It is not all hormones: Alternative explanations for sexual differentiation of the brain

Males and females of many species differ with regard to neurodevelopment, ongoing brain function and behavior. For many years, it was assumed that these differences primarily arose due to hormonal masculinization of the male brain (and to a lesser extent hormonal feminization of the female brain). Recent elegant experiments in model systems have revealed that, while gonadal hormones undoubtedly play an important role in sexual differentiation of the brain, they are not the only possible mechanism for this phenomenon. In the present review, we discuss the concept that genes residing upon the sex chromosomes (which are asymmetrically inherited between males and females) may influence sexually dimorphic neurobiology directly, and suggest possible mechanisms. Future work will be directed towards understanding the extent and specificity with which sex-linked genes and hormones define brain structure and function, and towards elucidating potential interactions between the two mechanisms. Ultimately, it is hoped that such studies will provide insights into why men and women are differentially vulnerable to certain mental disorders, and will enable the development of effective sex-tailored therapeutics.