Sexual differentiation of the brain: Mode, mechanisms, and meaning

This is an exciting time to study sex differences in the brain. Fifty years of building on the foundations established by the organizational/activational hypothesis of steroid hormone action proposed by Phoenix and colleagues to explain steroid action on the brain has provided an increasingly complex and nuanced view of how the brain develops differently in males and females. In this chapter, we first discuss the things we know; there are sex differences in physiology and behavior, in susceptibility to diseases of the nervous system, including mental health disorders, and in neuroanatomical and neurochemical measures. These sex differences depend on androgens, estrogens, and sometimes sex chromosomal complement (XX vs. XY) acting during development as well as in adulthood, and yet the manifestation of these sex differences may be context dependent. There are four key cellular processes (ell birth, cell death, cell migration, and cell differentiation) that could potentially underlie sexual differentiation of the brain and we discuss the evidence for each in detail. Lastly, we review what we consider major, unanswered, and profound questions regarding the importance of sex differences, how they are established, why they persist, and what they mean.