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

Summary

Using activity-dependent tagging in LPS and CLP models, the authors identified a glutamatergic neuron population in the vlPAG that causally drives hypothermia and cardiovascular depression during systemic inflammation. Optogenetic manipulation supported a functional role for this circuit in the hypometabolic state linked to septic shock mortality.

Key Findings

• Activity-dependent genetic labeling in LPS and CLP models identified a discrete glutamatergic neuron population in the vlPAG activated by systemic inflammation.
• Optogenetic stimulation of the identified vlPAG neurons drove hypothermia and cardiovascular depression, indicating a causal role in the hypometabolic state.
• The work provides a central neural mechanism linking systemic inflammation to thermometabolic and cardiovascular suppression relevant to septic shock mortality.

Clinical Implications

While preclinical, these findings suggest that targeted neuromodulation of the vlPAG or its downstream pathways could mitigate hypothermia and cardiovascular depression in septic shock. They also caution that indiscriminate induction of hypothermia may have neural circuit–level consequences.

Limitations

• Findings are limited to murine models; human translational relevance remains to be established.
• The abstract does not detail downstream targets or broader network interactions.

Future Directions

Map downstream projections and inputs to the vlPAG circuit, test neuromodulatory interventions in severe infection models, and explore biomarkers of circuit engagement for potential translation.