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 Pr...