I was turning down guaranteed positions as an HHMI Investigator. In retrospect, these decisions were likely beneficial because in 1996 we had not finished cloning the Clock gene and moving the lab at that time would have been very disruptive to our effort to clone the gene. Luckily for me, I became an HHMI investigator in the 1997 competition.

NSF STC Center for Biological Timing

From 1991 to 2002, I was privileged to be a member of an NSF Science and Technology Center (STC) led by Gene Block at the University of Virginia (UVa) called the Center for Biological Timing. There were three institutions in the Center: UVa, Northwestern, and Rockefeller with Mike Young. This NSF STC was critical for the field of circadian biology because it allowed for a new effort that I led called the “Clock Genome Project.” This project involved conducting forward genetic screens for circadian mutants using Arabidopsis, Drosophila, and mouse. Steve Kay had created a circadian promoter::luciferase reporter in Arabidopsis, and Andrew Millar and Steve had isolated all of the critical circadian mutants in Arabidopsis during this time. Mike Young had been conducting screens for circadian mutants on the Drosophila autosomes, and eventually, we recruited Michael Rosbash and Jeff Hall at Brandeis into the NSF STC to corner the market in Drosophila circadian labs. The NST STC funded our work on cloning the Clock gene as well as the cloning of the hamster tau gene (which was a missense mutation in Casein Kinase 1 epsilon). At that time, it was not possible to fund this work through the NIH because it was too risky. Indeed, David King, Phil Lowrey, and Sharon Low all had their F31 NRSA applications declined because they were “too ambitious and too risky.” David was the first author of the 1997 Cell paper positionally cloning Clock; Phil was the first author of a Science article cloning the hamster tau mutant using genetically directed representational difference analysis; and Sharon was the first author of a two-author paper in Cell using chimeric mice to study the interaction of wildtype and Clock mutant cells in vivo for the generation of circadian activity rhythms. Sharon was awarded the Donald B. Lindsley Prize in Behavioral Neuroscience in 2002 from the Society for Neuroscience which is awarded to the best doctoral thesis in neuroscience in the previous year. These examples, exemplify the conservative nature of the NIH review process. Thank goodness we did not depend on the NIH to support our work on these “ambitious and risky” endeavors!

Mechanism of the Circadian Clock in Mammals

Going back to 1997, I contacted Mike Young, Michael Rosbash, and Jeff Hall and informed them that we had cloned the Clock gene and asked them if they would like to collaborate to identify the Drosophila ortholog. All three said they were too busy and that they would have to remove a student or postdoc from a project to take this on. So, Steve Kay and I decided to find the fly orthologs ourselves. We rapidly found fly-expressed sequence tags (ESTs) similar to mouse Clock and were able to clone and sequence full-length cDNAs of Drosophila Clock. At the same time, we knew that bHLH-PAS proteins worked as heterodimers; therefore, there should be a partner for CLOCK. Chuck Weitz at Harvard had just successfully found Drosophila TIMELESS, the partner of PER, using yeast two-hybrid (Y2H) screening methods. Chuck had made a hamster hypothalamus cDNA Y2H library, and we decided to collaborate to find the partner of CLOCK. In less than a year, we found that a novel bHLH-PAS protein, BMAL1, interacted with CLOCK, and the CLOCK-BMAL1 complex could transactivate the Drosophila period gene using reporter assays.¹⁰⁷ The mammalian Period1 gene had been cloned in September 1997 in both mouse and human, and we tested the upstream promoter region of mouse Per1 in transactivation assays with CLOCK and BMAL1. The CLOCK-BMAL1 heterodimeric complex was a strong activator of mouse Per1; thus, connecting CLOCK and BMAL1 to the Period1 gene. Steve and I were then able to clone the Drosophila ortholog of Bmal1. In 1998, at an NSF STC meeting, Rosbash and Hall reported the map positions of two arrhythmic Drosophila mutants that they had isolated in screens. Because Steve and I had cloned the Drosophila orthologs of mouse Clock and Bmal1, we knew the map positions of these genes and could see that they mapped to the two arrhythmic Drosophila mutants from Brandeis. At an HHMI Science meeting at which Rosbash and I were in attendance, I revealed to Michael that Steve and I had likely cloned the two Brandeis mutants. We had a conference call with Steve, and we agreed to cooperate and to coordinate our submissions for publication. In addition, Steve asked for the Brandeis Clock mutant, which appeared to be a truncation, and in return Michael asked for the Drosophila Clock EST sequence that we had determined at Northwestern. Sometime later Michael contacted us and said that we should submit our papers separately. In the end, Weitz and I published the identification of BMAL1 as the heterodimeric partner of CLOCK,¹⁰⁷, and Steve, Chuck, and I published the cloning of Drosophila dClock and dBmal1, with the additional finding that Drosophila PER and TIM fed back on dClock and dBmal1 to repress transcription, thus, closing the feedback loop of the clock mechanism.¹⁰⁸ Rosbash and Hall published two papers in Cell reporting the cloning of their two arrhythmic mutants as dClock and cycle (aka dBmal1). These results were all reported verbally in a symposium session at the 1998 Society for Research on Biological Rhythms meeting. The session was stunning because we had solved the initial core elements of the circadian clock mechanism in mammals and flies.

In mammals, the core mechanism included CLOCK and BMAL1 as upstream activators of the Period and later Cryptochrome (in 1999) genes whose protein products acted as feedback repressors of CLOCK-BMAL1 activation. In 1998, Mike Young’s group reported the cloning of the Drosophila doubletime mutant, which was encoded by Casein kinase 1. Later in 2000, we reported the cloning of the hamster tau gene, which turned out to be Casein kinase 1 epsilon.¹⁰³ Casein kinase 1 is now known to be a critical component of the clock mechanism that regulates the stability of the PERIOD feedback elements. Thus, by 2000, the conserved core mechanism of the circadian clock in mammals and Drosophila was solved.¹⁰⁹

Ubiquitous Expression of Circadian Clock Genes and Peripheral Oscillators

One of the surprises when we cloned Clock in 1997 was that the gene was expressed ubiquitously.¹⁰⁵,¹¹⁰ Our preconceived notion was that all clock genes would be expressed in neurons because the SCN was the locus of the circadian pacemaker in mammals. We now accept that clock genes are housekeeping genes and are expressed in essentially all cells.

Initially, in collaboration with John Hogenesch, Satchin Panda, and Steve Kay, who were working at the Scripps Genomics Institute of the Novartis Foundation (GNF), we used microarray technology to profile circadian gene expression in the SCN and liver of mice.¹¹¹ This was the beginning of our ability to observe the impact of the circadian clock system on gene expression in a genome-wide manner and led to the finding that circadian gene expression was largely tissue specific and affected a number of signaling pathways in the SCN and metabolic pathways in the liver.

What was perhaps even more surprising was the observation using circadian gene reporter technology that essentially every peripheral organ system and tissue has the capacity to express autonomous circadian rhythms.¹¹² This work was pioneered by one my most productive visiting graduate students and subsequent postdoc, Seung-Hee Yoo, who created the PER2::LUCIFERASE fusion gene targeted transgenic mouse in 2004. This mouse line has been distributed to hundreds of laboratories across the globe and has become one of the main circadian reporter mouse lines used in the field. Shin Yamazaki was an essential collaborator in this work because he pioneered the technology for long-term bioluminescence recording in rodent explants in the Menaker lab.

In retrospect, the ubiquitous expression of clock genes is a reflection of the universal capacity for most tissues and cells to express circadian oscillations. These distributed circadian oscillators are cell autonomous and can function independently of the central clock located in the SCN.112–¹¹⁴ The realization that the body is composed of a multitude of cell-autonomous clocks has raised a number of questions concerning the organization of the clock system and the role of the SCN clock in “circadian organization.” My laboratory also contributed to our understanding of the role of the SCN as a master pacemaker to synchronize peripheral oscillators,¹¹²,¹¹⁵–¹¹⁸ as well as the role of intercellular coupling in robustness of the SCN oscillator in work with Caroline Ko, Andrew Liu, Steve Kay, David Welsh, and Danny Forger.¹⁰²,¹¹⁷,¹¹⁹,¹²⁰

Ethan Buhr, a talented graduate student, explored how the SCN synchronizes peripheral oscillators and discovered that the circadian body temperature rhythm in the mouse is a powerful and universal entraining agent for peripheral oscillators.¹¹⁷ Interestingly, Ethan found that the SCN is resistant to temperature resetting and found that the intercellular coupling within the SCN accounted for this resistance. When the SCN network was uncoupled with tetrodotoxin treatment, the SCN became sensitive to temperature signals and behaved similar to that seen with peripheral tissues. Ethan went on to show that HSF1 was a mediator of temperature-induced phase shifts and may also be involved in temperature compensation of circadian period. This work and similar work from Ueli Schibler’s lab¹²¹,¹²² demonstrated that subtle circadian rhythms of body temperature can universally entrain all peripheral tissues and thus represents one of the entraining signals that the SCN utilizes to maintain systemwide synchrony.

Mariko Izumo, a talented postdoc, went on to show that conditional knockout of Bmal1 in the forebrain (BKO) of mice is sufficient to abolish circadian locomotor rhythms, and this led to a desynchrony of the phases of peripheral oscillators in constant darkness.¹²³ However, exposure of these BKO mice to LD cycles could rescue rhythms and maintain synchrony of peripheral oscillators. When time-restricted feeding (TRF) was imposed on BKO mice in constant darkness, digestive organs such as the liver and kidney could be entrained by the feeding cycles; however, other tissues became desynchronized and were not influenced by the feeding cycles. Therefore, peripheral circadian oscillators are dichotomous with some requiring SCN signals and others responding to feeding/nutrient cycles.

The discovery of peripheral circadian clocks also led to a deeper understanding of the role of peripheral clocks in organismal physiology. Perhaps the most profound discovery back in 2005 was the finding that the original Clock mutant mouse became obese with age and that this was greatly exacerbated by high-fat diet (HFD).¹²⁴ Joe Bass and Fred Turek went on to show that Clock mutant mice expressed a metabolic syndrome-like phenotype on HFD. This observation, and that from Dan Rudic and Garret FitzGerald,¹²⁵ clearly linked circadian mutations in mice with metabolic defects. Since that time, it has become clear that metabolism is one of the primary targets of the circadian clock system.¹²⁶,¹²⁷ My close friend and colleague Joe Bass and I have explored many aspects of circadian metabolism, including the regulation of the NAD+ salvage pathway by CLOCK and BMAL1, and the role of Bmal1 and Clock in glucose and insulin regulation in pancreatic beta cells.¹²⁸,¹²⁹

Mouse Genetics and Genomics

Between 1997 and 2000, I was invited to be a member of the National Mental Health Advisory Council of the NIMH by the director, Steve Hyman (see volume 10).¹³⁰ Two of us on the council were hardcore basic scientists: Richard Scheller¹³¹ and me. Steve Hyman was a strong proponent of using genetics to understand the mechanisms of mental health disorders, and we wrote a consensus working group statement on the “Future of Genetics of Mood Disorders Research.”¹³²

Harold Varmus was the director of the NIH, and he was a strong proponent of mouse and human genetics and genomics during the early days of the Human Genome Project. I was actively involved in four NIH committees that set priorities for mouse genetics and genomics between 1998 and 2000. It was an exciting time both for human and mouse genome sequencing as well as mouse phenotyping. During this period, the NIH finally began to support ENU mutagenesis projects for neuroscience and behavior, and three large-scale ENU mutagenesis centers were funded to conduct ENU screens for behavioral and physiological phenotypes in the mouse at the Jackson Laboratory, the Tennessee Consortium, and Northwestern University.¹³³,¹³⁴

The overall objective of the Neurogenomics Project at Northwestern was to produce, identify, and distribute mice with new neurobehavioral mutations in five phenotypic domains: learning and memory with Eric Kandel¹³⁵ at Columbia, circadian rhythmicity with Turek and me, vision with Larry Pinto and Val Sheffield at Iowa, responses to stress, and responses to psychostimulants with Marc Caron at Duke.¹³⁴ New mutations were produced by chemical mutagenesis using ENU. Our goal was to produce and screen 10,000 mice per year at a rate of 200 mice per week. We developed and scaled these phenotypic tests so that we could achieve 200 mice screened per week. Mice that were isolated as hits in the screens were bred to produce stable mutant lines, and their progeny were phenotypically screened for alterations in these phenotypic domains to confirm transmission of the mutant phenotypes. High-priority mutations were then genetically mapped to low resolution (50–100 meioses). Data and information regarding the mice, and the mutants themselves, were freely available to the wider scientific community. During our five-year screening effort, we isolated more than 200 mutant lines in the five phenotypic domains and dozens of the mutants were cloned. In the vision screen, a number of new mutants were isolated and cloned.¹³⁶–¹³⁹ In the circadian domain, new circadian genes, Fbxl3 and Fbxl21, were isolated, cloned, and mechanistically assigned novel functions within the circadian clock mechanism. FBXL3 and FBXL21 were shown to be novel F-box proteins that defined E3 ubiquitin ligase complexes that target the CRYPTOCHROME proteins for ubiquitylation and degradation by the proteosome complex.¹⁴⁰,¹⁴¹

At the peak of our screen, our mouse census reached 6,500 cages, and 2,000 cages were required for the ENU mutagenesis and production of 10,000 mutagenized progeny per year. In addition, the breeding and validation of heritability of the hundreds of mutant hits and the mapping of high priority mutants quickly increased our cage census. After about two years into the ENU center award, a new NIMH director, Tom Insel, was appointed, and the ENU centers were not a high priority for him. At the end of our five-year award, the NIMH did not allow us to apply for a renewal. All three centers were faced with figuring out how to continue and how to maintain the hundreds of mutant lines that we had isolated. I was able to obtain a number of NIH awards to support the cloning of circadian mutants and a private foundation grant that Zach Hall arranged from the Zaffaroni Foundation, called the Consortium for Mouse Genetics of Addiction, involving Marc Caron at Duke and Barak Caine at Harvard. I was also able to obtain a Silvio O. Conte Center for Neuroscience Research: Chemical and Genetic Manipulation of Circadian Systems from the NIMH that involved Michael Menaker at UVa; Steve McKnight at University of Texas Southwestern; Carla Green at UVa; John Hogenesch at Penn; and Louis Ptacek from University of California, San Francisco, which helped support the mouse costs along with my HHMI support.

The Allen Brain Institute

In 2002, I was invited to a very interesting event—it was a “charette” organized by Paul Allen to discuss and brainstorm about the possible creation of an institute devoted to the study of the brain. James Watson (CSHL) and Mark Boguski (NCBI) were the initial advisers to Paul Allen, and the charette took place on one of Allen’s yachts (named Tatoosh) anchored at Paradise Island in the Bahamas. The venue was quite remarkable. Tatoosh was a 303-foot yacht, and I was one of the lucky ones to be able to stay on board for the three days of the meeting. My room was like a Four Seasons hotel room with an Italian marble bathroom. The yacht had a crew of 32 to maintain and operate the vessel. The attendees were Paul Allen, James Watson, Mark Boguski, David Anderson, Cori Bargmann, Mark Adams, Gregor Eichele, Bruce Hamilton, Larry Katz, Marc Tessier-Lavigne, Arthur Toga, Carrolee Barlow, and me. At the time, Allen was one of the top five wealthiest people in the world, and Watson was hoping to convince Allen to donate a $1 billion endowment to fund the new institute. Unfortunately, the dot-com crash had occurred, and Allen decided not to create an endowment but rather to fund the new institute with operating funds. We had wide-ranging discussions on what the institute might do and how it might operate. In the end, the consensus was to create an institute whose initial goal was to map anatomically every gene expressed in the mouse brain and to create a gene expression atlas of the mouse brain that was freely available to all users. Thus, this was the genesis of the Allen Brain Atlas, which was launched in 2003 with a $100 million donation from Paul Allen. I had the privilege of serving on the scientific advisory board (SAB) for the first 10 years (2002–2012) of the institute. Paul Allen was highly engaged with the project and attended all of our SAB meetings. The initial mouse brain atlas was completed in 2007¹⁴² and the Allen Institute has grown and evolved substantially over the years.¹⁴³ The model of conducting large-scale projects that could not be achieved in either academia or industry was groundbreaking and has led to innumerable resources for the scientific community.

UT Southwestern

In 2008, returning to my lab and the mouse mutants we had isolated in our ENU mutagenesis center, I was no longer able to maintain these mutant mouse lines at Northwestern given the per diem costs for thousands of mouse cages, and so I began to look for alternative solutions. Shirley Tilghman at Princeton, a prominent mouse geneticist who worked on imprinting, had become the president of Princeton and therefore closed her HHMI lab and her large mouse colony. The empty Princeton mouse colony was the perfect solution for our mice, and I was offered a position as professor at Princeton. I then had to be approved for tenure at Princeton and was asked for letters of recommendation. One of my letter writers was Steve McKnight at UT Southwestern who said, “sure Joe, I’ll write you a letter, but I’m going to recruit you too.” Steve was the chair of the search committee for the new chair of the Department of Neuroscience, which had been vacated when Tom Sudhof went to Stanford in 2008. In the end, after offers from Princeton, Penn, and UCSD, I decided to go to UT Southwestern. I had not been looking for a chair position because at Northwestern I was associate chair for many years under Fred Turek and was acting chair for one year when Fred went on sabbatical. That experience taught me that while an interesting position, at Northwestern, it took significant time and effort and this I felt was not good for my research career. Once I became an HHMI investigator, Hughes did not like Investigators to be chairs (with a few exceptions), and so I was able to escape being chair at Northwestern because of this policy. By the time I went to UT Southwestern in 2009, however, there were many HHMI Investigators who also were chairs, including my predecessor, Tom Sudhof. Al Gilman who hired me at UT Southwestern was easily able to get approval for my appointment as chair from HHMI. I went to UT Southwestern for a number of reasons. They solved my mouse situation because per diems were much lower, and I had reduced my colony size. My charge as chair was to double the size of the Neuroscience Department, which included 10 tenure-track faculty and 2 research-track faculty when I began. UT Southwestern had a long tradition of having basic science chairs continuing to be strong scientists and, therefore, they kept administrative duties to a minimum to satisfy the HHMI requirement that we devote 75 percent of our time to research. UT Southwestern has outstanding scientists and by a number of measures (e.g., HHMI investigators, NAS and NAM members) is head and shoulders above Northwestern in the biological sciences. Finally, and perhaps most important, UT Southwestern cares about what you discover, not how much grant money you bring in. This atmosphere and tradition make UT Southwestern an exceptional place to do science.

In my role as chair, I have come to appreciate how rewarding it is to recruit talented junior faculty and to see them grow and prosper. I have recruited and hired 15 tenured or tenure-track faculty into the Department of Neuroscience. So far, all of my junior faculty hires have been promoted with tenure and have gone on to respected careers. These include Tae-Kyung Kim, Gena Konopka, Julian Meeks, Ryan Hibbs, Todd Roberts, Helen Lai, Brad Pfeiffer, Lenora Volk and Wei Xu. Of course, some of my faculty have been recruited away, which is sad for us but a good sign for them as they have gone on to bigger and better places for them.

At UT Southwestern, my lab was able to pursue two new avenues that were difficult to accomplish at Northwestern: (1) next-generation sequencing (NGS), and (2) structural biology. When I moved my lab to UT Southwestern in April 2009, there were no NGS machines on campus. Helen Hobbs and I were able to get the first NGS machine from HHMI instrumentation support. Together with Tae-Kyung (TK) Kim, who came from Mike Greenberg’s lab at Harvard and who discovered “enhancer RNAs,”¹⁴⁴ Nobu Koike in my lab used RNA-seq and ChIP-seq methods to perform a comprehensive global analysis of circadian transcription factor binding in the mouse liver in which all core components of the clock gene pathway were interrogated.¹⁴⁵ In addition, we also analyzed the genome-wide regulation of nascent transcription, RNA polymerase II occupancy, and epigenomic regulation of chromatin by the circadian clock. Although the most robust circadian pre-mRNA cycling occurred at target genes enriched for occupancy of the entire ensemble of core circadian transcriptional regulators, surprisingly, the most pervasive circadian regulation observed on a genome-wide scale were rhythms in RNAPII occupancy, H3K4me3, H3K9ac, and H3K27ac, which occurred at the majority of expressed genes whether or not RNA cycling could be detected. Thus, chromatin modifications associated with RNAPII initiation and transcription were very sensitive indicators of circadian regulation on a genome-wide level.

In addition to the genomics of circadian biology, we were able to solve the crystal structure of the CLOCK:BMAL1 bHLH-PAS heterodimeric complex.¹⁴⁶ By good fortune, when Hans Deisenhofer retired, I was able to recruit one of his senior lab members, Yoga Chelliah, who was an expert in baculovirus expression and purification. Yoga was able to quickly obtain crystals of the CLOCK:BMAL1 complex. The crystal structure revealed an unusual asymmetric heterodimeric conformation of the complex with the three domains of the two subunits, bHLH, PAS-A, and PAS-B, tightly intertwined around each other. Three distinct protein interaction interfaces were revealed in the structure and provided insight into how CLOCK and BMAL1 interacted as well as predicted how these proteins could interact with other regulatory proteins, such as CRY and PER. Thus, the structure of the CLOCK:BMAL1 complex provided insight into the assembly of multiprotein complexes required for circadian function and represented a foundation for decoding the mammalian clock mechanism at an atomic level. Indeed, little was known at the structural level for the entire bHLH-PAS family, which includes 16 members in mammals and is involved in a wide array of functions, including responses to environmental contaminants (Aryl hydrocarbon receptor, AHR), hypoxia (hypoxia inducible factor, HIF), neurogenesis (SIM1), synaptic plasticity (NPAS4), and circadian regulation (CLOCK, NPAS2, BMAL1).¹⁴⁷ In contrast, the structures of modular PAS domains and their interactions with small molecule ligands, such as heme and flavin cofactors, were well understood, especially among microorganisms and lower eukaryotes, where PAS domains serve important roles in two-component signaling and blue-light detection.¹⁴⁸ Although the PAS fold is widely conserved, it has intrinsic flexibility and can adapt to different conformations depending on bound ligands or interacting partners.¹⁴⁹ Despite our understanding of PAS domains and their modular interactions, the intact heterodimeric structure of bHLH-PAS proteins had previously eluded crystallographic solution, perhaps because of their inherent flexibility.¹⁴⁹ Thus, at the time, this was the first crystal structure for any bHLH-PAS transcription factor. The structures for a number of the bHLH-PAS proteins have now been solved and revealed surprising diversity in heterodimeric interactions among the proteins.¹⁵⁰

Forward Genetics in Mice: Reprise

Since the initial success of our screen that identified the Clock mouse mutant in 1994,⁹³ I have sought to apply forward genetics in the mouse for gene discovery of other complex behaviors.¹⁵¹ Because the majority of behaviors that we study are complex at many levels and despite the massive scale of our knowledge of genomic sequence, gene expression, and the rapid use and value of optogenetics to manipulate neural circuits, many behavioral and physiological processes remain a mystery. Genomics and gene editing have made reverse genetics (from gene to phenotype) facile and commonplace, but this approach still requires preexisting knowledge of a relevant pathway or well-supported candidate gene to be effective. I would argue that many interesting behaviors and processes still suffer from incomplete knowledge, and as such, would benefit from an unbiased approach for studying mechanism. This is the power of forward genetics, and in the current era of NGS, classic mutagenesis and screening approaches are having a renaissance.¹⁵² This is true for two primary reasons. First, in mice, loss-of-function alleles are limiting because of lethality (cannot study behavior for lethal genes) and because of paralogous genes (overlapping function). The classic one-third lethal, one-third no phenotype, and one-third with a phenotype still holds true in mouse genetics.¹⁵³,¹⁵⁴ Thus, despite the existence of the knockout mouse project whose goal was to create null mutations in all mouse genes in ES cells,¹⁵³,¹⁵⁵ two-thirds of genes are not readily accessible by loss-of-function analysis in vivo in mice. This is why point mutagenesis with ENU in mice remains important. More subtle mutants can remain viable and dominant negative mutants can overcome paralogous redundancy. The key to this approach today is that the previously arduous and rate-limiting step of positional cloning has been dramatically accelerated by NGS.

More recently, my lab was able to identify and clone a number of mouse mutants, including circadian F-box proteins (Fbxl3 and Fbxl21), led by Seung-Hee Yoo¹⁴⁰,¹⁴¹ as described previously. In addition, the psychostimulant screen at Northwestern done by a talented postdoc, Vivek Kumar, led to the identification of Cyfip2 as a gene that reduces the hyperlocomotion response to cocaine in mice.¹⁵⁶,¹⁵⁷ Importantly, Vivek found that a missense mutation in Cyfip2 occurs in the C57BL/6N substrain from NIH and is also found in C57BL/6 substrains distributed by Charles River (C57BL/6NCrl) and Taconic (C57BL/6NTac) in the United States.¹⁵⁷ Thus, caution should be exercised when using different C57BL/6 mouse strains because we and others have found that there are more than 50 genes carrying sequence variants that are likely to have functional consequences in C57BL/6N compared with C57BL/6J (the gold standard mouse strain and genome reference mouse strain).¹⁵⁷,¹⁵⁸

The most difficult phenotype for gene identification in our behavioral screens was context-dependent fear conditioning. As I mentioned earlier, the coefficient of variation for the freezing score in fear conditioning was a whopping 40 percent, which meant that individual mice could not be reliably scored as mutant or WT in this test. Therefore, the mutants that we isolated in the recessive screen were dominant mutations that could affect the entire pedigree quantitatively. A second problem was that mapping crosses to conventional inbred strains revealed quantitative trait locus (QTL) effects that increased the variance of the assay and masked the effects of the original mutant. Thus, it was not until an extremely persistent and rigorous postdoc, Pin Xu, took over the task of cloning the underlying genes involved that we succeeded in cloning fear conditioning genes. First to overcome the QTL effects of inbred strains, Pin used a closely related strain, C57BL/10J, to create mapping crosses with the mutant, which was on a C57BL/6J background. This greatly reduced the masking effects of QTLs and allowed mapping crosses to work. The first mutant that Pin identified was a line that exhibited very low freezing scores. Pin was able to show that this mutant was deficient in learning or encoding, and thus we named the mutant, Clueless. Eventually Pin was able to show that Clueless was caused by a point mutation in the potassium channel, Kcnc3,⁹¹ leading to a very strong loss-of-function in KCNC3 conductance. KCNC3 is highly expressed in dentate granule cells of the hippocampus, and thus, the likely site of action of the mutation occurs at this anatomical locus.

Perhaps one of the most demanding screens that we conducted was in a collaboration with Masashi Yanagisawa at UT Southwestern to find sleep genes. About two decades earlier at a biotech startup named Hypnion, which was initially founded by Emmanuel Mignot, Michael Rosbash, and myself, one of the goals was to identify sleep genes using ENU mutagenesis and EEG phenotyping. Unfortunately, the ENU screen was never accomplished at Hypnion. When I relocated to UT Southwestern, however, Masashi and I decided to do the screen. One of the reasons no had done such a screen was the massive effort involved. Each mutagenized mouse would have to be stereotaxically implanted with cranial electrodes, recover, and then sleep recorded by EEG for three days. The advantage of the EEG screen was that the phenotype was robust and quantitative, and Masashi’s lab demonstrated that most of the EEG phenotypes possessed low coefficients of variation so that we could isolate variants that were more than 3 standard deviations from the mean (or a Z-score >3.0). Using a dominant screen, we knew that it might require screening many thousands of mice to be successful. Masashi was undeterred by these numbers and developed methods to scale up the surgeries and EEG recordings. Initially at UT Southwestern, Masashi’s lab could screen 32 mice per week. Later, he doubled this capacity when he relocated to Japan to found and direct an institute devoted to the study of sleep at the University of Tsukuba. We published the ENU screen for sleep mutants in 2016 and described the first two mutants from the screen named Sleepy and Dreamless.¹⁵⁹ Sleepy, whose phenotype was excessive sleep time and sleep need, was caused by a point mutation in the splice donor site of exon 13 in the Sik3 gene, leading to an internal deletion of 52 amino acids in the SIK3 protein. Masashi and his colleague have gone on to show that SIK3 phosphorylation and HDAC4 acting in excitatory neurons regulate sleep need or drive, which is the homeostatic process underlying the process of sleep. The second mutant, Dreamless, whose phenotype was short REM episode duration, was caused by missense mutation in the Nacln gene.¹⁵⁹ NACLN is a sodium leak channel that leads to increased excitability of neurons in the brainstem that control the REM-off state. This work showed that despite decades of work on sleep mechanisms, forward genetics was able to reveal an entirely new pathway, SIK3, that regulated the homeostatic control of sleep and sleep need.

Circadian Rhythms and Parasites

A completely new area of research in my lab was pioneered Filipa Rijo-Ferreira who was initially a visiting graduate student in the lab. Filipa was the lynchpin forging a novel collaboration between my circadian laboratory at the UT Southwestern and the laboratory of Luisa Figueiredo at the Instituto de Medicina Molecular in Lisbon, Portugal. Filipa was a graduate student in the GABBA Program, a competitive doctoral program in the areas of basic and applied biology in Portugal. Filipa, under her own initiative, proposed to study Trypanosome brucei and circadian clocks for her graduate work. Because Luisa worked in the area of immunology, she thought that they would need more expertise in circadian rhythms; therefore, Filipa visited a number of circadian laboratories in the United States before selecting mine as the one with which she would like to collaborate. This was the beginning of one of the most interesting and productive collaborations that I have undertaken because it opened a new direction of research, and the discoveries that Filipa made were novel and unexpected.¹⁶⁰

In collaboration with my lab, Filipa pursued a project during her graduate studies on whether T. brucei, itself, has an endogenous circadian clock system. In Luisa’s lab, Filipa used RNA-seq to profile gene expression in cultured T. brucei that were synchronized by 24-hour temperature cycles and sampled over two circadian cycles. Filipa examined both bloodstream and insect forms of the T. brucei parasite. She found hundreds of RNA transcripts that expressed circadian oscillations, and these oscillations were completely independent of the cell cycle in these parasites (which had a cell division cycle period of about 7 hours). Thus, the trypanosome population expresses a circadian oscillation that transcends the cell division cycle. She found two major phase clusters of cycling genes, and these genes were enriched in a number of metabolic pathways. She then tested whether T. brucei exhibited a time-dependent circadian sensitivity to either metabolic insults (redox stress) or the drug suramin. She found in both cases that there was a circadian sensitivity to redox stress and mortality with suramin treatment. This provided evidence that circadian rhythms are physiologically significant in T. brucei.

In my lab, Filipa made two major discoveries in two areas of circadian biology and parasites. First, as a postdoctoral researcher in my lab, Filipa proceeded to address her original project on the effect of T. brucei infection on circadian rhythms and sleep in the mouse. Filipa discovered that T. brucei infection of mice not only induces characteristics of sleep sickness, but also has profound effects on the circadian system of mice. The regulation of sleep and circadian rhythms are related and linked, but each can be mechanistically separated at the molecular and brain circuit levels. In her initial work, Filipa found that as T. brucei infection progressed, the infected tissues displayed both an earlier circadian phase and a shortened circadian period. This occurred first in adipose tissue and then eventually in the brain and SCN, the site of the master circadian pacemaker in mammals. At the late stages of infection involving the brain, the behavior of the mice became more diurnal with an abnormally early phase of activity relative to uninfected controls that remained nocturnal. Body temperature circadian rhythms were also similarly affected. Thus, T. brucei infection clearly targets the circadian system as well as the sleep regulatory system. Thus, we proposed that “sleeping sickness” is actually a circadian disorder of the timing of sleep, which manifests in an excess of inappropriate sleep during the normal waking hours and a decrease in sleep during the normal sleeping hours of the day.

Second, Filipa delved into a new parasitic infection—malaria.¹⁶¹ She discovered that the periodic fevers that are characteristic of this disease are the result of the intrinsic clock in the Plasmodium parasite. We were intrigued by the fact that fevers occur every 24, 48, or 72 hours, depending on the species of Plasmodium, which means they are all multiples of 24 hours, or “modulo-24,” which is a signature of an underlying circadian process. (A well-known example of a modulo-24-hour process is the rodent estrous cycle, which is typically four to five days in length in mice, but the timing of ovulation is gated by the circadian clock.) The rhythmic aspect of this infection has been known for a long time, but the prevailing view in the field is that this was driven by the Plasmodium cell cycle and more recently by the host’s circadian rhythms. Through a series of elegant experiments Filipa dissected the different possible confounds, and she was able to show that the parasite population requires host cues to synchronize to each other but that the rhythms themselves are driven by an intrinsic parasite clock.

Importance of Circadian Time in Metabolic Function, Aging, and Longevity

Related to our work on the role of central vs. peripheral circadian oscillators,¹⁶² we found that peripheral tissue clocks are differentially synchronized by light cycles acting centrally as compared with nutrient cycles imposed by TRF.¹²³ When the light-dark cycle and the time of feeding are in conflict with their normal phase relationship, the brain and many peripheral organs remain locked to the light cycle, whereas “metabolic tissues,” such as the liver and kidney, can be reset by feeding cycles.¹²³,¹⁶³,¹⁶⁴ In addition to the entrainment of peripheral tissues by nutrient cycles, the timing of nutrient consumption has dramatic effects on metabolism. For example, my colleague at Northwestern, Fred Turek, showed that restricting an HFD in mice to either 12 hours during the daytime or 12 hours during the nighttime had completely different effects on body weight.¹⁶⁵ The mice that ate HFD at the wrong time during the day became obese, whereas the mice that ate the same HFD at the correct time at night were protected from weight gain. These types of TRF experiments have been replicated by many groups and restriction of overnutrition diets to the active night phase protects against weight gain and metabolic health in mice.¹⁶⁶,¹⁶⁷ This work has been translated to humans, and many studies have shown that time-restricted eating (TRE) in which nutrient consumption is restricted to 8- to 10-hour windows during the awake active phase has beneficial effects on weight loss, glucose regulation, and other health measures in people.¹⁶⁸ Thus, the timing of food consumption relative to the phase the circadian system in both mice and humans has important consequences on metabolism, body weight, and health.

Having become interested in TRF experiments and their health benefits in rodents, we wondered whether TRF might also have beneficial effects on aging. In the aging field, it has been known that caloric restriction (CR), a reduction in caloric intake without malnutrition, is the most effective nonpharmacological intervention for extending lifespan in model organisms.¹⁶⁹,¹⁷⁰ For example, a 30 percent reduction in calories leads to a 30 percent extension of lifespan in mice. However, despite the fact that this beneficial effect of CR was first reported more than 80 years ago,¹⁷¹,¹⁷² the underlying mechanisms are still largely unknown.

An extremely talented postdoc, Victoria (Vicky) Acosta-Rodriguez, took on this new project. We found profound effects of CR on the behavior of mice, and these effects raised some questions concerning the interpretation of classic CR experiments on longevity.¹⁷³ In these classic CR experiments, rodents were typically fed intermittently on Mondays, Wednesdays, and Fridays (for logistical reasons).¹⁷⁴ In addition, the food was given in the morning, a time when nocturnal rodents do not normally consume most of their food. As described earlier, timed food administration is a potent signal that entrains circadian clocks, particularly those in peripheral tissues, such as liver.¹⁷⁵,¹⁷⁶ Thus, in addition to reducing daily energy intake, CR resets complex circadian programs of gene expression in tissues throughout the body. Although the reduction in energy intake is commonly thought to be the critical factor that extends lifespan, it is possible that the timing of the food intake is a key component. For example, it is well known that high-fat diet (HFD) leads to obesity in mice. As described earlier, if the HFD is restricted to the nighttime, then mice do not gain weight.¹⁶⁶ In contrast, if the same HFD is given only during the daytime, then the mice become obese.¹⁶⁵ Thus, the obesogenic effect of HFD is caused primarily by consumption at the wrong time of the circadian cycle.

Once we began to contemplate conducting longevity studies on caloric- and time-restriction in mice, it became clear why previous CR longevity experiments used protocols in which the mice were not fed on a daily basis—these experiments could last as long as four years to complete, and it is a logistical challenge to feed the mice every single day without fail for the duration of the study. TRF experiments, if conducted manually, would require twice as much labor because the food would have to be given and taken away each day. Thus, to study the importance of time vs. calories, we developed our own automated feeding system.¹⁷³ We built our own automated feeders for two primary reasons: commercial products are too large, are expensive, and cannot be integrated with our circadian activity system. In my lab, we can record activity rhythms from more than 2,000 singly housed mice, and we have now added more than 1,500 automated feeders to our activity cages. This scale is required because ideally mice must be individually housed for longevity experiments to have continuous feeding and activity recordings, and as described earlier, the experiments take three to four years to complete, and large numbers of mice (>36–96 per condition) are required for Kaplan-Meier survival analysis.

Our automated feeding system revealed that different feeding schedules induced specific temporal patterns of food intake. We found that CR groups consumed their food within 2 hours regardless of the time of food availability (day or night) even though they had 24 hours of food access. This severe self-imposed TRF pattern suggested that a circadian component could contribute to the beneficial effects of CR.¹⁷⁷ Although a reduction in energy intake is commonly thought to be the critical factor that extends lifespan and well-being in the CR regimen, it is possible that the timing of the food intake is also a key component. Indeed, we found a profound difference in lifespan in C57BL/6J male mice that were calorically restricted to the same extent (30 percent CR), but that were allowed to consume food each day either immediately within 2 hours (self-imposed) or spread out over 24 hours. Surprisingly, the CR-spread fed mice had only a 10 percent longer median lifespan than ad libitum fed mice. Introducing a fasting interval but eating at the wrong circadian phase (CR-day fed) led to a 20 percent extension in median lifespan; in contrast, mice with circadian alignment of feeding (CR-night fed) had a 35 percent extension of median lifespan.¹⁷⁷ Thus, calorie reduction alone cannot lead to the dramatic extension of lifespan seen historically unless fasting and circadian alignment of feeding time are present.

Human studies are beginning to support the hypothesis that restricting the time of food consumption each day has beneficial effects.¹⁶⁷ Human studies also show that substantial degrees of CR (e.g., 30 percent) cannot be achieved by the majority of subjects for the prolonged times (decades?) necessary to extend lifespan.¹⁷⁸ Thus, TRE may be a more practical way to achieve health benefits in people.¹⁶⁸ We believe that our work will have the potential to affect the health of people in a direct and significant way.

Texas and Colorado

Having moved from Northwestern University to UT Southwestern in 2009, a lot of changes occurred in my life. Sadly, I separated from my first wife, Barbara, and later divorced. When I first split with my wife in 2008, Joe Bass took me in and I lived with Joe in his house until I moved to Dallas in 2009. Joe was also divorced so it was truly a wonderful time for the two of us to spend time drinking coffee in the mornings and having dinner and wine in the evenings discussing science, politics, and life. I will always be grateful to Joe for giving me a safe place to rest and recover. Dallas was very different from Chicago, but both cities are surprisingly ethnically diverse. The food scene in Dallas is very strong and interesting. Being a foodie, I was pleasantly surprised to find that Dallas has extremely good Japanese restaurants owned and run by Japanese chefs.

Once I moved to Dallas, I was able to recruit one of my circadian colleagues, Carla Green, from UVa. Our labs work closely together on many aspects of circadian biology. I was able to recruit a third circadian colleague, Shin Yamazaki, from Vanderbilt University in 2013. The three labs form a circadian core group, and we have a joint weekly/biweekly lab meetings together. Our UT Southwestern circadian group then became members of the Texas Society for Circadian Biology and Medicine, which meets annually at the three major circadian hubs in the state at Texas A&M, UT Health Houston, and UT Southwestern. Carla Green and I were friends for a long time, and in Dallas, we began to spend time together. In 2019, we were married. We both loved to play tennis and ski and like to go on vacation in Colorado for both skiing and hiking. Our favorite place in Colorado is the Roaring Fork Valley where Aspen, Snowmass, Basalt, Carbondale, and Glenwood Springs are located. Hiking in the “valley” is simply stupendous. Every valley/river/creek flowing into the Roaring Fork River is beautiful, but in addition, each is also unique in its terrain and flora. There is Independence Pass with its high alpine terrain; Castle Creek, Maroon Creek, and Snowmass Creek with their abundant aspen, fir, and spruce trees; the Frying Pan River valley with it red rocks and mixed coniferous forest; Sopris Creek valley, which is drier, with Gambel oak, piñon pine, and juniper forests interwoven with sagebrush meadows; and the Crystal River valley, a mix of both Gambel oak and mixed coniferous forest. Glenwood Canyon and the hot springs in Glenwood Springs cap off the end of the valley. By a stroke of good fortune, we stumbled upon a beautiful property overlooking Mount Sopris in Basalt along West Sopris Creek Road. It is a unique find because it is located in a relatively undeveloped valley so that it feels remote, yet it is only 15 minutes away from old town Basalt in one direction and 15 minutes away from two grocery stores and a modern complex in the other direction. In addition, Aspen is only 20 miles away with all its culture, art, and music. Finally, there are five ski resorts within a 30-minute drive. We plan on building a house there and eventually retiring there. I have always wanted to have a season ski pass and be able to look outside and decide if I wanted to go skiing that day or not.

Gratitude

In closing, throughout my career I have been blessed with exceptional mentors, students, postdocs, colleagues, collaborators (too many to have described here), and supportive institutions (Northwestern, HHMI, and UT Southwestern). In addition to my mentors who I have already mentioned (Ken Rawson, Pat DeCoursey, Mike Menaker), I am grateful for the support that I received from Colin Pittendrigh and Jurgen Aschoff who founded the field of circadian rhythms and who I was fortunate to interact with. Special thanks are due to my friend and colleague Fred Turek, at Northwestern, who recruited me there and helped launch my academic career. I feel extremely fortunate to have been selected as an HHMI Investigator, and my association with HHMI was clearly essential for taking my career to new levels. During my journey, I was very fortunate to have met and interacted with Eric Kandel (see volume 9),¹³⁵ Zach Hall, Floyd Bloom (see volume 7), and Solomon Snyder (see volume 6)¹⁷⁹ all of whom were very supportive of my career, including inviting me to serve on scientific advisory boards (e.g., Eric Kandel: Bristol-Myers Squibb Neuroscience Award Selection Committee; The Klingenstein Fund, Neuroscience Advisory Committee) or nominating me to the National Academy of Sciences (Sol Snyder). In the field of mouse genetics, Bill Dove, Wayne Frankel, Jeff Friedman, Eric Lander, Allan Bradley (HHMI and Sanger), and Steve Brown (Harwell) as well as many colleagues at the Jackson Laboratory were very supportive and welcoming to me as I entered my second career as a mouse geneticist. At UT Southwestern, Steve McKnight, Al Gilman, Dan Podolsky, and David Mangelsdorf have given me unwavering support. In the molecular genetics of circadian clocks, Michael Rosbash, Mike Young, and Ueli Schibler have been my close friends and colleagues for decades as we navigated the path to where we are today. Finally, I want to thank my wife Carla, my close friend Joe Bass, and my family (especially my son Matthew and my daughter Erika) for putting up with me through the years and having such a good time!

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Shimon Ullman

BORN:

Jerusalem, Israel

January 28, 1948

EDUCATION:

Hebrew University Jerusalem, BSc, Mathematics, Physics, Biology, summa cum laude (1973)

Massachusetts Institute of Technology, PhD, Electric Engineering and Computer Science (1977)

APPOINTMENTS:

Research Associate, AI Lab, MIT (1977–1979)

Principal Research Scientist, AI Lab, MIT (1979–1980)

Associate Professor, Brain & Cognitive Sciences, MIT (1981–1985)

Associate Professor of Computer Science, Weizmann Institute (1981–1985)

Professor, Brain & Cognitive Science, MIT (1986–1993)

Professor of Computer Science, Weizmann Institute (1985–present)

HONORS AND AWARDS (SELECTED):

The David. E. Rumelhart Prize in Human Cognition (2008)

Cognitive Science Society Fellow (2008)

Member, Israeli Academy of Sciences and Humanities (2011)

The Israel Emet Prize for Art, Science and Culture (2014)

The Israel Prize in Computer Science (2015)

Foreign member, American Academy of Arts and Sciences (2016)

A. Rosenfeld Award for lifetime achievement in computer vision (2019)

Shimon Ullman used computational modeling, at both functional and network levels, to study information processing in the cortical visual stream. His studies combine computational, psychophysics, and collaborations in biological experimentations. His earlier work focused on the topics of motion perception and object recognition. In the motion area, he established conditions under which a three-dimensional structure can be recovered from dynamic scenes, and he developed the first method for recovery of structure from motion. In object recognition, his early models were the first to combine bottom-up with top-down segmentation, and to localize objects and their parts and subparts in a single bottom-up, top-down cycle. Moving from objects to complete scenes, Ullman developed a model that performs human-like scene interpretation, using iterative bottom-up and top-down processing in a “counter-streams” structure motivated by cortical circuitry. Using data from visual learning by infants, Ullman developed models that can learn complex concepts from dynamic visual scenes, without supervision or annotated data. This modeling shows how innate domain-specific “proto concepts” can guide the visual system to acquire meaningful concepts and reveals how a rich conceptual system can gradually arise from the combination of innate mechanisms and visual experience.

Shimon Ullman

Stormy Beginning

I was born in the midst of a raging war, in a makeshift facility in downtown Jerusalem. Only three hours later, I was carried with my mother in an armored vehicle to the well-equipped Hadassah Mount Scopus Hospital, just outside the city, to spend the night and the following day. The hospital had to close down its operation a couple of months later, following the Hadassah medical convoy massacre, when a convoy carrying supplies to the hospital was ambushed. Only a few of the medical staff in the convoy survived the attack, among them my father, Theodor David Ullman (“Theo” for us), who was a physician in Hadassah. He found shelter in a ditch not far from the road and hid there until night time. He then made his way to our apartment in Jerusalem, avoiding the Arab villages along the way, and arriving home by dawn. My mother heard about the fate of the Hadassah convoy from the radio news, and I can only imagine, since she never described to me, how she felt when Theo appeared at the doorstep in the early morning hours.

The apartment we lived in was in a place called the “Mandelbaum gate,” which ended up in a no-man’s-land between Israel and Jordan. During the 1948 war, it was very close to the frontline and became a place of increasing hostilities. It was hit by snipers’ bullets several times, and at one point, a larger projectile landed inside our apartment. When this happened, my parents carried the children, my sister Edna and me, and left the apartment, leaving all the belongings behind, never to come back.

I recalled these events many years later, when I was standing with my wife Chana in a demonstration in the Palestinian neighborhood of Sheikh Jarrah in East Jerusalem. The demonstration was in support for Palestinian residents who were being evacuated from apartments they had moved into during the 1948 war. The place where the demonstration took place was about midway between the apartment we had to leave during the war and the place where the Hadassah convoy was ambushed, a short walking distance from both. The past memories and the demonstration formed an eerie mix, underscoring for me in a personal way the need to resolve the ongoing Israeli-Palestinian conflict.

Family and Early Life

My father was a German Jew, born in Würzburg to a large orthodox family. He studied medicine in Würzburg and Berlin, and came to Israel in 1934. He was a physician in Hadassah hospital and a professor at the Hebrew University in Jerusalem, specializing in nephrology. After spending a year at the Mount Sinai Hospital in New York, he was the first to introduce kidney dialysis to Israel. I remember him telling me about the ethics committee established in the hospital, which had to make painful decisions regarding who would be eligible for dialysis treatment, because it was impossible to treat all the patients needing treatment. He was a brilliant thinker, was quiet and hard-working, and had immense general knowledge.

My mother, Lisa Findler, was born and raised in Vienna, until the age of 16. She left after the Anschluss of 1938 and went on her own via Italy to Palestine. Her parents were supposed to join a few weeks later, but never made it out. After finishing British matriculation exams by correspondence, she enrolled into a nursing school and became a nurse in Hadassah Hospital, where she met my father. She kept working as a nurse and later as a laboratory assistant, until I left home years later, and then started academic studies at the Hebrew University, in the classics department. She eventually became a staff member in the university, teaching Greek and Latin, and became a scholar and a translator. At the age of 77, she undertook the daunting task of translating from the Greek Josephus’s first-century book The War of the Jews. This is a major book, described by the historian Steve Mason as “perhaps the most influential non-biblical text of Western history,” and one of the first books printed by Gutenberg in the 15th century. The translation took 10 years of hard work, and when it was published, it was an immediate literary and commercial success. I remember that in one of his visits to Israel, Eric Kandel was at our house and met my mother. He was delighted to meet a fellow Viennese who, like him, was interested and highly knowledgeable in literature, art, and music.

My sister, Edna, was only a year and a half older than me. We have been very close, and her early death in 2010 was an immense, life-transforming loss for me. She was a philosopher and was interested in issues of rationality as well as decision-making problems, from simple to transformational, and problems of social order. The issues she was interested in and worked on had bearing not only on philosophy but also on political science, psychology, sociology, cognitive science, economics, law, and public policy. Her personal life echoed her philosophy; she was a highly rational person, and at the same time, she was passionate about the values she studied and believed in. She was the chair of the Association for Civil Rights in Israel and on the management of the New Israel Fund and of B’Tselem (The Israeli Information Center for Human Rights in the occupied territories). She was also a gifted translator, in both science and literature. She translated to Hebrew Wittgenstein’s Philosophical Investigations and On Certainty from the original German, and her wonderful poetry translations from both German and English appeared in Haaretz’s literary supplements. I think one can get a wonderful glimpse of who Edna was from a New Yorker piece called “The Unmothered,” written by her daughter Ruth Margalit (https://www.newyorker.com/books/page-turner/the-unmothered).

During my school days, both elementary and high school, I was an avid reader, taking books out of the school library several times a week and enjoying reading them. I now have grandchildren who do the same, and I enjoy seeing their enthusiasm and watching how reading enriches their inner worlds. In high school, I became highly interested in science, reading well beyond the material covered in school. I was fortunate to have an inspiring teacher of mathematics, a young woman in her twenties who had the gift of conveying the beauty and rigor of mathematical thinking.

When high school ended, it was time to enlist to military service, which is compulsory in Israel. It was clear to me by that time that my future would be in academic research, but I decided to spend my service doing something completely different and joined the air force for more than five years. This was an eventful and challenging period, but I will not elaborate on it, as this period was about as far from an academic path as one can imagine.

Starting Academic Life: The Hebrew University

After a long break from any form of academic studies, I was eager to start my scientific education. At the Hebrew University, you could either focus on a single field, such as physics, mathematics, or biology, or combine two fields, taking half of your academic credits in each field. I knew I wanted to take mathematics as a major field, but after some deliberations, I decided to combine mathematics and physics. Math was my major field, and I joined an accelerated track that had an expanded curriculum. The beginning was demanding, as the academic year started before I was released from service, and it took a while before I could devote my full time to the academic studies. This did not detract from my excitement, and I thoroughly enjoyed delving deeply into math and physics. Math was particularly rewarding, as I was taught by brilliant mathematicians and teachers, such as Hillel Furstenberg, Azriel Levy, and Yakar Kannai, who were able to get across not only mathematical knowledge but also their personal ways of thinking about mathematics. Regarding physics, although I enjoyed it, I was not sure whether this was in fact the field of science I wanted to get into. I therefore attended during the first year a couple of classes in neuroscience, to learn a bit about the brain, which I thought was a fascinating topic and on which I knew relatively little. At the end of the first year, I found myself in a Frostian dilemma in “the road not taken,” facing diverging roads, and being “sorry I could not travel both, and be one traveler.” It felt like a major crossroads, choosing between exploring the external universe of physics, and the internal universe of the brain, thought processes, and the subjective world of awareness and consciousness. Like many big decisions, this was not a utilitarian choice but rather an opportunity to imagine what would be for me more exciting and rewarding. It took some time, but I chose the internal universe, and although I find the big questions of physics fascinating, I did not regret the choice. The practical outcome of these deliberations was that I added a full program in neurobiology, without giving up physics, to my undergraduate program.

Toward the end of my undergraduate studies, I started to have a general notion of the kind of basic scientific problems I would like to pursue. I wanted to study how the brain works, by somehow combining aspects of biology with some form of mathematical or theoretical work. I was more attracted toward the theoretical side, but I wanted to stay close to the actual anatomy and physiology of the brain. On the theoretical side, I was starting to think about models that would be able to mimic some of the functions of the human brain. I was wondering if somewhere there were research groups or individuals working along such lines. Searching for relevant information was not as straightforward as it is today, but at some point, I came across descriptions of the artificial intelligence (AI) laboratory at Massachusetts Institute of Technology (MIT), and I was highly intrigued. There were reports, many in the form of internal AI memos, describing attempts to develop computer models that were trying to replicate some forms of human thinking. At the same time, MIT had a strong group of neuroscientists, housed at the time at MIT’s psychology department, headed by Hans-Lukas Teuber. This appeared to me to be a wonderful unique opportunity, to study at MIT, combining neuroscience with the research laboratory with the strange name of AI. I applied, describing my interests, and when I was accepted, the decision was immediate: I would go to MIT to follow these research interests.

During my undergraduate studies at the Hebrew University, I met my future wife, Chana. We were introduced by a classmate of my sister, who told Chana “you must meet Edna’s little brother.” We met, and for me, it was an immediate click. She was (still is) beautiful and highly intelligent, with a unique personality, sensitive, empathic, original, and perceptive. When it was time for me to leave for MIT to start the school year, she was in the last stages of finishing her master of science degree in psychology at the Hebrew University. We decided that I would go initially on my own, and she would join me a few months later, as soon as she hands in her thesis. In late August 1973, I flew to Boston to start my MIT studies. We did not know then that we would meet again sooner than expected, under strange circumstances.

A Student at MIT: Human and Computational Vision

I settled down in Cambridge, and started the school year, when life took a sudden turn, without a warning. It was an early Saturday morning of October 6, 1973, when breaking news started to broadcast stories about intense fighting raging between Israel and its neighbors, Egypt on the south and Syria on the north. There was initially considerable confusion, and it was unclear whether these were border skirmishes or an all-out war. I was trying to get more information in a series of phone calls with friends in Israel and in the Boston area, and with the Israeli embassy. The situation began to look serious enough, and I decided to fly home immediately. Flights had been suspended, but there was one last El Al flight leaving New York’s Kennedy airport in the afternoon, and the embassy informed me that there was a seat reserved from me on this flight. I took the car I just purchased in Cambridge, and drove to JFK as fast as I could to catch the flight. With me, I took a fellow student at MIT, Benjamin (Bibi) Netanyahu. I knew his brother, Yoni (later killed while leading the rescue raid at Entebbe Airport in Uganda), who told me to look up his brother who was already an architecture student at MIT.

When we arrived in Israel (the stewardess wished us “a pleasant stay in Israel”), I took a cab to my base, where I was greeted by my squadron commander, Udi. Good natured, and always calm, he told me “have a good night’s sleep; you will have a busy day tomorrow.” The next day, Monday, was indeed a busy day, during which Udi was unfortunately shot down. I was supposed to have my first exam at MIT that day, but instead, I found myself over the Suez Canal in the morning, and over the Golan Heights in the afternoon.

When the war was over I came back to MIT, and a few days later I met David Marr, a meeting that had a profound impact on my academic life. Within a short time, he became my academic mentor, and later also a close and dear friend. David arrived at MIT only a few months before me, from Trinity College in Cambridge, England. I was struck by his scientific thinking and intelligence, and by the close fit between what I was looking for, and what he was already doing in his research. Initially, he could not be my formal doctoral supervisor, because his position was of a researcher rather than faculty member. Marvin Minsky, who was then director of the MIT AI lab, graciously agreed to act as my formal supervisor, but let David do the actual supervision. David already had a brilliant scientific record from his Cambridge doctorate and subsequent work. During this work, he produced a mathematical theory of three major parts of the brain: the archicortex, cerebellum, and neocortex. This work, in particular the cerebellum theory, had a large impact on the neuroscience community. David became dissatisfied with the general kind of modeling developed in his own work, however, and started to form a new modeling direction he wanted to pursue.

This new direction took several years to develop and take form, but the main ingredients were clear from the beginning. A basic aspect of the new direction was the combination of brain and computation. This meant combining empirical studies of the brain with computational models that could carry out functions performed by the brain. In the domain of vision, the computational challenge was to create computer models that could carry out tasks that our visual system performs for us and to use the modeling to analyze and interpret empirical findings as well as to guide new experiments. Many of the functions carried out by our visual system are complex and difficult to imitate by computational models. Constructing successful computational models is therefore likely to reveal useful information about the nature of the task and about possible processes that the visual system may be using to carry out the tasks in question. Marr realized from his own work how difficult it is to go from empirical data obtained by neuroscientists to an understanding of how the brain functions. Computational modeling offered a complementary way to gather relevant information, and combining the two sources of information became the foundation of the emerging field of computational neuroscience. This potential integration motivated Marr to move to MIT’s AI lab, because this was a research laboratory where researchers where trying to develop functioning brain-like computational models. My own motivation in coming to MIT was similar, and I was fortunate to meet Marr upon my arrival to the AI lab. It was true that MIT AI researchers were trying to develop computational models with some capacities of the human brain, but not much attention has been paid to possible relationships between the models and the human brain. Luckily, when I arrived, the AI lab already had the most qualified person in the world to lead this research direction.

Because my knowledge of human vision was limited, I spent significant time reading and studying the anatomy, physiology, and psychophysics of the primate visual system. MIT had wonderful people to learn anatomy and physiology from, and I learned a lot from them, in particular Mike Sryker (see volume 11) and Peter Schiller (see volume 7). Anatomy looked to me initially somewhat dry and boring, but I gradually learned to appreciate its importance and even elegance. At some point during this early period, I went with Marr to visit Francis Crick at the Salk Institute, who became highly interested in the brain in general and the visual system in particular. He knew David from their Cambridge days and invited him often to learn from him and discuss novel ideas and approaches. I was struck by Crick’s emphasis on the anatomy of the visual system. He became an expert on the detailed structure of the visual cortex, and he even constructed some three-dimensional models of parts of the system. This was perhaps related in part to his DNA work in which structure and function were of course intimately related, and he similarly used cortical structures as a source of insight about functional mechanisms.

Along with getting more familiar with the visual system, I started to think about different visual functions, and what it would take to perform them by computational models. I wanted the model to be able to approximate human performance, but also to consider possible implementations in biologically plausible network models and possibly comparisons with neurophysiological or psychophysical data. In trying to model visual tasks, I soon learned to appreciate the complexity and sophistication of the visual process. Even for seemingly simple visual tasks, obtaining a model that can rival human performance can be surprisingly challenging. I will describe briefly an example of a visual problem I was concerned with early on in my studies, which can illustrate some aspects of the state of the art at the time, and early developments in dealing with computational vision.

The problem was to characterize the shape of subjective contours generated by the visual system and to provide a model for their generation. These contours do not exist objectively in the image, but they are generated by our visual system under some conditions that suggest the existence of an invisible surface occluding the background. There has been considerable work on the conditions that make the visual system infer, or suggest, the existence of such invisible surface. However, there was no empirical or theoretical analysis of the shape of the subjective contours generated by the visual system. Because subjective contours are generated by the visual system, the analysis of their shape may provide clues about the mechanisms that generate them. The theoretical analysis suggested that the shape of a contour that fills in the gap between two boundary edges is composed of the arcs of two circles, tangent to the boundary edges, meeting smoothly, and minimizing the total curvature along the contour. This shape was derived from a number of general global assumption made about the contours, based on empirical observations (isotropy, smoothness, locality, and minimal curvature). If these properties are assumed, the two-arc shape of the entire contour can be derived analytically. This conclusion about the circular arcs as elements of the full contour is also consistent with later work about the facilitation in the primary visual cortex between cocircular contour segments [1]. As my first attempt in network modeling, a simple network model was proposed for generating the full subjective contours given the visible edge fragments. The model is based on local interaction between neighboring line elements that depend on their orientation difference, and eventually selecting the most active line element at each point.

In related work some 10 year later, the model for subjective contours was extended to a model that constructs a saliency map, which is a representation of the image emphasizing salient locations [2,3]. This work was done together with my then-student Amnon Shashua, who later on, as a professor at the Hebrew University, became the cofounder of Mobileye, a leader of the autonomous cars industry. Amnon was a superb student, sharp and creative, and it was clear early on that he has an unusual combination of scientific talents together with a practical sense and leadership qualities. When he finished his master of science work at the Weizmann Institute, he moved to MIT to do his doctorate with Tommy Poggio (see volume 8).

The Interpretation of Visual Motion

The main part of my doctoral research was concerned with visual motion—that is, how the visual system measures the velocity of objects in the image, and how objects’ motion is used to recover their three-dimensional shape. I was fascinated by the ability of the human visual system to recover the three-dimensional shape of moving objects based on motion information alone, even when each static image contained no information about the objects’ shape. Consider, for example, a cloud of points moving together rigidly in space. A single projection of this configuration onto an image produces just a random-looking arrangement of image points, which does not reveal the three-dimensional structure of the actual object. However, as soon as the object starts to move, the dynamic pattern of the moving object gives rise to a vivid perception of the true three-dimensional object. This has been a long-known phenomenon in the study of visual perception, called the “kinetic depth effect,” first described by the great experimental psychologist Hans Wallach and coworkers in the 1950s. In the perception literature, it was sometimes explained in terms of a “tendency” of the perceptual system to perceive rigid objects. But behind this “tendency” lies a striking capacity of the visual system to solve a complex problem: given a collection of points moving on a plane, the visual system is able to determine whether they can come from the projection of an object (or perhaps more than a single one) moving rigidly in space and then recover the three-dimensional configuration of the points in space.

I referred to this recovery as the “structure from motion” computation and was interested in both the computational and empirical aspects of this visual capacity. The computational challenge was to understand the conditions under which the problem can be solved and to develop a model that could perform the task: given a dynamic image, it will be able to identify whether it could originate from the projection of a three-dimensional object, or perhaps several objects, moving in space, and recover their three-dimensional shape. It was unclear at the time whether the recovered structure was unique or whether there were always multiple possible three-dimensional shapes and motions, which were all compatible with the observed changing image. On the empirical side, the goal was to study psychophysically the properties of humans’ perception of structure from motion. Another long-term goal was to eventually identify and understand the brain mechanisms involved in this visual capacity.

I examined the computational problem in detail, under somewhat different conditions (such as objects close to the observer, or more distant objects, where perspective effects are weak). For the case of distant objects, it turned out that three views of four non-coplanar points are sufficient to guarantee a unique three-dimensional structure. The uniqueness is in fact up to a depth-reversal (reflection about the frontal plane). This ambiguity is inherent, because the parallel projection of a rotating object is identical to the projection of the reversed object rotating in the opposite direction. My initial analysis and method for recovering the object used five points, and an extension by D. Fremlin (in a personal communication) reduced the configuration to four points. Following this analysis, uniqueness results and shape-extraction methods have been extended to a variety of conditions. An important development was the formulation by Longuet-Higgins of an algorithm for recovering the structure of objects based on two perspective projections using the notion of a “fundamental matrix,” which became a standard in the field [4]. The recovery of structure from motion developed to become a rich field, going in a variety of directions, and producing over the years advanced and sophisticated methods for shape recovery.

What is the relation between these computational results and human perception of structure from motion? It turns out that the shape recovery method based on the computational analysis was qualitatively consistent on a range of properties with perceptual phenomena discovered in empirical studies. There was, however, one difference that I found intriguing, where human perception performed better than the computational scheme. Human perception can also recover the structure of moving objects that are not entirely rigid but that distort and change while they are moving. Dealing with such distorting objects suggested a novel scheme for the recovery of structure from motion, which had another advantage: it appeared to be more appealing from the point of view of biological plausibility. The modified scheme did not recover the object’s shape by solving some set of mathematical equations. Instead, it proposed an initial approximation to the shape and continuously improved the solution as more data became available when the object continued to move [5].

The recovery of structure from motion is an impressive achievement of the visual system and its use of motion information, and it was the first problem in the area of visual motion I was attracted to. But the first problem faced by a vision system that analyzes visual motion is the surprisingly complex problem of measuring visual motion. The motion of elements and regions in the image is not given directly, but must be computed from more elementary measurements. The initial registration of light by the eyes is in terms of light intensity and its changes over time. From this, the visual system extracts measurements of the direction and velocity of motion across the visual field. Extracting such motion information with sufficient detail and accuracy that will allow, for example, the recovery of structure from motion, turned out to be a challenging task, and even today the problem is not yet entirely solved. Based on past work, I suggested that the visual system uses two complementary methods for extracting visual motion, one is intensity based, and the second uses localized feature matching to estimate the motion [6].

In the doctoral work, I focused on the feature-matching method, because it is more directly relevant to the extraction of structure from motion. The study of visual motion, including the measurement of visual motion and the recovery of structure from motion became the subject matter of my doctoral work, completed in 1977, and published in book titled The Interpretation of Visual Motion [7].

During my doctoral period, Marr and I gradually became close friends. He was amazing, both in terms of scientific guidance and as a human being. Working with David was always challenging, exciting, and rewarding. It was hard work, but it was a lot of fun. I had the pleasure of interacting with, and learning from, a number of other faculty members, in particular Whitman Richards in the psychology department and Patrick Winston in the AI lab. Whitman was a rich source of knowledge about human vision and was always willing to entertain new and unconventional views. Patrick was my main source of learning about AI, combining broad knowledge with insightful intuitions. Both Whitman and Patrick realized and appreciated from the very start David’s vision and the value of the program he started at MIT.

Another colleague who was central from the beginning in the work with Marr, and quickly became a close personal friend, was Tommy Poggio. Tommy visited the AI lab in 1973 and quickly became a scientific collaborator and close personal friend of David. Marr was highly impressed by Tommy’s work and by his outstanding scientific qualities. I remember David telling me about the exciting work of Poggio on the fly’s visual system, which he conducted at the Max-Planck Institute in Tübingen. Eventually, Marr convinced Tommy to join MIT on a permanent basis, and Tommy and his wife Barbara and their two children relocated to Boston. I remember this period very warmly; it was a wonderful time both scientifically and in terms of personal friendships. The three of us became close friends, spending time together in scientific discussions, outside work, at dinners, and on vacations with our families. At some later time, as the work progressed, we entertained the idea of starting together some sort of an entity, a consulting group or a company, exploring potential applications of computer vision. We gave it the name Cambridge Intelligent System and had stationary with this title printed over it, but we never got much beyond this point. Unfortunately, this period did not last very long, and our lives came to a sharp turn when David became seriously ill. David’s illness came as a shock. He did not feel well one evening in December 1977 and was admitted to MIT’s infirmary to undergo some tests. He called me from the MIT infirmary the next day and asked me to close my office door. He then said briefly and without any introduction that he was just diagnosed with acute leukemia.

The period that followed was very painful. What made it bearable, and for a meaningful time even a happy period, was David’s meeting with Lucia Vaina and their falling in love. They met a few months after David’s initial diagnosis and became very close within a short time, despite the ominous uncertainty. Lucia’s love and support helped David through the most difficult times. For extended periods, he maintained an almost normal routine, doing intensive scientific work, some of it in collaboration with Lucia. Twice during his illness, we thought that there was some hope. The first was during his first remission. Everyone hoped that perhaps, by some miracle, the disease would not come back. We took a vacation together in Vermont, and he resumed his work with his usual intensity. After a period, he felt weaker and went to the hospital for tests. He came to my office to call the hospital about the tests results and found out that it was indeed a relapse. We sat in my office for a long time devastated by the news. The second hope came when a physician in Cambridge, England, had some initial success with a vaccine against leukemia. David was hospitalized in Addenbrooke’s hospital in Cambridge. He was very weak and worked on his book. When I came to visit, I met the physician, who was very supportive and promised to help as much as he could. When David came back to the United States, Tommy Poggio managed to bring some of the Cambridge vaccine with him, but the vaccine did not work for David (and it did not prove effective in later clinical trials).

The final period, when David already suspected that the battle was lost, was in fact a quietly happy one. He was happily married to Lucia and was working intensively on his book and a number of other projects. In his premature death, the scientific world lost an intellectual giant who, in the short time, made a huge impact on his field. I lost a warm, brilliant, exciting, and unusual friend.

During the doctoral time, on the last day of 1974, Chana and I got married. The wedding took place in the MIT chapel. This is a charming and nondenominational place on campus, which can be quickly transformed to fit any type of service. The wedding was a small and very pleasant event, with close family members, old friends, and some new friends we met in Cambridge, and who remained friends to this day. Shortly after our marriage, Chana enrolled in the doctoral program in psychology at Boston University, and after graduation she started her career as a clinical psychologist.

Researcher at the AI Lab

Following my doctorate, I had a research position at the AI lab for three years, first as a research associate and then as a principal research scientist. My MIT mentors, David and Whitman Richards, thought that this would be a good way to continue research at MIT before applying for an MIT faculty position.

During my doctoral research, I found a range of open problems related to visual motion I wanted to look into, and I continued to study aspects of visual motion well beyond the doctoral period. A study of visual motion from 1981 was one of the only two papers Marr and I published together, a paper titled “Directional Selectivity and Its Use in Early Visual Processing” [8]. The other paper was in a collaboration with Tommy Poggio, on a topic suggested by Tommy. He was intrigued by the power of sparse edges in the image to capture the image content, and we looked together on the mathematical power of zero-crossings, used by Marr as precursors of image edges and contours, to capture image information [9]. David and I worked together on the directional selectivity paper extensively for a period of a few months. It was for me the first, and one of the only times, that I wrote a paper with someone in this mode, actually sitting together for long hours at a time, composing sentence after sentence, and discussing each paragraph we wrote. The experience was very intense and enjoyable. I think we both enjoyed it and were both exhausted by the time the paper was finished. With a British restraint, a footnote on the first page of the published paper read: “During the course of the publication of this paper it was learnt with regret of the death of Dr. David Courtenay Marr at the early age of 35.”

As I studied different aspects of visual motion, I was continuously impressed by the complexity of the problem from a computational standpoint, and by the various mechanisms devised by biological systems to deal with the measurement and the use of motion information. Sophisticated mechanisms for extracting and utilizing visual motion are found even in simple animals, such as the frog and the housefly. As already mentioned, it appears that the visual system uses two complementary methods for extracting visual motion. One based directly on the local changes in light intensity (intensity-based methods). The other measures motion by the matching of features (such as edges, corners, blobs) across space and time (feature-matching schemes). My initial studies focused on feature-matching schemes, and their contribution to the perception of structure from motion. I later became more focused on intensity-based schemes, studying computationally how to measure visual motion based on image intensity changes and considering possible biological mechanisms for the task.

Computationally, intensity-based motion measurement is difficult, because the motion measurements are locally ambiguous, because of what I termed the “aperture problem” [10]. A spatial integration stage is required to resolve the measurement ambiguities. The integration is a difficult problem, which is still not entirely resolved. Because of integration problems, computational schemes for motion measurement tend to produce blurry and inaccurate velocity measurements at motion boundaries (e.g., between a moving object and its background). Ellen Hildreth, my first doctoral student, worked on the motion measurement problem for her excellent dissertation, published in a book form under the title The Measurement of Visual Motion as an Association for Computing Machinery Distinguished Dissertation [11].

Other studies of intensity-based motion measurement, focusing on models of biological mechanisms, were conducted in collaboration with my close friend Jacob (Kobi) Richter. Kobi has been a friend since my air force days. He was somewhat senior to me and already a well-known ace pilot when we met. We spent time together training to become flight instructors and kept close connections since. Independently, Kobi’s wife Judith and my wife Chana were friends even before I met Chana. Kobi was (and still is) a multitalented person, excelling in everything he puts his mind to. He remained in active air force service, but in parallel to his service, he completed a doctorate in physiology at Tel-Aviv University. In 1979, he took a three-year leave of absence from service, obtained a fellowship and research position at MIT, and came to Boston with Judith and their three children. At MIT he worked with me on computational modeling and with Peter Schiller on monkey V1 recordings. Kobi quickly became an accomplished programmer and modeler. In a number of publications we had together, modeling temporal aspects of retinal ganglion cells and V1 simple cells, Kobi provided the empirical data and participated on equal footing in the modeling work [12–14].

In addition to visual motion and some other modeling work, a topic that occupied me conceptually was the role of computational modeling in understanding brain and cognition. Related to this were attempts to explain to colleagues and fellow scientists what we were trying to do and in what ways computational theories and models could complement empirical studies. This was not always easy. A well-known professor from Yale invited me once to give a seminar in his department. He asked me, however, to “please leave out the computational and theoretical parts,” because he did not think his colleagues would have any interest in these directions. As a part of this general direction I wrote a paper, which gave rise to a lively discussion, about Gibson’s theory of direct perception [15].

James Gibson was a distinguished psychologist who made important contributions to the study of visual perception, including studies of the optical flow during locomotion, the role of texture gradients in the perception of surfaces, and introducing the interesting notion of “affordances.” On the theoretical side, Gibson opposed any use of the terms “computation” and “representation” in the study of perception. In his view, information about the environment is “picked up directly” by the observer, without any need for further elaboration. Because this position is diametrically opposite to computational theories, it was of interest to analyze what “direct perception” means, what is exactly the argument, and what is it based on. The critique I wrote about direct perception was not about Gibson’s contributions, but rather about his theoretical stance, which I find untenable as a scientific explanation.

In other work along the same goal of making connections between neuroscience and computer science, I wrote several general overviews, aimed at either computer scientists discussing relevant neuroscience aspects [10] or aimed at neuroscientists, discussing relevant computational aspects [6,16]. Over the years, there has been a continuous shift in the degree of understanding and collaboration between the biological, behavioral, and computational studies of vision. Many of the neuroscience graduate students I have met in recent years at the Weizmann Institute, MIT, and other places are highly sophisticated in their computational background and skills, and they use these skills in their neuroscience work.

On the Applied Side: Orbotech

Toward the end of my term as a research scientist and before starting my faculty appointment, I spent six months as a visitor at the Weizmann Institute of Science in Israel. Chana and I felt that after spending seven years in Boston, we wanted to spend a significant time period with family and friends back in Israel. I thought initially of spending this time at my Alma mater, the Hebrew University in Jerusalem, by I got a phone call from an ex-teacher of mine in mathematics at the Hebrew University, who had moved in the meantime to the Weizmann Institute, urging me to come instead to the Weizmann, to the mathematics and computer science department. The Institute welcomed us warmly, arranging lovely accommodations and a nice office space.

During this stay, I gave in the department a class on computer vision. This was the first class on computer vision at the Weizmann, and in Israel in general, and it was well attended by both students and faculty members. Among the listeners in the class was a computer engineer, Zvi Lapidot, who found this new field highly exciting. We discussed topics in computer vision frequently after class and soon became good friends. Zvi was a part of a group in the computer science department that actually designed and built computers, building the hardware and writing the software to run it. This activity had begun already in the 1950s, with construction of the first computer in Israel, and one of the first large-scale computers in the world, called the Weizac. Building such computers during the 1950s was still a pioneering effort, and the Weizmann recruited for the task several scientists and engineers from the United States. The project had an advisory committee, which included John von Neumann, Albert Einstein, and Robert Oppenheimer as its members. Following the Weizac, two additional generations of computers were designed and built at the Weizmann, the Golem and its successor, the Golem B, which was a large-scale mainframe computer. Zvi was a software engineer in the Golem project, and because the Golem team was small and closely knit, he acquired deep knowledge of computer systems in general. As an engineer with a bright and curious mind, he was intrigued by the field of computer vision and the possible applications it could offer.

By the time my short term at the Weizmann was over, Zvi was excited by the possibility of moving into this new field. He took a leave from the Institute and found a job in a computer vision startup in the Boston area. He wanted to learn about the applied aspects of computer vision and to consider potential applications in the field. He eventually reached a conclusion that the manufacturing of printed circuit boards was at a critical stage in terms of moving into automatic visual inspection. Many in the industry were skeptical about the possibility of automating the inspection process. Zvi raised the problem with me, and after a while, we reached the conclusion that new methods from computer vision could be of use for automating the inspection process. We added to the discussion two close friends: a computer engineer from the Weizmann named Ami Caspi who worked for years with Zvi, and my friend Kobi. Ami was a superb hardware engineer, and Kobi was superb at anything he became interested in. This was quite a unique group, and within a short time, we had the initial blueprints for a vision system for printed boards inspection. The plans moved quickly forward. When Zvi went back to Israel, a company was formally formed (under the name Orbot), funds where raised, and a small group of engineers was hired. Within two years, several systems were already operating in several printed circuit manufacturing facilities. After a merger with another Israeli company in the same area, the company name was changes to Orbotech. It was listed on Nasdaq in 1984 and expanded in a number of additional directions, including the visual inspection of flat-panel displays. In 2019, the company was acquired by KLA, a leader in process control for the semiconductor industry.

For me, working with the initial group of talented friends from different disciplines was highly stimulating and rewarding. Professionally, some of the problems involved in the high-speed analysis of complex patterns were interesting and challenging, in part as problems in vision and in part from more mathematical or algorithmic perspectives. As the company matured, my own involvement became small, but I stayed connected with the company until its final acquisition.

Faculty, between MIT and Weizmann

Following three years in a research position, I started my faculty appointment at MIT in 1981, at the rank of associate professor. The following year, 1982, was quite transformative for me and my family in three directions. First, Chana and I had our two sons Tomer and Yonatan. Second, my MIT position became tenured. Third, I also accepted a position in the computer science department at the Weizmann Institute of Science, in parallel with the MIT position. It was agreed that I will spend about half of my time at each institution, alternating every one or two years. The most dramatic transformation for us was of course becoming a family and starting to raise our children. I don’t think that I fully anticipated how profound and gratifying this transformation would turn out to be. Many years have passed since then, and Tomer and Yonatan are now going through a similar experience, raising their own families. Yonatan chose to be an artist—a painter and sculptor. Tomer chose to be a scientist and is now a faculty member at Harvard’s Psychology department. I think that both chose to pursue what they were always passionate about, which I hope will bring them lifelong satisfaction.

During this period my scientific research focus started to shift to increasingly higher levels of visual perception. My intellectual interests were in fact biased from the beginning of my studies of vision toward the higher levels of vision and the integration of vision and cognition, problems that include, for instance, object recognition, scene understanding, and aspects of visual awareness. Research in computer vision in its early days had very little to do with such topics, focusing instead on lower-level aspects of vision, such as edge detection, feature detection, texture separation, motion measurement and depth estimation. In my own work on motion, I was surprised by the complexity of the problems involved in motion perception and the sophistication of the computations performed by the brain in measuring visual motion and recovering three-dimensional structure from motion, as discussed earlier. One can certainly devote a rich lifelong scientific career to the study of vision at different levels; the move toward higher, more cognitive levels was not because I thought that lower levels of visual processing were already well understood, but I just following my personal scientific interests.

Visual Routines

One general topic I became curious about is the general nature of perception when performing complex visual tasks, such as scene understanding. Rather than a single application of a bottom-up process, behavioral evidence and computational considerations suggested the use of a sequential process, guided by top-down processes, to accomplish goals of interest. I addressed this general topic initially in the context of what I called “visual routines,” first in computational studies [17], combined later with psychophysical studies.

To take a concrete example, consider the relation of inside versus outside, which is performed by the human perceptual system with intriguing efficiency. For instance, suppose that the visual input consists of a single closed curve and a small X figure. The visual task is to determine whether the X lies inside or outside the closed curve. If the shape is not highly convoluted, the “insideness” relation pops out immediately. But what is the visual process that allows us to reach this conclusion? A popular method that has been proposed for “insideness” in practical applications uses the so-called ray-intersection method. Starting from the x location, draw a ray in any direction to the edge of the image, and count the number of intersections along the ray. If the number is odd, the x lies inside, and otherwise it is outside the closed contour. This ray-intersection method works correctly only under limited conditions—for instance, it must be assumed that the curve is closed, and it must also be isolated, because the presence of additional contours can create extraneous intersections. It turns out that seeking a robust solution of the “insideness” problem is a challenging problem. For human vision, we also seek a biologically plausible computation. Biological plausibility is not a simple and well-defined criterion, but the ray-intersection computation, for instance, appears to be an unlikely candidate. A method that is more computationally effective and fits better with human perception is based on spreading activation. Starting from a given point, the area around it in the internal representation is somehow activated. This activation spreads outward until a boundary is reached, but it is not allowed to cross the boundary. Depending on the starting point, either the inside or the outside of the curve, will be eventually covered by the spreading activation. This can provide a basis for separating inside from outside. Additional stages are still required to complete the procedure, and the additional stages will depend on the specific problem at hand. I will not consider here further “insideness” or visual routines in general, because the topic is too specialized for an overall review. Note, however, that the basic themes that played a central role in studying the perception of spatial relations by visual routines came up repeatedly in other studies of higher-level aspects of vision. Performing complex visual tasks, such as scene understanding, often employs an evolving sequential process, guided by top-down processes, to accomplish some goal of interest. In the study of visual routines, one of my goals was to combine the computational studies with empirical psychophysical and physiological data. Together with a wonderful psychophysics colleague, Pierre Jolicoeur, we have conducted a number of studies, focusing primarily on the task of boundary or curve tracing [18,19]. Some of this work was also followed subsequently by creative studies at the physiological level by Pieter Roelfsema and others [20,21].

Object Recognition

When I started to work on the broad and difficult problem of object recognition, I was asked by one of my colleagues whether I decided to stop working on vision. People worked at the time on aspects of pattern recognition, but studying natural object recognition was at its infancy, and at least some researchers considered object recognition as belonging more to higher level cognition than to vision research. Views regarding the relations between vision and cognition shifted over time to an almost opposite view. Object recognition became a central part of vision research, and current methods for object recognition perform very successfully, without employing more cognitive aspects, such as world knowledge, logical inference, or symbolic representations. The same methods that proved useful for object recognition, based on deep convolutional networks, are also being applied to a more cognitive and abstract level of using vision, such as scene understanding or visual question-answering. My own view is that application of these methods, with only minor alteration, to the higher and more abstract levels, is going to run into difficulties. I have worked on object recognition for a long time, and I think that my personal history during this period reflects much of the general evolution of the field during this period. I will not get into technical details, but I will describe briefly some of the main attempts and conceptual shifts in object recognition and higher-level vision.

When I started this journey, the dominant approach to object recognition was based on three-dimensional representations and internal manipulations of these representations. Using three-dimensional representations to support recognition makes sense: I can recognize the object “car” from a large range of viewing directions, despite the large change in the car’s image as the viewing direction changes from a frontal, to side, or back views. Influential models using this approach were Marr’s generalized cylinders representation [22] and Biederman’s theory of recognition by components [23].

In both theories, objects were represented using a collection of three-dimensional primitive shapes. My own initial work on object recognition was also based on three-dimensional representation but from a different perspective. I describe next some of the work and how it developed over time. The main objective is not to discuss details of object recognition, but to recount my experience in exploring a complex and little understood research area, until reaching a conclusion that a basic shift is needed. A related theme is how the research was guided by a combination of modeling results with empirical neuroscience evidence.

The basic motivation for using three-dimensional models for visual recognition was to achieve view invariance. In the components-based approach, invariance was achieved using the fact that the object components and their arrangement remained invariant to changes in viewing directions. I thought that these representations were too qualitative for recognition, and instead of relying on a vocabulary of shape primitives, I proposed that view-invariant recognition could be obtained by alignment [24].

The initial work along this line was conducted with my student Dan Huttenlocher, now the dean of the MIT College of Computing. Dan was a brilliant and lively student who soon became also a colleague. During his doctoral work, he spend some time with me at the Weizmann in Israel. I asked him many years later if he remembered any of the Hebrew he acquired during this period in Israel. The expression he remembered best was “nine percent” (in Hebrew). It turned out that he found a particular cheese that was available in grocery stores across Israel, which was just called “9 percept cheese”; he loved this cheese, and the useful term was imprinted in his memory.

The work with Dan was published in the proceedings of what can be seen in retrospect as somewhat of a historic event—the first meeting of the International Conference on Computer Vision (ICCV), which later became a major meeting in computer vision with many thousands of participants, a broad range of workshops, and a commercial exhibition. The central idea was that to recognize an object, an internal object model was first aligned with the image using a small number of model and image features. We used for this alignment results from the structure-from-motion work. For example, by identifying three corresponding feature points in the model and the image, it becomes possible to compensate changes in position, scale, and spatial orientation between the model and the image, and then to compare the image directly with the aligned object projection.

The method was efficient and highly accurate, but it had drawbacks as a candidate model for natural object recognition. For example, it could recognize well a specific object, such as a specific car model, but had difficulties dealing with differences between individual objects that belonged to the same class, such as the general “car” class. We explored over a number of years some modifications and extensions. For example, aligning not only object contours but also more abstract shape descriptions, or using multiple local alignments rather than a single global one [25], I was gradually led to the conclusion that, in general, human recognition of natural objects does not rely on the use of three-dimensional object models. This conclusion was based primarily on computational considerations, namely the difficulty that such models have dealing with general classification and with highly flexible objects.

About 10 years after our initial work on alignment, evidence from neuroscience also started to supply evidence against the involvement of internal three-dimensional manipulation in object recognition. Psychophysical work by Shepard [26] showed that humans can perform some form of internal manipulation to bring three-dimensional alignment, a capacity known as “mental rotation.” Such studies may seem to support the possibility of three-dimensional alignment in recognition. There are, however, good reasons to doubt the connection between mental rotation and object recognition. First, mental rotation is a slow process, unlikely to support fast object recognition. Second, brain imaging studies, starting in 1996 [27], showed that brain activation during mental rotation is mainly in areas not directly involved in natural object recognition.

The brain has an ability to perform some form of objects rotation and alignment, but this capacity appears to be associated more with tasks related to motor planning, such as inserting one object into another. The internal object manipulation can still be useful for recognizing objects from unfamiliar views. Humans can recognize objects from completely novel views, and their ability in this task surpasses the ability of the leading computer vision models available today [28]. This ability may be attributed at least in part to an internal alignment process, but I became convinced that general object recognition by humans relies on other methods, still to be explored.

I find that the history of using three-dimensional object models and alignment methods provides a nice example of useful interactions between computational modeling and direct neuroscientific evidence. The computational investigations by themselves provided evidence regarding the limitations of alignment methods for general object recognition. The neuroscientific data supplied more direct evidence against alignment methods, and more generally influenced me and others in our thinking about possible mechanisms and models of object recognition.

The work on high-level vision up to these early recognition models included some interesting topics not described here, in particular image saliency, done with my long-time friend Christof Koch [29], and an early model of combining bottom-up with top-down processing in the visual cortex [30]. These topics are summarized in the book High-Level Vision: Object Recognition and Visual Cognition [31].

Recognition by Image Patches

The shift from three-dimensional modeling to a different approach to recognition was a pretty extreme one. Instead of focusing on differences caused by changes in viewing directions, it appeared to me to be more important to focus on dealing with the difference in appearance caused by differences between objects belonging to different classes. Humans are better at recognizing objects at the class level (e.g., a car or motorcycle) than recognizing individual cars and can also easily tolerate complex nonrigid transformations. They also do not need the entire object; a partial view, sometimes even a small part of an object, may be sufficient. These and related considerations led me to the direction of basing the recognition of a class of objects based on selected image patches that are specific to a class of objects, taken directly from example views of objects in the same class. That is, the shape fragments used to represent faces, for instance, would be different from the shape fragments used to represent cars or letters in the alphabet. These fragments can be used as a set of common building blocks to represent, by different combinations of the fragments, different objects belonging to the class. The patch-based representation appealed to me for the purpose of object classification based on general observations, but it was also supported by empirical tests, showing that objects from the same class shared many similar local patches and that local patches by themselves are highly informative for the class identity. The problem of recognition across different viewing directions became secondary. It can be approached by the class-based fragments approach by using for each class a number of related models, from different viewing directions [32,33].

We introduced the patch, or fragment-based approach in the late 1990s, along with a general method for selecting the most informative patches of a class for the purpose of recognition. The selection of representative class fragments was based on a natural notion from information theory called mutual information. Without getting to the technical details, the notion is quite intuitive. Suppose you know that an object was placed in one of eight boxes, but you do not know which box. Suppose also that you get a hint—that the box containing the object is red, and four of the eight boxes are red. The hint about the color reduces the uncertainty of the choice from eight to four possibilities. Measured in bits, the uncertainty was reduced from three bits (the number 8) to two (the number 4). The saving of one bit was the mutual information supplied by the color hint. In a similar manner, one can measure how the presence of a particular patch in an object’s image reduces the uncertainty about the object class and then can select, in an automatic procedure, class patches that are the most informative for classification. An interesting finding with some biological and computational implication was that the most informative fragments for classification were class fragments of intermediate complexity, compared with smaller local features or complex patches that covered most of the object [34].

The processes of selecting informative object features can proceed in a hierarchical manner, using small informative patches to detect larger patches. One gets from this object representations in terms of a hierarchy of informative patches, which often correspond to semantically meaningful parts and subparts. An exciting possibility offered by such hierarchical object representations was that recognition may take place at all levels simultaneously, recognizing not only the object, say a face, but also its parts and small subparts, such as eyes as well as the eyelids, lashes, and pupil. In a model that brought together much of our work on fragment-based recognition, we obtained this kind of full recognition. An interesting finding was that such a full object interpretation, identifying and localizing parts at all levels, required a combination of bottom-up with top-down processing. The interpretation used a single cycle of this kind, a bottom-up pass that identified the object class, followed by a top-down pass, which used the recognition of one level to identify parts at a lower level. The top-down pass used the context at a higher level to disambiguate parts at a lower level, which could not be recognized using the bottom-up recognition [35].

Current deep network models for object classification also create a hierarchy of increasingly complex features, which lead to excellent classification results. In their current state, however, these models do not combine object classification with the recognition of parts and subparts at multiple levels. It would be interesting if future work could combine deep net models for object classification with a parts recognition stage, perhaps using a similar approach to the bottom-up, top-down cycle discussed earlier.

As in other areas, I tried to combine the computational modeling with empirical behavioral and physiological data to examine the applicability of the models to human vision. In one study, [36], we collaborated with Shlomo Bentin, a highly creative neuroscientist from the Hebrew University, to test the role of informative features in human vision using electroencephalogram (EEG) and behavioral tests. We showed subjects images of different fragments, for which we calculated the mutual information they provided for classification, and measured the subjects’ classification accuracy and EEG responses. We found that categorization performance correlated with the measured mutual information level as well as with the amplitude of a posterior temporal potential, peaking around 270 milliseconds. Another study, in collaboration with Rafi Malach [37], obtained similar results using functional magnetic resonance imaging (fMRI): it was possible to use the objective measure of mutual information between an image patch and a class to predict the level of fMRI activation in human object areas. For me, there was some scientific satisfaction in the ability to take an image patch and make a prediction about classification accuracy and the brain response it would induce when shown to a human observer.

The ability to recognize objects based on local patches and other forms of reduced information had a revival some 10 years later, when we examined what we called “atoms of recognition” in human vision [38]. This was another attempt to identify the visual features and representations used by the brain to recognize objects. The studies of informative class fragments described earlier identified object fragments for classification. An object in the image would typically be covered by multiple fragments, which together, by summing up their individual contributions, would lead to the object’s classification. In studying “atoms of recognition,” we used a large-scale psychophysical study to systematically search for the minimal images that are sufficient for reliable recognition. For each class of image we tested, such as a horse, bird, bicycles, and flies, we found multiple “minimal images” that were sufficient on their own for a reliable recognition of the object in the image. An interesting finding was that at the level of minimal recognizable images, a minute change in the image can have a drastic effect on recognition, thus identifying features that are critical for the classification task. Simulations then showed that existing recognition models could not explain this sensitivity to minor changes, and, more generally, they did not learn to recognize minimal images at a human level. The role of the critical features for recognition is revealed uniquely at the minimal level, where the contribution of each feature is essential.

In a study led by Marlene Behrmann from Carnegie Mellon University [39], we used the set of minimal images we identified to probe the responses of class-specific cortical regions in humans using fMRI. In particular, we compared the minimal images with subminimal images—these were slightly reduced versions of the minimal images, which were only slightly different but essentially unrecognizable. As expected, because of their similarity, in early visual cortex, the minimal and subminimal produced similar responses. Higher-level, class-specific regions, however, exhibited greater activation for minimal images compared with their subminimal counterparts. Moreover, minimal images from each category elicited enhanced activation in corresponding category-selective regions—for example, the parahippocampal place area showed selectivity in its response already at the minimal image level.

Object classification is often considered today to be a solved problem, because deep network models excel in this task. This is a remarkable achievement both in practice as well as in our understanding of biological mechanisms of classification. Human classification performance, however, is still qualitatively better than models in various aspects (e.g., unsupervised learning, out-of-distribution examples, adversarial examples, unfamiliar viewing directions, or minimal images), and additional studies and comparisons with human vision are still required to fully understand the object classification task.

Digital Baby

Learning to recognize objects is an interesting and challenging problem in understanding vision, but it is only a part of a much larger problem, of using vision to learn about the world. This learning process starts in infancy, when much of the knowledge about the world emerges from the combination of innate mechanisms and visual experience. I have been, and still am, fascinated by this larger problem, and for a number of years, I have been engaged in a research project I called the “digital baby,” exploring basic issues within this large domain. The ultimate goal of such a project is to develop a digital baby model that, through perception and interaction with the world, will develop on its own representations of complex concepts, which will allow it to understand the world around it, in terms of objects, categories, events, agents, actions, goals, social interactions, and the like.

This emergence of understanding is a major challenge in the study of vision, cognition, and the brain. Current computational theories dealing with the acquisition of knowledge about the world through visual perception still cannot cope with this major challenge. They have made an impressive and substantial progress over the past decade, but as far as I can judge, current methods are unable to acquire spontaneously and deal effectively with natural cognitive concepts, which depend not only on statistical regularities in the sensory input but also on their significance and meaning to the observer.

A major part of the problem in my view is that current computational approaches to visual learning are too empiricist in nature. As has been shown by a rich body of developmental studies, the human cognitive system is equipped through evolution with basic innate structures that facilitate the acquisition of meaningful concepts and categories. These are used to obtain a true understanding of the world, which goes beyond correlations and statistical regularities. In 2010, the Cognitive Science Society published a brochure titled “Outstanding Questions in Cognitive Science.” In it, I suggested that a basic open question in cognitive science is a theory of “computational nativism”—a computational theory of cognitively and biologically plausible innate structures and how they guide the cognitive system along specific paths through its acquisition of knowledge to continuously acquire meaningful concepts and useful representations.

I will describe briefly a couple of examples from the digital baby studies that illustrate the power of plausible innate structures to guide the spontaneous acquisition of meaningful concepts. The goal in describing these examples is not to present our work in detail, but rather to discuss major issues in perception and cognition that I have been interested in for a long time and to describe briefly my general views on some of these issues.

In the first example, we developed a model that tackled two notable problems in which the gap between computational difficulty and infant learning is particularly striking: learning to recognize hands and learning to recognize gaze direction [40]. Hands are known in computer vision to be objects that are particularly difficult to recognize; because they are highly articulated, they can appear in a large variety of different shapes. In addition, in many cases, their size in the image may be small, and their recognition is obtained not based on their own appearance, but mainly by the context of other body parts. And yet, hands are one of the first objects to be recognized reliably by infants, starting already around the age of three months. Direction of gaze, and the target of someone’s gaze, are similarly difficult, but again, gaze direction is learned early in infants’ development. Unlike computational models, this learning is obtained in an unsupervised manner, that is, without any help or guidance by a teacher or by annotated images. Infants just look at the world around them and spontaneously develop the ability to recognize hands and direction of gaze.

The model we proposed shows similar capabilities: it is shown a stream of natural videos, and it learns without any supervision to detect human hands by appearance and by context, as well as by direction of gaze, in complex natural scenes. How can such complex learning take place spontaneously by “mere looking”? We propose that the learning process is guided by an innate mechanism—that is, the detection of what we called “mover” events in dynamic images. Such an event is defined by a moving image region causing a stationary region to move or change after contact. The proposal is based on two types of evidence. The first is evidence regarding infants’ sensitivity to special types of motion, similar to mover events. From an early age, infants are sensitive to visual motion, and they use motion to separate moving regions from a stationary background and to track a moving region. They are also sensitive to specific types of motion, similar to our proposed “movers,” including so-called launching events, as well as to active motion (causing other objects to move) or to self-propelled motion. The second part of the evidence comes from our computational studies, which demonstrate that having the capacity to detect specific motion events in dynamic images can naturally lead to the automatic acquisition of increasingly complex concepts and capabilities, which do not emerge without domain-specific biases. The detection of mover events on their own are not sufficient for hand recognition: they do not identify the hand as an object, they are not sufficiently reliable, and they detect hands and some hand configurations but not others. However, reliable and general hand detection can evolve from a combination of the teaching signal provided to the mover events, with existing methods for supervised learning of object recognition, using mover events as providing the supervision. After exposure to video sequences containing people performing everyday actions, and without external supervision, the model develops the capacity to locate hands in complex configurations by their appearance and by surrounding context.

This combination of internal structures with learning appears to me to be a powerful and general combination. Infants learn to recognize hands in a spontaneous manner early in their development, despite the fact that hand recognition is difficult and does not emerge in learning models by just looking at the world. This is obtained in the model not by using innate hand detectors, but by using simpler “proto concepts” for hands, which guide the learning process along a trajectory that leads to hand recognition. Note that during the learning trajectory leading to hand recognition, hands become naturally associated with some of their meaningful properties, such as hands being the mover of objects, and they are used for object manipulation and actions. Developmental studies show that young infants indeed expect a human hand, and not an inanimate object, to be the primary cause of an inanimate object’s motion [41].

The model for learning to recognize hands was also extended using similar principles to the learning of extracting direction of gaze. I will not get into any details of gaze detection, except to mention what was the teaching signal used in this case to guide the learning. Based on empirical observations, we made the assumption that when people make a contact with an object, to grasp and manipulate it, they almost invariably look directly at the object. They can subsequently move the object around without looking at it, but at the point of making the initial contact, the contact location is a reliable cue to the direction of gaze. Again, the target concept, gaze direction in this case, is difficult to learn by just looking. It appears early and spontaneously not based on an innate structure in our visual system that serves for gaze detection, but rather by the use of a proto concept in a learning process that leads to the reliable acquisition of the final target capacity. This learning process also naturally links the gaze direction and the gaze target with the goal and attention of the looker. As in the hands example, internal structures guide the system to acquire meaningful concepts, which are significant to the observer but statistically inconspicuous in the sensory input.

We recently had an opportunity, in a study led by Ehud Zohary, to test the implications of the gaze-recovery model with a special population of patients in Ethiopia who had early bilateral congenital cataract, diagnosed and treated at late childhood [42]. This sight restoration provided a unique opportunity to directly address basic issues on the roles of “nature” and “nurture” in development, as it caused a selective perturbation to the natural process, eliminating some gaze-direction cues while leaving others still available. Of particular interest was the ability of the group of patients who did not have sufficient visual acuity before surgery to recover fine details (e.g., the position of the irises) needed to recover the direction of gaze. Following surgery, the patients’ visual acuity typically improved substantially, allowing for fine discrimination of eye position. Yet, the recovered patients failed to show eye-gaze following behavior, and they also fixated less on the eyes of a viewed face, two reflexive behaviors seen in controls, even years after vision was restored. This is a natural expectation of the model, assuming that the specialized internal guiding signals that normally enable the learning of eye-based gaze direction are no longer available at a later stage, when the correcting surgery was performed. As expected, their gaze-following behavior based on head rather than eye direction was typically normal, which was consistent with the available visual acuity before surgery.

Another digital baby example of innate structures guiding learning is the surprising acquisition of concepts related to containment and containers [43]. Containment is one of the earliest spatial relations to be learned, starting around three months of age, and preceding other common relations (e.g., support, in between). Computationally, containment often depends on subtle cues in the image, and it is unclear how this relation is acquired so early in development and without supervision. The model we proposed can explain infants’ capacity of learning containment and related concepts by “just looking,” along with their empirical development trajectory. Learning occurs in the model fast and without guidance, relying only on perceptual processes that are present in the first months of life. As in the learning of hands and gaze direction, instead of labeled training examples, the model provides its own internal supervision to guide the learning process. We showed how the detection of so-called paradoxical occlusion provides natural internal supervision, which guides the system to gradually acquire a range of useful containment-related concepts. During early development, even earlier than acquiring containment, infants develop sensitivity to occlusion relations. The digital baby model includes a similar capacity—that is, to use visual motion to learn occlusion relations along with dynamic and static object segregation [44]. We showed how the notion of containment can naturally arise from a simple combination of occlusion relations, which I will not describe here in more detail. The model works well, and it acquires different aspects of containment in an order that is similar to the temporal learning order by infants [45].

Overall, these examples of the digital baby model illustrate how natural complex concepts can be acquired visually without requiring elaborate external supervision. The results show how combining perceptual learning of the kind obtained by deep learning with brain-like innate structures may guide models toward human-like learning [46].

In my view, future models of human vision, as well as intelligent AI vision systems, will be closer to the general structure suggested by the digital baby model than current models, which utilize primarily unguided bottom-up processing. Unlike networks that start from a tabula rasa state and that learn using extensive supervision and huge amounts of annotated data, human-like models will incorporate rich innate structures that guide the learning along useful learning trajectories with limited supervision. Guided by innate structures, the learning process will construct a rich conceptual system for understanding the world around us.

Top-Down Processing, Linking Perception and Cognition

Another major topic of interest to me for many years has been the role of top-down processing in vision, and the integration of vision and cognition in scene perception. Anatomically, we know that the visual system combines closely interacting bottom-up and top-down processing streams. The bottom-up pathways go from early to higher level areas, including more abstract and cognitive brain regions, and the top-down pathways proceed in the opposite direction, from high to lower regions. The cortical circuitry suggests that the top-down stream plays a major role in vision and in cortical computations in general, because it is often at least as massive as the bottom-up stream. The exact function of the top-down projections is still unclear, and given its importance, this is obviously a major open question, which may shed light on basic aspects of brain processing and on the integration of vision with higher-level cognitive functions. As noted, current deep network models, which excel in visual object recognition, perform the task relying almost exclusively on bottom-up processing. If the complex task of visual recognition can be performed well without requiring a top-down component, what can be the core contributions of the top-down pathway?

In my own work, starting around 2000, the initial direction I followed was to explore the use of the top-down stream for the specific task of object segmentation, also called figure-ground separation. When we recognize an object in the image (e.g., a horse), we can also identify the exact image region that contains the horse. Most approaches to segmentation at the time assumed that separating an object from its background is performed based on image properties, such as uniformity of color and texture, or the smoothness and continuity of the object’s bounding contours in the image. The problem is that natural objects can be highly nonuniform, with multiple colors and textures and jagged boundaries, and can still be well segmented and separated from their background. It is therefore plausible that once we become familiar with a given type of object (e.g., what a horse looks like), we have some form of model of the object in higher-level visual areas, which can be used for guiding the segmentation process at lower levels. In work with E. Bornstein, we proposed a model that showed for the first time how an object model can be learned from a set of images, and then be used to guide a top-down segmentation process [47,48].

The most flexible and accurate segmentation model was obtained by combining bottom-up and top-down processes [49,50]. The object-model can combine object parts that are highly variable in terms of image properties. In contrast, low-level image properties, such as the exact location of edges, are highly informative for delineating precisely the object’s boundaries. It is not surprising, therefore, that in current deep network models of vision, the segmentation task is usually performed by a top-down network, combined with the bottom-up one. Experimental evidence from the neuroscience and psychophysics of perception has provided detailed evidence supporting the general view that bottom-up analysis of the retinal image is combined with top-down processing that include stored memories and guiding signals to obtain accurate and useful perceptual interpretation [51]

In subsequent work, we proposed another task in which bottom-up and top-down processing complement each other well, which is the task of recognizing and segmenting object parts and subparts at multiple levels (e.g., a person, arm, hand, finger) and even finer details (e.g., a fingernail), if the resolution is sufficient. This work was mentioned earlier, in the context of performing patch-based image interpretation, using a bottom-up, top-down cycle. The use of a top-down component is again natural for the task, because the identification of a given part supplies context that can be used to disambiguate parts at a lower level, which could not be recognized using the bottom-up recognition alone [35].

In both of these models, object segmentation and multilevel parts recognition, the connections between the bottom-up and top-down streams go in one direction only, from the bottom-up to the top-down stream. In more recent work, we developed a more general framework, in which the connections are bidirectional, and the goal is more ambitious: to obtain scene interpretation by an iterative bottom-up, top-down processing [52].

Scene Interpretation

Full scene perception is still a major open problem in understanding and modeling human vision. This is a complex and challenging task, because it requires the extraction and representation of scene components, such as objects and their parts, people, and places, along with their individual properties, as well as relations and interactions between them. Computational models of scene perception, also called “scene interpretation” models, have focused on training network models to extract a structural representation of the entire scene, with all its components, and the relationships between the components. In contrast, humans’ scene perception focuses on selected structures in the scene, starting with a limited interpretation (the scene “gist”) and evolving sequentially, in a goal-directed manner. It seems to me that extracting a full scene description is both infeasible and unnecessary, and therefore the selective interpretation produced by human perception offers an attractive alternative to current models. However, it also raises new difficulties, of extracting selected scene structures of interest in a goal-guided manner and applying a sequential process that depends on both the image content and the current observer’s goal.

In our work, we proposed to obtain human-like goal-directed scene interpretation, using an iterative bottom-up, top-down processing, in a “counter-streams” structure motivated by cortical circuitry. In this iterative process, each cycle is composed of a bottom-up and a top-down part. The bottom-up part is a standard visual stream, which delivers useful visual representations to the higher, more cognitive components of the perceptual system. At this higher level, the extracted visual representation can be augmented with relevant nonvisual information. The higher-level areas also provide input to the top-down stream, which selects the relevant information to extract next. The top-down stream then guides the visual stream to extract the selected information in the next cycle. This guidance is obtained using the cross-stream connections, from the top-down to the bottom-up streams: through these connections, the next bottom-up pass takes place in the context of the top-down representation, and consequently, the information extracted by the bottom-up visual stream will depend on both the image and the top-down instruction provided by the higher levels.

I will not discuss the scene perception process in more detail, but only note that the interactions between the bottom-up and top-down streams seem to me to be a key factor in the continuous integration of vision and cognition in the perceptual process. As previously described, at each cycle of the scene interpretation process, visual and nonvisual information are combined in the extracted representations, and the combined representation then determines the top-down instruction for the next cycle. The results are, first, that the visual process can be guided effectively toward scene structures of interest to the viewer, and second, the perceptual outcome will naturally combine visual with nonvisual, more cognitive sources of information. This integration seems to be a key aspect for modeling human scene perception. It may also be critical to advanced AI vision systems, which currently excel at extracting visual information but seem to have difficulties with combining vision and cognition in the perception of visual scenes. The area of combining vision and cognition continues to be for me the main focus of continuing research, because it gets to the heart of the problem of using vision to understand the world.

Let me end with some comments on the role of my subarea of lifelong research within the huge and diverse field of the human brain and its functions, and on the way this subarea is currently going. The approach taken in this research area may be described as “functional computational neuroscience,” in which functional means that the models under investigation combine biological data, together with the capacity of the model to successfully perform relevant brain functions. For example, a model dealing with binocular vision in the brain, will consider the relevant anatomy and physiology of the visual cortex, and at the same time, it will also be able to perform the functional task of recovering three-dimensional scene structure from a corresponding pair of retinal images.

The power of functional models to help the modeling and understanding of brain structures recently received compelling support from the use of deep network learning, in particular in modeling visual processing in the primate visual stream. For example, a systematic study [53] compared a range of deep network models in terms of their performance in object recognition tasks, along with their precision in predicting spiking patterns in individual units along the visual pathway. The comparisons showed that, within a broad range, optimizing the model in terms of its performance in the visual task also tends to increase its ability to predict spiking responses to complex naturalistic images, at both the single site and population levels in different cortical areas. As a result of such relations between function and structure, attempts to develop functional models of the brain based at least in part on deep network learning became in recent years a highly active area. A large-scale example is an integrative effort, supported by the so-called brain-score project, which is a platform for evaluating models on how well they predict neural and behavioral brain measurements in different domains [54] (see also https://github.com/brain-score).

Although deep network models are making significant contributions to computational neuroscience, an open and intriguing question is whether this kind of modeling is sufficient to produce the perceptual and cognitive capacities of the human brain. Deep learning models are based on end-to-end learning using vast training datasets. The learning process is from scratch, in the sense that the initial model, before learning, is often a uniform structure, with minimal or without built-in modularity, and without specialized mechanisms that help both the development and the functioning of the mature system. In contrast, biological brains incorporate structures that have developed through evolution over a long period, which help both the development and the final functioning of the brain.

It might be argued that if we consider both evolution and individual learning together as a long trial-and-error learning, then an extended end-to-end learning process, combining evolution and individual learning, must be sufficient for acquiring all brain functions, including perception and cognition. However, the feasibility of such an extended learning approach with current deep learning technologies is still an intriguing open question.

Despite many impressive achievements in visual and cognitive tasks by current network models and training methods, fundamental challenges persist. One limitation, compared with human learning, is the extensive and continuously growing use of huge, supervised datasets. Another limitation is the limited capacity of current schemes to generalize well beyond the distribution represented by the training examples, and there are others. Such limitations may be related to the lack of innate mechanisms and built-in principles, which are incorporated in the brain but not in network models (as discussed in the digital baby examples). If these components are indeed essential, how might we discover and integrate them into functional models? One possibility is that similar components might naturally emerge using existing methods, with some improvements, but relying primarily on an increase in model size and the available training data. Alternatively, upscaling may not suffice, and the missing components might be discovered either by novel computational methods (e.g., some form of efficient evolutionary-like search) or by adopting methods that might be unraveled by ongoing and future studies of the human brain and human cognition. These are fundamental and important open questions, which will become clearer with future advances in both human and machine intelligence, including, in particular, functional computational neuroscience.

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Index

Abe, H., 278

Abrams, T., 166, 168

Abzug C., 100

Acosta-Rodriguez, V., 418

Acsádi, G., 139

Acsády, L., 123, 139

Adams, M., 411

Adams, S., 74

Adey, W. R., 89, 101

Adler, K., 25, 388

Adrian, E., 114

Aggleton, J., 232

Aguayo, A., 116

Ahanonu, B., 35

Ahn, A., 42

Aker, L., 253, 254

Akil, H., 13

Alberini, C., 185

Albright, T., 205, 217, 230, 252

Alder, J., 354

Aldrich, R., 320, 321, 323

Alkon, D., 165, 170

Allen, P., 410, 411

Allen, W., 158

Allman, J., 232

Alvarez-Bullya, A., 30

Amaral, D., 105, 115, 119, 121, 123

Amara, S., 352

Amarasingham, A., 139

Anastassiou, C., 139

Andersen, P., 100, 102, 106, 110, 170, 356

Anderson, C., 349

Anderson, D., 411

Anderson, S., 21

Andrews, K., 74

Angelaki, D., 252

Anikeeva, P., 262, 263

Antoch, M., 403

Apkarian, V., 38, 39

Appel, S., 306

April, B., 150

Aquinas, T., 209, 210

Aschoff, J., 394, 421

Asplund, M., 139

Astorga, G., 284, 285

Astratyan, E., 99

Audesirk, T., 165

Augustine, G., 306

Axel, R., 26

Axelrod, J., 392, 393

Ayala, G., 305, 306, 308, 309

Azevedo, F., 261

Bachevalier, J., 179, 232

Bagh, Y. B., 239

Bailey, J., 199

Bakin, J., 277

Baldauf, D., 257

Banker, G., 362

Bargmann, C., 411

Barlow, H., 229

Barnes, C., 102

Barthó, P., 139

Basbaum, A. I., 1–53

Baskerville-Hyde, J., 200

Bassant, M., 68

Bass, J., 409, 420, 421

Bastos, A., 239

Baudry, M., 170

Baxter, D., 168, 169, 173, 178, 179, 182, 309

Baxter, M., 70

Baylor, D., 153, 393

Bean, A., 179

Bear, M., 170, 247

Behrmann, M., 458

Beierlein, M., 180

Belluscio, M., 139

Ben-Ari, Y., 127, 132

Benchenane, K., 135, 139

Bender, D., 227, 228

Benjamin, P., 183

Bennett, G., 15

Bennett, J., 276

Bentham, J., 210

Bentin, S., 458

Bentley, D., 360

Benzer, S., 350, 398, 399

Berényi, A., 130, 139

Berg, D., 347

Berger-Sweeney, J., 54–81

Berlind, A., 168

Bernard, C., 127

Bernier, L., 181

Berson, D., 395

Berthoz, A., 127

Bertini, G., 238

Besson, J.-M., 2, 38, 39

Best, B., 184

Bichot, N., 256, 258

Bickford, R., 114, 120

Biederman, I., 455

Bi, G., 358, 360

Bittner, G., 169, 389

Bizzi, E., 261

Björklund, A., 112, 113, 116

Bland, B., 106, 110, 111, 127

Blankenship, J., 150, 154

Bliss, T., 102, 110, 111, 116, 170, 185

Bloch, V., 110, 111

Block, G. D., 390

Bloom, F., 122, 421

Boas, F., 215

Boesch, C., 212

Boguski, M., 411

Bonhoeffer, T., 185

Bonica, J., 20

Bonner, J. T., 346

Borges, J. L., 84

Boriss-Krimsky, C., 148

Borle, A., 156

Bornstein, E., 464

Box, G., 183

Boyden, E., 129, 185, 253, 254, 262, 263

Bradley, A., 421

Brager, D., 324, 326

Bragin, A., 122, 124

Braz, J., 29, 30

Brembs, B., 174

Brenner, S., 359

Bronson, F., 389

Brown, B., 244, 245

Brown, F. Jr., 394

Brown, S., 421

Brownstein, M., 393

Brown, T., 169, 310, 311

Bruce, C., 227, 228

Brunelli, M., 154

Bryan, N., 309

Buchanan, J., 352, 353

Buffalo, B., 69, 185, 204, 238, 239

Buhl, D., 139

Buhr, E., 408

Bullock, T., 114, 115, 121

Buonomano, D., 167

Burnett, C., 59

Butera, R., 177

Buzsáki, G., 82–142, 111, 127

Byrne, J. H., 144–192

Caine, B., 410

Cajal, S. Ramon y, 103, 150, 356

Calin-Jageman, I., 176

Calin-Jageman, R., 176

Canavier, C., 177

Cancedda, L., 361

Cannon, W., 92

Cao, L., 139

Cao, Y.-Q., 22, 42

Carew, T., 150, 154, 156, 161, 165, 166, 170, 173, 176, 181, 184, 305

Carnevale, T., 302, 310

Caron, M., 409, 410

Carpi, D., 124

Cashmore, A., 392

Cash, S., 359

Caskey, T., 167

Caspi, A., 452

Castellucci, V., 150, 151, 153, 154, 171, 305

Cavallari, J., 149

Cavanaugh, D., 42

Cave, N., 246

Chadwick, A., 139

Chai, R., 261

Chalfie, M., 354

Chalmers, D., 207, 208, 209

Chambers, W., 8, 12

Changeux, J., 170

Chang, H., 364, 367

Changjian, J., 251

Chao, W., 342

Charlton, M., 306

Charney, D., 242

Chelazzi, L., 238

Chelliah, Y., 413

Chen, J., 176

Chen, L., 247

Chen, S., 136

Chen, Y., 261

Chitwood, R., 323

Chomsky, N., 201, 204

Chou, J., 139

Chrobak, J., 124, 139

Chun, M., 231

Chuquet, J., 139

Churchland, A., 69

Churchland, M., 207

Churchland, P. M., 198, 199, 201, 203, 204, 205

Churchland, P. S., 115, 120, 194–219

Clark, J., 177

Cleary, L., 168, 169, 171, 179, 184

Clinton, B., 25

Cohen, M., 349

Colbert, C., 316

Cole, K., 346

Colgin, L., 320, 321, 326

Colwill, R., 173, 185

Cone, R., 344, 345, 350

Connor, J., 326

Constantine-Paton, M., 261

Conti, A., 139

Corbett, E., 261

Corder, G., 43

Correa, C., 246

Cossart, R., 127

Cotman, C., 309

Cowan, M., 105

Coyle, J., 64, 65, 67, 72

Crair, M., 313, 319

Creese, I., 121, 125

Crick, F., 115, 120, 204, 205, 342, 343, 358, 359, 360, 443

Crist, R., 276

Crittenden, J., 246

Cropper, B., 173

Crouch, R., 272

Crow, T., 161, 165, 179

Crowther, A., 35

Csicsvári, J., 130, 133, 139

Cummings, A., 251

Cumpelik, A., 139

Cushman, S., 320, 321

Czéh, B., 139

Czopf, J., 111

Daan, S., 390

Dahlquist, F., 391

Dani, J., 313, 319

Dan, Y., 354, 355, 360

Darian-Smith, C., 278

Das, A., 276, 278, 279

Dash, P., 179

da Silva, F. L., 110, 111

Davidson, A., 148

Davis, B., 65, 66

Davis, F., 389

Davis, J., 165

Dawkins, R., 212

Dayan, P., 205

DeCoursey, P., 387, 388, 389, 391, 393, 421

Deisenhofer, H., 413

Deisseroth, K., 129

Delbruck, M., 350, 351

Deming, E., 207

Demir, S., 177

Denk, W., 129, 278, 279

Dennett, D., 202, 204

De Oliveira, E. F., 139

DePaulo, R., 243

De Schutter, E., 178

Desimone, R., 220–267

DeValois, K., 229

DeValois, R., 229

Devinksy, O., 136

de Waal, F., 214

DeWeerd, P., 238

Diba, K., 130, 131, 135, 139

DiCarlo, J., 261

Dichter, M., 150

Dickens, C., 74

Dieringer, N., 154, 162

Dietrich, B., 401

Do Monte, F., 180

Dong, X., 392

Doupe, A., 20, 185

Dove, W. F., 398, 421

Dowling, J., 346

Doyle, W., 136

Dragoi, G., 130, 131, 135, 139, 185

Dragoi, V., 180

Draguhn, A., 132

Drew, M., 320

Dror, R., 177

Duan, S., 365

Dubner, R., 15, 16, 42

Dubocovich, M., 396

Dudai, Y., 170

Du, J., 359

Duncan, J., 236

Dunlap, J., 392

Ebbinghaus, H., 181

Eccles, J., 93, 151

Eckland-Olson, S., 319

Eichele, G., 411

Eichenbaum, H., 63, 68, 131, 185

Eichler, R., 139

Eidelberg, E., 102, 103, 106, 113, 114

Einstein, A., 117, 270, 451

Elliot, J., 389

Emlen, J. T., 387

Emlen, S. T., 387, 388

Engel, D., 403

Engert, F., 360

English, D., 139

Enright, J. T., 388

Epstein, D., 71, 72

Erickson, C., 240

Ernst, J., 92

Escueda, T., 308

Eskin, A., 176, 178, 393

Fain, A., 345

Fan, J., 248

Federenko, E., 258, 262

Fee, M., 129, 261

Felleman, D., 179

Feng, G., 246, 249, 259, 260, 261, 262

Fentress, J., 391

Fernald, R., 391

Fernandez-Ruiz, A., 133, 135, 139

Fields, H., 2, 15, 16, 17, 18, 20, 21, 22, 24

Fiete, I., 262, 320

Figueiredo, L., 416

Fischbach, G., 244, 349

FitzGerald, G., 409

Fitzsimonds, R., 359

Fiumelli, H., 361

Fleming, J., 230

Florez, J. C., 397, 398

Flyg, K., 246

Fodor, J., 201, 202, 204

Foot, P., 198

Forbes, P., 128

Forger, D., 408

Fossesca, M., 261

Foster, R., 395

Fox, J., 260

Fox, S., 103, 104, 110, 111

Frankel, W., 421

Frank, K., 157

Freeman, W., 93, 94, 105

Freiwald, W., 231

Fremlin, D., 445

French, D. K., 113, 114

French, J. D., 113

Freund, T., 113, 117, 120, 122, 123, 136

Frick, A., 316

Frick, K., 67, 70

Friedman, J., 401, 402, 421

Fries, P., 238, 239

Froemke, R., 136

Fromm, E., 270

Frost, B., 182

Frost, J., 308

Fujisawa, S., 130, 139

Furstenberg, H., 440

Furuyashiki, T., 139

Fu, Y., 392

Gabbiani, F., 313

Gabeau, D., 69

Gabrieli, J., 262, 263

Gabrieli, S., 263

Gagarin, Y., 89

Gage, F., 103, 112, 113, 114, 116, 117, 118, 120

Galambos, B., 114

Gallup, G., 202

Gamow, G., 342

Ganguly, K., 361, 366

Garcia, J., 105, 163

Gardner, D., 149, 172

Gardner, E., 150, 153, 154

Garrels, J., 397

Garten, C., 11, 16, 25

Gattass, R., 227, 232

Gazzaniga, M., 203, 252

Geisler, C., 139

Gelinas, J., 139

Gelperin, A., 165

Gereau, R., 313, 319

Gerschenfeld, H., 170

Gershon, M., 19

Gesteland, R., 272

Gibson, J., 450

Gilbert, C. D., 268–292

Gill, B., 184

Gilman, A., 412, 421

Gingrich, K., 165

Ginty, D., 396

Girardeau, G., 133, 135, 139

Giuditta, A., 112

Glanzman, D., 172

Gobel, S., 16

Goddard, G., 102, 116

Godukhin, O., 139

Golden, S., 392

Golding, N., 321

Goldman-Rakic, P., 230, 235

Goldwater, B., 89

Golowash, J., 182

Goltz, J., 321

Gomes, B., 255

Gong, N., 368

Goodman, C., 357, 360

Gosling, J., 198

Grastyán, E., 93, 94, 95, 99, 101, 102, 107, 109, 110, 111, 113, 117

Graybiel, A., 261

Gray, G., 11, 16

Gray, R., 317, 323, 326

Greenberg, M., 263, 396, 412

Green, C., 410, 420

Greene, P., 139

Greengard, P., 354, 356

Green, L., 139

Gregoriou, G., 254

Griffin, D., 203

Griffith, L., 185

Grinvald, A., 276

Grosmark, A., 139

Gross, C., 203, 226, 227, 228, 230, 231, 232, 233, 239, 264

Groves, P., 115, 120

Grush, R., 209

Gumnit, B., 308

Haas, H., 101, 116, 122

Hablitz, J., 308, 309

Hagins, B., 344

Hainmüller, T., 139

Halliday, D. M., 258, 259

Hall, J., 392, 406, 407

Hall, Z., 404, 410, 421

Halrgen, E., 111

Hamill, G., 349

Hamilton, B., 411

Hamm, H., 389

Hand, P., 9, 10

Han, X., 253

Hardin, P., 178

Harnet, M., 262

Harris, B., 358

Harris, J., 243

Harris, K., 130, 139, 320, 321, 322

Harter, D., 405

Hastings, W., 392

Hattar, S., 395

Hausser, M., 314

Hawgood, S., 41

Hawkins, B., 166, 169, 172

Hawkins, R., 155

Hazan, L., 130, 139

Hebb, D., 232

Hebb, D. O., 5

Heberlein, U., 12

Heckers, S., 70

Heeger, D., 136

Heidelberger, R., 179

Heiligenberg, W., 115, 388

Heilshorn, S., 362

Heinricher, M., 22

Heintz, N., 403

Heisenberg, M., 170, 174

Heller, H. C., 390

Henze, D., 123, 139

Herbert, E., 391

Herr, H., 262, 263

Heuser, J., 15

Hibbs, R., 412

Hicke, L., 323

Hildebrand, J., 185

Hildreth, E., 449

Hillyard, S., 115, 120

Hilten, K., 150, 154

Hinton, G., 205

Hirase, H., 129

Hirsch, J., 275

Hobbs, H., 412

Hockfield, S., 42

Hodgkin, A. L., 162, 163

Hoffman, D., 316

Hogenesch, J., 407, 410

Hohmann, C., 65, 67, 72

Hökfelt, T., 20, 393

Holland, P., 185

Holleman, E., 139

Holt, C., 357, 358

Hopfield, J., 89

Hopkins, B., 309

Horváth, Z., 121

Horvitz, B., 247, 261

Hoyle, G., 165, 391

Hoy, R., 184

Hsieh, N., 342

Hsu, M., 120, 121, 124

Hu, B., 139

Hubel, D., 272, 273, 277, 359

Hughes, H., 89, 412

Hume, D., 212

Humphrey, H., 6

Hunt, S., 28

Huszár, R., 139

Huttenlocher, D., 455

Huxley, A. F., 162, 163

Hyman, S., 240, 241, 242, 244, 245, 409

Inema, I., 139

Insel, T., 260, 410

Ip, N., 355

Isaacson, R., 93, 103, 105, 108, 112

Isbrandt, D., 139

Isomura, Y., 139

Ito, M., 170, 276

Izumo, M., 408

Jacklet, J., 155

Jaenisch, R., 70, 71

Jaffe, D., 314

Jaffe, L., 346, 347, 348

Jalbert, M., 246

James, W., 229

Jandó, G., 139

Jan, L., 351

Janz, R., 179

Jasanoff, A., 261

Jazayeri, M., 262

Jennings, C., 260

Jensen, F., 185

Jiang, M., 261

John, E. R., 93, 94

John, R., 109

Johnson, L., 167

Johnston, D., 294–337

Jolicoeur, P., 454

Jones-Davis, D., 69

Jones, L., 46

Jones, T., 231

Jordan, L., 200, 201, 206

Julius, D., 26, 27

Kaas, J., 232

Kamondi, A., 123, 139

Kandel, E., 149, 151, 152, 153, 154, 158, 159, 160, 161, 163, 164, 165, 166, 168, 169, 170, 171, 176, 181, 185, 302, 305, 404, 409, 421, 439

Kannai, Y., 440

Kanwisher, N., 231, 258, 261

Kapadia, M., 276

Kaplan, B., 241

Karmos, G., 94, 99

Karplus, J. P., 9

Karpova, A., 247

Kasal, C., 389

Kastner, S., 236

Katz, L., 411

Katzman, R., 113, 118, 121

Kauer, J., 185

Kaya, E., 139

Kay, S., 392, 405, 406, 407, 408

Keefe, P. R., 41

Keeton, W. T., 388

Keiffer, B., 28

Keizer, J., 178

Kekesi, F., 111

Kellaway, P., 308

Kelley, D., 354

Kelly, D., 184

Kelly, J., 272

Kelner, K., 404

Kendler, K., 243

Kennedy, D., 390

Kennedy, M., 170, 185

Kerr, F., 8

Kety, S., 241

Khazipov, R., 127, 139

Khodagholy, D., 136, 139

Kiljan, S., 139

Kimmel, C., 391

Kim, T., 412

King, C., 139

King, D., 401, 406

King, F., 105

King, T., 41

Kirk, M., 173

Klausberger, T., 124, 139

Klaver, L., 139

Kleinfeld, D., 129

Klein, M., 164

Kluth, E., 390

Knierim, J., 179

Knight, R., 133

Knobil, E., 156, 157, 158, 160, 161, 163, 167, 172, 174, 179, 180, 184

Knowlton, B., 185

Ko, C., 408

Koch, C., 123, 457

Kocsis, B., 139

Koester, H., 320

Koester, J., 154, 161, 162, 163, 164, 185, 305

Koester, S., 241, 242, 244

Koike, N., 412

Komisaruk, B., 104

Konishi, M., 115, 170

Konopka, G., 412

Konopka, R., 398, 399

Konorski, J., 97

Kopin, I., 393

Kornhauser, J., 396, 402

Kreidl, A., 9

Kriegstein, A., 30, 305

Kubie, J., 104, 110, 111

Kuffler, S., 274, 346, 347, 356

Kumar, V., 414

Kupalov, P. S., 98

Kupfermann, I., 149, 151, 154, 155, 163, 172, 173

Kutas, M., 115

Lacroix, M., 139

Lai, H., 412

Lamour, Y., 67

Lander, E., 400, 401, 404, 421

Landis, S., 242, 244

Lane, R., 391

Lapidot, Z., 451, 452

Lappi, D., 69

Larichev, P. A., 89

Larimer, J., 389

Larsen, K., 161

Lawson, J., 58, 59

Lazar, M., 392

Lebeda, F., 309

Lechner, H., 173

LeDoux, J., 185

Lee, M.-G., 124, 139

Lee, W., 171

Lee, Y., 342

Leibovitz, B., 150

Leinekugel, X., 127, 139

Lerner, M., 352

Leung, L., 106

Leung, S., 110, 111

Levenstein, D., 139

Levine, J., 24

Levinthal, C., 354

Levitan, I., 185

Levitt, M., 7, 8

Levy, A., 440

Levy, W., 104, 110, 111

Lewin, B., 404

Lewis, S., 271

Liang, F., 261

Liberti, G., 261

Li, C., 366

Lichtman, J., 355

Liebeskind, J., 21

Lim, B., 362

Lin, D., 136

Lisberger, S., 20, 185

Lisman, J., 314, 315

Lissák, K., 92, 93, 109

Liu, A., 136, 408

Liu, C. N., 12

Liu, J., 8, 15, 16, 252

Liu, R.-Y., 181, 182

Liu, Y., 179

Liu, Z., 367

Livingston, B., 120

Livingstone, M., 252

Li, W., 276, 280, 283

Llewellyn-Smith, I., 30

Llinás, R., 101, 117, 133, 136, 206, 306

Logothetis, N., 258, 313, 319, 366

Lohof, A., 355

Long, J., 139

Long, M., 136

Long, X., 139

Lorenzetti, F., 174

Lorenz, K., 115, 386

Lörincz, A., 139

Louie, S., 41

Love, W., 343

Lowet, E., 255

Low, M. D., 167, 184

Lowrey, P., 402, 406

Low, S., 406

Lo, Y., 355

Lu, B., 248, 364

Lu, J., 366

Lukowiak, K., 155

LuLu, Z., 248

Lutchen, G., 246

Lu, Y., 363, 364

Lynch, G., 309

Macagno, E., 184, 354

MacFarquhar, L., 204

Machold, B., 136

Magee, J., 129, 314, 316, 323, 324

Mahoney, D., 184

Major, A., 239

Malach, R., 458

Malenka, R., 185

Malinow, R., 185

Mallot, D., 387

Malmberg, A., 42

Mangelsdorf, D., 421

Manji, H., 242

Mantyh, P., 22

Mao, D., 139

Marcus, E., 184

Marik, S., 279

Marr, D., 442, 443, 447, 448, 449, 455

Marshall, L., 139

Marshall, T., 58

Martin, B., 387

Martinez, J., 72, 101, 105

Martin, K., 181, 185

Martin, W., 42

Mason, P., 22

Matthies, H., 101

Mauk, M., 179, 320, 323, 326

Maunsell, J., 313, 319

Mayer, D., 13

Mayo, K., 396

McCarthy, J., 270

McClain, K., 139

McClosky, M., 351

McDermott, J., 231

McDonald, J. D., 398

McEwen, B., 125

McGaugh, J., 101, 105, 390

McGovern, L., 245, 246, 247, 248, 260, 261

McGovern, P., 245, 246, 247, 248, 261, 264

McKenna, T., 177

Mckenzie, S., 139

McKerracher, L., 357

McKnight, S., 410, 411, 421

McManus, J., 278, 283

McNaughton, B., 101, 102

Meda, K., 32, 34

Meeks, J., 412

Mei, L., 364

Mellman, I., 363

Melzack, R., 5, 6, 31, 32

Menaker, M., 388, 389, 390, 391, 392, 393, 394, 410, 421

Mendoza-Halliday, D., 239

Menegas, W., 261

Menétrey, D., 28

Menzel, R., 170

Merickel, M., 326

Merrill, G., 12

Merzenich, M., 12, 20, 170

Mészáros, I., 111

Meyers, E., 236

Migliori, M., 139

Mignot, E., 415

Miles, R., 122, 123

Millar, A., 405

Miller, E., 239, 240, 245

Miller, K., 20

Mill, J., 210

Milner, B., 286

Ming, G., 357

Minsky, M., 442

Mishkin, M., 105, 170, 185, 230, 231, 232, 233, 234, 238, 240, 264

Mitrovic, I., 42

Mizuseki, K., 130, 131, 139

Mogil, J., 31

Molnár, L., 111

Molnár, M., 111

Momohara, Y., 175

Monconduît, L., 139

Monroe, M., 158

Montague, R., 205, 313

Montgomery, S., 139

Moore, J., 302, 303, 309

Moran, J., 234

Morrison, B., 94

Morris, R., 72, 110, 111

Moss, M., 20

Mountcastle, V., 153

Movshon, T., 136

Muller, B., 110, 111

Murray, B., 232

Nádasdy, Z., 124, 139

Nakamura, R., 230

Nakayama, K., 277

Narahashi, T., 302

Narayanan, R., 324

Nargeot, R., 173, 174, 175

Nathan, P., 13, 14, 24

Nelson, D., 394

Nestler, E., 185

Netanyahu, B., 442

Neveu, C., 175

Newsom, G., 45

Newton, I., 74

Ngai, J., 360

Nicholls, J., 151, 153, 157

Nichols, J., 356

Nicoll, R., 23, 104, 170, 185

Nikaido, S., 395

Nishiyama, H., 320

Nixon, R., 6

Noordenbos, W., 9

Norell, G., 393

Nottebohm, F., 185

Nudo, R., 179

Occor, K., 168

O’Keefe, J., 13, 110, 111

O’Leary, F., 171

Oliva, A., 139

Olton, D., 64, 70

Oppenheimer, R., 117, 451

Orgel, L., 205

Orida, N., 348

Ory-Lavollée, L., 67

Ozen, S., 139

Page, T. L., 390

Palkovits, M., 393

Pallas, S., 313

Panda, S., 407

Pantalion, K., 321

Papp, E., 139

Pastalkova, E., 131, 139

Pasternak, T., 237

Pate, K., 260

Patel, N., 348

Patel, J., 139

Patrick, J., 313, 318

Pearson, K., 185

Peng, A., 249

Penrose, R., 208

Penttonen, M., 124, 139

Peretz, B., 155, 156

Perin, M., 313

Petersen, P., 139

Peyrache, A., 133, 135, 139

Pfaffinger, P., 313, 321

Pfeiffer, B., 412

Phillips, G., 181

Phillips, J., 388

Pierce, J., 321

Pignatelli, M., 139

Pine, J., 124

Pinsker, H., 149, 150, 151, 152, 182

Pinto, L., 409

Pinto, L. H., 398

Pittendrigh, C. S., 388, 389, 390, 394, 421

Platkiewicz, J., 139

Plum, F., 21

Podolsky, D., 421

Poggio, T., 236, 261, 444, 447, 448

Poitras, J., 262, 263

Poitras, P., 262, 263

Pollak, G., 389

Pollard, M., 139

Poo, M., 133, 338–375

Popov, S., 370

Portenoy, R., 41

Posner, M., 391

Pouget, A., 205

Prague, J. B., 117

Pratt, B., 395

Preston, A., 320

Pribram, K., 229, 231, 233

Priebe, N., 321

Prince, D., 311

Prohaska, O., 120

Provencio, I., 395

Pryor, J., 246

Ptacek, L., 392, 410

Purves, D., 355

Qiu, Z., 367

Quartz, S., 205

Quilichini, P., 139

Quinn, C., 185

Quinn, W., 166

Raab-Graham, K., 320

Rakic, P., 170

Rall, W., 309

Ralston, H.,” 18, 20

Ramalingam, N., 283

Ramsey, M., 304

Ranck, J., 103, 104, 110, 111

Rankin, C., 185

Rankin, M. A., 319, 320, 323

Rao, Y., 364

Rapp, P., 119

Rasmussen, H., 166

Rawson, K., 386, 387, 388, 421

Raymond, J., 167, 185

Read, H., 139

Redman, S., 316

Reed, L., 148

Reese, T., 16

Repucci, M., 139

Rescorla, R., 185

Reymann, K., 110, 111

Reynolds, D. V., 12

Reynolds, J., 236, 237, 238

Ribak, C., 105

Richardson, M., 258

Richards, W., 447, 448

Richmond, B., 234

Richter, J., 449, 450, 452

Rijo-Ferreira, F., 416, 417

Rinzel, J., 136, 178

Robbe, D., 139

Robertson, L., 395

Roberts, T., 412

Robinson, K., 348

Rocha-Almeida, F., 139

Roelfsema, P., 454

Rogers, S., 139

Rohde, D., 42

Rolls, E., 170

Rosa-Casillas, M., 35

Rosbash, M., 392, 405, 406, 407, 415, 421

Rosenberg, C., 205

Rosenthal, A., 25

Rosenzweig, M., 105

Roskies, A., 115

Ross, B., 314, 315

Rossi, A., 254

Routh, B., 326

Roux, L., 133, 135, 139

Royer, S., 129, 135, 139

Rozman, P., 139

Ruben, E., 403

Rubenstein, J., 30

Rubinow, D., 241, 242

Rudic, D., 409

Rudy, B., 136

Rusak, B., 396

Rustioni, A., 10

Sadile, A., 112, 126

Saffman, P., 350

Saggau, P., 313

Sahley, C., 185

Sainsbury, B., 110, 111

Sakmann, B., 314

Sancar, A., 392

Sangoram, A., 402, 403

Sarah, S., 101

Saunders, R., 238

Saxe, R., 262

Schacher, S., 171, 182

Schaevitz, L., 69, 74

Schartzkroin, P., 123

Schein, S., 231

Scheller, R., 409

Scherrer, G., 28, 42, 43

Schibler, U., 392, 408, 421

Schiller, J., 314

Schiller, P., 230, 443, 450

Schinder, A., 361

Scholz, K., 167, 171

Schomburg, E., 139

Schreiner, C., 20

Schulman, J., 139

Schultz, S., 156, 157, 158, 160, 178, 179, 180

Schwartz, E., 230

Schwartz, J., 150, 165, 169, 176, 181, 185

Schwartz, W., 396

Seethapathi, N., 262

Segal, M., 101

Sehgal, A., 392

Sejnowski, T., 89,120, 205, 206

Sellars, W., 199

Selzer, M., 150

Senzai, Y., 139

Seress, L., 105

Shafer, B., 254

Shapiro, E., 162

Sharif, F., 139

Sharif-Naieni, R., 42

Sharma, J., 261

Sharp, P., 244, 247, 261

Shashua, A., 444

Shatz, C., 360

Shedlovsky, A., 398

Sheffield, V., 409

Shelly, M., 362

Shen, F., 217

Shepard, R. N., 456

Shepherd, G., 155

Sheppard, J., 306

Sherman, M., 185

Shi, Y., 251, 352

Shmoel, N., 254

Shoichet, B., 36

Shong, H., 247, 248

Shouval, H., 176, 179

Shultz, S., 167

Siebert-Altavini, T., 285

Sigman, M., 275, 285

Sik, A., 124, 139

Silk, J., 214

Simmons, J., 391

Simons, D., 161

Singer, W., 170, 238

Sirota, A., 128, 130, 131, 133, 135, 139

Sjulson, L., 139

Skinner, B. F., 96, 98, 386

Slater, G., 306

Smith, A., 212

Smith, A. D., 120

Smith, M., 13

Smith, S., 306, 352, 353

Smolen, P., 178, 183

Snider, W., 181

Snyder, S., 421

Socrates, 209, 210, 216

Sodickson, D., 136

Sohal, V., 32

Sokolov, E., 102

Solt, V., 139

Sommer, F., 89

Somogyi, P., 110, 113, 117, 120, 122, 123, 136

Somogyvári, Z., 139

Song, A., 363

Song, E., 403

Song, H., 357, 359

Song, W., 403

Soula, M., 139

Spain, B., 316

Sparks, D., 313, 319

Spencer, A., 150, 151, 153

Sperry, R., 353

Spitzer, H., 235

Spitzer, N., 185, 347, 356

Sprague, J., 105

Spruston, N., 313

Squire, L., 105, 115, 185, 203, 204, 240

Srinivasan, K., 255

Sryker, M., 443

Stafstrom, C., 306

Stahl, F., 391

Stambrook, F., 201

Stapelfeld, E., 316

Stark, E., 139

Stellar, E., 8

Stent, G., 360, 371

Steriade, M., 115

Stetson, M., 389

Stettler, D., 276, 278

Stevens, C., 164, 205, 311, 352, 354

Stevens, F., 317

Stewart, O., 104

Streisinger, G., 391

Strick, P., 8

Strittmatter, W., 309

Stryer, L., 393

Stuart, A., 314, 345, 346

Stuart, G., 314

Sudhof, T., 252, 411, 412

Sugita, S., 169

Sullivan, D., 139

Sumbre, G., 360

Summer, L., 245

Sun, Q., 367

Sun, Y., 353

Susswein, A., 168, 172, 173

Sutherland, R., 110, 111

Su, V., 261

Suzuki, W., 115, 185, 240

Svoboda, K., 129

Swan, J. G., 215

Swanson, L., 105

Swanson, R., 139

Sweatt, D., 313, 319

Szentágothai, J., 93

Takahashi, A., 258

Takahashi, J. S., 376–434

Tallal, P., 121

Tamamaki, N., 122

Tan, H., 263

Tank, D., 129

Tanzi, E., 150

Tao, H., 358, 359, 360

Taub, A., 15

Tauc, L., 174, 355

Tayebi, B., 139

Taylor, B., 42, 43

Tepper, J., 115, 121

Terry, B., 115

Terzuolo, C., 153

Tessier-Lavigne, M., 357, 411

Teuber, H., 441

Thal, L., 121

Thalmann, B., 309

Thompson, C., 321

Thompson, R., 105, 170, 185

Thurston, F., 302

Tilghman, S., 411

Tinbergen, N., 386

Tingley, D., 139

Toga, A., 411

Tolbert, L., 185

Toschi-Chambers, L., 41, 46

Townsel, J., 71

Traub, R., 118

Triesman, A., 236

Trudeau, L., 171

Tsai, L.-H., 247

Tsao, D., 231

Tsien, D., 136

Tsien, R., 132, 133

Ts’o, D., 276, 313

Tsuchiya, H., 252, 253

Tsujikubo, R., 251

Turek, F., 389, 394, 398, 409, 412, 418, 421

Turing, A., 362

Ullman, S., 278, 436–471

Ungerleider, L., 231, 232, 233, 236, 238, 243

Vaina, L., 447

Valenzuela, C., 261

Valero, M., 139

van Buskirk, R., 389, 390

Vandecasteele, M., 139

Vanderwolf, C., 99, 100, 101, 106, 107, 108, 109, 110, 111, 114

Van Essen, D., 185, 232

Varga, V., 139

Varmus, H., 148, 240, 241, 409

Vereczkey, L., 111, 139

Vernberg, F. J., 388

Vernberg, W., 388

Villa, V., 111

Villeda, S., 46

Vinogradova, O., 122

Vinoly, R., 244

Vitaterna, M., 398, 399, 401

Volk, L., 412

von Frisch, K., 386

von Mises, L., 128

von Neumann, J., 117, 451

Vöröslakos, M., 139

Wachtel, H., 149, 302

Waddell, S., 185

Wainwright, M., 171

Wallach, H., 445

Wall, P. D., 5, 8, 9, 11, 12, 13, 15, 16, 35

Walsh, J., 167, 169, 184

Walter, G., 93

Walters, T., 155, 165, 166

Walter, W. G., 114

Walton, K., 306

Wang, F., 262

Wang, L., 248

Wang, X., 125, 136, 139

Wang, Y., 364

Wang, Z., 366

Watson, B., 139

Watson, J., 342, 343, 410, 411

Waxham, N., 179

Weems, W., 186

Wei, K., 251, 252

Weinrich, J., 34

Weisblat, D., 360

Weiss, K., 172, 173

Weiss, P., 347

Weitz, C., 406, 407

Wells, D., 246

Welsh, D., 408

Wenk, G., 64

Wercberger, R., 41

Werner, G., 153, 156

Wertheimer, M., 275

Westerfield, M., 391

Westheimer, G., 276

Weston, J., 391

Wheeler, J., 208

White, J., 170

Wienisch, M., 260

Wiesel, T., 229, 272, 273, 274, 275, 276, 277

Wiley, R., 69

Williams, S., 391

Wilsbacher, L., 402, 403

Wilson, B., 302, 305

Wilson, W., 304

Winckler, B., 363

Winson J., 100, 104

Winston, P., 447

Wintroub, B., 44

Wise, K., 124, 125

Wishaw, I., 110, 111

Wisner, S., 391

Wittner, L., 139

Wolbarsht, M., 302

Woolf, C., 22, 36

Wu, C., 350, 364

Wu, F., 139

Wurtz, B., 231, 234

Wu, S., 317

Xu, B., 369

Xu, H., 261

Xu, N., 366

Xu, P., 415

Xu, R., 258

Xu, W., 412

Yaghmazadeh, O., 139

Yaksh, T., 13

Yamamoto, K., 45

Yamazaki, S., 408, 420

Yanagisawa, M., 415, 416

Yandong, L., 248

Yang, L., 263

Yang, R., 262

Yang, S., 249

Yau, K., 393

Yelich, T., 74

Yip, J., 161

Ylinen, A., 124, 139

Yoon, E., 136

Yoo, S., 408, 414

Young, J. Z., 126

Young, L., 211

Young, M., 392, 401, 405, 406, 407, 421

Young, S., 349

Yuste, R., 129

Zakon, H., 319

Zarate, C., 242

Zatz, M., 392, 393

Zeki, S., 232

Zemmelman, B., 320, 321

Zeng, H., 368

Zhang, B., 261

Zhang, F., 176, 260, 262, 263

Zhang, L., 358, 359, 360

Zhang, Q., 260

Zhang, S., 139

Zhang, X., 365

Zhang, Y., 139, 182, 183

Zhao, N., 352

Zhao, Y., 402

Zhao, Z., 139

Zhou, H., 248, 254, 256

Zhou, Q., 360

Zimmerman, T., 389

Zivin, J., 119

Zohary, E., 462

Zola-Morgan, S., 105, 115

Zola, S., 203

Zucker, B., 306

Zugaro, M., 130, 139

Zutshi, I., 139