title: The bed nucleus of the stria terminalis is critical for anxiety-related behavior evoked by CO2 and acidosis.
abstract: Carbon dioxide (CO2) inhalation lowers brain pH and induces anxiety, fear, and panic responses in humans. In mice, CO2 produces freezing and avoidance behavior that has been suggested to depend on the amygdala. However, a recent study in humans with bilateral amygdala lesions revealed that CO2 can trigger fear and panic even in the absence of amygdalae, suggesting the importance of extra-amygdalar brain structures. Because the bed nucleus of the stria terminalis (BNST) contributes to fear- and anxiety-related behaviors and expresses acid-sensing ion channel-1A (ASIC1A), we hypothesized that the BNST plays an important role in CO2-evoked fear-related behaviors in mice. We found that BNST lesions decreased both CO2-evoked freezing and CO2-conditioned place avoidance. In addition, we found that CO2 inhalation caused BNST acidosis and that acidosis was sufficient to depolarize BNST neurons and induce freezing behavior; both responses depended on ASIC1A. Finally, disrupting Asic1a specifically in the BNST reduced CO2-evoked freezing, whereas virus-vector-mediated expression of ASIC1A in the BNST of Asic1a(-/-) and Asic1a(+/+) mice increased CO2-evoked freezing. Together, these findings identify the BNST as an extra-amygdalar fear circuit structure important in CO2-evoked fear-related behavior.
authors: Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa 52242, Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242.
authors: Rebecca J
authors: RJ
authors: Taugher
authors: Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242.
authors: Yuan
authors: Y
authors: Lu
authors: Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242.
authors: Yimo
authors: Y
authors: Wang
authors: Medical Scientist Training Program, University of Iowa, Iowa City, Iowa 52242, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242.
authors: Collin J
authors: CJ
authors: Kreple
authors: Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242.
authors: Ali
authors: A
authors: Ghobbeh
authors: Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242.
authors: Rong
authors: R
authors: Fan
authors: Department of Neurology, University of Iowa, Iowa City, Iowa 52242.
authors: Levi P
authors: LP
authors: Sowers
authors: Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa 52242, Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, Medical Scientist Training Program, University of Iowa, Iowa City, Iowa 52242, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, Department of Neurosurgery, University of Iowa, Iowa City, Iowa 52242, and Department of Veterans Affairs Medical Center, Iowa City, Iowa 52246 john-wemmie@uiowa.edu.
authors: John A
authors: JA
authors: Wemmie
mesh_terms: D062565:Acid Sensing Ion Channels / Q000172:deficiency / Q000235:genetics; D000138:Acidosis / Q000150:complications*; D000818:Animals; D001007:Anxiety / Q000209:etiology*; D001362:Avoidance Learning / Q000187:drug effects; D002245:Carbon Dioxide / Q000633:toxicity*; D004195:Disease Models, Animal; D004572:Electrolysis; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010991:Plethysmography; D012686:Septal Nuclei / Q000166:cytology / Q000293:injuries / Q000502:physiology*
chemical_list: C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D005904:Glial Fibrillary Acidic Protein; C485184:enhanced green fluorescent protein; D002245:Carbon Dioxide; D049452:Green Fluorescent Proteins; D010751:Phosphopyruvate Hydratase
keywords: ASIC1A; CO2; anxiety; bed nucleus of the stria terminalis; pH; panic