The First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Neurorestoratology, Weihui, Henan 453100, China; The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China.
School of Nursing, Xinxiang Medical University, Xinxiang, Henan 453002, China.
J Affect Disord. 2025 Jan 15;369:547-558. doi: 10.1016/j.jad.2024.10.001. Epub 2024 Oct 6.
Endoplasmic reticulum stress (ERS), as a primary defense mechanism against stress, is closely related to mental disorders, but its pathogenesis is still unclear. This research seeks to explore the influence of ERS-nucleotide-bound oligomerized domain-like receptor protein 3 (NLRP3) signaling on mice's depressive-like behaviors and cognitive impairment.
We carried out a study on 32 male C57BL/6J mice to investigate how chronic unpredictable mild stress (CUMS) can give rise to depressive-like behaviors and cognitive dysfunction, randomly dividing them into control, model, inhibitor, and agonist groups. We utilized ELISA to quantify dopamine (DA) and 5-hydroxytryptamine (5-HT) levels. Using Nissl and hematoxylin and eosin (H&E) staining, we assessed the number and morphology of hippocampal neurons and cells. Western blot and immunofluorescence staining detected the changes in ERS and inflammation-related pathways in the hippocampus.
CUMS could induce ERS and activate NLRP3 inflammasome, causing neuronal damage and histopathological changes, eventually leading to depressive-like behaviors and cognitive impairment in mice. The abnormal activation of NLRP3 inflammasome could be restored by ERS blocker 4-phenyl butyric acid (PBA), thus reducing neuronal damage, and ameliorating depressive-like behaviors and cognitive disorder in mice.
Our study demonstrates a previously unknown link between ERS and NLRP3 inflammasome in CUMS mice. The ERS-NLRP3 signaling pathway may be activated by CUMS, potentially resulting in mice exhibiting depressive-like behaviors and cognitive dysfunction. Theoretical foundations for elucidating the pathogenesis of depression, as well as its prevention and treatment, will be established through the results.
内质网应激（ERS）作为一种对抗应激的主要防御机制，与精神障碍密切相关，但其发病机制尚不清楚。本研究旨在探讨 ERS-核苷酸结合寡聚结构域样受体蛋白 3（NLRP3）信号对小鼠抑郁样行为和认知障碍的影响。
我们对 32 只雄性 C57BL/6J 小鼠进行了一项研究，以探讨慢性不可预测轻度应激（CUMS）如何引起抑郁样行为和认知功能障碍，将它们随机分为对照组、模型组、抑制剂组和激动剂组。我们利用 ELISA 定量检测多巴胺（DA）和 5-羟色胺（5-HT）水平。采用尼氏染色和苏木精-伊红（H&E）染色评估海马神经元和细胞的数量和形态。Western blot 和免疫荧光染色检测海马 ERS 和炎症相关通路的变化。
CUMS 可诱导 ERS 激活 NLRP3 炎性小体，导致神经元损伤和组织病理学改变，最终导致小鼠出现抑郁样行为和认知障碍。ERS 抑制剂 4-苯基丁酸（PBA）可恢复 NLRP3 炎性小体的异常激活，减轻神经元损伤，改善小鼠的抑郁样行为和认知障碍。
本研究揭示了 CUMS 小鼠中 ERS 和 NLRP3 炎性小体之间以前未知的联系。CUMS 可能激活 ERS-NLRP3 信号通路，导致小鼠出现抑郁样行为和认知功能障碍。该研究结果为阐明抑郁症的发病机制以及预防和治疗提供了理论依据。
