Abstract
Chronic stress can impact brain function through various mechanisms, contributing to the development of anxiety disorders. Chronic unpredictable mild stress (CUMS) is a well-established model for studying the effects of chronic stress. This study assessed the impacts of different durations of CUMS on anxiety-like behavior, inflammation, and tryptophan metabolism in female C57BL/6N mice. The results revealed significant behavioral changes after 2-4 weeks of CUMS. Specifically, the open arms ratio and open arms time ratio in the elevated plus maze (EPM) decreased, the latency to feed in the novelty-suppressed feeding test (NSFT) was prolonged, and the number of transitions in the light/dark box (LDB) was decreased. After 1 week of CUMS, the levels of some pro-inflammatory cytokines (such as IL-1β and iNOS) and anti-inflammatory cytokines (including IL-10) began to rise. After 2 weeks of CUMS, most pro-inflammatory cytokines (IL-1β, IL-6, CD86, iNOS) and the anti-inflammatory cytokines TGF-β and CD11b showed an increase, while some anti-inflammatory cytokines (Arg-1, IL-10) began to decrease. After 3 weeks of stress, the pro-inflammatory cytokine TNF-α also significantly increased, while the anti-inflammatory cytokine TGF-β began to decline. By 4 weeks of CUMS, the anti-inflammatory cytokine CD11b also started to decrease. Regarding tryptophan metabolism, after 3-4 weeks of CUMS, serotonin (5-HT) levels in the hippocampus of the mice began to decrease. Additionally, the kynurenine pathway in tryptophan metabolism shifted more towards the KYN-QA branch, resulting in the reduction in the neuroprotective substance kynurenic acid (KYNA), while neurotoxic substances such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) accumulated. In summary, female C57BL/6N mice exhibit anxiety-like behavior after 2 weeks of CUMS, accompanied by inflammatory responses. After 3-4 weeks of CUMS, anxiety-like behavior persists, with exacerbated inflammatory responses and disturbances in tryptophan metabolism.