ArticleMolecular psychiatry2026
Standardized chronic restraint stress protocols reveal dynamic evolution of behavioral adaptations in male mice: implications for translational neuroscience.
Article in Molecular psychiatry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Reframing stress adaptation as a dynamic system failure along a threat-response continuum: towards a phase-specific, mechanism-driven framework.Molecular psychiatry · 2026Article
- Activity of VMS-projecting mPFC neurons encodes individual vulnerability to chronic restraint stress in male mice.Neurobiology of stress · 2026Article
- Targeting the posterior thalamic hub: hemispheric-specific encoding of pain-depression comorbidity after hemorrhagic stroke.BMC medicine · 2026Article
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Authors and funding
6 authors.
Funding
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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Registered trials
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