Engaging in affiliative social interactions predicts health and longevity. The hormone oxytocin, which is released by specialized neurons in the hypothalamus, has been shown to play an important role in affiliative behaviors. However, the mechanisms that control activity of oxytocin neurons and by which these neurons might then control engagement in social interactions, have not yet been elucidated. Our long-term goal is to dissect the neuroendocrine mechanisms driving voluntary engagement in affiliative social interactions. Our findings will facilitate the design of therapeutic interventions aimed at addressing the widening loneliness pandemic, as well as ASD. The objective of this grant is to characterize the role of oxytocin neuron activity patterns in initiation and reinforcement of social interactions. The central hypothesis is that spiking activity in oxytocinergic neural circuits plays a critical role in spontaneous and stress-induced social engagement, and that activity in distinct oxytocinergic circuits specifically controls either initiation or reinforcement of social engagement. In our specific aims we will use automated behavioral analysis of video recordings of mice living together for days, behaviorally synchronized neuronal recordings, optogenetics and chemogenetics to determine if neuronal activity of identified oxytocin neurons predicts or tracks social interactions (AIM 1). We will use optogenetics and chemogenetics to manipulate neuronal activity of specific oxytocinergic circuits to determine if they are required for the initiation or reinforcement of affiliative interactions (AIM 2). We will test if stressful contexts increase activity in specific oxytocinergic neurons to promote engagement in affiliative social interactions, as a defensive mechanism (AIM 3). Our work will significantly contribute to the field, as it will establish mechanisms that can be therapeutically targeted to drive social engagement. The proposed research is innovative because we investigate activity patterns in neuroendocrine circuits that predict spontaneously initiated and reinforced social interactions, which has not been done before. Our results will lay the bases for novel behavioral interventions and medications that could be used to prevent the negative effects of social isolation.