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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

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.

项目总结（项目二，合作项目：Lin， Buzsaki, Froemke, Tsien）