Surprising origins of sex differences in the brain

Abstract

Discerning the biologic origins of neuroanatomical sex differences has been of interest since they were first reported in the late 60’s and early 70’s. The centrality of gonadal hormone exposure during a developmental critical window cannot be denied but hormones are indirect agents of change, acting to induce gene transcription or modulate membrane bound signaling cascades. Sex differences in the brain include regional volume differences due to differential cell death, neuronal and glial genesis, dendritic branching and synaptic patterning. Early emphasis on mechanism therefore focused on neurotransmitters and neural growth factors, but by and large these endpoints failed to explain the origins of neural sex differences. More recently evidence has accumulated in favor of inflammatory mediators and immune cells as principle regulators of brain sexual differentiation and reveal that the establishment of dimorphic circuits is not cell autonomous but instead requires extensive cell-to-cell communication including cells of non-neuronal origin. Despite the multiplicity of cells involved the nature of the sex differences in the neuroanatomical endpoints suggests canalization, a process that explains the robustness of individuals in the face of intrinsic and extrinsic variability. We propose that some neuroanatomical endpoints are canalized to enhance sex differences in the brain by reducing variability within one sex while also preventing the sexes from diverging too greatly. We further propose mechanisms by which such canalization could occur and discuss what relevance this may have to sex differences in behavior.

Temporary Depletion of Microglia during the Early Postnatal Period Induces Lasting Sex-Dependent and Sex-Independent Effects on Behavior in Rats

“…These findings corroborate those of Lenz et al, (2013), who found microglia to be a key mediator of the masculinization of sex behaviors. Our understanding of how microglia may mediate organizational sex differences in the brain is still in its infancy, but interestingly, many of the mechanisms by which sex differences are established are also developmental processes that are heavily influenced by microglia (Lenz and McCarthy, 2015; McCarthy et al, 2015). Further investigation into how microglia may act to sculpt sexually dimorphic circuitry in the brain is critical to advancing our understanding of a fundamental aspect of brain development.…”

Multifaceted origins of sex differences in the brain

“…This statement preceded by a decade the discipline of neuroscience, which was not firmly established as an independent field until the 1970s. In the time since then, extensive research on animal models irrefutably established that gonadal hormone secretions from the male testis early in development act on the brain to masculinize it (reviewed in [14][15][16][17]). In rodents, the androgens produced by the testis are aromatized to oestrogens, an essential step in the masculinization process, whereas, in primates, androgens act directly (reviewed in [18]).…”

Sex differences in the gut microbiome–brain axis across the lifespan

“…This is supported by a wealth of research highlighting critical sex differences in downstream targets of this axis, including neuroendocrine and neuroimmune systems [53,54]. For instance, female-biased prevalence in functional gastrointestinal disorders, such as irritable bowel syndrome, may result from sex differences in gastrointestinal transit time, visceral sensitivity, central nervous system pain processing and hormonedependent effects on gut physiology [55][56][57][58].…”