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Using a water\u2010avoidance stress (WAS) rat model, this study identifies a glutamatergic projection from the anterior cingulate cortex (ACC\n                    <jats:sup>Glu<\/jats:sup>\n                    ) to the anterior insular cortex (AIC\n                    <jats:sup>Glu<\/jats:sup>\n                    ) that mediates stress\u2010induced visceral hypersensitivity and anxiety. Chemogenetic or optogenetic manipulation reveals that activation of glutamatergic neurons in AIC or the ACC\n                    <jats:sup>Glu<\/jats:sup>\n                    \u2010AIC\n                    <jats:sup>Glu<\/jats:sup>\n                    circuit mimics WAS\u2010induced both visceral hypersensitivity and anxiety. Conversely, inhibition of this circuit reverses WAS\u2010induced visceral hypersensitivity and anxiety. However, bidirectional chemogenetic manipulation of ACC\n                    <jats:sup>Glu<\/jats:sup>\n                    \u2010AIC\n                    <jats:sup>Glu<\/jats:sup>\n                    circuit fails to affect ovalbumin\u2010induced visceral hypersensitivity, indicating stress\u2010specific modulation. Additionally, at synaptic level, WAS rats exhibit elevated synaptosomal expression of GluA1\/A3\u2010containing AMPARs and NR2B\u2010containing NMDARs of ionotropic glutamate receptors (iGluRs) in the AIC, accompanied by enhanced AMPAR\u2010 and NMDAR\u2010mediated currents. These alterations are alleviated by chemogenetic inhibition of the ACC\n                    <jats:sup>Glu<\/jats:sup>\n                    \u2010AIC\n                    <jats:sup>Glu<\/jats:sup>\n                    pathway. Moreover, inhibition of GluA1\/A3 and NR2B receptors relieved visceral hypersensitivity and anxiety in WAS rats. Taken together, these findings reveal that AMPA and NMDA receptor trafficking driven by this circuit underlies stress\u2010induced comorbidity of visceral pain and anxiety, uncovering a circuit\u2010to\u2010synapse mechanism and highlighting potential therapeutic targets for circuit\u2010based treatment of this comorbidity.\n                  <\/jats:p>","DOI":"10.1002\/advs.76298","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T12:27:25Z","timestamp":1785328045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An Anterior Cingulate Cortex\u2010Anterior Insular Cortex Glutamatergic Circuit Gates Stress\u2010Induced Visceral Hypersensitivity and Anxiety via Ionotropic Glutamate Receptors Trafficking"],"prefix":"10.1002","volume":"13","author":[{"given":"Junwen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Tongji Institute of 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