CUMS induces depressive-like behaviors and cognition impairment by activating the ERS-NLRP3 signaling pathway in mice

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. •CUMS may lead to depressive behavior and cognitive dysfunction in mice by activating the ERS-NLRP3 signaling pathway.