Sex Differences in the Healthy Brain

A 2001 report by the National Institute of Medicine emphasized the urgent need to develop translational research on understanding sex differences in the brain and their impact on clinical medicine. Although substantial work has identified multiple ways in which one's sex impacts health and disease, we still do not fully understand the underlying neurobiological mechanisms that give rise to sex differences in the healthy brain as it develops over time, and how these differences change during the aging process. Understanding sex differences in the healthy brain is a critical first step toward understanding what processes go awry in psychiatric and neurologic disorders with known sex differences.

A number of animal and human studies, including our own, have demonstrated normal sexual dimorphisms of the brain. Early work in this area, primarily in rats, focused on the effects of sex steroid hormones on brain morphology during critical periods of early development. Current work identifies a direct effect of genes on sexual differentiation of the brain prior to gonad differentiation. In vivo imaging and postmortem studies of sexual dimorphisms in humans have also revealed that male and female brains develop at a different pace dependent on the brain region, hemisphere, and developmental timing period. In fact, sex differences in the brain are expressed throughout life, in particular around puberty and during the transition to menopause.

Our team is investigating the fetal and neonatal programming of sex differences in the healthy brain and the expression of these differences in adulthood. We are investigating the hormonal regulation of brain morphology and brain function using structural and functional MRI, diffusion tensor imaging, and hormonal studies in tandem with brain imaging. We have the unique opportunity to have followed a prenatal cohort as adults over the last 20 years, wherein adult offspring are now 50-years old, allowing us to investigate how early life events (in utero and in childhood) give rise to sex differences in the healthy adult brain.

Examples of Significant Findings:

  1. Hormonal and genetic processes that regulate the sexual differentiation of the brain during fetal development have enduring effects on sex differences in structural brain volumes in adulthood in healthy adults.

  2. Circulating hormones have significant effects on brain activity in stress response circuitry in healthy women across the menstrual cycle.

  3. Normal variations in hormonal changes in women significantly contribute to explaining sex differences in stress response circuitry in healthy adults. Women have a natural capacity to regulate the stress response that differs from men.