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However, the key neural circuits and molecular mechanisms underlying post\u2010TBI anxiety remain poorly understood. Here, we show that TBI patients with frontal lobe injuries and anxiety exhibited increased activity and enhanced functional connectivity in the anterior insular cortex (aIC) and lateral orbitofrontal cortex (lOFC). Mechanistically, we established a mouse model of moderate frontal lobe TBI, categorizing animals into anxious and non\u2010anxious TBI groups. BOLD\u2010fMRI and c\u2010Fos expression analyses revealed that mice with post\u2010traumatic anxiety also exhibited increased activity in the aIC and lOFC, as well as heightened activity in the aIC\u2010lOFC glutamatergic circuit. Optogenetic and chemogenetic modulation of this circuit bidirectionally regulated post\u2010traumatic anxiety. Single\u2010cell RNA sequencing of aIC glutamatergic neurons identified a specific downregulation of KCNC3 in anxious TBI mice. Functional validation confirmed that KCNC3 downregulation mediates hyperactivity in the aIC\u2010lOFC glutamatergic circuit and induces post\u2010traumatic anxiety. Together, these findings unveil a critical role of TBI\u2011induced KCNC3 downregulation in aIC glutamatergic neurons in driving hyperactivity of the aIC\u2013lOFC glutamatergic circuit and resulting post\u2011traumatic anxiety, and they suggest KCNC3 and the aIC\u2013lOFC circuit as promising therapeutic targets for post\u2011TBI anxiety.<\/jats:p>","DOI":"10.1002\/advs.76779","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:48:26Z","timestamp":1785156506000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the KCNC3\u2010Dependent Anterior Insular\u2010Lateral Orbitofrontal Cortex Glutamatergic Circuit Attenuates Post\u2010Traumatic Anxiety"],"prefix":"10.1002","volume":"13","author":[{"given":"Meng\u2010Ge","family":"Li","sequence":"first","affiliation":[{"name":"Center of Translational Medicine Department of Neurosurgery Department of Medical Imaging The 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