Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system

Abstract

Neuroscientists are likely to discover new sex differences in the coming years, spurred by the National Institutes of Health initiative to include both sexes in preclinical studies. This review summarizes the current state of knowledge of the cellular and molecular mechanisms underlying sex differences in the mammalian nervous system, based primarily on work in rodents. Cellular mechanisms examined include neurogenesis, migration, the differentiation of neurochemical and morphological cell phenotype, and cell death. At the molecular level we discuss evolving roles for epigenetics, sex chromosome complement, the immune system, and newly identified cell signaling pathways. We review recent findings on the role of the environment, as well as genome-wide studies with some surprising results, causing us to rethink often-used models of sexual differentiation. We end by pointing to future directions, including an increased awareness of the important contributions of tissues outside of the nervous system to sexual differentiation of the brain.

Sex differences in brain‐derived neurotrophic factor signaling and functions

“…The central nervous system (CNS) is different in structure, activity, development and chemistry between female and male mammals (Forger et al 2016; Raznahan et al 2010; Ruigrok et al 2014). Although these phenomena have long been recognized, the mechanism that causes the differences is still not clear (Cahill 2006).…”

The desA and desB genes from Clostridium scindens ATCC 35704 encode steroid-17,20-desmolase

“…Based on these studies, the concentration of cortisol metabolites in the ~0.4L human colon (26) downstream 5α-, 17β-reduced metabolites, are now thought to play an important role in activation of androgen receptor (27,28). The field of microbial endocrinology has emerged and recognizes the need to characterize androgen production by C. scindens [29][30][31][32][33][34]. Many host immune cells express androgen-receptor [35,36], and it is possible that C. scindens affects immune function through generation of androgens.…”

Understanding the epigenetic basis of sex differences in depression

“…While there are DNA and histone modifications that occur within sexually dimorphic brain regions such as the mPOA and BNST that may be tied to structural differentiation (Forger et al 2016; Shen et al 2015), more interesting perhaps are the greater number of genes undergoing DNA methylation in non-sexually dimorphic regions, such as the striatum (Forger 2016; Ghahramani et al 2014). Manipulation of testosterone at birth in females or a comparison of males and females did not show many sex differences in methylation patterns early in postnatal development.…”