Thermoregulation via Temperature-dependent PGD2 Production in Mouse Preoptic Area


Body temperature control is essential for survival. In mammals, thermoregulation is mediated by the preoptic area of the anterior hypothalamus (POA), where ~30% of the neurons are sensitive to local temperature changes and intermingled with temperature-insensitive neurons that mediate the homeostatic and autonomic behaviors, such as feeding, drinking, sleep, and parental behaviors. The temperature-sensitive POA neurons were thought to play a pivotal role in thermoregulation; this hypothesis, however, cannot be tested in the past 80 years, because electrophysiological recording has been the only way to identify the temperature-sensitive neurons since their discovery. My research surpassed this critical barrier by combining the cutting-edge technology of single-cell RNA-seq with whole-cell patch-clamp recording to profile POA neurons based on their transcriptomes and temperature-sensitivity. This screen identified the gene Ptgds as a marker for temperature-sensitive neurons in the POA. Using the mouse line of Ptgds-Cre, I demonstrated for the first time that the temperature-sensitive POA neurons are indeed involved in thermoregulation. This genetic tool will significantly facilitate the dissection of neural circuitry for thermoregulation in my future research. The approach applied in this research is distinguished from other high-throughput screen, because the outcome is not only genetic markers: my works further showed that the marker gene Ptgds is functionally involved in thermoregulation, by encoding the enzyme that synthesizes prostaglandin D2 (PGD2). In response to brain temperature increase, the temperature-sensitive POA neurons become more active in producing PGD2, which in turn activates its receptors (DP1) expressed in neurons of the ventral median POA. These downstream neurons integrate thermosensory inputs from both ambient and central temperature sensors, and mediate body temperature decrease by inhibiting thermogenesis and facilitating heat loss -- a negative feedback loop for thermoregulation.