An Anterior Cingulate Cortex‐Anterior Insular Cortex Glutamatergic Circuit Gates Stress‐Induced Visceral Hypersensitivity and Anxiety via Ionotropic Glutamate Receptors Trafficking

ABSTRACT The comorbidity between irritable bowel syndrome (IBS) and anxiety arises from impaired sensory‐emotional integration, yet its underlying neural circuit mechanisms remain elusive. Using a water‐avoidance stress (WAS) rat model, this study identifies a glutamatergic projection from the anterior cingulate cortex (ACC Glu ) to the anterior insular cortex (AIC Glu ) that mediates stress‐induced visceral hypersensitivity and anxiety. Chemogenetic or optogenetic manipulation reveals that activation of glutamatergic neurons in AIC or the ACC Glu ‐AIC Glu circuit mimics WAS‐induced both visceral hypersensitivity and anxiety. Conversely, inhibition of this circuit reverses WAS‐induced visceral hypersensitivity and anxiety. However, bidirectional chemogenetic manipulation of ACC Glu ‐AIC Glu circuit fails to affect ovalbumin‐induced visceral hypersensitivity, indicating stress‐specific modulation. Additionally, at synaptic level, WAS rats exhibit elevated synaptosomal expression of GluA1/A3‐containing AMPARs and NR2B‐containing NMDARs of ionotropic glutamate receptors (iGluRs) in the AIC, accompanied by enhanced AMPAR‐ and NMDAR‐mediated currents. These alterations are alleviated by chemogenetic inhibition of the ACC Glu ‐AIC Glu 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‐induced comorbidity of visceral pain and anxiety, uncovering a circuit‐to‐synapse mechanism and highlighting potential therapeutic targets for circuit‐based treatment of this comorbidity.