Sex-Dependent Effects of Juvenile and Adult Stress on LPA1 Receptor Expression and Depression-Like Behaviors in Mice

Abstract

Juvenile stress impacts brain development and increases the risk of stress-induced depression, often through inflammation-related mechanisms. Despite known sex differences, research remains scarce. This study examined how stress at different developmental stages affects depression-like behaviors and lysophosphatidic acid receptor 1 (LPA1 receptor) expression in male and female C57BL/6J mice (N=48, 24 males, 24 females). Given the limited efficacy of antidepressants, alternative mechanisms such as inflammation and the LPA1 receptor signaling are gaining attention. Mice were divided into control (C), juvenile stress (JE), adult stress (AE), and combined juvenile-adult stress (DE) groups for each sex. Stress was induced through unpredictable mild stressors. Behavioral assessments included the Open Field Test (OFT) for anxiety-like behavior and locomotor activity and the Tail Suspension Test (TST) for depression-like behavior. Western blot analyses measured the LPA1 receptor expression in brain tissue. Results showed that stress increased LPA1 receptor expression, particularly when stress occurred during the juvenile period, with a stronger effect in females. Pearson correlation analysis revealed a significant positive correlation between LPA1 receptor expression and immobility time in the TST in males (r=0.485, p<0.05), suggesting a link between increased LPA1 receptor levels and depressive-like behavior. No significant correlations were found between LPA1 receptor expression and behavior in females. These findings suggest that juvenile stress upregulates LPA1 receptor, with sex-dependent differences. The correlation with depressive-like behavior in males highlights a potential role for LPA1 receptor as a biomarker for stress-induced depression, warranting further investigation into its function in sex-specific stress responses.