ESPE Abstracts (2019) 92 S10.1

Multifaceted Origins of Sex Differences in the Brain

Erin Reinl, Margaret McCarthy


University of Maryland School of Medicine, Baltimore, USA


Sex is one of the strongest biological factors influencing neural development, and yet our understanding of the molecular underpinnings of sexual differentiation is only just beginning. Just like the bipotential gonads, which only differentiate upon expression of SRY in XY males, the brain is also bipotential and differentiates due to a combination of genetic, epigenetic, environmental, and hormonal exposures. A period of testosterone production by the testes, which occurs as early as the second trimester in humans and during the late embryonic and early postnatal period in rodents, defines a critical period of sexual differentiation that drives the organization of enduring differences in circuitry and neuroanatomy between male and female brains. In the absence of gonadal hormones during this period, the brain develops in a female-typical fashion but is sensitive to masculinization by treatment with exogenous hormones. The cellular and molecular mechanisms induced by testosterone (converted to estradiol in the brain) are multifaceted and include neurogenesis, cellular differentiation, axon guidance, synaptic pruning, apoptosis, and phagocytosis. These pathways are both guided by and impact neurons and astrocytes. However, we have also found surprising roles for the immune system, including the innate immune cells of the brain, microglia, and even peripheral immune cells, like mast cells, which play critical roles in establishing sex differences. Although hormones dominate as purveyors of brain sexual differentiation, there is emerging evidence that genetic contribution by the sex chromosomes, even beyond SRY expression, contribute as well, and our understanding of these mechanisms are only in their infancy. As interest in sex differences and inclusion of both sexes in preclinical research continues to grow, it is likely that the list of multifaceted and sometimes surprising mechanisms of sex differences will grow as well.

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