Testosterone action in the sexual differentiation of the mammalian nervous system and behaviour

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Sex is a fundamental feature of biology, and its great importance for virtually all species is reflected by striking anatomical, physiological and behavioural sex differences that have evolved through sexual selection. In our own species, secondary sexual characteristics have enormous influence on our psychology and social identity. Less obvious but equally dramatic sex differences exist in virtually all cells and organ systems. The role of these biological sex differences in shaping gender in humans has been debated extensively, but there is little scientific study of this topic. Sex differences homologous to those seen in humans exist in laboratory rodents, providing a powerful opportunity to study the mechanisms that govern sexual differentiation of the mammalian brain and behaviour. In mice and rats, sex-typical production of testosterone through the lifespan largely accounts for neuroanatomical and behavioural sexual dimorphisms (i.e. polarized sex differences). This elegant and apparently simple endocrine signal governing sexual differentiation has nonetheless proven to be quite complex mechanistically and we have only a limited understanding of how or even where testosterone acts to produce sexual dimorphisms in the nervous system and behaviour. We have been using mice with mutations that allow for selective expression of the gene which codes for receptors for testosterone (androgen receptor or Ar) to gain insight into the site of androgen action in producing sex differences in neuroanatomy and behavior. We have been focusing on relative contributions of neural and non-neural Ar in the sexual differentiation of the hypothalamus and sociosexual behaviour. We find that global but not neural overexpression of masculinizes copulatory behaviour, likely via actions on genitals. Similarly, global but not neural overexpression of Ar interferes with male typical sexual behaviour, likely due to a peripheral deficit in sensation of olfactory sexual cues. Conversely, both neural and global overexpression of Ar interferes with male typical aggressive responses and also masculinizes the structure of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in females. We now propose to use these conditional Ar overexpression mice, as well as conditional loss of Ar function mice to further localize testosterone's site of action in sexual differentiation of neuroanatomy and sociosexual behaviour. To do so, we will use tissue-specific genetic drivers as well as a method developed by my lab to activate conditional mutations in a spatially restricted manner. These studies will focus on the roles of the genitals as well as peripheral and central components of the olfactory system in producing sex differences in neural structure and behaviour.