The GABAergic pathway from anterior cingulate cortex to lateral hypothalamus area regulates irritable bowel syndrome in mice and its underlying mechanism

Abstract Irritable bowel syndrome (IBS), which is characterized by chronic abdominal pain, has a high global prevalence. The anterior cingulate cortex (ACC), which is a pivotal region involved in pain processing, should be further investigated regarding its role in the regulation of visceral sensitivity and mental disorders. A C57BL/6J mouse model for IBS was established using chronic acute combining stress (CACS). IBS‐like symptoms were assessed using behavioral tests, intestinal motility measurements, and abdominal withdrawal reflex scores. Fluoro‐Gold retrograde tracing and immunohistochemistry techniques were employed to investigate the projection of ACC gamma‐aminobutyric acid‐producing (GABAergic) neurons to the lateral hypothalamus area (LHA). Chemogenetic approaches enabled the selective activation or inhibition of the ACC–LHA GABAergic pathway. Enzyme‐linked immunosorbent assay (ELISA) and western blot analyses were conducted to determine the expression of histamine, 5‐hydroxytryptamine (5‐HT), and transient receptor potential vanilloid 4 (TRPV4). Our findings suggest that CACS induced IBS‐like symptoms in mice. The GABA type A receptors (GABAAR) within LHA played a regulatory role in modulating IBS‐like symptoms. The chemogenetic activation of ACC–LHA GABAergic neurons elicited anxiety‐like behaviors, intestinal dysfunction, and visceral hypersensitivity in normal mice; however, these effects were effectively reversed by the administration of the GABAAR antagonist Bicuculline. Conversely, the chemogenetic inhibition of ACC–LHA GABAergic neurons alleviated anxiety‐like behaviors, intestinal dysfunction, and visceral hypersensitivity in the mouse model for IBS. These results highlight the crucial involvement of the ACC–LHA GABAergic pathway in modulating anxiety‐like behaviors, intestinal motility alterations, and visceral hypersensitivity, suggesting a potential therapeutic strategy for alleviating IBS‐like symptoms. image