Insular cortex mediates chronic restraint stress-induced irritable bowel syndrome-like behaviors via glucocorticoid signaling

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by chronic abdominal pain and altered bowel habits. Currently regarded as a disorder of gut-brain interaction, the specific brain regions involved remain incompletely understood. In this study, we employed a chronic restraint stress (CRS) paradigm to induce IBS-like symptoms in mice, which were accompanied by anxiety-like behaviors and hyperalgesia. Immunostaining for c-Fos revealed neuronal activation within the insular cortex (IC) following CRS. Chemogenetic inhibition of IC activity alleviated these IBS-like and associated behaviors, whereas chemogenetic activation of the IC was sufficient to induce them. Furthermore, elevated plasma corticosterone was identified as a key mediator of CRS-induced effects, and glucocorticoid receptor blockade with mifepristone mitigated the symptoms. Finally, administration of lamotrigine, an inhibitor of neuronal hyperexcitability, was found to attenuate CRS-induced IBS-like symptoms, anxiety-like behaviors, hyperalgesia, and IC activation. These results highlight the IC as a critical cortical node in IBS pathophysiology and suggest lamotrigine as a potential therapeutic agent.