Animals in Research

Animals in Research / Resources for Medical Students

Resources for Medical Students

Animals in Research

The resources presented here include videos from leading clinicians in the field and illustrate the interaction between humane animal research and clinical observations that have led to treatments for brain diseases.

These resources will help doctors-in-training:

  1. become aware of the current state of research on therapies for brain diseases.
  2. understand how animals are used to develop and evaluate treatments.
  3. develop individual treatment plans for their patients.

Carefully regulated, humane animal research enables scientists to study fundamental processes underlying brain function. Animals can also be used to model diseases and symptoms so that scientists can evaluate important clinical questions.

These resources, funded by The Esther A. & Joseph Klingenstein Fund, Inc., aim to teach medical students about the essential role animal research has played in the advancement of therapeutics for brain diseases. The Klingenstein Fund supports basic research that it hopes will lead to a better understanding of neurological and psychiatric disorders.

Disease Topics
Joseph Coyle
Parkinson's Disease
Anne Young
Jeffery Noebels
Rett Syndrome
Huda Zoghbi
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Joseph Coyle is the chair of psychiatry and neuroscience at Harvard Medical School. In addition to his clinical research and patient care, he has extensive experience with rodent models of neuropsychiatric disorders to develop more effective treatments. During his junior year of college, he worked as an orderly in a psychiatric ward. When a friend's brother was admitted with schizophrenia, he became interested in studying psychiatry. He wanted to know more about how drugs affect the brain, so after receiving his degree from Johns Hopkins School of Medicine in 1969, he started doing scientific research in that area. Coyle joined Harvard as a faculty member in 1975. He continues to run a research lab alongside his medical practice.

Clinician Background

Joseph Coyle

Joseph Coyle, MD

Joseph T. Coyle holds the Eben S. Draper Chair of Psychiatry and Neuroscience at Harvard Medical School. From 1991 to 2001, he served as chairman of the consolidated department of psychiatry at Harvard Medical School, which included the nine hospital programs of psychiatry affiliated with the medical school. After graduating from Holy Cross College, he received his medical degree from Johns Hopkins School of Medicine in 1969. Following an internship in pediatrics, he spent three years at NIH as a research fellow in the laboratory of Nobel laureate Julius Axelrod. Coyle returned to Hopkins in 1973 to complete his psychiatric residency, an area in which he is board certified, and joined the Harvard faculty in 1975. In 1980, he was promoted to professor of neuroscience, pharmacology and psychiatry; and in 1982 he assumed the directorship of the division of child and adolescent psychiatry, being named a distinguished service professor in 1985. In addition to his clinical research and patient care, Coyle has extensive experience in working on rodent models of neuropsychiatric disorders to develop more effective treatments. Coyle is a past president of the Society for Neuroscience.

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Anne Young is the chief neurology service director of MassGeneral Institute for Neurodegenerative Diseases. She first encountered Parkinson's disease as a teenager, when she visited a friend whose aunt had a severe case. Her interest in the disease and in neuroscience led her to get involved in scientific research during college. She went on to receive an MD and a PhD in pharmacology from Johns Hopkins and then completed residency training in neurology at the University of California, San Francisco. After 13 years on the neurology faculty at the University of Michigan, she became the first female chief at Massachusetts General Hospital. There, she established the MassGeneral Institute for Neurodegenerative Disease.

Clinician Background

Anne Young

Anne Young, MD

Young and her late husband John B. Penney, Jr. provided the most widely cited model of basal ganglia function (the basal ganglia are the brain regions affected by Huntington's (HD) and Parkinson's (PD) diseases). The model has provided the springboard for testing novel interventions in HD, PD, and related disorders. Young's work includes several animal models such as rodents, macaque monkeys, cats, and fruit flies (Drosophila).

Young established the MassGeneral Institute for Neurodegenerative Disease (MIND). MIND brings together scientists at Mass General concentrating on studies of Alzheimer's, PD, HD, and amyotrophic lateral sclerosis. Young spearheaded the comprehensive drug discovery efforts at MIND and has been successful in identifying drug targets for PD, HD, and other neurodegenerative diseases.

Young received an MD and PhD in pharmacology from Johns Hopkins University and then completed residency training in neurology at the University of California, San Francisco. After 13 years on the neurology faculty at the University of Michigan, she was recruited to Massachusetts General Hospital as its first female chief.

Young is a past president of the Society for Neuroscience.

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Jeffrey Noebels directs the developmental neurogenetics laboratory at the Baylor College of Medicine and is an international leader in epilepsy research. He started as a psychology major at Reed College and promptly fell in love with the brain. He chose to work in an epilepsy lab at Stanford University during graduate school because he wanted to record intracellularly from neurons in cortical circuits. After completing a postdoctoral fellowship at Harvard, he received his MD from the Yale School of Medicine, trained in neurology at Massachusetts General Hospital, and started his own lab to study naturally occurring epilepsies using single gene mutations in the mouse.

Clinician Background

Jeffrey Noebels

Dr. Jeffrey Noebels

Jeffrey Noebels is professor in the departments of neurology, neuroscience, and molecular and human genetics at the Baylor College of Medicine. He holds the Endowed Chair of the Cullen Trust for Health Care and is director of the Blue Bird Circle Developmental Neurogenetics Laboratory, an international leader in epilepsy research. He received a PhD in neurological science from Stanford University and trained in neurogenetics as a William G. Lennox Postdoctoral Fellow at Harvard Medical School. After receiving his MD from the Yale School of Medicine, he returned to genetic research as a Klingenstein Fellow at Children's Hospital in Boston, and completed his neurology training at Massachusetts General Hospital. Noebels pioneered the genetic approach to basic epilepsy research using single gene mutations in the mouse, and his laboratory has now defined more than 25 genes linked to various seizure disorders. His research now includes work on ion channel gene expression in human brain tissue.

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Huda Zoghbi is professor in the departments of pediatrics, molecular and human genetics, neuroscience, and neurology at the Baylor College of Medicine. Although she was initially interested in cardiology, Zoghbi soon found herself drawn to disorders that affect the brain. In her second year of residency, she encountered a puzzling patient who made a huge impression on her. Zoghbi was inspired to go into research to determine what could have caused the patient's sudden neurological deterioration - Rett syndrome.

Clinician Background

Huda Zoghbi

Dr. Huda Zoghbi

Huda Zoghbi is the Ralph D. Feigin Professor in the departments of pediatrics, molecular and human genetics, neurology, and neuroscience at the Baylor College of Medicine. She is also the director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and an investigator at Howard Hughes Medical Institute. Born and raised in Beruit, Lebanon, Zoghbi began medical school at American University in Beirut. However, when war erupted in Lebanon, her family moved to the United States and she finished her medical training at Meharry Medical College in Nashville. Zoghbi and her collaborators have done groundbreaking work on a number of devastating neurological disorders, including Rett syndrome and spinocerebellar ataxia type 1 (SCA1). Animal models, specifically mice and Drosophila, have proved to be the most useful in her research, leading to discoveries that have provided new ways of thinking about more common neurological disorders, which could ultimately lead to better treatments for such diseases.

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Schizophrenia Resources

Schizophrenia is a severe brain disorder that causes hallucinations, delusions (unshakable false beliefs that may be bizarre), and serious cognitive impairments that often lead to disability. Prior to the discovery of antipsychotic medications, many patients with schizophrenia spent years in hospitals. Although medications do not treat all symptoms and have significant side effects, their use, along with psychosocial treatments, now allows most people to lead independent lives. A wide variety of antipsychotic drugs have been developed through animal research.

The very first antipsychotic drug, chlorpromazine, was found to treat hallucinations and delusions based on serendipitous observations in humans. The ability to develop new drugs began with the side effects of chlorpromazine. Scientists noticed issues such as tremor and stiffness with chlorpromazine - symptoms similar to in Parkinson's disease - and wondered if there was a common factor. Using rats, Nobel Prize winner Arvid Carlsson discovered that a neurotransmitter called dopamine was involved. He noted that the side effects of chlorpromazine and the symptoms of Parkinson's disease both result from a decrease of dopamine. The realization that decreasing dopamine helped alleviate psychotic symptoms lead to the development of medications with milder side effects. Investigations into dopamine's role in schizophrenia have led to relatively effective treatments for the positive symptoms of schizophrenia - hallucinations and delusions. However, current treatments are less likely to improve the negative symptoms - such as the loss of drive and pleasure - or the cognitive symptoms - impairments in memory, decision making, and focus. Recent discoveries, including genetic work, have shown that other neurotransmitters and neuromodulators play an important role in those symptoms. Schizophrenia is heritable. There is no single gene for schizophrenia. Rather, many genes interact to produce risk of this disorder. One of the most important models in which to study schizophrenia-risk genes is in the mouse brain. In recent years, scientists have identified more than fifty genes associated with an increased risk for schizophrenia. They have begun to study what these genes do in order to develop a new generation of treatments.

A surprising connection between this genetic work and drugs of abuse has focused recent research on the neurotransmitter glutamate. After scientists realized the illicit drug phencyclidine (PCP) could trigger schizophrenia-like symptoms in humans, animal research showed the PCP blocked a receptor for glutamate. Additionally, a number of the schizophrenia-risk genes affect glutamateric signaling, a fact important during development, indicating the harm from these mutations could begin early in life.

Since the glutamatergic deficit seems to drive negative and cognitive symptoms, scientists hope that continued animal research will help in the development of treatments able to target all of the symptoms. Eventually, scientists hope to understand and treat the underlying causes of schizophrenia.

Credit: Illustration by Lydia Kibiuk. Adapted from Brain Facts, published by the Society for Neuroscience

Scientists have developed medications that can help minimize or eliminate the psychotic symptoms of schizophrenia. These drugs mostly block receptors to the neurotransmitter dopamine, reducing activity in the dopamine pathways of the brain.

From The New England Journal of Medicine, Richard L. Suddath, George W. Christison, E. Fuller Torrey, et al., Anatomical Abnormalities in the Brains of Monozygotic Twins Discordant for Schizophrenia, 322, 789-794. Copyright © (1990) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

MRI coronal views from two sets of monozygotic twins discordant for schizophrenia showing subtle enlargement of the lateral ventricles in the affected twins (panels B and D) as compared with the unaffected twins (panels A and C), even when the affected twin had small ventricles.

Photo courtesy of Campden Instruments.

A mouse solving a touchscreen object-location paired-associates learning task. Schizophrenic patients are impaired in touchscreen object-location paired-associates learning.

Powerpoint courtesy Dr. Peter Talbot of the University of Manchester
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Parkinson's Disease Resources

Parkinson's disease (PD) is a chronic progressive disorder first described in the early 1800s by James Parkinson and is characterized by slowness, stiffness, and tremor. These symptoms are due to the loss of midbrain dopaminergic neurons, which causes the depletion of dopamine within the basal ganglia and the disruption of motor and cognitive circuitry. The disease, however, affects many other neuronal systems, resulting in a wide range of motor (balance impairments) and non-motor symptoms that can precede the motor deficits by many years. Although the cause of PD remains unknown, environmental and genetic interactions are thought to underlie disease etiology. A number of animal models have provided insight about pathophysiology and treatment. These models include pharmacological, neurotoxin, and genetic-based approaches, with the overall goal of replicating aspects of the human condition, including, but not limited to, dopamine depletion and cell death. Historically, pharmacological approaches were valuable in first elucidating dopamine as an important neurotransmitter for motor and basal ganglia function. Using rabbits exposed to reserpine, Arvid Carlsson, who shared the Nobel Prize in 2000, linked motor behavioral impairments with depletion of the neurotransmitter dopamine. This discovery led to the strategy of replacing the missing neurotransmitter through the oral administration of levodopa (L-DOPA), a dopamine precursor, combined with carbidopa, a peripheral inhibitor of dopamine metabolism.

Two well-established neurotoxin models, using 6-hydroxydopamine (6-OHDA) and 4-methyl, 1,2,3,6 tetrahydropyridine (MPTP), have enabled scientists to replicate PD in rodents and non-human primates. This can enable the identification of compounds effective for anti-Parkinsonian symptomatic treatment, as well as exploring novel therapeutic approaches such as transplantation and gene therapy. Genetic animal models are particularly useful for examining mechanisms of pathology, including the role of protein misfolding, the mitochondria, and autophagy. In addition, these models are used to develop and test neuroprotective therapies to stop the course of disease.

Studies using non-human primates helped locate the aberrant circuit activity resulting from dopaminergic neuron death in a region of the brain called the basal ganglia during PD. Small regions in this circuit now serve as a target for surgical approaches such as deep brain stimulation, which compensates for the loss of dopaminergic signaling, thereby alleviating PD symptoms as well as motor complications.

Copyright Anne Young

Positron emission tomography, or PET, allows for the visualization of brain activity. This series of images taken over a period of four years of a patient with Parkinson’s disease show the decrease in basal ganglia activity.

Copyright Anne Young

Dopamine neurons in the substaintia nigra die during Parkinson’s disease. The image on the left shows a healthy aging brain with no cell death. The image on the right shows the loss of dopamine neurons characteristic of Parkinson’s disease.

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Epilepsy Resources

Epilepsy encompasses an array of brain activity disorders. Symptomatically, epilepsy can range from dramatic tonic-clonic seizures to subtle alterations in awareness that characterize absence seizures.

Over the last several decades, animal research has led to the development of increasingly effective treatments that have made life more manageable for people with epilepsy. Through the expanding field of epilepsy research using animals and their cells and tissues in vitro, multidisciplinary researchers are fine-tuning their understanding of the many genetic and environmental factors that contribute to epilepsy and are using this knowledge to develop improved treatments.

Some causes of epilepsy are clear — damage from trauma or other illnesses often underlie epilepsy — but about 70 percent of cases stem from unknown causes. In fact, the causes and manifestations of the disease are so varied that doctors now commonly refer to the affliction as “the epilepsies,” to reflect their diversity.

Seizures reflect abnormally synchronized patterns of activity in neural networks. These can remain localized to one brain region (e.g., partial seizures) or spread throughout the brain (generalized seizures). Initial understanding of the events that go awry during a seizure - and between seizures - came from electroencephalograms (EEG) of patients, which revealed distinctive signatures of abnormal brain activity. Early treatments for epilepsy were not ideal. Physicians recognized quickly that sedatives, such as bromides and barbiturates, suppressed seizures but were overly sedating. Surgery was crude and often took out too much healthy tissue. When doctors removed an epilepsy patient's medial temporal lobes bilaterally, it created one of the most studied cases of amnesia in medical history. The patient, who famously became known as HM, was cured, but lost the ability to create new memories. Today, thanks to the vital role of animal research, more than 12 antiepileptic drugs are available to control seizures with far fewer side effects. Common mechanisms include the blockade of sodium and calcium channels, currents which tend to increase neuronal excitation. Others facilitate inhibitory GABA neurotransmission, which serves to dampen the overall excitation in the brain. In addition to drugs, targeted surgeries to alleviate epilepsy use magnetic resonance imaging (MRI) and electrophysiological mapping techniques. Although the antiepileptic drugs and targeted surgeries have evolved tremendously over the past few decades, many patients don't benefit from them.

Animal research has already contributed heavily to the progress made in understanding causes and developing treatments for epilepsy. A major breakthrough came in the late 1970s using electrocorticography (ECG), with the observation that mice known for their wobbly gait, referred to as “tottering,” displayed spike-wave seizure activity remarkably similar to that seen in humans with epilepsy. Eventually, scientists traced the mouse epilepsy to a mutation in a specific gene, Cacna1a, which encodes a voltage-activated calcium channel, a protein that plays an important role in regulating neurons' cellular and electrical properties, including release of neurotransmitters. This provided the initial clue that even a single ion channel defect could produce epilepsy. Since then, more than 100 genes have been identified as contributing to epilepsy in mice and humans. Some of the mutations seen in mice arise spontaneously. Others have been genetically engineered into rodents, which has propelled scientists' ability to dissect the genetic influences of individual mutations and the ways they affect brain activity. While few forms of human epilepsy are caused by individual gene mutations, scientists are discovering that more subtle alterations in combinations of these genes can make a person more susceptible to epilepsy in the face of other influences (i.e., concussions, tumors, etc.).

Part of the difficulty in elucidating the root causes of epileptic seizures is that scientists have just begun to understand the ways that neurons and circuits signal to one another in normal, healthy brains. Researchers agree that most epileptic conditions likely arise from abnormalities in the two main functions of cortical networks: “firing” and “wiring.” “Firing” describes the intrinsic properties of the neuron's excitable membrane that allow it to rapidly signal with other cells, whereas problems with “wiring” of the network during development affect the way that cells communicate on a broader scale. Firing problems can often be traced to defects or mutations in ion channels, whereas wiring abnormalities are more likely to stem from mutations in proteins key to the transmission of signals at synapses, as well as the correct migration pattern of cells in the developing brain.

Other aspects of epilepsy that have more recently come to light from animal research are the importance of tonic inhibition (which keeps the brain in a resting state), the ability of the brain to reorganize its synapses, and the function of glial cells. Animal models allow critical opportunities to move these new findings toward treatments. For example, optogenetic technology now allows for cell-specific control of network firing to prevent seizures. Other researchers have repaired epileptic brain networks by transplanting interneuron precursor cells. Finally, mice have provided essential evidence underlying the relationship of epilepsy to conditions that come with it, such as memory impairment and even sudden death due to cardiac arrhythmias. As in many areas of neuroscience, future research in epilepsy is being guided by findings in animal models, which will provide clues to the human condition that cannot yet be discovered or advanced in the clinic.


Baraban SC, Southwell DG, Estrada RC, Jones DL, Sebe YJ, et al. Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice. Proceedings of the National Academy of Sciences of the United States of America. Sep 8; 106(36): 15472-15477 (2009).

Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL. Arrhythmia in Heart and Brain: KCNQ1 Mutations Link Epilepsy and Sudden Unexplained Death. Science Translational Medicine. Oct 14; 1(2): 2ra6 (2009).

Krook-Magnuson E, Armstrong C, Oijala M, Soltesz I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nature Communications. Jan 22; 4: 1376 (2013).

Noebels JL, Sidman RL. Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science. June 22;204:1334-1336 (1979).

Palop JJ, Mucke L. Epilepsy and Cognitive Impairments in Alzheimer Disease. Archives of Neurology. April; 66(4): 435 (2009).

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Rett Syndrome Resources

Rett syndrome is a rare genetic neurodevelopmental disorder that affects about 1 in 10,000 girls in early childhood. After seemingly developing normally, girls in their second year of life begin to regress, losing learned skills like talking, using their hands, and other movements, and develop autistic behaviors. The disease varies widely among patients in its course and severity, but it can progress to severe intellectual and physical disabilities, sometimes including loss of controlled movement and epileptic seizures. After this initial decline, girls with Rett syndrome usually stabilize and live into adulthood. Although there is no cure for Rett syndrome, researchers have recently made major progress in understanding the genetic and molecular basis of this disease largely through work in animal models.

In 1954, when Austrian pediatrician Andreas Rett noticed a peculiar hand-wringing behavior in a number of his young female patients, the era of modern medical research had barely begun, and information moved at a pace that today seems archaic. Rett traveled throughout Europe conducting research about the disease and sharing information with colleagues, but the disease was not widely recognized until 1983 when Swedish physician Bengt Hagberg described the syndrome, naming it for Rett, in the widely read Annals of Neurology. Even then, doctors and researchers had little clue about what caused the disease, but the pattern seen in very rare familial cases suggested a dominant genetic mutation of a gene found on the X chromosome. (Although X-linked mutations often affect boys, Rett syndrome arises from a mutation of a gene so critical that male infants carrying the mutation seldom survive, and girls carrying even just one copy of the mutation develop the disease.)

A major breakthrough in understanding Rett syndrome came in 1999, when researchers at Baylor College of Medicine tracked down the gene that causes Rett syndrome by analyzing the sequences of genes on the X chromosome from individuals with the disease. The long search revealed mutations in a gene called MECP2, which encodes methyl-CpG-binding protein 2. Since then, the pace of research on Rett syndrome has accelerated rapidly. Among the most important developments for understanding Rett syndrome has been the generation of several mouse models of the disease, in which the MECP2 gene is either mutated or “knocked out.” Powered by the ability to genetically engineer mice and other animals, these studies have revealed information not just about Rett syndrome and the function of MECP2, but also about larger questions like gene regulation, neuronal plasticity, and neural function in general.

Although no animal model of disease can exactly recapitulate the human situation, animals genetically engineered to lack or have mutations to MECP2 give researchers the ability to isolate and examine the factors that contribute to the disease. Mice provide a key tool because researchers can manipulate their genes and observe their disease-related behaviors. Largely through work in the mouse models, the protein encoded by MECP2 has emerged as a critical regulator of neural gene expression, preventing other genes from making proteins when they are not needed. The mutations in MECP2 change the regulatory abilities of the protein, thereby altering the expression of many other genes. Nearly 300 different mutations have been reported in girls with Rett syndrome, but most are clustered around eight “hot spots” on the gene. Through animal studies, scientists are elucidating how each of these mutations affects the protein and its function throughout development. Rett syndrome has been called the “Rosetta stone” for understanding neurodevelopmental disorders, since the animal model work is informing scientists' understanding of so many other brain disorders.

In ongoing work in model animals, scientists are manipulating the MECP2 gene in specific subsets of brain cells to learn about their functions — information that could illuminate many other neurological disorders and even healthy behaviors. Rett research provides an elegant example of how a rare human disease, modeled in animals, has revealed a tremendous amount of information about the human nervous system.


Amir R, Van den Veyver IB, Wan M, Tran C, Francke U, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics. Oct;23(2):185-8 (1999).

Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Annals of Neurology. Oct 14:471-479 (1983).

Neul JL. The relationship of Rett syndrome and MECP2 disorders to autism. Dialogues in Clinical Neuroscience. Sep; 14(3): 253-262 (2012).

Copyright Dr. Huda Zoghbi

Behavioral Assessment of Mice: Nest Building

Mice build nests for shelter, protection from predators, and heat conservation when suitable material is present. Nest building can be used to determine social skills. In the laboratory, mice are given squares of pressed cotton. Wild-type mice typically build a nest in the shape of a cocoon, with well developed walls and a partial roof (A). Mice carrying a genetic mutation similar to Rett Syndrome only partially shred nesting material, or build a shallow nest without walls (B and C).

Modified with permission from Baker SA et al. Cell, 2013

Function of MeCP2

The wild-type MeCP2 protein binds regions of DNA that is bound in chromatin through its Methyl binding domain and to AT-rich DNA sequences through conserved basic amino acids (+++). Such binding leads to changes in chromatin architecture which suppresses the expression of certain genes. When MeCP2 is mutated, as during Rett, the altered chromatin architecture changes the expression of other genes.