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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE283250 | GEO | 2024/12/04

REPOSITORIES: GEO

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Project description:Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions and psychosocial stress, and how these determinants of stress response interact. Animals were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interaction and anxiety-like behavior. Adolescent enrichment caused bLR rats to display less social avoidance, more social interaction, less submission during defeat, and resilience to the prolonged effects of social stress on corticosterone, while enrichment caused bHR animals to show greater aggression during defeat and during a neutral social encounter, and decreased anxiety-like behavior. To gain insight into the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. These findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.

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

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