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.
Project description:Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome.Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats.Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ?FosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners.Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.
Project description:Exercise alone is often ineffective for treating obesity despite the associated increase in metabolic requirements. Decreased nonexercise physical activity has been implicated in this resistance to weight loss, but the mechanisms responsible are unclear. We quantified the metabolic cost of nonexercise activity, or "off-wheel" activity (OWA), and voluntary wheel running (VWR) and examined whether changes in OWA during VWR altered energy balance in chow-fed C57BL/6J mice (n = 12). Energy expenditure (EE), energy intake, and behavior (VWR and OWA) were continuously monitored for 4 days with locked running wheels followed by 9 days with unlocked running wheels. Unlocking the running wheels increased EE as a function of VWR distance. The metabolic cost of exercise (kcal/m traveled) decreased with increasing VWR speed. Unlocking the wheel led to a negative energy balance but also decreased OWA, which was predicted to mitigate the expected change in energy balance by ∼45%. A novel behavioral circuit involved repeated bouts of VWR, and roaming was discovered and represented novel predictors of VWR behavior. The integrated analysis described here reveals that the weight loss effects of voluntary exercise can be countered by a reduction in nonexercise activity.
Project description:Chronic social defeat stress (CSDS) is a well-established rodent model of depression that induces persistent social avoidance. CSDS triggers molecular adaptations throughout the mesocorticolimbic reward circuit, including changes in the activity of dopamine neurons in the ventral tegmental area (VTA), that may also influence drug reward. One limitation of traditional, physical CSDS (PS) is that injury complicates the study of opiate drugs like morphine. Thus, we sought to characterize a variation of CSDS, termed emotional CSDS (ES), that eliminates this confound. We assessed the effect of PS and ES on mesocorticolimbic circuit activation, VTA gene expression, and morphine intake. We found that PS and ES similarly induced ΔFosB in the hippocampus, but only PS significantly increased ΔFosB expression in the prefrontal cortex and striatum. In contrast, cFos expression was similarly reduced by both PS and ES. Interestingly, we found that PS and ES similarly increased voluntary morphine consumption immediately following stress, despite differences in the magnitude of the depressive phenotype and striatal ΔFosB expression at this time point. Combined, these data suggest that both stress paradigms may be useful for investigation of stress-induced changes in drug behavior.
Project description:Exercise improves many aspects of human health, yet many people remain inactive even when exercise is prescribed. We previously created a backcross (BC) between mice selectively bred for high levels of voluntary wheel running (VWR) and fixed for "mini muscle" (MM), a recessive mutation causing approximately 50% reduction in triceps surae mass. We previously showed that BC mice having the MM trait ran faster and further than mice without MM and that MM maps to chromosome 11. Here, we genotyped the BC with genome-wide single nucleotide polymorphisms to identify quantitative trait loci (QTL) controlling voluntary exercise and tissue and body mass traits and to determine whether these QTL interact with the MM locus or with sex. We detected 3 VWR QTL, representing the first voluntary exercise QTL mapped using this high running selection line, and 5 tissue mass QTL. Several interactions between trait QTL and the MM locus as well as sex were also identified. These results begin to explain the genetic architecture of VWR and further support MM as a locus having major effects, including its main effects on the muscle phenotype, its pleiotropic effects on wheel running and tissue mass traits, and through its interactions with other QTL and with sex.
Project description:Reproducible animal models to recapitulate the pathophysiology of non-alcoholic fatty liver disease (NAFLD) are urgently required to improve the understanding of the mechanisms of liver injury and to explore novel therapeutic options. Current guidelines recommend life-style interventions as first-line therapy for NAFLD and these types of intervention are considered standard-of-care. The current study establishes a reproducible mouse model of a life-style intervention in NAFLD using voluntary wheel running (VWR). Male C57BL/6J mice were fed a high-fat, high-carbohydrate diet (HFD) to induce NAFLD or a corresponding control diet for 12 weeks. Starting at week 9 of the obesogenic NAFLD diet, mice were randomized to either free access to a running wheel or being single caged resembling a sedentary (SED) life-style. VWR induced a transient weight reduction in HFD-fed mice up until week 10. In contrast to the SED mice, VWR mice exhibited normal ALT at the end of the intervention, while the metabolic alterations including elevated fasting glucose, insulin, triglyceride, and total cholesterol levels remained almost unchanged. Additionally, VWR prevented HFD-induced hepatic steatosis by alterations in key liver metabolic processes including the induction of fatty acid β-oxidation and lipogenesis inhibition following increased AMP-activated protein kinase (AMPK)-α activity. Phosphorylation of the serine kinase Akt in hepatic tissue was enhanced following VWR. Furthermore, VWR mice were protected from HFD-induced expression of pro-inflammatory cytokines, chemokines and liver macrophage infiltration. The SED/HFD group exhibited increasing activity of hepatic nuclear factor (NF)-κB p65, which was absent following exercise in the VWR/HFD group. In summary, in an obesogenic mouse model of NAFLD physical exercise improves fatty acid and glucose homeostasis and protects from macrophage-associated hepatic inflammation.
Project description:Exercise training (ET) is recommended for lower extremity artery disease (LEAD) management. However, there is still little information on the hemodynamic and metabolic adaptations by skeletal muscle with ET. We examined whether hindlimb perfusion/vascularization and muscle energy metabolism are altered differently by three types of aerobic ET. ApoE-/- mice with LEAD were assigned to one of four groups for 4 weeks: sedentary (SED), forced treadmill running (FTR), voluntary wheel running (VWR), or forced swimming (FS). Voluntary exercise capacity was improved and equally as efficient with FTR and VWR, but remained unchanged with FS. Neither ischemic hindlimb perfusion and oxygenation, nor arteriolar density and mRNA expression of arteriogenic-related genes differed between groups. 18FDG PET imaging revealed no difference in the steady-state levels of phosphorylated 18FDG in ischemic and non-ischemic hindlimb muscle between groups, nor was glycogen content or mRNA and protein expression of glucose metabolism-related genes in ischemic muscle modified. mRNA (but not protein) expression of lipid metabolism-related genes was upregulated across all exercise groups, particularly by non-ischemic muscle. Markers of mitochondrial content (mitochondrial DNA content and citrate synthase activity) as well as mRNA expression of mitochondrial biogenesis-related genes in muscle were not increased with ET. Contrary to FTR and VWR, swimming was ineffective in improving voluntary exercise capacity. The underlying hindlimb hemodynamics or muscle energy metabolism are unable to explain the benefits of running exercise.
Project description:Myelin of the central nervous system exhibits strong plasticity, and skill learning exercise promotes oligodendrogenesis and adaptive myelination. Increasing evidence shows that brain structures and functions are affected by physical activity. However, the impact of voluntary physical activity on central myelination and its underlying mechanism remains unclear. The present study aimed to investigate the effect of voluntary wheel running (VWR) on central oligodendrogenesis and adaptive myelination in mice. Adult C57BL/6 J mice were placed in running wheels and allowed for voluntary running 2 weeks. Myelin levels in the central nervous system were detected using western blotting, qRT-PCR, immunohistochemical staining, and electron microscopy. Oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs) were detected using immunohistochemical staining and 5-bromo-2-deoxyuridine (BrdU) assays. Motor abilities of the animals were examined using open-field, rotarod running, and beam-walking behavioral paradigms. Vital molecules of Wnt signaling were detected, and the involvement of such molecules was verified using in vitro culture of OPCs. Our results showed that VWR significantly enhanced the myelination in the motor cortex. VWR promoted the proliferation and differentiation of OPCs, and the maturation of OLs. The VWR-regulated myelination was associated with the improved motor skill and decreased mRNA level of Wnt3a/9a, whereas stimulation of Wnt signaling pathway with Wnt3a or Wnt9a suppressed OPCs proliferation and differentiation in vitro. The present study demonstrated that physical activity is highly efficient at promoting myelination in the motor cortex, by enhancing the proliferation of OPCs and accelerating the generation of myelin, providing a step forward in understanding the beneficial effects of physical activity on central myelination and its underlying mechanism.
Project description:The purpose of this investigation was to compare the antitumorigenic effects of the natural product Nexrutine to voluntary wheel running (VWR) in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Forty-five, 10-week old TRAMP mice were randomized to either receive free access to the running wheel, Nexrutine pelleted into chow at 600 mg/kg or no treatment control. Mice were serially sacrificed at weeks 4, 8,12 and 20 weeks. Palpable tumors, body weight, food consumption and running wheel activity were monitored weekly. At necropsy, tumors and serum were harvested and stored for analysis. Serum was used to quantify circulating cytokines in 4 and 20 week time points. Nexrutine supplementation led to a 66% protection against high grade tumors. Exercise resulted in a 60% protection against high grade tumors. Both interventions reduced concentrations of IL-1?. Exercise also significantly lowered concentrations of eotaxin, IL-5, IL-12(p40) and VEGF. While there were no significant differences at baseline, exercise mice had significantly lower IL-5 and VEGF compared to control at the 20 week time point. Nexrutine also significantly reduced circulating IL-9 concentrations. No significant differences were observed when compared to the control group. Immunohistochemistry of tumor sections showed significantly lower expression of pAkt in Nexrutine fed mice with no visible differences for NF?B. In conclusion, both Nexrutine and exercise suppressed tumor growth. Though similar outcomes were seen in this comparative effectiveness study, the mechanisms by which exercise and Nexrutine exert this benefit may focus on different pathways.
Project description:Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility.SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The reduction of Slc6a15 occurs selectively in the NAc D2-neurons. Genetic reduction of Slc6a15 induces susceptibility to a subthreshold stress, while genetic overexpression in D2-neurons prevents social avoidance after chronic social defeat stress.
Project description:BACKGROUND:Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical, as increased DA signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress is unknown. METHODS:We used CSDS with repeated optogenetic activation and pharmacologic manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. We measured BDNF protein expression and DA release in this model. RESULTS:Pharmacologic blockade of BDNF-tyrosine receptor kinase B (TrkB) signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were blocked as well by local knockdown of BDNF in VTA. CONCLUSIONS:These findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS and they establish BDNF-TrkB signaling as a pathologic mechanism during periods of chronic stress.