PROJECT SUMMARY In social species, social relationships can exert profound influences on individuals’ behavioral and physiological states. In particular, social interactions can help reduce negative emotional state induced by physical or psychological stressors, a phenomenon known as social buffering. Social buffering provides an important means by which the social environment facilitates stress coping and resilience and benefits health and well-being. Despite the conservation of social buffering in a wide range of species from rodents to humans, how incoming social information modulates stress-related neural activity to mitigate stress responses remains poorly understood. A better grasp of the neural circuitry underlying social buffering will provide critical insights into principles governing the intricate interaction between social experience and emotional state. Conceptually, the long-lasting negative emotional state that often ensues from acute stress exposure is likely underpinned by persistent changes in neural states in stress-related brain areas. Supporting this notion, the Zhang lab recently showed that this long-lasting negative emotional state is represented and controlled by a persistent increase of neural activity in glutamatergic (Vglut2) neurons in the medial preoptic area (MPOA) (Zhang 2021). Interestingly, recent work from the Hong lab found that GABAergic (Vgat) neurons in the medial amygdala (MeA), a key node in social information processing, mediates positive valence associated with social interactions and acutely suppresses anxiety-like behavior through the projections of these neurons to the MPOA (Hu 2021). These findings led us to propose a conceptual model for social buffering in which social interactions mitigate stressor-induced negative state by attenuating persistent neural activity that maintains this state. We hypothesize that activation of MeA GABAergic neurons during social interactions leads to enhanced inhibitory input into MPOA glutamatergic neurons, resulting in a long-lasting suppression of their persistent activity and a consequent amelioration of stressor-induced negative emotional state. Our collaborative team will combine in vivo calcium imaging, electrophysiological recording, functional manipulation, and computational modeling to address a series of important questions: (1) How is stressor-induced persistent activity in MPOA Vglut2 neurons modulated by social interaction (Aim 1)? (2) Do social signals from MeA Vgat neurons drive activity changes in MPOA Vglut2 neurons and is this modulation functionally important for social buffering (Aim 2)? (3) How is social modulation of persistent neural activity in MPOA Vglut2 neurons relayed to downstream circuits to mediate social buffering (Aim 3)? (4) Can computational models that incorporate different cellular/synaptic mechanisms explain stress-induced activity dynamics and its social modulation in MPOA Vglut2 neurons and downstream circuits (Aims 1–3)? Collectively, our collaborative research team aims to develop a novel model for the neural basis of social buffering and to provide new insights into the circuit and synaptic mechanisms underlying the social modulation of persistent neural activity.

Project Narrative Social relationships have profound impacts on the mental and physical well-being of social species including humans; social isolation and loneliness, such as that seen during the COVID-19 pandemic, can have deleterious effects on mental health, such as increased risk of anxiety and depression, whereas positive social interactions can benefit health and well-being throughout life. The proposed research is relevant to public health because it studies the fundamental mechanisms through which social interactions mitigate stress and promote a positive emotional state. The proposed research could help reveal fundamental principles that are potentially applicable to the human brain, and could help guide the development of effective interventions to alleviate the negative effects of stress both in everyday life and in stress-related mental conditions such as post-traumatic stress disorder and major depression.