Differential physiological, behavioral, and medial prefrontal cortex transcriptomic responses to chronic restraint stress between BALB/c and C57BL/6J mice

Multiple factors have been implicated in the pathology of depression and stress resilience. Nevertheless, the molecular mechanisms underlying stress responses are not yet fully elucidated. Chronic restraint stress (CRS) is widely used as a rodent model of stress-induced depressive-like phenotypes. A previous study has demonstrated strain-dependent differences in hair corticosterone and testosterone levels, as well as behavioral responses to CRS, between C57BL/6J and BALB/c mice. However, the mechanisms underlying these differences remain unclear. In this study, male C57BL/6J and BALB/c mice were subjected to CRS for 6 hours per day for 21 consecutive days. Following CRS, behavioral responses were evaluated, and serum corticosterone levels along with oxidative stress-related markers were quantitatively analyzed using LC-MS/MS. In addition, comprehensive gene expression profiling of the medial prefrontal cortex was performed using next-generation sequencing, followed by Gene Ontology (GO) analysis. Control mice without CRS exposure in both strains showed increased body weight. BALB/c mice exhibited significant weight loss and elevated serum corticosterone levels, whereas C57BL/6J mice showed no change in body weight after 21 days and no significant changes in serum corticosterone levels. Oxidative stress analysis revealed a decrease in biological antioxidant potential (BAP) and an increase in derivatives of reactive oxygen metabolites (d-ROMs) in BALB/c mice, whereas C57BL/6J mice showed only an increase in d-ROMs. Behavioral analyses demonstrated that BALB/c mice exhibited increased immobility in the tail suspension test and forced swim test, as well as reduced sucrose preference following CRS. In contrast, C57BL/6J mice showed increased immobility only in the forced swim test. IPA canonical pathway analysis revealed that pathways associated with immune signaling, tissue remodeling, and metabolic processes were elevated in C57BL/6J mice compared with BALB/c mice under basal conditions. Under CRS exposure, pathways related to cell cycle progression, mitotic regulation, DNA damage response, cytoskeletal dynamics, and apoptosis were differentially regulated between the two strains. These results demonstrate marked strain-dependent differences in susceptibility and resilience to CRS. Distinct molecular programs operating at baseline and in response to stress may underlie these differences.