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

• 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
• 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

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.

项目概要（项目2，共同主要研究者：Lin、Buzsaki、Froemke、Tsien） 在一个复杂的社会群体中，学会接近谁和避开谁的能力对于成功至关重要， 生存老鼠，就像人类一样，在被攻击和击败后，很快学会了躲避恶霸。这次失败- 诱导性社会学习对于建立稳定的社会等级制度至关重要。动物学习它们的等级关系 在每一轮比赛后都给一个竞争者。这种反复的过程导致了“啄食顺序”。神经 支持社会失败后行为改变的机制仍然难以捉摸。项目2的目标是 理解在社会等级形成的背景下社会学习的神经过程， 特别关注催产素。我们最近的研究发现，下丘脑一个小区域的催产素信号， 下丘脑腹内侧前腹外侧部（aVMHvl）是失败诱导的社交活动的重要组成部分。 学习具体地，在失败的动物中，aVMHvl中的催产素受体（OXTR）表达细胞 （aVMHv 10 XTR）特异性地增加对赢家产生的线索的响应。这种增长在功能上 重要的是，VMHv 10 XTR细胞的失活损害了对赢家的回避，而VMHv 10 XTR细胞的光遗传学激活则是重要的。 这些细胞甚至在不败的动物中也能诱导回避。我们进一步发现aVMHvl中的OXTR本身是 由于其在促进突触增强中的作用，失败诱导的社交回避是必要的。 有趣的是，aVMHv 10 XTR细胞从附近的视交叉后上核接受催产素的私人来源。 核（SOROXT），在失败过程中被激活，对失败诱导的行为具有重要的功能 变化 根据这些令人兴奋的发现，我们目前的建议旨在深化和扩大我们的 理解OXTR信号在社会学习中的社会层次结构形成的背景下，通过三个具体的 目标。目标1将解决OXTR信号传导是否对初始社会学习（记忆形成）至关重要 或学习后记忆（记忆保留）。目标2将检验社会地位调节 在aVMHvl处的OXTR信令以调整社交回避学习的速率，即，易被打败最后，在 目的3，我们将研究OXTR信号转导在形成和维持社会等级中的作用，通过长期的研究， 长期行为记录，遗传操作和计算建模，需要以下基本服务： 本U19中建议的每个核心设施。该项目从所有U19 PI和内核中汲取了各种专业知识， 工具，包括转录组学分析，在体内和体外记录，功能操作，和理论 建模该项目提供了对社区生活/养育子女至关重要的成人社会互动的关键数据 对于项目1，依赖于将在项目3中进行的机理研究和数据，并作为 在项目4中开发的电路级扰动。