Scientists sizing up the brains of both sexes began using their main finding--that female brains tend to be smaller--to bolster the view that women are intellectually inferior to men.

To date, no one has uncovered any evidence that anatomical disparities might render women incapable of achieving academic distinction in math, physics or engineering. And the brains of men and women have been shown to be quite clearly similar in many ways. Nevertheless, over the past decade investigators have documented an astonishing array of structural, chemical and functional variations in the brains of males and females.

These inequities are not just interesting idiosyncrasies that might explain why more men than women enjoy the Three Stooges. They raise the possibility that we might need to develop sex-specific treatments for a host of conditions, including depression, addiction, schizophrenia and post-traumatic stress disorder (PTSD). Furthermore, the differences imply that researchers exploring the structure and function of the brain must take into account the sex of their subjects when analyzing their data--and include both women and men in future studies or risk obtaining misleading results. Sculpting the Brain Not so long ago neuroscientists believed that sex differences in the brain were limited mainly to those regions responsible for mating behavior. In a 1966 Scientific American article entitled "Sex Differences in the Brain," Seymour Levine of Stanford University described how sex hormones help to direct divergent reproductive behaviors in rats--with males engaging in mounting and females arching their backs and raising their rumps to attract suitors. Levine mentioned only one brain region in his review: the hypothalamus, a small structure at the base of the brain that is involved in regulating hormone production and controlling basic behaviors such as eating, drinking and sex. A generation of neuroscientists came to maturity believing that "sex differences in the brain" referred primarily to mating behaviors, sex hormones and the hypothalamus. Differences in the size of brain structures are generally thought to reflect their relative importance to the animal. For example, primates rely more on vision than olfaction; for rats, the opposite is true. As a result, primate brains maintain proportionately larger regions devoted to vision, and rats devote more space to olfaction. So the existence of widespread anatomical disparities between men and women suggests that sex does influence the way the brain works. Other investigations are finding anatomical sex differences at the cellular level. For example, Sandra Witelson and her colleagues at McMaster University discovered that women possess a greater density of neurons in parts of the temporal lobe cortex associated with language processing and comprehension. On counting the neurons in postmortem samples, the researchers found that of the six layers present in the cortex, two show more neurons per unit volume in females than in males. Similar findings were subsequently reported for the frontal lobe. With such information in hand, neuroscientists can now explore whether sex differences in neuron number correlate with differences in cognitive abilities--examining, for example, whether the boost in density in the female auditory cortex relates to women's enhanced performance on tests of verbal fluency. Differences in the size of brain structures are generally thought to reflect their relative importance to the animal. For example, primates rely more on vision than olfaction; for rats, the opposite is true. As a result, primate brains maintain proportionately larger regions devoted to vision, and rats devote more space to olfaction. So the existence of widespread anatomical disparities between men and women suggests that sex does influence the way the brain works. Other investigations are finding anatomical sex differences at the cellular level. For example, Sandra Witelson and her colleagues at McMaster University discovered that women possess a greater density of neurons in parts of the temporal lobe cortex associated with language processing and comprehension. On counting the neurons in postmortem samples, the researchers found that of the six layers present in the cortex, two show more neurons per unit volume in females than in males. Similar findings were subsequently reported for the frontal lobe. With such information in hand, neuroscientists can now explore whether sex differences in neuron number correlate with differences in cognitive abilities--examining, for example, whether the boost in density in the female auditory cortex relates to women's enhanced performance on tests of verbal fluency. Such anatomical diversity may be caused in large part by the activity of the sex hormones that bathe the fetal brain. These steroids help to direct the organization and wiring of the brain during development and influence the structure and neuronal density of various regions. Interestingly, the brain areas that Goldstein found to differ between men and women are ones that in animals contain the highest number of sex hormone receptors during development. This correlation between brain region size in adults and sex steroid action in utero suggests that at least some sex differences in cognitive function do not result from cultural influences or the hormonal changes associated with puberty--they are there from birth. Inborn Inclinations Several intriguing behavioral studies add to the evidence that some sex differences in the brain arise before a baby draws its first breath. Through the years, many researchers have demonstrated that when selecting toys, young boys and girls part ways. Boys tend to gravitate toward balls or toy cars, whereas girls more typically reach for a doll. But no one could really say whether those preferences are dictated by culture or by innate brain biology. #1 To address this question, Melissa Hines of City University London and Gerianne M. Alexander of Texas A&M University turned to monkeys, one of our closest animal cousins. The researchers presented a group of vervet monkeys with a selection of toys, including rag dolls, trucks and some gender-neutral items such as picture books. They found that male monkeys spent more time playing with the "masculine" toys than their female counterparts did, and female monkeys spent more time interacting with the playthings typically preferred by girls. Both sexes spent equal time monkeying with the picture books and other gender-neutral toys. Because vervet monkeys are unlikely to be swayed by the social pressures of human culture, the results imply that toy preferences in children result at least in part from innate biological differences. This divergence, and indeed all the anatomical sex differences in the brain, presumably arose as a result of selective pressures during evolution. In the case of the toy study, males--both human and primate--prefer toys that can be propelled through space and that promote rough-and-tumble play. These qualities, it seems reasonable to speculate, might relate to the behaviors useful for hunting and for securing a mate. Similarly, one might also hypothesize that females, on the other hand, select toys that allow them to hone the skills they will one day need to nurture their young. Simon Baron-Cohen and his associates at the University of Cambridge took a different but equally creative approach to addressing the influence of nature versus nurture regarding sex differences. Many researchers have described disparities in how "people-centered" male and female infants are. For example, Baron-Cohen and his student Svetlana Lutchmaya found that one-year-old girls spend more time looking at their mothers than boys of the same age do. And when these babies are presented with a choice of films to watch, the girls look longer at a film of a face, whereas boys lean toward a film featuring cars. Of course, these preferences might be attributable to differences in the way adults handle or play with boys and girls. To eliminate this possibility, Baron-Cohen and his students went a step further. They took their video camera to a maternity ward to examine the preferences of babies that were only one day old. The infants saw either the friendly face of a live female student or a mobile that matched the color, size and shape of the student's face and included a scrambled mix of her facial features. To avoid any bias, the experimenters were unaware of each baby's sex during testing. When they watched the tapes, they found that the girls spent more time looking at the student, whereas the boys spent more time looking at the mechanical object. This difference in social interest was evident on day one of life--implying again that we come out of the womb with some cognitive sex differences built in. Under Stress In many cases, sex differences in the brain's chemistry and construction influence how males and females respond to the environment or react to, and remember, stressful events. Take, for example, the amygdala. Goldstein and others have reported that the amygdala is larger in men than in women. And in rats, the neurons in this region make more numerous interconnections in males than in females. These anatomical variations would be expected to produce differences in the way that males and females react to stress. To assess whether male and female amygdalae in fact respond differently to stress, Katharina Braun and her co-workers at Otto von Guericke University in Magdeburg, Germany, briefly removed a litter of Degu pups from their mother. For these social South American rodents, which live in large colonies like prairie dogs do, even temporary separation can be quite upsetting. The researchers then measured the concentration of serotonin receptors in various brain regions. Serotonin is a neurotransmitter, or signal-carrying molecule, that is key for mediating emotional behavior. (Prozac, for example, acts by increasing serotonin function.) The workers allowed the pups to hear their mother's call during the period of separation and found that this auditory input increased the serotonin receptor concentration in the males' amygdala, yet decreased the concentration of these same receptors in females. Although it is difficult to extrapolate from this study to human behavior, the results hint that if something similar occurs in children, separation anxiety might differentially affect the emotional well-being of male and female infants. Experiments such as these are necessary if we are to understand why, for instance, anxiety disorders are far more prevalent in girls than in boys. Another brain region now known to diverge in the sexes anatomically and in its response to stress is the hippocampus, a structure crucial for memory storage and for spatial mapping of the physical environment. Imaging consistently demonstrates that the hippocampus is larger in women than in men. These anatomical differences might well relate somehow to differences in the way males and females navigate. Many studies suggest that men are more likely to navigate by estimating distance in space and orientation ("dead reckoning"), whereas women are more likely to navigate by monitoring landmarks. Interestingly, a similar sex difference exists in rats. Male rats are more likely to navigate mazes using directional and positional information, whereas female rats are more likely to navigate the same mazes using available landmarks. (Investigators have yet to demonstrate, however, that male rats are less likely to ask for directions.) Even the neurons in the hippocampus behave differently in males and females, at least in how they react to learning experiences. For example, Janice M. Juraska and her associates at the University of Illinois have shown that placing rats in an "enriched environment"--cages filled with toys and with fellow rodents to promote social interactions--produced dissimilar effects on the structure of hippocampal neurons in male and female rats. In females, the experience enhanced the "bushiness" of the branches in the cells' dendritic trees--the many-armed structures that receive signals from other nerve cells. This change presumably reflects an increase in neuronal connections, which in turn is thought to be involved with the laying down of memories. In males, however, the complex environment either had no effect on the dendritic trees or pruned them slightly.

But male rats sometimes learn better in the face of stress. Tracey J. Shors of Rutgers University and her collaborators have found that a brief exposure to a series of one-second tail shocks enhanced performance of a learned task and increased the density of dendritic connections to other neurons in male rats yet impaired performance and decreased connection density in female rats. Findings such as these have interesting social implications. The more we discover about how brain mechanisms of learning differ between the sexes, the more we may need to consider how optimal learning environments potentially differ for boys and girls.