Q Neuron-Induced Hypothermia Promotes Functional Recovery and Suppresses Neuroinflammation after Brain Injury

Abstract

Traumatic brain injury (TBI) triggers a cascade of secondary pathologies—such as neuroinflammation and glial activation—contributing to progressive neuronal loss and hindering functional recovery. While therapeutic hypothermia has shown neuroprotective potential, its clinical application is limited by systemic complications. Recent discoveries have identified hypothalamic Q neurons, whose activation induces a reversible, hibernation-like hypothermic state, termed Q neuron-induced hypothermic/hypometabolic states (QIH), without the need for external cooling. However, whether QIH can mitigate brain injury remains unknown. In this study, we examined the therapeutic effects of QIH following acute brain injury in male mice. Using a dorsal striatal stab injury model, we found that QIH-treated mice displayed significantly improved motor performance and grip strength compared with controls. Histological analyses revealed enhanced neuronal survival in the perilesional striatum, accompanied by markedly reduced astrocytic gliosis and microglial accumulation at the injury site. To investigate the mechanisms underlying these improvements, we employed a medial prefrontal cortex injury model and observed that QIH robustly suppressed astrocytic and microglial activation, as indicated by reduced GFAP and Iba1 expression. Additionally, QIH decreased the number of CD16/32- and CD68-positive microglia and downregulated iNOS expression, suggesting that QIH dampens both oxidative and phagocytic inflammatory responses. Morphometric analysis further revealed a shift toward ramified and rod-shaped microglia, phenotypes associated with neuroprotection. Our findings demonstrate that QIH ameliorates early neuroinflammation, preserves neuronal integrity, and promotes functional recovery following brain injury. These results highlight QIH as a novel and physiologically grounded neuroprotective strategy that may overcome the limitations of conventional hypothermia-based interventions.