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.

项目总结(项目2，合作项目：林、布萨基、弗罗姆克、钱学森) 在一个复杂的社交群体中，学习接近和避开谁的能力对于成功甚至是至关重要 生死存亡。老鼠和人类一样，在受到攻击并被击败后，很快就会学会躲避欺凌弱小的人。这场失败- 诱导式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亲属 在每一轮比赛之后都会给一名竞争对手。这一迭代过程导致了一种“权衡顺序”。神经学 支持社会失败后行为变化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理解潜在的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，催产素信号在下丘脑的一个小区域， 下丘脑腹内侧前腹外侧部(AVMHvl)在失败性社交活动中起重要作用 学习。具体地说，在战败的动物中，aVMHvl中表达催产素受体(OXTR)的细胞 (AVMHvlOXtr)特别增加了对获胜者产生的提示的反应。这一增长在功能上是 重要的是，VMHvlOXTR细胞的失活会损害获胜者的避免，而光基因激活 即使在未被击败的动物身上，这些细胞也能诱导回避。我们进一步发现，aVMHv1中的OXTR本身 对于失败诱导的社交回避来说是必要的，因为它在促进突触增强方面的作用。 有趣的是，一个VMHvlOXtr细胞从附近的视交叉后上叶接受催产素的私人来源 核团(SOROXT)，在失败过程中被激活，在失败诱导的行为中起重要作用 改变。 根据这些令人振奋的发现，我们目前的建议旨在深化和扩大我们的 在社会等级形成的背景下，通过三个具体的研究来理解OXTR信号在社会学习中的作用 目标。目标1将讨论OXTR信号是否对最初的社会学习(记忆形成)是必要的 或在学习后记忆(记忆保持)。目标2将检验社会地位调节的假设 在aVMHvl处发出OXTR信号以调节社交回避学习的速率，即对失败的敏感性。最后，在 目标3，我们将研究OXTR信号在形成和维持社会等级结构中的作用，通过长时间的 术语行为记录、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和核心中汲取不同的专业知识，使用 工具包括转录图谱、体内和体外记录、功能操作和理论 模特儿。该项目提供了成人社交方面的重要数据，这些数据对共同生活/养育子女很重要 对于项目1，依赖于将在项目3中执行的机械研究和数据，并作为 在项目4中开发的电路级扰动。