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

Chronic stress changes behavior in both people and animals. By testing different chronic restraint stress (CRS) protocols in male mice, researchers identified that short, intense stress (6 hours/day for 3 days) caused persistent avoidance and repetitive behaviors, while longer, milder stress (2 hours/day for 10–14 days) progressively reduced reward-seeking and coping behaviors. A 10-day CRS protocol marked a threshold for reward-seeking deficits and served as a model combining avoidance and reward-processing impairments. The antidepressant ketamine reversed reward-seeking and coping deficits, while paroxetine alleviated both repetitive/avoidance behaviors and coping/reward-seeking deficits. These findings support CRS as a valid male mouse model of stress-related neuropsychiatric disorders.

Study at a glance

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.