title: Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus.
abstract: Fever is induced by a neuronal mechanism in the brain. Prostaglandin (PG) E2 acts as a pyrogenic mediator in the preoptic area (POA) probably through the EP3 subtype of PGE receptor expressed on GABAergic neurons, and this PGE2 action triggers neuronal pathways for sympathetic thermogenesis in peripheral effector organs including brown adipose tissue (BAT). To explore pyrogenic efferent pathways from the POA, we determined projection targets of EP3 receptor-expressing POA neurons with a special focus on rat hypothalamic regions including the dorsomedial hypothalamic nucleus (DMH), which is known as a center for autonomic responses to stress. Among injections of cholera toxin b-subunit (CTb), a retrograde tracer, into hypothalamic regions at the rostrocaudal level of the DMH, injections into the DMH, lateral hypothalamic area (LH) and dorsal hypothalamic area (DH) resulted in EP3 receptor immunolabelling in substantial populations of CTb-labeled neurons in the POA. Bilateral microinjections of muscimol, a GABA(A) receptor agonist, into the DMH and a ventral region of the DH, but not those into the LH, inhibited thermogenic (BAT sympathetic nerve activity, BAT temperature, core body temperature and expired CO2) and cardiovascular (arterial pressure and heart rate) responses to an intra-POA PGE2 microinjection. Further immunohistochemical observations revealed a close association of POA-derived GABAergic axon swellings with DMH neurons projecting to the medullary raphe regions where sympathetic premotor neurons for febrile and thermoregulatory responses are localized. These results suggest that a direct projection of EP3 receptor-expressing POA neurons to the DMH/DH region mediates febrile responses via a GABAergic mechanism.
authors.affiliation: Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. nakamura@ohsu.edu
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsumura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Shaun F
authors.initials: SF
authors.lastname: Morrison
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology; D002452:Cell Count / Q000379:methods; D002772:Cholera Toxin / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004302:Dorsomedial Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*; D007839:Functional Laterality; D018755:GABA Agonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008959:Models, Neurological; D009118:Muscimol / Q000494:pharmacology; D009434:Neural Pathways / Q000166:cytology / Q000276:immunology / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011301:Preoptic Area / Q000166:cytology*; D011749:Pyrogens / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013564:Sympathetic Nervous System / Q000187:drug effects; D014162:Transfection / Q000379:methods; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018755:GABA Agonists; C545649:Ptger3 protein, rat; D011749:Pyrogens; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D049452:Green Fluorescent Proteins; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D002772:Cholera Toxin; D015232:Dinoprostone