title: Identification of sympathetic premotor neurons in medullary raphe regions mediating fever and other thermoregulatory functions.
abstract: Sympathetic premotor neurons directly control sympathetic preganglionic neurons (SPNs) in the intermediolateral cell column (IML) of the thoracic spinal cord, and many of these premotor neurons are localized in the medulla oblongata. The rostral ventrolateral medulla contains premotor neurons controlling the cardiovascular conditions, whereas rostral medullary raphe regions are a candidate source of sympathetic premotor neurons for thermoregulatory functions. Here, we show that these medullary raphe regions contain putative glutamatergic neurons and that these neurons directly control thermoregulatory SPNs. Neurons expressing vesicular glutamate transporter 3 (VGLUT3) were distributed in the rat medullary raphe regions, including the raphe magnus and rostral raphe pallidus nuclei, and mostly lacked serotonin immunoreactivity. These VGLUT3-positive neurons expressed Fos in response to cold exposure or to central administration of prostaglandin E2, a pyrogenic mediator. Transneuronal retrograde labeling after inoculation of pseudorabies virus into the interscapular brown adipose tissue (BAT) or the tail indicated that those VGLUT3-expressing medullary raphe neurons innervated these thermoregulatory effector organs multisynaptically through SPNs of specific thoracic segments, and microinjection of glutamate into the IML of the BAT-controlling segments produced BAT thermogenesis. An anterograde tracing study further showed a direct projection of those VGLUT3-expressing medullary raphe neurons to the dendrites of SPNs. Furthermore, intra-IML application of glutamate receptor antagonists blocked BAT thermogenesis triggered by disinhibition of the medullary raphe regions. The present results suggest that VGLUT3-expressing neurons in the medullary raphe regions constitute excitatory neurons that could be categorized as a novel group of sympathetic premotor neurons for thermoregulatory functions, including fever.
authors.affiliation: Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. kazu@mbs.med.kyoto-u.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsumura
authors.forename: Thomas
authors.initials: T
authors.lastname: Hübschle
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hioki
authors.forename: Fumino
authors.initials: F
authors.lastname: Fujiyama
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Boldogköi
authors.forename: Matthias
authors.initials: M
authors.lastname: König
authors.forename: Heinz-Jürgen
authors.initials: HJ
authors.lastname: Thiel
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Gerstberger
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
mesh_terms: D002001:Adipose Tissue, Brown / Q000503:physiopathology; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D026922:Amino Acid Transport Systems, Acidic / Q000378:metabolism*; D000818:Animals; D001833:Body Temperature Regulation; D002352:Carrier Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D005334:Fever / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000494:pharmacology; D011558:Herpesvirus 1, Suid; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins; D008845:Microinjections; D009474:Neurons / Q000378:metabolism*; D011903:Raphe Nuclei / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012845:Sindbis Virus; D013564:Sympathetic Nervous System / Q000166:cytology / Q000503:physiopathology*; D022722:Thermogenesis / Q000187:drug effects; D050599:Vesicular Glutamate Transport Protein 2; D050496:Vesicular Glutamate Transport Proteins; D033921:Vesicular Transport Proteins
chemical_list: D027322:Amino Acid Transport System X-AG; D026922:Amino Acid Transport Systems, Acidic; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C493475:Slc17a6 protein, rat; C482103:Slc17a8 protein, rat; D050599:Vesicular Glutamate Transport Protein 2; D050496:Vesicular Glutamate Transport Proteins; D033921:Vesicular Transport Proteins; D018698:Glutamic Acid; D015232:Dinoprostone