A new view of sexual differentiation of mammalian brain

Establishment of enduring sex differences in brain and behavior occurs during pre- or perinatal development, depending on species. For over 50 years the focus has been on gonadal steroid production by male fetuses and the impact on developing brain. An increasing awareness of the importance of sex chromosome complement has broadened the focus but identifying specific roles in development has yet to be achieved. Recent emphasis on transcriptomics has revealed myriad and unexpected differences in gene expression in specific regions of male and female brains which may produce sex differences, serve a compensatory role or provide latent sex differences revealed only in response to challenge. More surprising, however, has been the consistent observation of a central role for inflammatory signaling molecules and immune cells in masculinization of brain and behavior. The signal transduction pathways and specific immune cells vary by brain region, as does the neuroanatomical substrate subject to differentiation, reflecting substantial complexity emerging from what may be a common origin, the maternal immune system. A working hypothesis integrating these various ideas is proposed.