Glutamatergic supramammillary nucleus neurons respond to threatening stressors and promote active coping

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a 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. SuM has many projections and a poorly understood diversity of neural populations. In studies using mice, we identified a unique population of glutamatergic SuM neurons (SuM^VGLUT2+::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuM^VGLUT2+::POA neurons have extensive arborizations. SuM^VGLUT2+::POA neurons project to brain areas that mediate features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and habenula (Hb). Thus, SuM^VGLUT2+::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuM^VGLUT2+::POA neurons are recruited by diverse threatening stressors, and recruitment correlated with active coping behaviors. We found that selective photoactivation of the SuM^VGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuM^VGLUT2+::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior. Also, activation of SuM^VGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuM^VGAT+) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas and evokes flexible active coping behaviors.