The role of hypothalamic oxytocin signaling in defeat-induced social learning

下丘脑催产素信号在失败诱导的社会学习中的作用

基本信息

批准号：
10705988
负责人：
Dayu Lin
金额：
$ 65.82万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705988
关键词：
Address Adult Ally Animals Anterior Automobile Driving Avoidance Learning Beds Behavior Behavior monitoring Behavioral Cell Nucleus Cells Chemosensitization Complex Computer Models Core Facility Cues Data Elements Funding Goals Human Hypothalamic structure Impairment In Vitro Individual Learning Maintenance Memory Modeling Molecular Mus OXT gene Oxytocin Oxytocin Receptor Play Predisposition Privatization Process Receptor Cell Receptor Signaling Role Services Signal Transduction Social Hierarchy Social Interaction Social status Source Synapses Testing Theoretical model Time Work bullying commune dyadic interaction fighting genetic manipulation in vivo insight memory retention neural neural circuit neuromechanism optogenetics parent project receptor expression response social social defeat social group social learning social relationships success supraoptic nucleus tool transcriptomic profiling

Address Adult Ally Animals Anterior Automobile Driving Avoidance Learning Beds Behavior Behavior monitoring Behavioral Cell Nucleus Cells Chemosensitization Complex Computer Models Core Facility Cues Data Elements Funding Goals Human Hypothalamic structure Impairment In Vitro Individual Learning Maintenance Memory Modeling Molecular Mus OXT gene Oxytocin Oxytocin Receptor Play Predisposition Privatization Process Receptor Cell Receptor Signaling Role Services Signal Transduction Social Hierarchy Social Interaction Social status Source Synapses Testing Theoretical model Time Work bullying commune dyadic interaction fighting genetic manipulation in vivo insight memory retention neural neural circuit neuromechanism optogenetics parent project receptor expression response social social defeat social group social learning social relationships success supraoptic nucleus tool transcriptomic profiling

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项目摘要

Project Summary (Project 2, Co-PIs: Lin, Buzsaki, Froemke, Tsien) In a complex social group, the ability to learn who to approach and who to avoid is essential for success or even survival. Mice, just like humans, quickly learn to avoid a bully after they are attacked and defeated. This defeat- induced social learning is essential for establishing stable social hierarchies. Animals learn their ranking relative to a competitor after each round of fighting. This iterative process leads to a “pecking order”. The neural mechanisms supporting the behavioral change after social defeat remain elusive. The goal of Project 2 is to understand the neural process underlying social learning in the context of social hierarchy formation, with a special focus on oxytocin. Our recent study found that oxytocin signaling in a small hypothalamic region, the anterior ventrolateral part of ventromedial hypothalamus (aVMHvl), is essential for defeat-induced social learning. Specifically, in defeated animals, oxytocin receptor (OXTR)–expressing cells in the aVMHvl (aVMHvlOXTR) specifically increase responses to cues generated by the winner. This increase is functionally important as inactivation of VMHvlOXTR cells impairs avoidance of the winner, whereas optogenetic activation of the cells induces avoidance even in undefeated animals. We further found that OXTR in the aVMHvl is itself necessary for the defeat-induced social avoidance thanks to its role in facilitating synaptic potentiation. Interestingly, aVMHvlOXTR cells receive a private source of oxytocin from the nearby retrochiasmatic supraoptic nucleus (SOROXT), which is activated during defeat and functionally important for defeat-induced behavioral changes. Following up on these exciting findings, our current proposal is aimed at deepening and broadening our understanding of OXTR signaling in social learning in the context of social hierarchy formation via three specific aims. Aim 1 will address whether OXTR signaling is essential for the initial social learning (memory formation) or remembering after learning (memory retention). Aim 2 will test the hypothesis that social status modulates OXTR signaling at the aVMHvl to adjust rate of social avoidance learning, i.e., susceptibility to defeat. Lastly, in Aim 3, we will examine the role of OXTR signaling in forming and maintaining social hierarchies through long- term behavior recording, genetic manipulation, and computational modeling, requiring the essential services of each Core facility proposed in this U19. This project draws diverse expertise from all U19 PIs and cores, using tools including transcriptomic profiling, in vivo and in vitro recordings, functional manipulations, and theoretical modeling. This Project provides critical data on adult social interactions important for communal living/parenting for Project 1, relies on mechanistic studies and data to be performed in Project 3, and serves as a test-bed for circuit-level perturbations developed in Project 4.

项目摘要（项目2，Co-Pis：Lin，Buzsaki，Froemke，Tsien）在一个复杂的社会群体中，学习接近谁，避免谁对成功甚至是至关重要的能力生存。就像人类一样，老鼠在攻击和击败后迅速学会避免欺负。这个失败 - 诱导的社会学习对于建立稳定的社会等级制度至关重要。动物学习他们的排名每一轮战斗后给竞争对手。这种迭代过程导致“啄食顺序”。中立在社交失败之后支持行为改变的机制仍然难以捉摸。项目2的目标是在社会等级形成的背景下了解社会学习的基础神经过程，特别关注氧气。我们最近的研究发现，在一个小的下丘脑区域中的氧信号传导，腹侧下丘脑（AVMHVL）的前腹侧部分对于失败引起的社会至关重要学习。具体而言，在失败的动物中，氧受体（OXTR）表达AVMHVL的细胞（AVMHVLOXTR）特别增加了对获胜者产生的提示的反应。这种增加在功能上重要的是，VMHVloxTR细胞的失活会损害赢得胜利者的避免，而光遗传激活即使在不败的动物中，细胞也会引起避免。我们进一步发现AVMHVL中的OXTR本身是对于失败引起的社会回避所必需的感谢您在支持突触潜力中的作用。有趣的是，AVMHVloxTR细胞从附近的逆转录型上获得私人氧气来源核（soroxt），在失败期间被激活，对于失败引起的行为在功能上很重要更改。跟进这些令人兴奋的发现，我们目前的建议旨在加深和扩大我们通过三个特定目标。 AIM 1将解决OXTR信号是否对于初始社会学习至关重要（记忆形成）或在学习后记住（保留记忆）。 AIM 2将检验社会地位调节的假设 AVMHVL的OXTR信号传导调整社会回避学习的速度，即失败的敏感性。最后，在 AIM 3，我们将研究OXTR信号在长期形成和维持社会等级中的作用术语行为记录，基因操纵和计算建模，需要本U19中提出的每个核心设施。该项目从所有U19 PI和核心中汲取了多样的专业知识包括转录组分析，体内和体外记录，功能操纵和理论在内的工具造型。该项目提供有关成人社会互动的关键数据，对公共生活/育儿很重要对于项目1，依赖于项目3中执行的机械研究和数据，并用作测试床电路级扰动在项目4中开发。