Glutamatergic Supramammillary Nucleus Neurons Promote Active Coping to Stress

Abstract

AbstractThreat-response neural circuits are conserved across species and have roles in normal behaviors and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is psychosocial factor associated with resilience against stress induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat and found to have efferent connections to stress-sensitive brain regions. We identified a unique population of glutamatergic SuM neurons that project to the POA. Using retrograde adeno associated viral (AAV) and combinatorial genetic tools we delineated the extensive arborization of these cells, identifying projections to brain nodes which mediate various features of the stress and threat response including the paraventricular nucleus (PV), periaqueductal gray (PAG), and the habenula (Hb). Here we report that the POA projecting subset of SuM neurons are activated by acute threatening stressors, based on fiber photometry measurements. We found that selective photoactivation of the target SuM population drives aversive and active coping behaviors. Furthermore, activation of these SuM neurons is sufficient to convert passive coping strategies to active behaviors. These findings indicate new circuit mechanisms which governs state transitions between active and passive responses to stress offering opportunities for furthering our neurobiological understanding of stress while helping to identify putative treatments for common psychiatric conditions.