Dissecting the role of vasopressin in regulating the critical period for social reward learning

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PROJECT SUMMARY: The overall objective of the studies proposed in this revised R01 application is to elucidate the molecular mechanisms underlying regulation of social brain development, a first step in a larger project aimed at identifying circuit based approaches which improve therapeutics for neurodevelopmental disorders characterized by social impairments, as well as diseases which may be the consequence of social injury during brain development. Based on extensive preliminary findings, our overall hypothesis is that developmental upregulation of arginine vasopressin (AVP) signaling constrains social reward learning to a critical period, and that these functions are enabled by presynaptic AVP receptors in the ventral pallidum (vPD). The goal of this R01 application is to explore this understudied area and to develop tools to test our hypothesis directly in vivo and ex vivo. Three specific aims have been proposed to achieve our goal. Specifically: Specific Aim 1: To map and characterize the AVP neuronal projection from the hypothalamus to the vPD. Here we will test the hypothesis that the vPD receives a parvocellular AVP neuronal projection from the hypothalamus. Specific Aim 2: To determine whether AVP evokes synaptic plasticity in the vPD across development. Here we will test the hypothesis that the magnitude of AVP induced synaptic plasticity in the vPD is increased across development. Specific Aim 3: To determine whether AVP1a receptors in the vPD are required for constraining the social reward learning critical period. Here we will test the hypothesis that AVP1a receptors in the vPD are required for the closure of the social reward learning critical period. We predict these studies will demonstrate the reciprocal regulation of OT and AVP as a mechanism underlying the establishment of a critical period for social reward learning. In addition, these studies are designed to identify a novel manipulation (blockade of the AVP1aR) that can reinstate social reward learning in adulthood, which will have important implications for future clinical trials of mechanism-based therapies for the treatment of autism, schizophrenia, addiction and post-traumatic stress disorder. Moreover, because these studies characterize a quantifiable measure of social reward learning (social conditioned place preference) that can be used in both humans and mice, they dramatically improve the translational validity of these studies for future development of therapeutic interventions.