Sexually Dimorphic Vasopressin Circuits in the Control of Social Interest

Project Summary Disorders of social behavior are increasingly prevalent and pose a substantial burden to society. These disorders often show sex differences in prevalence, expression, and severity. One explanation for these differences reflects dysfunction in the sexually differentiated social brain. A particularly relevant neuropeptide system in this respect is the arginine vasopressin (AVP) innervation of the brain, which shows marked sex differences across many species, including humans, and has been implicated in aggressive as well as affiliative behavior. Indeed, the main receptor for AVP in the brain, V1aR, has been linked to social behavior, including that of humans. Despite the significance of this system, few studies have directly assessed how, when, and where AVP and V1aR systems interact to influence social interest in adults. Here we focus on the interaction between the sexually dimorphic AVP cells of the bed nucleus of the stria terminalis (BNST) and its major target, the lateral septum (LS), an area with the highest expression of V1aR in vertebrate brains. In the first aim, we will test the necessity of LS V1aR cells for social interest by optogenetic inhibition of these cells or by genetically knocking out V1aR in LS. In addition, we will combine optogenetic stimulation of BNST AVP cells and V1aR knockdown in LS in vivo and ex vivo to test whether AVP from the BNST specifically acts on LS V1aR cells to alter behavior and cellular physiology. The second aim will test whether V1aRs in the LS are sufficient for driving social interest by optogenetic excitation of these cells. The third aim will test whether V1aR cells in the LS encode social interest in a sexually dimorphic manner, and whether this encoding is altered by BNST AVP cell activity (via chemogenetic inhibition). This project will significantly enhance our mechanistic understanding of how the brain controls social behavior differently in males and females and may give insight as to why many behavioral disorders show striking sex differences in morbidity. Although recently major advances have been made in understanding the neural basis of social behavior, how such behavior is controlled differently in males and females is, by and large, unknown. This grant will address these issues.