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

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 (ACCGlu) to the anterior insular cortex (AICGlu) that mediates stress-induced visceral hypersensitivity and anxiety. Chemogenetic or optogenetic manipulation reveals that activation of glutamatergic neurons in AIC or the ACCGlu-AICGlu 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 ACCGlu-AICGlu 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 ACCGlu-AICGlu 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.