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.

项目摘要：在此修订的R01应用中提出的研究的总体目的是阐明分子社会大脑发展监管的基础机制，这是一个针对大型项目的第一步识别基于电路的方法，以改善神经发育障碍的治疗疗法具有社会障碍的特征以及可能是社会伤害期间的疾病大脑发育。基于广泛的初步发现，我们的总体假设是发展精氨酸加压素（AVP）信号的上调将社会奖励学习限制为关键时期，并且这些功能是通过腹侧粒子（VPD）中突触前AVP受体启用的。目标的目标 R01应用程序是探索这个研究的领域，并开发直接在体内检验我们的假设的工具和ex vivo。已经提出了三个具体目标来实现我们的目标。具体：特定目的1：地图并表征从下丘脑到VPD的AVP神经元投影。在这里我们将测试 VPD从下丘脑接收副细胞AVP神经元投射的假设。具体的目标2：确定AVP是否会唤起VPD的突触可塑性。我们在这里将检验以下假设：VPD中AVP诱导的突触可塑性的大小在整个VPD中增加发展。特定目标3：确定VPD中是否需要AVP1A受体限制社会奖励学习关键时期。在这里，我们将测试AVP1A的假设 VPD中的受体是关闭社会奖励学习关键时期所必需的。我们预测这些研究将证明OT和AVP的相互调节是一种机制建立关键时期进行社会奖励学习。此外，这些研究旨在确定可以在成年后恢复社会奖励学习的新颖操作（AVP1AR的封锁），这将对基于机制的疗法的未来临床试验具有重要意义，以治疗自闭症，精神分裂症，成瘾和创伤后应激障碍。而且，因为这些研究是可以在两者中使用的可量化社会奖励学习（社会条件地点偏好）人类和小鼠，它们显着提高了这些研究对未来发展的转化有效性治疗干预措施。