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.

项目摘要（项目 2，联合负责人：Lin、Buzsaki、Froemke、Tsien） 在复杂的社会群体中，了解该接近谁、该避开谁的能力对于成功甚至是至关重要的。 老鼠和人类一样，在受到攻击并被击败后很快就学会了躲避欺凌者。 诱导性社会学习对于建立稳定的社会等级制度至关重要。动物学习它们的相对等级。 每轮战斗后，这个迭代过程都会产生“啄食顺序”。 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： 了解社会等级形成背景下社会学习的神经过程， 我们最近的研究发现，催产素信号传导在下丘脑的一个小区域，即 下丘脑腹内侧前外侧部分（aVMHvl）对于失败引起的社交至关重要 具体来说，在失败的动物中，aVMHvl 中表达催产素受体（OXTR）的细胞。 (aVMHvlOXTR) 特别增加对获胜者产生的提示的反应，这种增加是功能性的。 重要的是，VMHvlOXTR 细胞的失活会损害对获胜者的回避，而光遗传学激活 我们进一步发现 aVMHvl 中的 OXTR 本身就是诱导回避的细胞。 由于其在促进突触增强方面的作用，对于失败引起的社交回避是必要的。 aVMHvlOXTR 细胞可能从附近的视交叉后视上接受私人来源的催产素 细胞核（SOROXT），在失败时被激活，对于失败引起的行为具有重要的功能 变化。 继这些令人兴奋的发现之后，我们当前的提案旨在深化和扩大我们的研究范围。 通过三个特定的方式理解社会等级形成背景下社会学习中的 OXTR 信号传导 目标 1 将解决 OXTR 信号对于初始社会学习（记忆形成）是否至关重要。 或学习后记忆（记忆保留）将检验社会地位调节的假设。 aVMHvl 上的 OXTR 信号调节社交回避学习的速率，即失败的敏感性。 目标 3，我们将研究 OXTR 信号在长期形成和维持社会等级制度中的作用。 术语行为记录、基因操作和计算建模，需要以下基本服务 本 U19 中提出的每个核心设施该项目利用了所有 U19 PI 和核心的不同专业知识。 工具包括转录组分析、体内和体外记录、功能操作和理论 该项目提供了对公共生活/育儿很重要的成人社交互动的关键数据。 对于项目 1，依赖于项目 3 中要执行的机制研究和数据，并作为测试平台 项目 4 中开发的电路级扰动。