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Standardized chronic restraint stress protocols reveal dynamic evolution of behavioral adaptations in male mice: implications for translational neuroscience

Molecular Psychiatry (2026)Cite this article

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Abstract

Chronic stress induces neurobiological adaptations that manifest as altered behavioral patterns in both humans and animal models. To enhance the translational value of preclinical research, we systematically evaluated chronic restraint stress (CRS) protocols in mice through longitudinal tracking of behavioral outcomes across multiple validated assays. By comparing various CRS parameters, we identified specific protocols that elicited persistent behavioral adaptations across distinct measurements in male mice. Short-duration, high-intensity CRS (6 h/day for 3 days) induced persistent phenotypes of avoidance-related and repetitive behaviors in multiple assays of approach-avoidance conflict, whereas prolonged CRS exposure (2 h/day for 10-14 days) progressively disrupted reward-seeking and behavioral coping phenotypes. When prolonging CRS exposure, we observed a behavioral transition from the initial phenotypes of avoidance/repetitive behavior to the later deficits of reward seeking/behavioral coping, accompanied by a progressive dissociation between these behavioral domains. The 10-day CRS protocol represents a critical threshold for inducing reward-seeking deficit, as well as a comorbid model of avoidance-related response and reward-processing impairment. Rapid antidepressant ketamine reversed impairments of reward seeking and behavioral coping, and typical antidepressant/anxiolytic paroxetine alleviated both repetitive/avoidance-related behaviors and coping/reward-seeking deficits. These findings demonstrated the face, construct, and predictive validity of CRS as a male mouse model of stress-related neuropsychiatric disorders. Leveraging comprehensive behavioral characterization across diverse CRS protocols, our study provides standardized protocols for recapitulating clinically-relevant behavioral adaptations to chronic stress.

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Fig. 1: Increasing the intensity of single restraint session is sufficient to induce persistent avoidance-related and repetitive behaviors across distinct assays.
Fig. 2: Increasing the days of exposure to 2-hour restraint fails to induce consistent avoidance-related or repetitive behaviors across distinct assays.
Fig. 3: Increasing the days of exposure to 2-hour restraint progressively disrupts behavioral coping and reward seeking.
Fig. 4: Increasing the days of exposure to 6-hour restraint induces persistent deficits of coping/reward-seeking rather than phenotypes of avoidance/repetitive behaviors, with distinct whole-brain activation pattern compared with 3-day restraint.
Fig. 5: Correlations between avoidance-related/repetitive behaviors and coping/reward-seeking deficits turn from positive to negative after increasing the days of CRS exposure.
Fig. 6: Predictive validity of CRS as a model of avoidance/repetition behavioral domains in anxiety, and coping/reward-seeking behavioral domains in depression.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

We thank Dr. Peng Shi for technical support. This work was supported by grants from the STI2030-Major projects (2022ZD0211700 to Y. Cui); the National Natural Science Foundation of China (32400830 to Y. Dong).

Author information

Author notes

  1. These authors contributed equally: Zijian Lv, Qifeng Xie.

Authors and Affiliations

  1. Department of Psychiatry of Sir Run Run Shaw Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Zijian Lv, Qifeng Xie, Kecan Li, Zhouhong Fan, Yihui Cui & Yiyan Dong

  2. State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650201, China

    Zijian Lv, Qifeng Xie, Kecan Li, Zhouhong Fan, Yihui Cui & Yiyan Dong

  3. Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650201, China

    Zijian Lv, Qifeng Xie, Kecan Li, Zhouhong Fan, Yihui Cui & Yiyan Dong

  4. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650201, China

    Zijian Lv, Qifeng Xie, Kecan Li, Zhouhong Fan, Yihui Cui & Yiyan Dong

Authors
  1. Zijian Lv
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  2. Qifeng Xie
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  3. Kecan Li
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  4. Zhouhong Fan
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  5. Yihui Cui
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  6. Yiyan Dong
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Contributions

Conceptualization, Funding acquisition, Supervision: Y Dong, Y Cui; Data curation: Z Lv, Q Xie, K Li, Z Fan; Formal analysis: Z Lv, Q Xie, Y Dong; Visualization: Z Lv, Q Xie; Investigation: Z Lv, Q Xie, K Li, Z Fan, Y Cui, Y Dong; Methodology: Z Lv, Q Xie, Y Dong, Y Cui; Writing – original draft: Y Dong, Y Cui, Z Lv; Writing – review and editing: Y Dong, Y Cui, Z Lv, Q Xie, K Li.

Corresponding authors

Correspondence to Yihui Cui or Yiyan Dong.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All methods performed in this study were conducted in accordance with the relevant guidelines and regulations. Ethical approval was obtained from the Animal Care and Use Committee of the animal facility at Zhejiang University (reference number ZJU20220377 and ZJU20230320).

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Lv, Z., Xie, Q., Li, K. et al. Standardized chronic restraint stress protocols reveal dynamic evolution of behavioral adaptations in male mice: implications for translational neuroscience. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03569-5

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