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

项目总结： 在这个修订的R01申请中提出的研究的总体目标是阐明分子 社交大脑发育调控的基本机制，这是一个更大项目的第一步，旨在 确定改善神经发育障碍治疗方法的基于电路的方法 以社会损伤为特征的，以及可能是社会伤害的后果的疾病 大脑发育。基于广泛的初步发现，我们的总体假设是发育 精氨酸加压素(AVP)信号上调将社会奖励学习限制在关键时期，并且 这些功能是由腹侧苍白球(VPD)中的突触前AVP受体激活的。这样做的目的是 R01的应用是探索这一未被研究的领域，并开发工具直接在体内测试我们的假设 和体外实验。为实现我们的目标，我们提出了三个具体目标。具体：具体目标1： 定位并描述AVP神经元从下丘脑到VPD的投射。在这里，我们将测试 从下丘脑接受小细胞AVP神经元投射的假说。特定的 目的2：研究血管紧张素转换酶(AVP)是否在VPD发育过程中引起突触可塑性。在这里我们 将检验AVP在VPD中诱导的突触可塑性的大小是跨 发展。具体目标3：确定VPD中的AVP1a受体是否需要 制约社会奖励学习的关键时期。在这里我们将检验AVP1a的假设 VPD中的受体是关闭社会奖赏学习关键期所必需的。我们预测到了这些 研究将证明OT和AVP的相互调节是一种潜在的机制 建立社会奖励学习关键期。此外，这些研究旨在确定一种 新奇的操作(封锁AVP1aR)可以在成年后恢复社会奖励学习，这将 对未来治疗自闭症的基于机制的疗法的临床试验具有重要意义， 精神分裂症、成瘾和创伤后应激障碍。此外，由于这些研究的特点是 社会奖励学习的可量化测量(社会条件位置偏好)，可用于两者 人类和老鼠，他们极大地提高了这些研究的翻译有效性，用于未来的发展 治疗干预措施。

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.