Understanding Ourselves: Gender Differences in the Brain

What a difference a brain makes - small changes in the brain can show up in big ways in life. If you've read my last two newsletters you'll see that this year the focus of my newsletters has been on the brain. This issue examines gender differences in brain structures and hormones that contribute to behaviors in the workplace. I emphasize the word contribute because our behavior is based of a number of factors, including evolution, biology, our developmental environment, and the choices we make. As I pointed out in my last newsletter, we can change the wiring of our brains through practice, but first we need to understand how men and women use their brains differently.

Differences Begin Early
Estrogen and testosterone influence brain development, although the process of the way in which hormones and the brain interact to influence behavior is very complex. Louann Brizendine, MD, author of The Female Brain, points out that gender differences start before birth: female brains are flushed in utero with estrogen hormones, while male brains are washed with testosterone. Females begin studying faces as babies, which shapes their brain development. Research demonstrates that the skills of baby girls in making eye contact and facial gazing increases over 400% in the first three months of life, while facial gazing skills in boys doesn't. In one study, year-old girls looked at their mothers faces 10 to 20 times more than boys checking for signs of approval or disapproval. While the boys, driven by testosterone, moved around the room to investigate their environment and rarely glanced at their mothers.

During puberty, estrogen, progesterone, and testosterone continue influencing development. Teenage girls, flooded with estrogen, get stressed around relationships and ease their fear by banning together and being socially connected. Yes, they can be mean and use their language skills - passive aggressive rumor spreading - to undermine rivals in their competition for the boys (from an evolutionary perspective sexual competition is part of the survival mechanism). But they can apologize and re-bond when necessary. Testosterone flooding the brain of teenage teen boys has the opposite effect: the teenage boy wants to be left alone. He's not interested in conversation because testosterone decreases his desire to socialize except in pursuit of sex or sports. Teenage boys at this time get stressed around challenges to their independence and authority and seek to be respected and find their place in the male pecking order through competition and conflict. They don't look for connection in same way as girls do. These are brain-based behavioral patterns that continue to influence men and women throughout adulthood.

Evolution: The Historical Perspective
It is believed that women's ability to read faces enabled them not only to interpret what a child who couldn't yet speak needed, but also enabled them to predict what a bigger more aggressive male was going to do so that they could protect themselves and their children. Protection was essential: if a woman could band together with other women she was in a better position to protect her children and fend off any attacks. Women's brains, according to Brizendine, were programmed to keep social harmony.

Men on the other hand were programmed to compete in order to reproduce and pass on their genes. In Sex on the Brain, Deborah Blum, sums up the basic beliefs of evolutionary psychology this way: "We descend from a mating system in which males must compete hard in order to become fathers, and in which females work hard to raise and support the young. That male reality demanded aggression and rules with which to contain it - hierarchy, competition, dominance. The testosterone drive is part of that. While females also had to compete, sometimes for mates and sometimes for food, their primary goals were social support, child care, and child protection."

The present problem is that our environment has changed dramatically; yet, our brains, still influenced by these hormones, haven't changed as quickly.

Gender-Driven Behaviors at Work
This ability of the female brain to read others and strive for connection pushes women to be more alert to others' reactions and to look for the approval that will create relationships. Deborah Tannen's research on gender differences in the workplace demonstrates that women in Western business cultures still seek eye contact and watch people's faces seeking cues for approval or disapproval. Men can interpret this behavior as a sign of insecurity rather than a skill of observation and assessment.

The same research indicates that men position their bodies in conversation differently than women, turning sideways or standing shoulder to shoulder in contrast to face-to-face. Women who desire that face-to-face connection can interpret this male body language as a demonstration of lack of interest and listening. These interpretations can escalate: if a woman misinterprets the male body posture as lacking interest or approval, her insecurity buttons can get pushed. This in turn reinforces the male interpretation that the woman lacks confidence. Women, attuned to reading body language, must understand what male body language means in today's world and learn how to manage their own emotional triggers. Otherwise, a woman can find herself caught in a downward confidence spiral.

Men, driven by a need to compete even in subtle ways with each other, can view a woman as less of a leader if she doesn't take a competitive stance. I have coached women whose male bosses have told them they are not aggressive enough. One client's boss told her she needed to fight more in meetings. He wanted her to show her strength in a way that he would and judged her accordingly. But the psychological stress of conflict registers more deeply in the female brain, so it wasn't surprising that my client didn't know what to do with this information. She was competitive (a marathoner and tri--athlete) and a successful businesswoman, but she wasn't going to attack others and get in verbal fights. She wanted to connect, not separate by flexing her muscles to find a space in the male hierarchy. Men need to be more aware of these differences, especially in situations where there might be only one or two females present, for example, at the upper most layers of most organizations. Women have had to learn how to cope with men jockeying for position, but find it very tiresome. It would be beneficial for men to recognize the value of learning less competitive behaviors to decrease the political maneuvering at higher levels of organizations, especially if they want diversity at the top. One of the key reasons women leave organizations is that they don't want to engage in the political power struggles that occur at the top layers, which they see as energy draining and counterproductive.

Differences in Brain Structures
The amygdala is an ancient part of the brain, influenced by hormones, that processes fear, triggers aggression and action, and stimulates competitiveness. It alerts us to danger and switches on the rest of the body. The amygdala in men's brains is larger than in women's. Moreover the male amygdala has testosterone receptors that heighten responses, providing a biological reason for why men compete with each other more aggressively than females and why men can quickly escalate situations and enjoy the fight.

Men and women respond differently to fear signals coming from the amygdala. When the amygdala fires a fear signal, a "fight or flight" reaction is triggered. We have now learned, however, that women's response can be different from men's: women's hormones, based on the evolution of their brains, tell them the way to safety is to gather in a group. So their response can be "tend and befriend." Women can reduce stress and promote a feeling of safety by connecting. When I wrote Success on Our Own Terms in the late '90s, one senior executive female told me that when she is stressed she needs to get out of her office and talk to others, while she noticed that the men at her level who were stressed tended to withdraw into themselves. What's important, as I mentioned in the last newsletter, is that if we are more conscious of the signals coming from our amygdala, we can change the way we respond to fear and adapt our behaviors to serve us better in today's world.

The prefrontal cortex is the decision-making executive center of the brain. It oversees emotional information and puts a check on the amygdala. The prefrontal cortex is larger in women and matures faster in women than in men. This difference, combined with the fact that women have less testosterone and more estrogen flowing through their brains, enables women to look for solutions to conflict, even if it means they might give up more themselves to resolve the situation. For me, this helps to explain the difference I've seen in my coaching practice in the way men and women approach negotiations or handle customers. Women tend to look for ways to compromise and serve the needs of others, even at their own expense. Men tend to look for ways to come out on top, even with their own customers.

The anterior cingulate cortex, which is another part of the rational decision making center of the brain that weighs options, is also larger in women, and has been labeled as the "worrywart" center of a woman's brain. Research demonstrates that anxiety is four times more common in women than men. So while evolution prompted women to be extremely cautious and collaborative so that they could protect their young, this cautiousness in today's business world can be interpreted, particularly by men influenced by risk-taking testosterone, as not being confident enough to step-up and take risks.

The brain is divided into two hemispheres: the left hemisphere deals with language and verbal abilities as well as the ability to process information in an orderly, logical way. The right deals with visual and spatial information, as well as abstract thinking and emotional responses. The corpus callosum, which is the part of the brain that connects both hemispheres, is thicker in women enabling them to use both the right and left sides of the brain in a more connected way than men do. Women use both sides of their brains for visual and verbal processing, and use both sides to respond to emotional experiences, while men use the right side of their brain for spatial skills and the left for verbal skills. Even within the language-centered, left-hand side of the brain, there are differences between men and women's brains. Anne Moir and David Jessel, authors of Brain Sex, claim that "the difference in the layout of the average male or female brain is found to have a direct effect on the way men and women differ in their ways of thinking -- differences in brain organization in men and women will lead to differences in the efficiency with which they perform certain tasks."

The hippocampus is the center for learning, memory and emotion and is larger and more active in the female brain. It is also estrogen sensitive and is a relay station for processing memories into words. Women have 11% more neurons than men in the brain centers for language and hearing. The connections between the two sides of women's brains enable them, on average, to be better at expressing emotions and remembering details of emotional events and communicating them. They use language to talk about feelings and develop consensus more efficiently than men do. Men's brains, more specifically organized and with fewer connections, enable men, on average, to focus more intensely and not be as distracted by superfluous information. Men using only the right side of their brains are able to zone in more quickly than women on certain kinds of tasks, for example, activities requiring spatial skills. Using both sides of their brains for processing spatial information takes women longer, while men take longer to process emotional information and to use certain language skills because of the location of these functions in the male brain. Several years ago, I conducted a 360-feedback process for one of my female clients. When I interviewed her male boss, he told me one of the characteristics he most admired about my client was her ability to read the emotions of people. He often took her with him to meetings because he recognized she could read people's emotions better than he could. Afterwards, she would debrief him, helping him interpret what he might not have been able to figure out as quickly by himself.

Both men and women experience advantages and disadvantages from these brain differences. A strong belief in coaching is that the more you understand your strengths and weaknesses, the better able you will be to devise a plan to leverage those strengths and compensate for those weaknesses. Knowing the advantages and disadvantages of the biological basis of who you are can help you to understand how to best use the advantages your brain provides, what to be aware of around the disadvantages, and how to make changes that will enhance your ability to succeed in your present environment. Knowledge is power and we shouldn't be afraid of understanding the biological component that contributes to making us who we are.

 

HORMONES

Chemicals that impact the structure and operation of the brain and interact with the brain to influence behavior.

Estrogen.A hormone found in much greater abundance in women than in men that enhances female brain circuits helping women master nuanced social skills of communication, observation, and intuition. Estrogen protects physical health and mental wellbeing. It moves women toward developing harmonious relationships, staying connected, and toward a preference for avoiding conflict, and increases a woman's ability to literally feel gut sensations more than men.

Oxytocin. A hormone that drives desire for connection, nurturing and bonding behavior, especially when combined with estrogen. In women, the feeling of connection reduces stress.

Progesterone.A hormone that works in conjunction with estrogen - sometimes mellowing; sometimes the opposite.

Testosterone. A fast-acting, aggressive, hormone and driver of sex. Men have 10 to 100 times more testosterone than women, enabling men to engage in interpersonal conflict and competition. The higher the level of testosterone, the more interest there is in winning the game, gaining the power, and defending the territory through strength, and the less interest there is in high quality social relationships.

Vasopressin. When combined with testosterone this hormone has a subtle aggressive impact; when combined with oxytocin it supports connection, bonding and socializing.

Cortisol.A highly sensitive hormone, made in the adrenal glands, that is activated under emotional and physical stress. Research on cortisol levels suggest that leaders with lower cortisol levels know how to relax under pressure and stay cool when facing challenges.

Dopamine. A neurochemical that stimulates pleasure circuits in the brain and provides a sense of well being.

Serotonin. A neurochemical that provides a sense of ease and calm, controls impulses and aggression. Women, in general, have about 30% more serotonin than men. Women whose ovaries make the most estrogen and progesterone are more resistant to stress because they have more serotonin. Women with less estrogen and progesterone are more sensitive to stress and have less serotonin.

Copyright © 2008 Ginny O'Brien All Rights

The brain differences

The Differences

Structural Differences

The size of the brain is established at an early age, with the whole brain volume at 95% of its adult size by the age of 4. However, the brain continues to develop through the teen age, with many of these changes being sex specific. In the adult brain, the overall cerebral size is larger in men than women, but there are specific parts that are larger in women. These include the caudate nucleus, hippocampus, some prefrontal cortical regions, superior temporal gyrus, and some white matter structures such as the anterior commisure . In the male, the hypothalamus, stria terminalis, cerebral ventricles, and the splenium and genu of the corpus callosum are proportionally larger. In regions where the volume of the structure may not be different, there may be a difference in neuron density. For example, a region of the suprachiasmatic nucleus contains twice as many neurons in men until middle age, when the sex difference reverses and then ultimately disappears.

Frederikse et.al. found sex differences in the inferior parietal lobule (IPL) of the brain (the IPL is shown in yellow in the above diagram). The IPL, a neocortical region, is part of the heteromodal association complex (HASC), which includes the Broca's area among other parts. The IPL is believed to have a role in processing information from the visual, auditory and somatosensory association cortices as well as having connections with other HASC regions, the limbic system and the hypothalamus. In their study of 15 pairs of normal male and female subjects, Frederikse et.al. concluded that men have a larger total IPL volumes than women, with this difference primarily as a result of a larger left male IPL volume. This study supports previous evidence that men tend to outperform women on tasks of visuospatial processing, a function primarily of the left side of the IPL.

Use difference
Research found that men tend to use one side of their brain (particularly the left side for verbal reasoning) while women tend to use both cerebral areas for visual, verbal and emotional responses. These differences in brain use cause a difference in behavior between men and women. Women tend to be better at sensing emotional messages in conversations, gestures, and facial expressions, and are thus more sensitive. Women start to speak and read at an earlier age than men and are generally better in verbal skills, such as learning a different language. They tend to have a better grasp on grammar and spelling, and girls have better handwriting than boys do. Women have better sight at night and have a more acute sense of smell, taste and hearing.

Men are better in spatial coordination and have a better sense of direction (usually!). They excel in math and are great at interpreting three-dimensional objects. They have a better hand-eye coordination and more precise control of large muscle movement. They have poor peripheral vision but better sight in bright light and a better sense of perspective. Since they use one side of their brain more than the other, they tend to use the left side for verbal reasoning and the right for visual and emotional activities (if they are right handed).

These differences are not rules. It is easy to find women who excel in math and men who have excellent language skills (and it is even easier to find men with no sense of direction). Chances are the above statements are not going to work for your everyday situation, but these have been shown to be true in scientific studies, based on large, diverse populations. When looking at large populations, these differences between men and women become evident, and proper statistical analysis takes care of the exceptions.

Differences in brain structure cause very interesting difference in behavior and are thus important to the paleoanthropological study of humans. It is often these variations in behavior that aid researchers in determining the functions of brain areas. Whether these could be correlated to behavior will depend on the way the study is performed, but anthropologists should take the variations between men and women into consideration as they study human societies.

His Brain, Her Brain

May 2005 Scientific American

It turns out that male and female brains differ quite a bit in architecture and activity. Research into these variations could lead to sex-specific treatments for disorders such as depression and schizophrenia

By Larry Cahill

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.

Although the hippocampus of the female rat can show a decrement in response to acute stress, it appears to be more resilient than its male counterpart in the face of chronic stress. Cheryl D. Conrad and her co-workers at Arizona State University restrained rats in a mesh cage for six hours--a situation that the rodents find disturbing. The researchers then assessed how vulnerable their hippocampal neurons were to killing by a neurotoxin--a standard measure of the effect of stress on these cells. They noted that chronic restraint rendered the males' hippocampal cells more susceptible to the toxin but had no effect on the females' vulnerability. These findings, and others like them, suggest that in terms of brain damage, females may be better equipped to tolerate chronic stress than males are. Still unclear is what protects female hippocampal cells from the damaging effects of chronic stress, but sex hormones very likely play a role. The Big Picture Extending the work on how the brain handles and remembers stressful events, my colleagues and I have found contrasts in the way men and women lay down memories of emotionally arousing incidents--a process known from animal research to involve activation of the amygdala. In one of our first experiments with human subjects, we showed volunteers a series of graphically violent films while we measured their brain activity using PET. A few weeks later we gave them a quiz to see what they remembered. We discovered that the number of disturbing films they could recall correlated with how active their amygdala had been during the viewing. Subsequent work from our laboratory and others confirmed this general finding. But then I noticed something strange. The amygdala activation in some studies involved only the right hemisphere, and in others it involved only the left hemisphere. It was then I realized that the experiments in which the right amygdala lit up involved only men; those in which the left amygdala was fired up involved women. Since then, three subsequent studies--two from our group and one from John Gabrieli and Turhan Canli and their collaborators at Stanford--have confirmed this difference in how the brains of men and women handle emotional memories. The realization that male and female brains were processing the same emotionally arousing material into memory differently led us to wonder what this disparity might mean. To address this question, we turned to a century-old theory stating that the right hemisphere is biased toward processing the central aspects of a situation, whereas the left hemisphere tends to process the finer details. If that conception is true, we reasoned, a drug that dampens the activity of the amygdala should impair a man's ability to recall the gist of an emotional story (by hampering the right amygdala) but should hinder a woman's ability to come up with the precise details (by hampering the left amygdala). Propranolol is such a drug. This so-called beta blocker quiets the activity of adrenaline and its cousin noradrenaline and, in so doing, dampens the activation of the amygdala and weakens recall of emotionally arousing memories. We gave this drug to men and women before they viewed a short slide show about a young boy caught in a terrible accident while walking with his mother. One week later we tested their memory. The results showed that propranolol made it harder for men to remember the more holistic aspects, or gist, of the story--that the boy had been run over by a car, for example. In women, propranolol did the converse, impairing their memory for peripheral details--that the boy had been carrying a soccer ball. In more recent investigations, we found that we can detect a hemispheric difference between the sexes in response to emotional material almost immediately. Volunteers shown emotionally unpleasant photographs react within 300 milliseconds--a response that shows up as a spike on a recording of the brain's electrical activity. With Antonella Gasbarri and others at the University of L'Aquila in Italy, we have found that in men, this quick spike, termed a P300 response, is more exaggerated when recorded over the right hemisphere; in women, it is larger when recorded over the left. Hence, sex-related hemispheric disparities in how the brain processes emotional images begin within 300 milliseconds--long before people have had much, if any, chance to consciously interpret what they have seen. These discoveries might have ramifications for the treatment of PTSD. Previous research by Gustav Schelling and his associates at Ludwig Maximilian University in Germany had established that drugs such as propranolol diminish memory for traumatic situations when administered as part of the usual therapies in an intensive care unit. Prompted by our findings, they found that, at least in such units, beta blockers reduce memory for traumatic events in women but not in men. Even in intensive care, then, physicians may need to consider the sex of their patients when meting out their medications. Sex and Mental Disorders ptsd is not the only psychological disturbance that appears to play out differently in women and men. A PET study by Mirko Diksic and his colleagues at McGill University showed that serotonin production was a remarkable 52 percent higher on average in men than in women, which might help clarify why women are more prone to depression--a disorder commonly treated with drugs that boost the concentration of serotonin. A similar situation might prevail in addiction. In this case, the neurotransmitter in question is dopamine--a chemical involved in the feelings of pleasure associated with drugs of abuse. Studying rats, Jill B. Becker and her fellow investigators at the University of Michigan at Ann Arbor discovered that in females, estrogen boosted the release of dopamine in brain regions important for regulating drug-seeking behavior. Furthermore, the hormone had long-lasting effects, making the female rats more likely to pursue cocaine weeks after last receiving the drug. Such differences in susceptibility--particularly to stimulants such as cocaine and amphetamine--could explain why women might be more vulnerable to the effects of these drugs and why they tend to progress more rapidly from initial use to dependence than men do.   Certain brain abnormalities underlying schizophrenia appear to differ in men and women as well. Ruben Gur, Raquel Gur and their colleagues at the University of Pennsylvania have spent years investigating sex-related differences in brain anatomy and function. In one project, they measured the size of the orbitofrontal cortex, a region involved in regulating emotions, and compared it with the size of the amygdala, implicated more in producing emotional reactions. The investigators found that women possess a significantly larger orbitofrontal-to-amygdala ratio (OAR) than men do. One can speculate from these findings that women might on average prove more capable of controlling their emotional reactions. In additional experiments, the researchers discovered that this balance appears to be altered in schizophrenia, though not identically for men and women. Women with schizophrenia have a decreased OAR relative to their healthy peers, as might be expected. But men, oddly, have an increased OAR relative to healthy men. These findings remain puzzling, but, at the least, they imply that schizophrenia is a somewhat different disease in men and women and that treatment of the disorder might need to be tailored to the sex of the patient. Sex Matters in a comprehensive 2001 report on sex differences in human health, the prestigious National Academy of Sciences asserted that "sex matters. Sex, that is, being male or female, is an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of biomedical and health-related research." Neuroscientists are still far from putting all the pieces together--identifying all the sex-related variations in the brain and pinpointing their influences on cognition and propensity for brain-related disorders. Nevertheless, the research conducted to date certainly demonstrates that differences extend far beyond the hypothalamus and mating behavior. Researchers and clinicians are not always clear on the best way to go forward in deciphering the full influences of sex on the brain, behavior and responses to medications. But growing numbers now agree that going back to assuming we can evaluate one sex and learn equally about both is no longer an option. LARRY CAHILL received his Ph.D. in neuroscience in 1990 from the University of California, Irvine. After spending two years in Germany using imaging techniques to explore learning and memory in gerbils, he returned to U.C. Irvine, where he is now an associate professor in the department of neurobiology and behavior and a Fellow of the Center for the Neurobiology of Learning and Memory.

Sex Differences in the Brain

How male and female brains diverge is a hotly debated topic, but the study of model organisms points to differences that cannot be ignored.

By Margaret M. McCarthy | October 1, 2015

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"We have raised our children in a gender-neutral household since the day they were born, and we never allowed any sort of weapons, not even a water pistol," a young mother told me emphatically from the microphone in the lecture hall where I'd just given a talk on the differences between male and female brains. "But the other day my seven-year-old son bit his peanut butter and jelly sandwich into the shape of a gun and started shooting his little sister with it!" The audience laughed appreciatively; everyone had a similar story. "What did we do wrong?" she pleaded.

This story is a common refrain I hear when discussing my research on sex differences in the brain. There is no single correct answer when it comes to human behavior. Some researchers would insist that there is nothing parents can do to suppress the innate tendencies of boys to gravitate to guns and trucks while girls prefer dolls and tea sets. Others would disagree, arguing that there is no inherent biological difference between the brains of boys and girls. Rather, it is the parents' own implicit biases and those of society at large that influence their children to behave in gender-typical ways. In the end, my response is that sex differences in the brain are more than some would like and less than others believe.

Just how large those differences are, however, is the crux of an ongoing debate in science. And how much a brain's function can be attributed to biology versus cultural expectations is a challenging question to answer. Confounding the issue is the concept of gender, a purely human construct that can itself influence brain development. Gender refers to both personal and societal perceptions of one's sex, and embodies all the complexities of cultural expectations, inherent biases, and predetermined norms of behavior, each of which differs for boys and girls and can affect the young brain. Debates are most heated on questions of sex differences in cognitive abilities and emotionality, and for good reason: biological evidence of superior cognitive ability in one sex could have devastating consequences for equality.

To justify this male bias in laboratory experiments, most research­ers maintain that there are no sex differ­ences in brain function outside of the con­text of reproduction.

Studies of laboratory animal models—for which social biases and constructs such as gender are absent—have revealed significant anatomical differences between the brains of males and females that arise in fetal and early postnatal development, as well as a role for hormones, which differ greatly between the sexes, in the functioning of the adult brain. For these reasons, researchers assiduously avoid experimenting with female animals. A recent comparison of the representation of male and female animals in preclinical research found the discipline of neuroscience to be one of the most strongly skewed toward the exclusive study of males, with five times more studies conducted solely with male animals than with females or a mixture of the sexes.¹ To justify this male bias in laboratory experiments, most researchers maintain that there are no sex differences in brain function outside of the context of reproduction, and that the so-called masculinization of the male brain occurs only in those areas that govern reproductive behaviors.

But there is now increasing evidence that differences in brain function are prevalent across the sex divide, and that these differences manifest in surprising ways in animal models of both health and disease. (See "Gender bias in neuropsychiatric disorders.") Many sex differences in adult brain structure and behaviors are the result of in utero organizational effects of gonadal steroid hormones, in particular androgens and their aromatized derivatives, estrogens, both of which are present in substantially higher concentrations in male fetuses due to testicular steroidogenesis. Brain differences between the sexes can also arise from diverse factors, including the expression of genes carried on the sex chromosomes and discrepancies in maternal treatment of male and female progeny. Together, these factors mediate differences in neurogenesis, myelination, synaptic pruning, dendritic branching, axonal growth, apoptosis, and other neuronal parameters.

This is not to say that everything is different. Indeed, much of the brain and its functions are indistinguishable between the two sexes. But when it is different, the question is, how did the differences come about? By what cellular mechanisms did the course of development change in a particular region that differs between males and females?

Early studies have focused on the usual suspects: neurotransmitters, neurotrophins, and transcription factors, for example. But we are now in the midst of a major rethinking of the origins of sex differences in the mammalian brain with a shift in emphasis away from traditional agents and a new understanding of steroid hormone action.

Female by default

SEX ON THE BRAIN: A mammalian embryo is female by default. Males develop when the Sry gene of the Y chromosome is expressed, spurring the development of testes. During fetal development, the testes produce large amounts of testosterone, much of which is converted to estrogen. Both hormones then act on the brain, inducing the cellular process of masculinization.
See full infographic: WEB | PDF© EVAN OTO/SCIENCE SOURCEThe gonads of the developing fetus are the epicenters of sex determination. All other primary and secondary sex characteristics depend on hormones emanating from the testes or ovaries at specific points later in development. By default, the gonadal precursor will differentiate into an ovary; formation of a testis requires a transcription factor coded for by the Sry gene on the Y chromosome. Likewise, the brain will develop as a female brain by default and be directed towards masculinization only if exposed to the steroids produced by the testis.

Developmental masculinization of the brain leads to significant structural differences in the brains of the two sexes. (See illustration.) Some brain regions are larger in males; others are smaller. Collections of cells that constitute nuclei or subnuclei of the brain differ in overall size due to differences in cell number and/or density, as well as in the number of neurons expressing a particular neurotransmitter. The length and branching patterns of dendrites and the frequency of synapses also vary between males and females—in specific ways in specific regions—as does the number of axons that form projections between nuclei and across the cerebral hemispheres. Even nonneuronal cells are masculinized. Astrocytes in parts of the male brain are more "bushy," with longer and more frequent processes than those in the same regions of the female brain. And microglia, modified macrophages that serve as the brain's innate immune system, are more activated in parts of the male brain and contribute to the changes seen in the neurons.

Steroid hormones induce such changes by binding to transcription factors that then translocate to the cell nucleus to initiate gene transcription. For example, estradiol binds to its receptor to induce expression of the gene for cyclooxygenase, which mediates the rate-limiting step in the production of a short-lived signaling molecule called prostaglandin E2 (PGE2). A little more than 10 years ago, my colleagues and I made the surprising discovery that PGE2 is both necessary and sufficient for the fetal masculinization of the preoptic area, a brain region that is essential for sexual behavior in male mice.² In males, levels of PGE2 are upregulated selectively in this brain region by estradiol-induced synthesis of the cyclooxygenase enzyme. PGE2 then initiates a signal transduction cascade that leads to activation of AMPA glutamate receptors and the formation and stabilization of synapses on the dendrites of neurons in this brain region. As a result, male mice have twice the density of excitatory synapses in the preoptic area as females, and this positively correlates with expression of male copulatory behavior in adulthood.³

We subsequently discovered that microglia, which have recently begun to be appreciated for their role in sculpting neuronal circuits,6 are the predominant source of PGE2.⁴ Not only are there more of these innate immune cells in young male brains, their morphology reflects a more activated state, and they produce more PGE2 than do the microglia in female brains. Pharmacological treatments given early in development to shift microglia away from an activated state resulted in lower PGE2 production and prevented masculinization induced by estradiol.⁵ Thus, a nonneuronal cell, microglia, and an inflammatory mediator, PGE2, are essential for the normal masculinization of the preoptic area in mice.

Another region of the brain that is masculinized during development is the amygdala, which in addition to its roles in the processing of emotions is a key region regulating social play behavior by juveniles, sometimes called rough-and-tumble play, which differs markedly in males and females across a wide range of species. The dimorphism in the frequency and intensity of play is particularly interesting in that it is expressed during a time of life when there are minimal to no circulating steroids, and thus any differences in males and females are either genetic or the result of earlier organizational effects of steroids on the brain.⁷ Sex differences in the synaptic patterning of the amygdala are not as readily apparent as in the preoptic area, but there is a notable difference in cell genesis during the neonatal sensitive period—at least the first four days of life in mice and up to a week in rats—with the amygdala of females making more new neurons and astrocytes than the same region in males.⁸

This particular sex difference appears to be mediated by endocannabinoids, natural ligands for the receptors that are activated by the psychoactive components of marijuana. Specifically, higher endocannabinoid levels in the male amygdala act to suppress cell genesis. Increasing endocannabinoid levels or administering endocannabinoid mimetics to females during the first week of life reduces the level of cell genesis in their amygdalas to that of males. And, quite interestingly, this correlates with an increase in rough-and-tumble play by these females as juveniles.

Although it is unknown how endocannabinoids reduce cell genesis in the amygdala, emerging evidence suggests the resident microglia of this brain region may be critical mediators of cell number, just as they are elsewhere in the brain. Microglia can regulate cell number in two ways: by phagocytosing dead or dying cells, or by engulfing and actually killing live cells, a process recently termed phagoptosis.⁹ Appropriate control of cell number is critical to a healthy brain. If dying cells are not efficiently removed, toxic cell contents are spilled into the extracellular space, leading to additional cell death. Conversely, if cells proliferate excessively, the ability to form and maintain organized connections is lost. Microglia are essential guardians of both these processes, and ongoing work suggests that this is likely also true in the control of sex differences in cell number in specific subnuclei.

Epigenetics and the brain

The hormonally mediated masculinization of the brain is referred to as an "organizational" event in recognition of its relative permanency, but how this state endures has been unknown. In the preoptic area, an area closely associated with the hypothalamus and which controls male sexual behavior, we find consistent sex differences in synaptic density across rodent life stages. Males have about twice as many synapses for a given length of a neuronal dendrite as females have, and this is true in newborn rats, adolescents, and adults.³ Something is maintaining the spacing of the synapses.

One likely suspect is epigenetic modifications to the genome, which we now know can store such cellular memory. By interfering with DNA methyltransferases (DNMTs) to cause widespread demethylation of the genome, my group found evidence of greater DNMT activity in female rats that correlated perfectly with an increase in DNA methylation for the brain region controlling masculinization of sexual behavior.¹⁰ Inhibiting DNMTs in females during the first week of life resulted in rats that were more male-like in both brain structure and behavior, presumably as a consequence of reduced DNA methylation and increased expression of a suite of genes critical for masculinization. Surprisingly, if we treated females with a DNMT inhibitor outside of the sensitive period, they were still masculinized, suggesting that DNA methylation is critical to the maintenance of feminization by actively repressing masculinization genes. The same was found to be true for mice in which the enzyme DNMT3a was genetically deleted in the preoptic area. Identification of what genes are emancipated by the loss of methylation is ongoing, but early analysis implicates genes associated with microglia and with mast cells, another component of the innate immune system of the brain.

Changes in the epigenome are a component of sexual differentiation of the brain, but we are only beginning
to crack this complex code.

The role of DNA methylation in brain sex differences is not cut-and-dried, however. The canonical view is that epigenetic marks are established early and then endure. But studies have found there can also be a delayed epigenetic response to early hormonal treatment, a sort of epigenetic echo. For example, geneticist Eric Vilain of the University of California, Los Angeles, and colleagues observed many more sex differences in DNA methylation in adult mice than in newborns, both in the striatum and the preoptic area, and that treatment of newborn female mice with testosterone shifted their DNA methylation profile to that of males, but not until they were adults.¹¹ In a similar study, researchers at the University of Maryland in Baltimore found sex differences in methylation of the promoter regions of the estrogen and progesterone receptors in the hippocampus, preoptic area, and hypothalamus, but the pattern of methylation changed over the course of the animals' lives, from neonate to adolescent to adult.¹² There is clearly an organizational effect of hormones in the brain, but the appearance of those effects in the epigenome is not tied closely to the time of exposure. How this is occurring at the cellular level is currently a mystery.

Histone modifications also appear to be important in the differentiation of male and female brains. One particular histone modification, called H3K4me3, clusters at transcription start sites and is generally, but not exclusively, associated with increased gene expression. A genome-wide analysis in the murine preoptic area found some 250 genes with a sex difference in the amount of associated H3K4me3, more than 70 percent of which were higher in females. Many of these genes were involved in synaptic transmission, neuronal growth, and differentiation.¹⁴

Not surprisingly, there are also sex differences in the levels of histone deacetylases (HDACs), which mediate such epigenetic marks. There are higher levels of HDACs in the preoptic area of neonatal male mice, and these enzymes tend to be associated with the promoter regions of the estrogen receptor and the aromatase enzyme, which makes estradiol. Deacetylation is associated with decreased gene expression, and both the estrogen receptor and aromatase are more highly expressed in males prenatally, but decline after birth when testosterone levels drop and masculinization is finalized. Blocking HDAC activity during the first week of life impairs male sexual performance in adulthood, confirming the importance of deacetylation for normal masculinization.¹³

Thus, just as with DNA methylation, changes in the epigenome of the histones are a component of sexual differentiation of the brain, but we are only beginning to crack this complex code.

The mosaic brain

© ISTOCK.COM/RUDALL30/MARINAZAKHAROVASo to what extent do these brain sex differences identified in rodents also exist in humans? While we can't experiment on humans for obvious reasons, we can rely on "natural experiments" in which a hormonal profile or sensitivity has been altered due to genetic anomalies. Two well-studied examples are congenital adrenal hyperplasia (CAH), in which the adrenal glands produce excessive androgens during fetal development, and complete androgen insensitivity syndrome (CAIS), in which a mutation in the androgen receptor makes it incapable of binding testosterone and other androgens. In both cases, gonadal development occurs according to the chromosomally dictated sex—i.e., XX embryos will develop ovaries and XY embryos, testes—but the secondary sex characteristics often align with the opposite sex. CAH girls are born with masculinized genitalia, for example, due to their in utero androgen exposure, while CAIS boys appear as normal girls when born due to the lack of differentiation of the external male sex organs.

These conditions provide the opportunity to ask whether brain sex matches gonadal sex. In the case of CAIS, the answer is emphatically no, as these XY individuals consistently identify as females. This finding is in line with the notion that early life exposure to androgens is necessary for development of a male identity. For the CAH girls, the shift in hormonal profile is not as dramatic as that for CAIS individuals, and thus the changes in brain and behavior are also less dramatic. Still, there is typically evidence for a degree of "masculinization" of their brains when assessed for behavioral traits such as toy choice. Thus, despite some differences between humans and animal models, the preponderance of evidence supports the notion that humans undergo a hormonally mediated process of sexual differentiation of the brain just like animals.

The brain is a mix of relative degrees of masculinization in some areas and feminization in others.

However, while both the popular and scientific presses make reference to "male" and "female" brains, the brain is in reality not a unitary organ like the liver or the kidney. It is a compilation of multiple independent yet interacting groups of cells that are subject to both external and internal factors. This is abundantly true for hormonal modulation, with many and varied signal transduction pathways invoked. As a result, it is quite literally impossible for the brain to take on a uniform "maleness" or "femaleness." Instead, the brain is a mix of relative degrees of masculinization in some areas and feminization in others. On average, there are likely to be some areas that are more strongly feminized in a female and others that are more strongly masculinized in a male, but averages are never predictive of an individual's profile. Moreover, a mosaic is not a blend—there is not a continuum of maleness to femaleness—and there are many parameters that are neutral in regard to sex, with no consistent differences between males and females.

Evolutionarily, the creation of a maleness-femaleness mosaic within one brain makes sense, providing organisms with greater variability and therefore adaptability to changing environments. But another striking aspect of brain sexual differentiation that my colleagues and I have noted is that for each endpoint we examine, we find the magnitude of the sex difference to be constrained within the relatively low range of just one- to twofold. While this is still significantly greater than the extremely small variance within each sex, it is by no means colossal, as one might describe the difference between a male peacock's tail and that of a peahen. It is as if something is both pushing the brains of the sexes apart and keeping them together at the same time.

This interpretation is consistent with the concept of canalization, originally proposed by British biologist Conrad Waddington in the late 1940s and now embraced by evolutionary biologists as a means by which species maintain robustness in the face of ever-present internal and external challenges. Chaperone proteins and other agents act to buffer an organism against changes in pH or salinity and other environmental threats by assisting in proper protein folding or maintaining order in intracellular traffic, for example. We propose that, during embryonic development or during the first week of life, many sexually differentiated endpoints are subject to canalization, assuring that males will stay in one canal and females in another, and that the two canals will never merge or grow too far apart.

In humans, an additional canalization factor could be parental, societal, and cultural influences early in life. Gender-specific behaviors may be rewarded, for example, or punished if considered not in line with a child's sex. While these factors remain difficult to tease apart, it is clear that the brains of males and females diverge as they develop, and it should be self-evident that using only male animals to probe mammalian brain function does not reveal the whole picture. 

© ISTOCK.COM/FRIKOTA GENDER BIAS IN NEUROPSYCHIATRIC DISORDERS Some neuropsychiatric disorders are thought to originate during fetal development, even if patients are not typically diagnosed until adolescence or young adulthood. Of these, most are much more common in males. Other disorders begin to manifest at puberty or later in life, and these occur more frequently in females. The biological reasons for these sex biases in disease prevalence are currently under investigation. Major depressive disorder: One of the most common neuropsychiatric disorders, MDD is considered strongly gender biased, with women twice as likely as men to be diagnosed. This bias is seen worldwide, suggesting a biological as opposed to cultural origin. Dysregulation of the stress axis and its convergence with the dynamic nature of reproductive hormones in women are implicated as root causes of greater risk in women, although more recent evidence suggests this dysregulation may have its origins in very early childhood. However, the importance of other variables contributing to the gender bias, such as the willingness of women to seek help while men tend to self-medicate with drugs and alcohol, cannot be discounted. Anorexia nervosa: Strictly postpubertal in onset, anorexia nervosa is predominantly a young woman's disease, with a gender bias greater than 10:1 that is almost assuredly driven by perceived societal pressures. Interestingly, bulimia nervosa, a disorder of binge eating but in which normal body weight is maintained, is much less gender biased, with women only three times as likely as men to suffer the disorder. Autism spectrum disorder: While ASD was originally considered only twice as prevalent in boys, recent estimates put the ratio closer to 5:1. A currently popular but unproven theory postulates that elevated testosterone in utero leads to ASD-like behaviors by placing boys on the extreme end of the male spectrum. A counter-theory is that girls are underdiagnosed for ASD due to physician bias and a different presentation, with fewer social and cognitive defects. Others argue that girls are more resilient and require a greater load of genetic insult before the disorder manifests, and empirical evidence supports this view for those limited instances in which a genetic origin of ASD is clear. Attention deficit hyperactivity disorder: Reports of the degree to which ADHD occurs more frequently in boys than girls vary widely and are likely influenced as much by cultural factors as biological ones. Additionally, males tend to show greater impairments, making them at least four times more likely to be diagnosed. Schizophrenia: When considered for the population overall, there is no clear gender bias in the frequency of schizophrenia. However, diagnosis is much more common in boys and young men than in girls, whereas diagnosis in middle age or older is substantially more frequent in women. Differential responses to stress, with distinct brain regions being over- or underactivated in men versus women, further contribute to divergence in the disease. Biplolar disorder: Rates of bipolar disorder do not vary between men and women, yet a genetic polymorphism strongly associated with the disorder is relevant to risk in women but not men. This highlights how much we have to learn about the nature of sex differences in neuropsychiatric disorders and the multiple ways in which some differences can manifest.

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Margaret M. McCarthy is chair of the Department of Pharmacology and a member of the Program in Neuroscience at the University of Maryland School of Medicine in Baltimore.

References

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Correction (October 7): This story has been updated to correctly reflect that deacetylation is associated with decreased, not increased, gene expression. The Scientist regrets the error.