title: Activity ofTachykinin1-ExpressingPet1Raphe Neurons Modulates the Respiratory Chemoreflex.
abstract: Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by theTachykinin-1(Tac1) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression ofTac1and the serotonergic transcription factor genePet1, referred to as theTac1-Pet1neuron subtype. Transgenic cell labeling showedTac1-Pet1soma resident largely in the caudal medulla. Chemogenetic [clozapine-N-oxide (CNO)-hM4Di] perturbation ofTac1-Pet1neuron activity blunted the ventilatory response of the respiratory CO2chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO2Tac1-Pet1axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of aPet1neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. TheseTac1-Pet1neurons may act downstream ofEgr2-Pet1serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei.SIGNIFICANCE STATEMENTSerotonin (5-HT) neurons modulate physiological processes and behaviors as diverse as body temperature, respiration, aggression, and mood. Using genetic tools, we characterize a 5-HT neuron subtype defined by expression ofTachykinin1andPet1(Tac1-Pet1neurons), mapping soma localization to the caudal medulla primarily and axonal projections to brainstem motor nuclei most prominently, and, when silenced, observed blunting of the ventilatory response to inhaled CO2Tac1-Pet1neurons thus appear distinct from and contrast previously describedEgr2-Pet1neurons, which project primarily to chemosensory integration centers and are themselves chemosensitive.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Morgan L
authors.identifier: 0000-0002-4907-1956
authors.initials: ML
authors.lastname: Hennessy
authors.affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Corcoran
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Brust
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: YoonJeung
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756.
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Nattie
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and dymecki@genetics.med.harvard.edu.
authors.forename: Susan M
authors.identifier: 0000-0003-0910-9881
authors.initials: SM
authors.lastname: Dymecki
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011903:Raphe Nuclei / Q000166:cytology* / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C484684:Fev protein, mouse; D018398:Homeodomain Proteins; D037102:Lectins; C109220:NBPhox protein; C425303:Tachypleus plasma lectin-1; D014157:Transcription Factors; D002245:Carbon Dioxide; D049452:Green Fluorescent Proteins; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D003024:Clozapine; C079149:clozapine N-oxide