Voluntary exercise and depression-like behavior in rodents: are we running in the right direction?

Abstract

Acute or chronic exposure to stress can increase the risk to develop major depressive disorder, a severe, recurrent and common psychiatric condition. Depression places an enormous social and financial burden on modern society. Although many depressed patients are treated with antidepressants, their efficacy is only modest, underscoring the necessity to develop clinically effective pharmaceutical or behavioral treatments. Exercise training produces beneficial effects on stress-related mental disorders, indicative of clinical potential. The pro-resilient and antidepressant effects of exercise training have been documented for several decades. Nonetheless, the underlying molecular mechanisms and the brain circuitries involved remain poorly understood. Preclinical investigations using voluntary wheel running, a frequently used rodent model that mimics aspects of human exercise training, have started to shed light on the molecular adaptations, signaling pathways and brain nuclei underlying the beneficial effects of exercise training on stress-related behavior. In this review, I highlight several neurotransmitter systems that are putative mediators of the beneficial effects of exercise training on mental health, and review recent rodent studies that utilized voluntary wheel running to promote our understanding of exercise training-induced central adaptations. Advancements in our mechanistic understanding of how exercise training induces beneficial neuronal adaptations will provide a framework for the development of new strategies to treat stress-associated mental illnesses.

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

“…The VWR induction pattern of NAc ΔFosB observed in this study differs from the induction pattern observed after 28 d of juvenile environmental enrichment or 10 d of a 10% sugar dilution, naturally rewarding conditions that both show equal induction of ΔFosB in D1-and D2-MSNs in the NAc subregions [18]. It should, however, be noted that VWR transiently increases plasma corticosterone levels during the first 3 weeks of VWR and is associated with profound adaptations along the hypothalamic-pituitary-adrenal axis [22,49]. Thus, VWR should be considered a physiological stressor, especially during the initial weeks of VWR.…”

“…Although both the NAc, as well as ΔFosB have been heavily implicated in stress responses and mood disorders [7], our study is the first attempt to directly link NAc ΔFosB to the pro-resilient effects of VWR. Mechanistic studies in rodents, investigating the antidepressant potential of VWR, have previously indicated the involvement of several brain nuclei, most notably the hippocampus and the basolateral amygdala [22,[44][45][46]. Our findings now add the NAc to the brain circuitry involved in the beneficial effects of VWR on stress-related behavior.…”

“…Further work is needed to identify the role of the two MSN subtypes, the different striatal subregions, as well as temporal NAc neurotransmitter dynamics in mediating the beneficial effects of VWR on stress-related behavior. Potential neurotransmitters involved are brain-derived neurotrophic factor, dopamine, and lactate, as all of these factors are centrally modulated by physical exercise and involved in the modulation of depressive-like behavior [22,[51][52][53][54][55].…”

“…Physical exercise has beneficial effects on stress-related mental disorders [19][20][21][22][23][24][25][26], indicating tremendous and low-cost clinical potential. Despite these profound beneficial effects, the underlying neurobiology remains unclear [22]. Voluntary wheel running (VWR), a rodent model that mimics aspects of human physical exercise training, can be used for the preclinical etiological and mechanistic examination of resilience conferred by this behavioral intervention [22].…”

“…Despite these profound beneficial effects, the underlying neurobiology remains unclear [22]. Voluntary wheel running (VWR), a rodent model that mimics aspects of human physical exercise training, can be used for the preclinical etiological and mechanistic examination of resilience conferred by this behavioral intervention [22]. In rats and mice, 4-6 weeks of VWR increase ΔFosB expression in the NAc [27][28][29][30].…”