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Vol. LXIII, No. 9
April 29, 2011

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Male/Female Differences Offer Insight Into Brain Development

On the front page...

A recent NIMH-sponsored workshop showed that brain-based male/female differences offer an invaluable scientific opportunity for learning how the circuitry of the brain develops.

A recent NIMH-sponsored workshop showed that brain-based male/female differences offer an invaluable scientific opportunity for learning how the circuitry of the brain develops.

In nearly all neuropsychiatric disorders there are differences in prevalence and age of onset between males and females. In illnesses such as schizophrenia, the symptom profile and response to treatment differs markedly between males and females. Despite these observations, according to speakers at a recent workshop on sex differences in the brain, scientists in many cases are studying mostly males in their animal research on the brain, or including both sexes, but not examining whether they differ.

Brain-based male/female differences—a frequent topic of popular media coverage—in fact offer an invaluable scientific opportunity for learning how the circuitry of the brain develops. Speakers at the NIMH-sponsored workshop, “Sex Differences in Brain, Behavior, Mental Health and Mental Disorders,” offered a series of provocative findings and a view of the potential this work has for revealing how genes, hormones and experience shape the developing brain.


Studies that do track sex have reported intriguing findings related to brain development and function. Speaker Dr. Elizabeth Sowell, at the University of California, Los Angeles, noted that there are gender differences in the trajectory of gray matter maturation in adolescent girls and boys that may have lasting effects on the brain. Dr. Cheryl Sisk of Michigan State University reported on work in rats showing that pubertal hormones influence the addition of new cells to areas of the brain that show sex-related differences, thus demonstrating the role of these hormones in maintaining these structural differences.

Several speakers talked about sex hormone effects on learning and memory. Dr. Larry Cahill, University of California, Irvine, noted that, in women, stress hormones affect memory differently, depending on the phase of the menstrual cycle. Men and women viewing emotionally charged films show activation of different sides of the amygdala, a part of the brain that is central to emotional memory: in men, the right amygdala is activated, in women, the left amygdala is activated. Even the activity of the amygdala at rest is different in men and women. Dr. Tracey Shors of Rutgers University reported that, in work with rats, stress improves learning in males, but impairs it in females.

Even prenatally, stress has different effects on male and female offspring. Dr. Tracy Bale, at the University of Pennsylvania, reported on research in mice showing that maternal stress early in pregnancy affected how male offspring responded to stressful situations; they responded more like females. This work suggests differences in effects of early vs. late prenatal stress and may offer clues to why prenatal stress is associated with greater risk of such disorders as depression, anxiety, schizophrenia and autism.

One of the goals of this research is to identify how sex differences are established and maintained in the brain. Genes on the X and Y chromosomes set in motion the processes of sexual differentiation. The expression of numerous genes on non-sex, or autosomal, chromosomes, also differs according to whether they are inherited from the mother or father, a process called imprinting. Understanding imprinting could lead to therapies for disorders that are shaped by paternal or maternal inheritance of an abnormal gene.

During development, sex hormones have so-called organizational effects on the brain that persist once established, even if the hormones are removed, and activational effects, which depend on the continued presence of hormones.

Finally, experience can shape gene expression and with it, sexual differentiation and behavior. Speaker Dr. Anthony Auger of the University of Wisconsin reported that in rats, mothers groom male and female offspring differently; the differential can alter gene expression and can contribute to sex differences in the brain, with lasting effects on social and emotional behavior. Social deficits are a feature of some neurodevelopmental disorders; knowledge of these mechanisms could provide clues to therapy.

NIMH intramural investigator Dr. Jay Giedd, who has been using MRI to conduct a long-term study of brain development, emphasized that there is enormous variability among individuals. Differences between groups do not imply individual differences.Trajectories, rather than one-time measurements, determine IQ, health and illness and male/female differences.

Developmental trajectories also predict periods of vulnerability to illness and effective intervention. Dr. Arthur Arnold of UCLA speculated that identifying the factors that protect one or the other sex from disease could lead to novel therapies that enhance those factors.

In any event, the full range of sex differences in neural connectivity—and their implications for understanding and treating mental illness—remain to be fully explored. NIHRecord Icon

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