Prostaglandin EP3 receptor–expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling

The bidirectional controller of the thermoregulatory center in the preoptic area (POA) is unknown. Using rats, here, we identify prostaglandin EP3 receptor–expressing POA neurons (POA(EP3R) neurons) as a pivotal bidirectional controller in the central thermoregulatory mechanism. POA(EP3R) neurons are activated in response to elevated ambient temperature but inhibited by prostaglandin E(2), a pyrogenic mediator. Chemogenetic stimulation of POA(EP3R) neurons at room temperature reduces body temperature by enhancing heat dissipation, whereas inhibition of them elicits hyperthermia involving brown fat thermogenesis, mimicking fever. POA(EP3R) neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic (ceaseless) inhibitory signaling. Although many POA(EP3R) neuronal cell bodies express a glutamatergic messenger RNA marker, their axons in the DMH predominantly release γ-aminobutyric acid (GABA), and their GABAergic terminals are increased by chronic heat exposure. These findings demonstrate that tonic GABAergic inhibitory signaling from POA(EP3R) neurons is a fundamental determinant of body temperature for thermal homeostasis and fever.