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However, unpleasant, within-the body interoceptive signals can also regulate threat and emotion although underlying cell-circuit mechanisms are not well understood. Abnormal interoceptive sensitivity is associated with fear-associated psychiatric conditions such as panic disorder and PTSD. The ventromedial infralimbic (IL) subdivision of the prefrontal cortex plays a key role in threat appraisal and fear, however, IL engagement in interoceptive threat response and contributory afferent mechanisms are not known. Here, using an interoceptive clinical panicogen, carbon dioxide (CO\n                  <jats:sub>2<\/jats:sub>\n                  ) inhalation, we report IL-mediated regulation of fear in mice via afferents from the subfornical organ (SFO), a key viscero-humoral circumventricular organ lacking a traditional blood brain barrier. Chemogenetic inhibition of SFO-to-IL (but not SFO-to-BNST) projections regulated defensive behaviors during CO\n                  <jats:sub>2<\/jats:sub>\n                  inhalation and associative contextual fear. Notably, the SFO-IL circuit also modulated delayed CO\n                  <jats:sub>2<\/jats:sub>\n                  effects on contextual fear conditioning-extinction, but not startle, neuroendocrine response or motivated behaviors. We also established more specifically that SFO angiotensin II receptor type-1 (AT-1R)\n                  <jats:sup>+ve<\/jats:sup>\n                  neuronal afferents to the IL regulate CO\n                  <jats:sub>2<\/jats:sub>\n                  -associated fear and long-term deficits in contextual fear extinction. CO\n                  <jats:sub>2<\/jats:sub>\n                  inhalation reduced neuronal activation within the IL and optogenetic activation of SFO neurons activated inhibitory parvalbumin (PV) (but not somatostatin (SST)) interneurons in the IL. Collectively, these data reveal that aversive interoceptive signals can be directly conveyed to the IL via the SFO, a sensory hub for systemic perturbations, to regulate spontaneous and long-term fear. Our findings provide important mechanistic insights into fear-associated disorders with abnormal interoceptive threat sensitivity such as panic disorder and PTSD.\n                <\/jats:p>","DOI":"10.64898\/2026.05.15.725536","type":"posted-content","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:30:27Z","timestamp":1779211827000},"source":"Crossref","is-referenced-by-count":0,"title":["Projections from subfornical organ to infralimbic cortex modulate carbon dioxide associated fear"],"prefix":"10.64898","author":[{"given":"Katherine M.J.","family":"McMurray","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of Illinois Chicago, Chicago IL"},{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Winter","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Ahlbrand","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachi","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravind","family":"Kalathill","sequence":"additional","affiliation":[{"name":"RISE-UP Summer Research Program, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Gaulden","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Packard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan-Hermann","family":"Pool","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Department of Anesthesiology and Pain Management & Peter O\u2019Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayme R.","family":"McReynolds","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Herman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renu","family":"Sah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology & Neurobiology, University of Cincinnati"},{"name":"Veterans Affairs Medical Center, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052202101200000_2026.05.15.725536v1.1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2016.16030353"},{"key":"2026052202101200000_2026.05.15.725536v1.2","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1038\/s41467-024-46508-0","article-title":"Distributed neural representations of conditioned threat in the human brain","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026052202101200000_2026.05.15.725536v1.3","doi-asserted-by":"crossref","unstructured":"Vollmer, L. 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