Disorders of social behavior and communication 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 different social brain. A particularly relevant neuropeptide system in this respect is the vasopressin (VP) innervation of the brain, which shows marked sex differences across many species, including humans, and has been implicated in aggressive as well as affiliation behavior. Indeed, the main receptor for VP in the brain, V1aR, is now a major target for drug development for treating core symptoms of autism. Despite the significance of this system, few studies have directly assessed how, when, and where V1aR signaling influences communication behavior in adults. This lack of data is particularly acute in mice, a key biomedically-relevant species. We propose to remedy this by generating a new mouse line that expresses cre-recombinase (Cre) under the control of the Avpr1a promoter (Avpr1a-Cre), rigorously characterizing its behavioral phenotype in both sexes, then performing a targeted experiment manipulating V1aR in the lateral septum as a test of this new resource. As a comparison, we will also test the role of the oxytocin receptor in LS on social communication using identical experimental approaches. The availability of a validated Avpr1a-Cre line will enable rapid progress in mapping the connectional architecture and determining the behavioral/physiological functions of different V1aR cell populations using modern techniques. This, in turn, will uncover a fundamental mechanism by which the brain regulates social communication, and will contribute to identifying causes of, and treatments for, disorders of social communication in both males and females.
Targeting brain vasopressin receptors is a promising approach for treating psychiatric disorders, such as autism, that are characterized by dysfunctional social communication. Investigation of vasopressin receptor function is hindered by the lack of a genomic resource for precise manipulation of the cells bearing this receptor in specific brain areas and at specific times. This project will generate and validate a mouse line that will provide this resource.
