Abstract/Summary

17β-oestradiol significantly influences several physiological processes, many of which are linked to the central nervous system. Oestrogen receptors (ERs) are widespread thoughout the brain, including the social behaviour network (SBN): a conserved set of hypothalamic and limbic nuclei underlying sexually dimorphic social behaviours. Previous research has shown confirmed the brain’s capacity to synthesise its own oestrogens, termed neuroestrogens, albeit with a focus on the hippocampus. The hypothalamus has garnered less attention in this regard. Despite evidence that hypothalamic aromatase is active, direct quantification of neuroestrogens in this region or in the nodes of the social behaviour network have not been performed. This highlights a significant gap in knowledge, as neuroestrogens bear the potential to serve as critical modulators within the SBN. Furthermore, how neuroestrogen synthesis is regulated in the female in the face of abundant gonadal oestrogens is unknown. To address this gap, we developed a novel method to measure neuroestrogens within the SBN, allowing us to understand how neuroestrogen synthesis is regulated in two major hypothalamic SBN nuclei. We have demonstrated that neuroestrogens were still measurable in ovariectomised mice, underscoring the autonomous steroidogenic capacity of the SBN. We also demonstrated the presence of a novel, androgen-dependent regulatory pathway that regulates neuroestrogen synthesis in the female medial preoptic area (mPOA) but not in the ventromedial hypothalamus (VMH), suggesting nuclei-specific regulation of neuroestrogen production. We have demonstrated that disruption of this pathway in vivo has a subtle anxiogenic effect, correlated with dendritic atrophy and reduced spine density in the female mPOA, akin to that observed in ovariectomised mice. Finally, we used a unique conditional aromatase knockout mouse to understand how neuroestrogen synthesis within discrete hypothalamic SBN nuclei contributes to behaviour. In doing this, we showed hypothalamo-limbic aromatase regulates anxiety but not sex or aggressive behaviours in the male mouse.