Estrogen-Sensitive Medial Preoptic Area Neurons Coordinate Hypothermia and Hypometabolism in Mice

Homeotherms maintain a stable internal body temperature despite changing environments. During energy deficiency, some species can cease to defend their body temperature and enter a hypothermic and hypometabolic state known as torpor. Despite recent advances in our understanding of thermoregulation, the precise neurons that coordinate these profound thermoregulatory and metabolic changes remain largely unknown. Here, we demonstrate that estrogen-sensitive neurons in the medial preoptic area (MPA) are key drivers of hypothermia and hypometabolism in mice. We find that selectively activating estrogen-sensitive MPA neurons was sufficient to drive a coordinated depression of metabolic rate and body temperature similar to torpor, as measured by body temperature, physical activity, indirect calorimetry, heart rate, and brain activity. Inducing torpor with a prolonged fast revealed larger and more variable calcium transients from estrogen-sensitive MPA neurons during bouts of hypothermia. Finally, selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor. Together, these findings suggest a role for estrogen-sensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency. Overall design: Patch-seq to compare transcriptomes of heat responsive and heat non-responsive Esr1 positive neurons in the MPA