Journal of neuroscience methods · 2026
Optimization and evaluation of a chronic variable stress model of depressive-like behaviors in mice.
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Du Lei, Guo Yaru, Fang Suwen, Zuo Wenqiang, Xie Xiaoyan, Zeng Yuhan, Wang Qun, Kou Jiushe, Hou Wugang, Wang Minghui
Аннотация
BACKGROUND: Chronic variable stress (CVS) paradigms are essential for modeling depression- and anxiety-related disorders. However, methodological heterogeneity in stressor selection, duration, and scheduling frequently compromises reproducibility and behavioral consistency across studies.
NEW METHOD: We systematically optimized a CVS protocol in C57BL/6 J mice to reliably elicit robust depressive- and anxiety-like phenotypes while minimizing somatic injury and mortality. The protocol employed quasi-randomized application of restraint, social defeat, tail suspension, and foot shock, administered twice daily with a 2-hour inter-stressor interval over 12 days. Brief, non-injurious stressor variants were utilized to reduce physical harm without compromising efficacy.
RESULTS: A 12-day, but not 6-day, regimen induced stable and reproducible behavioral deficits. The 2-hour inter-stressor interval maximized behavioral impact. Utilizing induction stressors as post-stress behavioral assays introduced habituation confounds. The protocol demonstrated predictive validity, as chronic fluoxetine reversed depressive-like behaviors. While female mice exhibited immediate deficits comparable to males, longitudinal assessment revealed sexual dimorphism in recovery trajectories.
COMPARISON WITH EXISTING METHODS: Unlike conventional CVS protocols that vary widely in duration and stressor intensity, our optimized 12-day protocol achieves comparable behavioral outcomes within a shorter timeframe using brief, non-injurious stressor variants. Furthermore, we identified the confounding effect of stressor reuse in behavioral assessment, thereby enhancing interpretive clarity of stress-induced phenotypes.
CONCLUSIONS: This optimized CVS protocol provides a rapid, reproducible, and pharmacologically sensitive platform for investigating neural mechanisms underlying stress-related psychopathology, with applicability across both sexes and guidelines for avoiding common methodological pitfalls.
NEW METHOD: We systematically optimized a CVS protocol in C57BL/6 J mice to reliably elicit robust depressive- and anxiety-like phenotypes while minimizing somatic injury and mortality. The protocol employed quasi-randomized application of restraint, social defeat, tail suspension, and foot shock, administered twice daily with a 2-hour inter-stressor interval over 12 days. Brief, non-injurious stressor variants were utilized to reduce physical harm without compromising efficacy.
RESULTS: A 12-day, but not 6-day, regimen induced stable and reproducible behavioral deficits. The 2-hour inter-stressor interval maximized behavioral impact. Utilizing induction stressors as post-stress behavioral assays introduced habituation confounds. The protocol demonstrated predictive validity, as chronic fluoxetine reversed depressive-like behaviors. While female mice exhibited immediate deficits comparable to males, longitudinal assessment revealed sexual dimorphism in recovery trajectories.
COMPARISON WITH EXISTING METHODS: Unlike conventional CVS protocols that vary widely in duration and stressor intensity, our optimized 12-day protocol achieves comparable behavioral outcomes within a shorter timeframe using brief, non-injurious stressor variants. Furthermore, we identified the confounding effect of stressor reuse in behavioral assessment, thereby enhancing interpretive clarity of stress-induced phenotypes.
CONCLUSIONS: This optimized CVS protocol provides a rapid, reproducible, and pharmacologically sensitive platform for investigating neural mechanisms underlying stress-related psychopathology, with applicability across both sexes and guidelines for avoiding common methodological pitfalls.