Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ΔFosB

Abstract

Elucidating mechanisms by which physical exercise promotes resilience, the brain's ability to cope with prolonged stress exposure while maintaining normal psychological functioning, is a major research challenge given the high prevalence of stress-related mental disorders, including major depressive disorder. Chronic voluntary wheel running (VWR), a rodent model that mimics aspects of human physical exercise, induces the transcription factor ΔFosB in the nucleus accumbens (NAc), a key reward-related brain area. ΔFosB expression in NAc modulates stress susceptibility. Here, we explored whether VWR induction of NAc ΔFosB promotes resilience to chronic social defeat stress (CSDS). Male young-adult C57BL/6J mice were single housed for up to 21 d with or without running wheels and then subjected to 10 d of CSDS. Stress-exposed sedentary mice developed a depressive-like state, characterized by anhedonia and social avoidance, whereas stress-exposed mice that had been wheel running showed resilience. Functional inhibition of NAc ΔFosB during VWR, by viral-mediated overexpression of a transcriptionally inactive JunD mutant, reinstated susceptibility to CSDS. Within the NAc, VWR induction of ΔFosB was CREB-dependent, associated with altered dendritic morphology, and medium spiny neuron (MSN) subtype specific in the NAc core and shell subregions. Finally, when mice performed VWR following the onset of CSDS-induced social avoidance, VWR normalized such behavior. These data indicate that VWR promoted resilience to CSDS, and suggest that sustained induction of ΔFosB in the NAc underlies, at least in part, the stress resilience mediated by VWR. These findings provide a potential framework for the development of treatments for stress-associated mental illnesses based on physical exercise.

The role of nucleus accumbens CREB attenuation in rescuing low voluntary running behavior in female rats

“…ΔFosB (Mul et al, 2018). The findings presented herein support that low physical activity motivation may have a basis in elevated…”

Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases

“…Chronic exercise induces antidepressant-like behavior in mice subjected to learned helplessness, forced swim, and tail suspension tests [16]. Moreover, voluntary exercise promotes resilience to chronic social defeat stress (CSDS) by inducing changes in gene expression in the nucleus accumbens [15]. These results in animals have been substantiated in human studies [17].…”

“…Exercise has many positive effects on brain physiology [11,12]. It rescues many features of neurodegenerative disorders [13] and is linked to improved mental health [14,15]. Chronic exercise induces antidepressant-like behavior in mice subjected to learned helplessness, forced swim, and tail suspension tests [16].…”

Chronic environmental or genetic elevation of galanin in noradrenergic neurons confers stress resilience in mice

“…Clinical studies have consistently linked physical exercise to improvements in a wide array of neuropsychiatric disorders (Herring et al, 2010;Cooney et al, 2013;Ashdown-Franks et al, 2020). Individuals who regularly exercise are less likely to experience stress-related neuropsychiatric disorders, such as depression, anxiety, and post-traumatic stress disorder (Whitworth and Ciccolo, 2016;Chekroud et al, 2018;Harvey et al, 2018), and chronic voluntary wheel running increases resilience to various stressors in rodents (Sciolino et al, 2012;Kingston et al, 2018;Mul et al, 2018;Tanner et al, 2019). A multitude of biological changes occur as a result of chronically increased physical activity which may or may not be causally linked to alterations in stress resilience and mood; however, a promising candidate for mediating these beneficial effects is the neuropeptide galanin.…”