Targeted preoptic neuronal activation induces a hypothermic state with metabolic reprogramming and acute cerebroprotection

Abstract

Therapeutic hypothermia is cerebroprotective in experimental stroke but has shown limited clinical efficacy due to metabolically costly counter regulatory responses. Naturally occurring states such as torpor achieve hypothermia through coordinated regulation of temperature and metabolism are associated with cerebroprotection. Here, we tested whether selective activation of a genetically defined thermoregulatory neuronal population is sufficient to induce hypothermia after ischemic injury and whether temperature-dependent cerebroprotection is accompanied by metabolic remodeling. Using chemogenetic tools, kappa opioid receptor expressing neurons in the preoptic area were activated in mice subjected to transient middle cerebral artery occlusion. Core body temperature, metabolism, infarct volume, and motor recovery were assessed under conditions permitting hypothermia or maintaining normothermia. Untargeted metabolomic profiling was performed on whole brain tissue collected 30 minutes after activation in the absence of ischemia. Activation of kappa opioid receptor expressing preoptic neurons induced a hypothermic state with coordinated metabolic changes, reduced infarct volume and improved acute motor outcomes. These effects were attenuated when body temperature was maintained at normothermia. Metabolomic profiling revealed coordinated alterations in nucleotide, phospholipid, and sphingolipid pathways. These findings link temperature dependent cerebroprotection to coordinated metabolic remodeling, with translational relevance for stroke.