RESEARCH IN GENDER AND BRAIN SUGGESTS DIFFERENCES AT CELL LEVEL
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RESEARCH IN GENDER AND BRAIN SUGGESTS DIFFERENCES AT CELL LEVEL
ATLANTA, October 17, 2006 - New research into how sex influences brain function shows surprising and important implications for understanding and treating a variety of neurological diseases, that strike one sex more than another, such as autism, Alzheimer's disease, depression, and schizophrenia.
It's also helping to explain why women tend to experience pain more intensely than men -- and why they require higher doses of morphine and other analgesics to relieve that pain. Other new research is shedding light on the age-old observation that men and women's brains often work differently -- such as in how they select cues when navigating from one destination to another.
"Sex is a major variable influencing the brain's basic physiology and the risk for disease," says Arthur Arnold, PhD, of the University of California, Los Angeles. "Studying sex differences in the brain therefore is a major tool in helping us understand the basic processes underlying such things as cognitive performance, emotional memory, pain perception, and the onset and time course of diseases."
For more than half a century, scientists believed that gonadal steroid hormones -- "sex" hormones such as testosterone and estrogen -- were solely responsible for differences between male and female brains. Higher levels of testosterone during fetal development, for example, are known to cause the male brain to develop differently than the female brain, triggering cell death in some regions and fostering cell development in others.
In recent years, however, research has suggested that not all sex differences in the brain are the result of steroid action. In studies on mice and songbirds, Arnold and his colleagues have found that the sex chromosome genes within brain cells play an important role in making the brain masculine or feminine.
"We have found, for example, that XX and XY mice differ in their behavior and gene expression even when both mice have the same kind of gonad, either testes or ovaries." says Arnold. "The experiments suggest that male and female brain cells may be different because of genetic differences within the cells, not just because they are bathed in different types of gonadal hormones."
At the University of Maryland School of Medicine, Margaret McCarthy, PhD, has found that the effects of steroids on the developing brain are highly region-specific. "Different mechanisms are invoked in distinct regions," she says.
McCarthy and her colleagues discovered an unexpected role for hormone-like chemicals called prostaglandins in the masculinization of the preoptic area, a region of the brain that plays a critical role in sexual behavior. In studies on rats, they found that reducing prostaglandin production during late gestation and early lactation rendered males completely asexual as adults. Alternatively, exposing female rats to exogenous prostaglandin during the same developmental periods caused them to exhibit male-like sexuality as adults. Examination of the female animals' brains revealed a larger-than-typical number of synaptic connections in the preoptic area.
"The females showed normal female sexual behavior as well, illustrating the independence of neuronal networks controlling male versus female sexual behavior," says McCarthy.
The gonadal hormones testosterone and estrogen also modulate the production and release of the amino acid transmitters glutamate and gamma-aminobutyric acid (GABA), which are both involved in neural activity. "The actions of these neurotransmitters are different in male and female brains," says McCarthy. "Estrogen, for example, increases the sensitivity of neurons to GABA."
McCarthy and her team have also recently found that sex hormones induce differentiation of glial cells in the developing brain, resulting in differences in the glial structure between males and females. Once considered only a source of support for developing neurons, glial cells are now recognized as being active participants in establishing neural synapses, or transmissions between brain cells.
"Understanding these hormonally-mediated sex differences in the brain provides insight into the many neurological disorders and disease of mental health that exhibit strong gender bias, such as autism, dyslexia, stuttering, schizophrenia and attention deficit disorder," says McCarthy. "This research is also critical for evaluating the potential impact of endocrine-disrupting chemicals in the environment and of the exposure of the fetus and newborns to prescription and over-the-counter drugs."
Aspirin, for example, is a potent inhibitor of prostaglandin syntheses, and studies in rats have shown that it can alter the development of the male brain when administered to pregnant and lactating animals. These findings highlight the need for understanding sex-specific brain development for both therapeutic and preventive purposes.
New studies from Anne Murphy, PhD, of Georgia State University suggest that morphine, the primary analgesic prescribed for the alleviation of chronic pain, works quite differently within the brain and spinal cord of males and females. This finding helps explain why women typically require twice the dosage of morphine as men to achieve the same degree of pain relief.
When the body comes into contact with a painful stimulus, it responds by releasing endogenous opioids, such as endorphins. These opioids bind to the mu opiate receptors in cells within the brain and spinal cord, setting off a cascade of events that lead to a decreased perception of pain. Medically prescribed opiates, such as morphine, work in a similar manner.
Past studies that searched for the location of the mu opiate receptors in the brain and spinal cord have been conducted almost exclusively in males. "We decided to investigate, for the first time, the location of these receptors within the brain and spinal cord of females," says Murphy. "We tested the hypothesis that the mu opiate receptor is differentially expressed in the brains of males and females and that this difference provides the basis for sex differences in morphine analgesia."
Using a variety of techniques, Murphy and her team found that while the mu opiate receptor is located in similar brain regions in males and females, males had significantly greater levels of the receptor. "These results may help explain the observed differences in behavior between men and women when given morphine after painful situations such as chronic pain and post-operative pain," says Murphy.
Her team is now using gene therapy techniques to increase the expression of mu opioid receptors in the brains of female rats to see if they respond in a more 'male-like' manner to morphine. Together, these studies suggest the need for the development of therapies that take into consideration differences in the neurobiological composition of males and females.
In other work, results from a large Internet-based study conducted by a team of American and British researchers suggest that early exposure to sex steroids may play a role in why men and women perform differently on certain visuospatial tasks.
"Men and women don't differ in overall intelligence, but the average male and female do differ for a few specialized cognitive abilities, including a subset of visuospatial tasks," says Marcia Collaer, PhD, of Middlebury College.
In particular, men perform better than women, on average, on tests that require judging the slope of a line or mentally rotating pictures of 3-dimensional objects, while women tend to be better at remembering objects and their locations -- a skill known as landmark memory -- or at rapidly detecting fine-grained details of a visual image. Also, men and women tend to pay attention to different aspects of the environment when navigating a route. Men tend to be more aware than women of properties of space, such as cardinal directions (north, south, east and west) and distances traveled, while women tend to be more aware than men of the landmarks (items placed within that space, such as buildings).
To determine if early exposure to sex steroids, particularly testosterone, may influence one specific sex difference, Collaer and her colleagues, focused on individuals aged 12 to 58 years. Participants were recruited through a large Internet study hosted by the British Broadcasting Corporation that eventually involved more than 250,000 participants.
In addition to measures submitted by other researchers, each participant completed a recently developed visuospatial test known as the Judgment of Line Angle and Position test (JLAP-15). This task was modified from a neuropsychological instrument, the Judgment of Line Orientation task, that relies upon functioning of posterior regions of the right hemisphere. Participants were also asked to indicate their sexual orientation (heterosexual, homosexual, or bisexual) and to measure the lengths of their second and fourth fingers so researchers could calculate the ratio of their digits (2D:4D). This ratio has been suggested to be a marker of prenatal or early postnatal exposure to sex steroids, such as testosterone. Lower ratios suggest greater testosterone exposure.
"On average, men performed more accurately on the line judgment test than women," says Collaer, "although it's important to point out that a percentage of females earned perfect scores." In addition, among adults, heterosexual men outperformed homosexual or bisexual men, while homosexual or bisexual women outperformed heterosexual women. Individuals with more masculine (lower) 2D:4D ratios performed slightly better, on average, than those with higher ratios. This relationship held for both the right and left hands, and in both sexes.
A visuospatial difference favoring boys also was seen in a group of children aged 8 to 10 years, suggesting that the factors promoting this difference occur relatively early in life.
"These findings are consistent with the hypothesis that early sex steroid activity may exert a small influence on an interrelated set of neural, behavioral, and somatic characteristics," says Collaer. "Higher or lower testosterone levels may predispose certain regions of the brain to develop in slightly different fashions. However, given that a number of the obtained relationships were relatively weak, other factors, such as social and environmental influences, are likely to play a large role in cognitive development."
Future work will address how social and attentional factors may contribute to this sex difference, as well as how line judgment ability may relate to other cognitive skills, including navigation ability.