Prolonged activation of EP3 receptor-expressing preoptic neurons underlies torpor responses

Many species use a temporary drop in body temperature and metabolic rate (torpor) as a strategy to survive food scarcity. A similar profound hypothermia is observed with activation of preoptic neurons that express the neuropeptides Pituitary Adenylate-Cyclase-Activating Polypeptide (PACAP)¹, Brain Derived Neurotrophic Factor (BDNF)², or Pyroglutamylated RFamide Peptide (QRFP)³, the vesicular glutamate transporter, Vglut2^4,5 or the leptin receptor⁶ (LepR), estrogen 1 receptor (Esr1)⁷ or prostaglandin E receptor 3 (EP3R) in mice⁸. However, most of these genetic markers are found on multiple populations of preoptic neurons and only partially overlap with one another. We report here that expression of the EP3R marks a unique population of median preoptic (MnPO) neurons that are required both for lipopolysaccharide (LPS)-induced fever⁹ and for torpor. These MnPO^EP3R neurons produce persistent fever responses when inhibited and prolonged hypothermic responses when activated either chemo- or opto-genetically even for brief periods of time. The mechanism for these prolonged responses appears to involve increases in intracellular calcium in individual EP3R-expressing preoptic neurons that persist for many minutes up to hours beyond the termination of a brief stimulus. These properties endow MnPO^EP3R neurons with the ability to act as a two-way master switch for thermoregulation.