Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China.
Biomedical Center, Qingdao Medical College, Qingdao University, Qingdao, China.
J Neurochem. 2024 Sep;168(9):2814-2831. doi: 10.1111/jnc.16150. Epub 2024 Jun 15.
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.
肠易激综合征（IBS）以慢性腹痛为特征，具有较高的全球患病率。前扣带皮层（ACC）是参与疼痛处理的关键区域，应进一步研究其在调节内脏敏感性和精神障碍中的作用。使用慢性急性联合应激（CACS）建立了用于 IBS 的 C57BL/6J 小鼠模型。使用行为测试、肠动力测量和腹壁退缩反射评分评估 IBS 样症状。使用氟金逆行追踪和免疫组织化学技术研究了 ACC 产生γ-氨基丁酸（GABAergic）神经元向外侧下丘脑区域（LHA）的投射。化学遗传方法可选择性激活或抑制 ACC-LHA GABA 能通路。酶联免疫吸附测定（ELISA）和 Western blot 分析用于确定组胺、5-羟色胺（5-HT）和瞬时受体电位香草醛 4（TRPV4）的表达。我们的研究结果表明，CACS 诱导了小鼠的 IBS 样症状。LHA 中的 GABA 型 A 受体（GABAAR）在调节 IBS 样症状中发挥调节作用。ACC-LHA GABA 能神经元的化学遗传激活在正常小鼠中引起焦虑样行为、肠道功能障碍和内脏敏感性；然而，GABAAR 拮抗剂 Bicuculline 的给药有效地逆转了这些影响。相反，ACC-LHA GABA 能神经元的化学遗传抑制减轻了 IBS 样模型中小鼠的焦虑样行为、肠道功能障碍和内脏敏感性。这些结果强调了 ACC-LHA GABA 能通路在调节焦虑样行为、肠道动力改变和内脏敏感性中的关键作用，提示了一种缓解 IBS 样症状的潜在治疗策略。
