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

剖析加压素在调节社会奖励学习关键期中的作用

基本信息

批准号：
9885422
负责人：
Gul Dolen
金额：
$ 35.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-06 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885422
关键词：
Ablation Achievement Acute Address Adult Anatomy Animals Area Argipressin Axon Bathing Behavioral Blindness Brain Brain region Clinical Trials Data Development Disease FLP recombinase Frequencies Future Globus Pallidus Goals Human Hypothalamic structure Impairment Injury Knock-in Mouse Knock-out Knockout Mice Language Learning Long-Term Depression Maps Measures Mediating Methods Molecular Mus Nature Nervous system structure Neurodevelopmental Disorder Neurons Nucleus Accumbens Oxytocin Pathogenesis Physiologic pulse Post-Traumatic Stress Disorders Regulation Rewards Role Schizophrenia Sensory Signal Transduction Slice Social Behavior Social Conditions Social Environment Social Interaction Source Stimulus Synapses Synaptic plasticity Testing Therapeutic Therapeutic Intervention Time Touch sensation Up-Regulation V1a vasopressin receptor Vasopressins Vision addiction argipressin receptor autism spectrum disorder base conditioned place preference critical period deafness design experience functional genomics imprint improved in vivo insight magnocellular neural circuit novel novel therapeutic intervention novel therapeutics optogenetics paraventricular nucleus parvocellular patch clamp postnatal postsynaptic premature presynaptic receptor social synaptic function therapeutic development tool translational neuroscience translational study viral gene delivery

项目摘要

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.

项目概要：修订后的 R01 申请中提出的研究的总体目标是阐明分子社会性大脑发育调节的潜在机制，这是一个更大项目的第一步，旨在确定基于回路的方法来改善神经发育障碍的治疗以社会障碍为特征，以及可能因社会伤害而导致的疾病大脑发育。基于广泛的初步研究结果，我们的总体假设是，发育精氨酸加压素（AVP）信号的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) 的突触前 AVP 受体实现的。此举的目标 R01应用是探索这个待研究领域并开发工具来直接在体内检验我们的假设和离体。为了实现我们的目标，我们提出了三个具体目标。具体而言：具体目标 1：绘制并表征从下丘脑到 vPD 的 AVP 神经元投影。这里我们将测试 vPD 接收来自下丘脑的小细胞 AVP 神经元投射的假设。具体的目标 2：确定 AVP 是否在整个发育过程中引起 vPD 中的突触可塑性。在这里我们将检验以下假设：AVP 诱导的 vPD 中突触可塑性的幅度随着时间的推移而增加发展。具体目标 3：确定 vPD 中的 AVP1a 受体是否是制约社会奖励学习关键期。在这里我们将检验 AVP1a 的假设 vPD 中的受体对于社会奖励学习关键期的结束是必需的。我们预测这些研究将证明 OT 和 AVP 的相互调节是潜在的机制建立社会奖励学习的关键时期。此外，这些研究旨在确定新颖的操作（封锁 AVP1aR）可以恢复成年期的社会奖励学习，这将对未来基于机制的治疗自闭症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（社会条件位置偏好）的可量化衡量标准，可用于两者人类和小鼠，它们极大地提高了这些研究对未来发展的转化有效性的治疗干预措施。