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EP3R-expressing glutamatergic preoptic neurons mediate inflammatory fever

Machado, NLS;S Bandaru, S;Abbott, SBG;Saper, CB;

Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 (PGE2) action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPOEP3R neurons). To investigate the identity of MnPOEP3R neurons, we first used in situ hybridization to show co-expression of EP3R and the Vglut2 transporter in MnPO neurons. Retrograde tracing showed extensive direct projections from MnPOVglut2 but few from MnPOVgat neurons to a key site for fever production, the raphe pallidus (RPa). Ablation of MnPOVglut2 but not MnPOVgat neurons abolished fever responses but not changes in Tb induced by behavioral stress or thermal challenges. Finally, we crossed EP3R conditional knockout mice with either Vglut2-IRES-cre or Vgat-IRES-cre mice and used both male and female mice to confirm that the neurons that express EP3R and mediate fever are glutamatergic, not GABAergic. This finding will require rethinking current concepts concerning the central thermoregulatory pathways based on the MnPOEP3R neurons being GABAergic.Significant StatementBody temperature is regulated by the central nervous system. The rise of the body temperature, or fever, is an important brain-orchestrated mechanism for fighting against infectious or inflammatory disease, and is tightly regulated by the neurons located in the median preoptic nucleus (MnPO). Here we demonstrate that excitatory MnPO neurons mediate fever and examine a potential central circuit underlying the development of fever responses. Copyright 2020 the authors.