Work

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

Year: 2025

Type: article

Abstract: 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. • IC hyperactivity is necessary and sufficient for CRS-induced IBS-like behaviors. • Glucocorticoid signaling mediates CRS-induced activation of the IC activation. • Lamotrigine alleviates CRS-induced IBS symptoms and reduces IC hyperactivation.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.107180