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. Hence, approaches for exercise treatment as an antidepressant and anxiolytic intervention must consider individual variability. Examining individual adaptation to exercise provides insights into the biology of such variations. We investigated the efficacy of voluntary wheel running (VWR) exercise as a disease-modifying treatment for stress-susceptible (SS) mice subjected to chronic restraint stress. A multidimensional behavior analysis revealed significant variability in VWR efficacy among individuals; while some mice showed substantial behavior phenotypic improvements (SES), others displayed limited/no benefits (SER). A transcriptomic profiling of the ventral hippocampus, a brain region critical to emotional regulation, revealed molecular signatures that promote adaptive changes by restoring cellular repair, energy availability, and synaptic plasticity in SS mice. SER mice exhibited limited behavior resilience and distinct transcriptomic profiles enriched in structural adaptation without functional resilience and glial cell differentiation marked by astrocyte activation or differentiation. These findings suggest that while VWR can mitigates multiple behavior symptoms in stress-susceptible mice, its effectiveness is modulated by distinct biological mechanisms. We highlight the importance of a multivariate framework for behavior assessment and genetic underpinnings, clarifying the variability in responses to stress and exercise's therapeutic efficacy in stress-related disorders.