Project summary Thermoregulation is a fundamental process that affects virtually all aspects of animal physiology. In mammals, core body temperature is monitored by neurons in the preoptic area of the hypothalamus. Activity of these neurons determines the neuronal output that drives thermoregulation and controls body temperature. Despite its fundamental physiological significance, the molecular basis of temperature homeostasis under normal, adaptive and pathological conditions remains obscure. Mammalian hibernation is a cyclical reprograming of a thermoregulatory phenotype. This process is associated with dramatic physiological perturbations: heart and respiration rate decrease, core body temperature drops from 37°C to 2- 4°C. Upon arousal from hibernation, all physiological parameters return to normal within hours. This remarkable plasticity suggests the presence of specific adaptations in the thermoregulatory system of hibernators, but the underlying cellular and molecular mechanisms remain enigmatic. In this basic scientific proposal, we will employ a comparative multidisciplinary approach to understand cellular and molecular principles of reversible hypothermia at the level of POA, using a novel hypothermia-tolerant animal model, hibernating thirteen-lined ground squirrel, and laboratory mice, a non-hibernating species. Understanding how hibernators achieve reversible hypothermia will facilitate the development of pharmacology to induce and regulate hypothermia in mammals.