A sensory–preoptic circuit drives capsaicin-induced hypothermia

Summary Capsaicin, the principal agonist of the heat-sensitive transient receptor potential vanilloid 1 (TRPV1) channel, triggers profound hypothermia by suppressing thermogenesis and promoting heat loss. While TRPV1 has been extensively characterized as a molecular sensor of heat and inflammatory mediators, the neural circuits through which capsaicin drives body cooling remain poorly defined. Emerging work suggests that peripheral TRPV1 activation modulates afferent input to central thermoregulatory networks, yet how —and where— these signals are integrated within the central nervous system to induce hypothermia has remained unresolved. Intriguingly, optogenetic or chemogenetic activation of specific neuronal populations in the preoptic area (POA) of the hypothalamus has been shown to evoke deep hypothermia, raising the possibility that capsaicin engages overlapping thermoregulatory circuits. However, whether capsaicin-driven hypothermia depends on these POA neuron populations has not been directly tested. Here, we address this question by selectively and permanently silencing defined POA neuronal subtypes and assessing their contribution to capsaicin-evoked hypothermia. Silencing VMPO LepR or POA Vgat neurons attenuated the hypothermic response but did not abolish it, whereas silencing POA Vglut2 neurons nearly eliminated capsaicin-induced hypothermia. These findings identify POA Vglut2 neurons as a critical central node through which peripheral TRPV1 activation drives body cooling. Together, our results demonstrate that capsaicin induces hypothermia via afferent sensory pathways that converge onto hypothalamic preoptic thermoregulatory neurons, revealing a direct circuit-level link between peripheral TRPV1 signalling and central control of body temperature.