Sexual Differentiation of the Brain: A Fresh Look at Mode, Mechanisms, and Meaning

Abstract

This is an exciting time to study sex differences in the brain. Fifty-plus years of building on the foundations established by the organizational/activational hypothesis proposed by Phoenix and colleagues to explain steroid hormone 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 that could potentially underlie sexual differentiation of the brain: cell birth, cell death, cell migration, and cell differentiation, and we discuss the evidence for each in detail. Lastly, we review what we consider major emerging areas and unanswered questions in the field, including the function of sex differences, why they persist, and what they mean.