Differential behavior responses and genetic alteration underpinning exercise effectiveness in stress-susceptible mice

Stress susceptibility varies across individuals, influenced by genetic, molecular, and environmental factors. Considering the individual differences in response to stress, however, approaches for exercise treatment as an antidepressant and anxiolytic intervention are also not exempt from variability in effectiveness among individuals, and insight into the biology of those variations can be gained by examining the individual adaptation to exercise. Here, we investigated the efficacy of voluntary wheel running (VWR) exercise as a disease-modifying intervention for stress-susceptible (SS) mice subjected to chronic restraint stress (CRST). Multidimensional behavior analysis revealed significant variability in the efficacy of VWR among individuals, with some mice showing substantial behavior phenotypic improvements (e.g., behavior despair, anhedonia, aversion to open space, and compulsive behavior) (SES) while others displayed limited or no benefits (SER). Furthermore, transcriptomic analysis of the ventral hippocampus (vHPC), a critical brain region involved in emotional regulation and processing, demonstrated that SES mice exhibited molecular signatures promoting adaptive changes by restoring cellular repair, energy availability, and synaptic plasticity observed in SS mice, whereas SER mice exhibited limited behavior resilience and distinct transcriptomic profiles enriched in structural adaptation without functional resilience and glia cell differentiation, particularly marked by astrocyte activation or differentiation. These findings suggest that while VWR can alleviate multiple concurrent behavior symptoms in stress-susceptible mice; however, its efficacy is influenced by distinct biological processes. Collectively, our work highlights the importance of a multivariate framework for behavior assessment and genetic underpinnings to better understand the often-overlooked variability in response to stress and the therapeutic efficacy of exercise in stress-related disorders.