Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

The preoptic area (POA) is a key region controlling body temperature (Tb), dictating thermogenic, cardiovascular, and behavioral responses to regulate Tb. Known POA neuronal populations reduce Tb when activated; a population that increases Tb upon activation has not yet been reported. We now identify bombesin-like receptor 3 (BRS3)-expressing POA (POA BRS3 ) neurons as having this missing functionality. BRS3 is an orphan receptor that regulates energy and cardiovascular homeostasis, but the relevant neural circuits are incompletely understood. In mice, we demonstrate that POA BRS3 neuronal activation increases Tb, heart rate, and blood pressure sympathetically, via projections to the paraventricular nucleus of the hypothalamus and dorsomedial hypothalamus. Acute POA BRS3 inhibition reduces Tb. Long-term inactivation of POA BRS3 neurons increased Tb variability with exaggerated Tb changes, overshooting both increases and decreases in Tb set point. BRS3 marks preoptic populations that regulate Tb and heart rate, contribute to cold-defense and fine-tune feedback control of Tb. These findings advance understanding of homeothermy, a defining feature of mammalian biology. Graphical abstract