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 are 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 contains poorly understood diversity of populations. We identified a unique population of glutamatergic SuM neurons (SuMVGLUT2+::POA) based on projection to the POA and found SuMVGLUT2+::POA neurons have extensive arborizations. SuMVGLUT2+::POA neurons project to brain areas that mediate various features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and the habenula (Hb). Thus, SuMVGLUT2+::POA neurons are positioned as hubs connecting to areas implicated regulating stress responses. Here we report SuMVGLUT2+::POA neurons are recruited by diverse threatening stressors and recruitment of SuMVGLUT2+::POA neurons correlated with active coping behaviors. We found that selective photoactivation of the SuMVGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuMVGLUT2+::POA neurons in the absence of acute stressors evoked active coping behaviors and drove goal-directed behavior. Also, activation of SuMVGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. These findings establish a new node in stress response circuitry that has projections to many brain areas and evokes flexible active coping behaviors and offers new opportunities for furthering our neurobiological understanding of stress. ### Competing Interest Statement The authors have declared no competing interest.