title: Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear.
abstract: Carbon dioxide (CO2) inhalation, a biological challenge and pathologic marker in panic disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomic location of CO2-sensing systems that translate CO2-evoked fear remain unclear. We investigated contributions of microglial acid sensor T cell death-associated gene-8 (TDAG8) and microglial proinflammatory responses in CO2-evoked behavioral and physiological responses.
  
  
  
  CO2-evoked freezing, autonomic, and respiratory responses were assessed in TDAG8-deficient ((-/-)) and wild-type ((+/+)) mice. Involvement of TDAG8-dependent microglial activation and proinflammatory cytokine interleukin (IL)-1β with CO2-evoked responses was investigated using microglial blocker, minocycline, and IL-1β antagonist IL-1RA. CO2-chemosensitive firing responses using single-cell patch clamping were measured in TDAG8(-/-) and TDAG8(+/+) mice to gain functional insights.
  
  
  
  TDAG8 expression was localized in microglia enriched within the sensory circumventricular organs. TDAG8(-/-) mice displayed attenuated CO2-evoked freezing and sympathetic responses. TDAG8 deficiency was associated with reduced microglial activation and proinflammatory cytokine IL-1β within the subfornical organ. Central infusion of microglial activation blocker minocycline and IL-1β antagonist IL-1RA attenuated CO2-evoked freezing. Finally, CO2-evoked neuronal firing in patch-clamped subfornical organ neurons was dependent on acid sensor TDAG8 and IL-1β.
  
  
  
  Our data identify TDAG8-dependent microglial acid sensing as a unique chemosensor for detecting and translating hypercapnia to fear-associated behavioral and physiological responses, providing a novel mechanism for homeostatic threat detection of relevance to psychiatric conditions such as panic disorder.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati; Neuroscience Graduate Program, University of Cincinnati, Cincinnati.
authors.forename: Lauren Larke
authors.initials: LL
authors.lastname: Vollmer
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati; Neuroscience Graduate Program, University of Cincinnati, Cincinnati.
authors.forename: Sriparna
authors.initials: S
authors.lastname: Ghosal
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McGuire
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Ahlbrand
authors.affiliation: Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton.
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Santin
authors.affiliation: Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Ratliff-Rang
authors.affiliation: Department of Animal Morphology and Physiology, São Paulo State University, FCAV, Jaboticabal, São Paulo, Brazil.
authors.forename: Luis G A
authors.initials: LG
authors.lastname: Patrone
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rush
authors.affiliation: Division of Immunobiology, Children's Hospital Medical Center, Cincinnati.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Lewkowich
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati; Neuroscience Graduate Program, University of Cincinnati, Cincinnati.
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.affiliation: Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Putnam
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati; Neuroscience Graduate Program, University of Cincinnati, Cincinnati; Veterans Affairs (VA) Medical Center, Cincinnati, Ohio. Electronic address: sahr@uc.edu.
authors.forename: Renu
authors.initials: R
authors.lastname: Sah
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology*; D002628:Chemoreceptor Cells / Q000502:physiology*; D005239:Fear / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008845:Microinjections; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013356:Subfornical Organ / Q000378:metabolism
chemical_list: C513337:GPR65 protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D043562:Receptors, G-Protein-Coupled; D002245:Carbon Dioxide; D008911:Minocycline
keywords: Acid sensing; Carbon dioxide; Fear; Microglia; Panic; TDAG8