title: Functional link between the hypocretin and serotonin systems in the neural control of breathing and central chemosensitivity.
abstract: Serotonin (5-HT)-synthesizing neurons of the medullary raphe are putative central chemoreceptors, proposed to be one of potentially multiple brain stem chemosensitive cell types and loci interacting to produce the respiratory chemoreflex. Hypocretin-synthesizing neurons of the lateral hypothalamus are important contributors to arousal state, thermoregulation, and feeding behavior and are also reportedly involved in the hypercapnic ventilatory response. Recently, a functional interaction was found between the hypocretin system and 5-HT neurons of the dorsal raphe. The validity and potential significance of hypocretin modulation of medullary raphe 5-HT neurons, however, is unknown. As such, the purpose of this study was to explore functional interactions between the hypocretin system and 5-HT system of the medullary raphe on baseline respiratory output and central chemosensitivity. To explore such interactions, we used the neonatal in vitro medullary slice preparation derived from wild-type (WT) mice (normal 5-HT function) and a knockout strain lacking all central 5-HT neurons (Lmx1b(f/f/p) mice). We examined effects of acidosis, hypocretin-1, a hypocretin receptor antagonist (SB-408124), and the effect of the antagonist on the response to acidosis. We confirmed the critical role of 5-HT neurons in central chemosensitivity given that the increased hypoglossal burst frequency with acidosis, characteristic of WT mice, was absent in preparations derived from Lmx1b(f/f/p) mice. We also found that hypocretin facilitated baseline neural ventilatory output in part through 5-HT neurons. Although the impact of hypocretin on 5-HT neuronal sensitivity to acidosis is still unclear, hypocretins did appear to mediate the burst duration response to acidosis via serotonergic mechanisms.
authors: Department of Biology and Wildlife, and Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska; Departments of Neurology and Cellular & Molecular Physiology, Yale University, New Haven, Connecticut; Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire; andrea.e.corcoran@dartmouth.edu.
authors: Andrea E
authors: AE
authors: Corcoran
authors: Departments of Neurology and Cellular & Molecular Physiology, Yale University, New Haven, Connecticut; Veteran's Affairs Medical Center, West Haven, Connecticut; and Departments of Neurology and Molecular Physiology & Biophysics, University of Iowa, Iowa City, Iowa.
authors: George B
authors: GB
authors: Richerson
authors: Department of Biology and Wildlife, and Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska;
authors: Michael B
authors: MB
authors: Harris
mesh_terms: D000138:Acidosis / Q000503:physiopathology*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D006863:Hydrogen-Ion Concentration; D007002:Hypoglossal Nerve / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D018345:Mice, Knockout; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects; D059326:Serotonergic Neurons / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D010671:Phenylurea Compounds; C542397:SB 408124; D014157:Transcription Factors; D012701:Serotonin
keywords: chemosensitivity; hypocretin; serotonin; ventilation