Both neural and global androgen receptor overexpression affect sexual dimorphism in the mouse brain

Testosterone is the main endocrine mechanism mediating sexual differentiation of the mammalian brain, although testosterone signalling is complex and important mechanistic questions remain. Notably, the extent to which testosterone acts via androgen receptors (AR) in this process remains unknown and it is also not clear where testosterone acts in the body to produce sexual dimorphisms in neuroanatomy. To address these questions, we used a transgenic mouse model of Cre/loxP-driven AR overexpression in which AR was induced selectively in neural tissue (Nestin-cre) or in all tissues (CMV-cre). We then studied sexually dimorphic features of several well-characterised sexual dimorphisms: calbindin-immunoreactive neurones in the medial preoptic area (CALB-SDN), tyrosine hydroxylase neurones in the anteroventral periventricular nucleus, and vasopressin-immunoreactive neurones originating in the bed nucleus of the stria terminalis and their projections in the lateral septum. We additionally evaluated oestrogen receptor α immunoreactivity in these nuclei. Briefly, we found that global but not neural overexpression of AR resulted in masculinisation of CALB-SDN nucleus volume, cell number and cell size in transgenic females. Furthermore, neural AR overexpression resulted in increased oestrogen receptor α staining in females compared to males in the medial preoptic area. AR overexpression did not affect other measures. Overall, the results of the present study provide support for the hypothesis that androgenic mechanisms external to the nervous system can affect sexual differentiation of the brain.