title: Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics.
abstract: Serotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (5HT) dysregulation are commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of 5HT neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections-increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of 5HT neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth.
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Brust
authors.affiliation: Department of Physiology & Neurobiology, Geisel School of Medicine at Dartmouth, One Medical Center Road, Lebanon, NH 03756-0001, USA.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Corcoran
authors.affiliation: Departments of Neurology and Molecular Physiology & Biophysics, University of Iowa, 200 Hawkins Drive, 2151 RCP, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, 601 Highway 6 West, Iowa City, IA 52246, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: Richerson
authors.affiliation: Department of Physiology & Neurobiology, Geisel School of Medicine at Dartmouth, One Medical Center Road, Lebanon, NH 03756-0001, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Nattie
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: dymecki@genetics.med.harvard.edu.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Dymecki
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D001933:Brain Stem / Q000166:cytology* / Q000254:growth & development / Q000502:physiology; D002245:Carbon Dioxide / Q000378:metabolism; D002628:Chemoreceptor Cells / Q000378:metabolism / Q000502:physiology; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D006935:Hypercapnia / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D012018:Reflex; D012119:Respiration; D059326:Serotonergic Neurons / Q000145:classification* / Q000378:metabolism / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C484684:Fev protein, mouse; D014157:Transcription Factors; D002245:Carbon Dioxide; D012701:Serotonin