Sex specific metabolic predictors of stress responses in adult C57Bl/6 mice

Major depressive disorder results from complex genetic and environmental interactions, with chronic stress as a key precipitating factor. Yet, individual variability in stress resilience remains poorly understood. We combined longitudinal behavioral profiling with pre-stress whole-blood metabolomics in male and female C57BL/6 mice exposed to unpredictable chronic mild stress. Behavioral trajectories revealed sex-dependent dynamics: males displayed coherent, temporally stable stress responses, whereas females exhibited modular and variable behavioral patterns. Baseline metabolomic profiles may be associated to vulnerability in a sex-specific manner. In males, our data suggest that elevated 3-methyl-2-oxovaleric acid, valeric acid, valine, serine, and erythrose correlated with vulnerability; in females, succinic acid, serine, thymidine, and erythrose discriminated resilient from vulnerable subjects. Integrating multiple metabolic variables improved correlation with behavioural classification. These findings suggest pre-existing, sex-specific metabolic states which are associated with stress susceptibility, highlighting peripheral metabolism as a potential biomarker of either resilience or vulnerability to depression.