Project Summary/Abstract Heightened sensitivity to stress can lead to maladaptive coping behaviors, such as social withdrawal and aggression. Children that experience early-life adversity (ELA) have an increased risk of developing similar difficulties, particularly after experiencing subsequent stressful events in later life. Parental care, and paternal care in particular, can have protective effects on the development of social behavior and well-being. Yet, the impact of paternal care and the neuroendocrine factors that are involved in responsiveness to later life stress in offspring are vastly understudied, and an animal model for mammalian biparental care and stress responsiveness is greatly needed. Further, oxytocin (OT) and vasopressin (VP) are essential neuropeptides that modulate social behaviors but epigenetic modifications of their receptor genes in response to ELA have not been well characterized. I will develop a two-hit model of ELA and adolescent stress by using the bi-parental prairie vole (Microtus ochrogaster) to assess how paternal deprivation during a specific pre-weaning sensitive window biases sensitivity to adolescent chronic social defeat stress through OT- and VP-related changes in the lateral septum and neural activity therein. The effects of paternal deprivation from birth in prairie vole offspring have been reported to induce deficits in pair bonding, and region-specific and sex-specific modifications in OT and VP receptor expression. Yet there is a research gap in examining the consequences of disrupting direct paternal care or breaking father-offspring bonds, the interaction of paternal deprivation with chronic social defeat stress, and its collective impact on genetic, epigenetic, transcriptomic mechanisms the mediate offspring social behavior and brain development. This project will integrate multiple levels of analysis (behavioral, epigenetic, cell-specific gene and protein profiling, and neuronal function) to understand the mechanisms in the lateral septum through which paternal deprivation can mitigate reactivity to stressors in adolescence.