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

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.