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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE330744 | GEO | 2026/07/15

REPOSITORIES: GEO

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Project description:This study aimed to investigate the anxiolytic effects of GABA administration and its underlying molecular mechanisms in a chronic restraint stress (CRS)-induced anxiety model in C57BL/6J mice. CRS mice were established by placing the animals in well-ventilated 50 ml centrifuge tubes for 2 hours daily over 14 consecutive days, while control mice were housed under standard conditions. Behavioral assessments, including the elevated plus maze (EPM) test and open field test (OFT), were performed on days 15 and 16, respectively. GABA was administered intragastrically at various doses throughout the experiment, and prefrontal cortex (PFC) and hippocampal tissues were harvested on day 17 for further proteomic and biochemical analyses. Behavioral results demonstrated that GABA treatment exerted dose-dependent anxiolytic effects, as evidenced by increased time and entries in the open arms in the EPM and increased time and distance spent in the center area in the OFT. Furthermore, GABA treatment significantly elevated reduced GABA levels in the PFC. To elucidate the molecular mechanisms of GABA’s anxiolytic effects, a 4D-label-free quantitative proteomics approach was employed. Principal component analysis (PCA) and differential protein analyses revealed that CRS induced substantial proteomic alterations in the hippocampus, while GABA treatment partially reversed these changes. Functional clustering (Mfuzz) and gene ontology (GO) enrichment analysis identified critical pathways involved in the “humoral immune response,” “complement activation,” and “acute inflammatory response.” Key proteins such as C3, Cfh, C4b, and Cfi were found to overlap across these pathways, highlighting their involvement in CRS-induced neuroimmune dysfunction and GABA-mediated rescue effects. This integrated analysis provides valuable insights into the behavioral and neuroimmune mechanisms through which GABA alleviates anxiety-like behaviors, shedding light on its potential as a therapeutic agent for stress-related disorders.

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

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