Ohba, A.; Narushima, M.; Shao, C.; Hung, C.; Uchida, H.; Fukatsu, N.; Angarag, U.; Takemoto-Kimura, S.; Yamanaka, A.; Tainaka, K.; Ono, D.; Yamaguchi, Y.; Wake, H.; YAMAGUCHI, H.

Torpor is an adaptive hypometabolic state that enables homeotherm to survive periods of energetic challenge. This strategy ranges from short bouts of daily torpor to prolonged hibernation. During torpor, animals markedly suppress metabolic rate, body temperature, heart rate, and respiration, while retaining the ability to rewarm. Torpor therefore comprises two critical transitions -entry into a hypometabolic state and active rewarming- both essential for organismal viability. Although neural mechanisms controlling torpor entry have begun to emerge, the circuits that initiate active rewarming and restore euthermia remain poorly defined. Here we identify corticotropin-releasing hormone (Crh)-expressing neurons in the anterodorsal preoptic area (ADP) as a key population for rewarming from fasting-induced torpor in mice. These neurons become active around natural rewarming and are selectively required to limit the depth and duration of torpor. Unlike pathways mediating acute cold defence, stress hyperthermia, or LPS-induced fever, this circuit is dedicated to promoting timely recovery to euthermia. Closed-loop optogenetic activation of ADPCrh neurons during torpor entry rapidly initiates rewarming, and thermographic recordings show that brown adipose tissue (BAT) thermogenesis precedes locomotor arousal. ADPCrh neurons are predominantly GABAergic and project monosynaptically to the lateral preoptic area, whose terminal activation is sufficient to increase body temperature and locomotor activity. Finally, we find robust activation of ADPCrh neurons during rewarming in a hibernator, suggesting conserved logic for exiting deep torpor. Together, our results define a discrete preoptic circuit that drives recovery from torpor and provide a framework for understanding and potentially controlling timely rewarming from profound hypothermia.