Surprising origins of sex differences in the brain

This article is part of a Special Issue "SBN 2014". 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.