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Identification of novel mechanisms that can translate acidosis into fear will promote a better understanding of panic physiology. The current study explores a role of the subfornical organ (SFO), a blood\u2013brain barrier compromised brain area, in translating acidosis to fear\u2010relevant behaviors. We performed SFO\u2010targeted acidification in male, wild\u2010type mice and mice lacking microglial acid\u2010sensing G protein\u2013coupled receptor\u2014T\u2010cell death\u2010associated gene 8 (TDAG8). Localized SFO acidification evoked significant freezing and reduced exploration that was dependent on the presence of acid\u2010sensor TDAG8. Acidosis promoted the activation of SFO microglia and neurons that were absent in TDAG8\u2010deficient mice. The assessment of regional neuronal activation in wild\u2010type and TDAG8\u2010deficient mice following SFO acidification revealed significant acidosis and genotype\u2010dependent alterations in the hypothalamus, amygdala, prefrontal cortex, and periaqueductal gray nuclei. Furthermore, mapping of interregional co\u2010activation patterns revealed that SFO acidosis promoted positive hypothalamic\u2010cortex associations and desynchronized SFO\u2010cortex and amygdala\u2010cortex associations, suggesting an interplay of homeostatic and fear regulatory areas. Importantly, these alterations were not evident in TDAG8\u2010deficient mice. Overall, our data support a regulatory role of subfornical organ microglial acid sensing in acidosis\u2010evoked fear, highlighting a centralized role of blood\u2013brain barrier compromised nodes in interoceptive sensing and behavioral regulation. Identification of pathways by which humoral information can modulate fear behavior is relevant to panic disorder, where aberrant interoceptive signaling has been reported.<\/jats:p>","DOI":"10.1002\/jnr.25059","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T10:45:36Z","timestamp":1652352336000},"page":"1732-1746","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The subfornical organ regulates acidosis\u2010evoked fear by engaging microglial acid\u2010sensor TDAG8 and forebrain neurocircuits in male mice"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9142-7565","authenticated-orcid":false,"given":"Andrew","family":"Winter","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Systems Physiology University of Cincinnati  Cincinnati Ohio USA"},{"name":"Neuroscience Graduate Program University of Cincinnati  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M. 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