An excitatory circuit in the ventrolateral periaqueductal gray drives hypometabolic state during acute systemic inflammation

Summary Hypometabolism, characterized by hypothermia and cardiovascular depression, is associated with higher mortality in patients with septic shock. However, the neural substrates underlying the hypometabolic state during systemic inflammation remain poorly understood. Here, using activity-dependent genetic labeling of neurons activated by lipopolysaccharide (LPS) administration and cecal ligation and puncture (CLP) in mice, we identified a discrete population of glutamatergic neurons in the ventrolateral periaqueductal gray (vlPAG) that drives hypothermia and cardiovascular depression. Optogenetic stimulation of vlPAGvglut2 neurons induced hypothermia and cardiovascular depression in healthy mice, whereas their genetic ablation attenuated the reductions in core temperature and cardiovascular function observed during systemic inflammation. Furthermore, we demonstrated that projections from vlPAGvglut2 neurons to the nucleus tractus solitarius mediate these hypometabolic pathophysiological effects. Taken together, our findings reveal a vlPAG excitatory circuit that regulates hypometabolic responses to systemic inflammation, providing potential therapeutic targets for mitigating severe sepsis-induced hypothermia and cardiovascular dysfunction.