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

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.

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Comparison of changes in electrical activity, in isolated and in vivo hearts, induced by voluntary exercise in female rats

10.1101/2020.11.16.385021 ◽

2020 ◽

Author(s):

Rachel Stones ◽

Mark Drinkhill ◽

Ed White

Keyword(s):

Exercise Training ◽

Electrical Activity ◽

Wheel Running ◽

Left Ventricular ◽

Voluntary Exercise ◽

Female Rats ◽

Heart Weight ◽

Voluntary Wheel Running ◽

Voluntary Wheel

AbstractRegular mild exercise is recommended to the general population as beneficial to health. Regular exercise typically leads to structural and electrical remodelling of the heart but in human studies it is difficult to relate the extrinsic and intrinsic influences on intact hearts to changes seen at the single cell level. In this study we wished to test whether changes in electrical activity in intact hearts, in response to voluntary wheel running exercise training, were consistent with our previous observations in single cardiac myocytes and whether these changes resulted in altered susceptibility to arrhythmic stimuli.Female rats performed 5 weeks of voluntary wheel running. Implanted telemetry transmitters were used to measure electrocardiograms (ECGs) and determine heart rate variability (HRV) in conscious, unrestrained, trained (TRN) and sedentary (SED) animals. In isolated hearts, left ventricular epicardial monophasic action potentials (MAPs) were recorded and the responses to potentially arrhythmic interventions were assessed.Exercise training caused cardiac hypertrophy, as indexed by a significantly greater heart weight to body weight ratio. Consistent with previous measurements of action potential duration in single myocytes, MAPs were significantly longer at 50%, 75% and 90% repolarization. Arrhythmic susceptibility was not different between SED and TRN hearts. Trained animals displayed significantly altered HRV by week 5, in a manner consistent with reduced sympathetic tone, however resting ECG parameters, including those most associated with repolarisation duration, were unaltered. We conclude that intrinsic changes to cellular cardiac electrophysiology, induced by mild voluntary exercise, are not attenuated by the electronic loading that occurs in intact hearts. However, in vivo, extrinsic neuro-hormonal control of the heart may minimize the effects of intrinsic alterations in electrical activity.

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Novel quantitative phenotypes of exercise training in mouse models

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00694.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. R926-R934 ◽

Cited By ~ 104

Author(s):

J. P. De Bono ◽

D. Adlam ◽

D. J. Paterson ◽

K. M. Channon

Keyword(s):

Exercise Training ◽

Mouse Models ◽

Molecular Mechanisms ◽

Wheel Running ◽

Voluntary Exercise ◽

Maximum Speed ◽

Beneficial Effects ◽

Disease States ◽

Running System ◽

Exercise Activity

Regular physical exercise has beneficial effects in many human disease states, including cardiovascular diseases, cancer, and depression. Exercise training of genetically modified mouse models may provide insight into the molecular mechanisms that underlie the beneficial effects of exercise. Presently, there is relatively little understanding of the normal physiology of mouse exercise. In this paper, we describe a novel computerized voluntary wheel-running system capable of recording and analyzing individual wheel rotations. Using this system, we demonstrate that C57BL/6 mice run considerable distances during the night in short bouts and at a preferred speed: the cruising speed. We find that the vast majority of running occurs around this cruising speed, which is close to the maximum speed at which the animal can run but is significantly higher than the average speeds recorded by simple digital odometers. We describe how these parameters vary with exercise training and demonstrate marked sex differences in the patterns of voluntary exercise. The results of this study have important implications for the design and interpretation of both voluntary and forced exercise experiments in mouse models. The novel parameters described provide more physiological quantitative measures of voluntary exercise activity and training and will extend the physiological utility of exercise training as a phenotyping tool in genetic mouse models.

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Five months of voluntary wheel running downregulates skeletal muscle LINE-1 gene expression in rats

AJP Cell Physiology ◽

10.1152/ajpcell.00301.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1313-C1323 ◽

Cited By ~ 1

Author(s):

Matthew A. Romero ◽

Petey W. Mumford ◽

Paul A. Roberson ◽

Shelby C. Osburn ◽

Hailey A. Parry ◽

...

Keyword(s):

Skeletal Muscle ◽

Dna Methylation ◽

Exercise Training ◽

Mrna Expression ◽

Wheel Running ◽

Mobile Dna ◽

Voluntary Wheel Running ◽

L6 Myotubes ◽

Voluntary Wheel

Transposable elements (TEs) are mobile DNA and constitute approximately half of the human genome. LINE-1 (L1) is the only active autonomous TE in the mammalian genome and has been implicated in a number of diseases as well as aging. We have previously reported that skeletal muscle L1 expression is lower following acute and chronic exercise training in humans. Herein, we used a rodent model of voluntary wheel running to determine whether long-term exercise training affects markers of skeletal muscle L1 regulation. Selectively bred high-running female Wistar rats ( n = 11 per group) were either given access to a running wheel (EX) or not (SED) at 5 wk of age, and these conditions were maintained until 27 wk of age. Thereafter, mixed gastrocnemius tissue was harvested and analyzed for L1 mRNA expression and DNA content along with other L1 regulation markers. We observed significantly ( P < 0.05) lower L1 mRNA expression, higher L1 DNA methylation, and less L1 DNA in accessible chromatin regions in EX versus SED rats. We followed these experiments with 3-h in vitro drug treatments in L6 myotubes to mimic transient exercise-specific signaling events. The AMP-activated protein kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR; 4 mM) significantly decreased L1 mRNA expression in L6 myotubes. However, this effect was not facilitated through increased L1 DNA methylation. Collectively, these data suggest that long-term voluntary wheel running downregulates skeletal muscle L1 mRNA, and this may occur through chromatin modifications. Enhanced AMPK signaling with repetitive exercise bouts may also decrease L1 mRNA expression, although the mechanism of action remains unknown.

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Reduced metabolic disease risk profile by voluntary wheel running accompanying juvenile Western diet in rats bred for high and low voluntary exercise

Physiology & Behavior ◽

10.1016/j.physbeh.2015.09.004 ◽

2015 ◽

Vol 152 ◽

pp. 47-55 ◽

Cited By ~ 7

Author(s):

Gregory N. Ruegsegger ◽

Ryan G. Toedebusch ◽

Joshua F. Braselton ◽

Christian K. Roberts ◽

Frank W. Booth

Keyword(s):

Metabolic Disease ◽

Wheel Running ◽

Disease Risk ◽

Risk Profile ◽

Western Diet ◽

Voluntary Exercise ◽

Voluntary Wheel Running ◽

Metabolic Disease Risk ◽

Voluntary Wheel

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Abstract 1509: Exercise Training Started Before Myocardial Infarction Improves Survival but Aggravates Left Ventricular Dysfunction

Circulation ◽

10.1161/circ.116.suppl_16.ii_311-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Monique C de Waard ◽

Dirk J Duncker

Keyword(s):

Myocardial Infarction ◽

Exercise Training ◽

Wheel Running ◽

Left Ventricular ◽

Lv Function ◽

Cardiac Events ◽

Cross Sectional ◽

Voluntary Wheel Running ◽

Lv Dysfunction ◽

Voluntary Wheel

Introduction: Regular physical activity in patients with established coronary heart disease not only reduces the incidence of cardiac events, but also reduces the risk of all-cause mortality. Recently, we showed in mice that exercise training (EX) started immediately after myocardial infarction (MI) ameliorates left ventricular (LV) dysfunction. Here we tested the hypothesis that additional exercise training prior to an acute MI, i.e. a higher level of physical fitness at the time of MI, is associated with improved survival and attenuated LV dysfunction after MI. Methods and Results: MI was induced by permanent coronary ligation in 128 C57Bl/6 mice and subsequently followed by 8 weeks of voluntary wheel running (MI-EX) or sedentary housing (MI). In a third group, voluntary wheel running was started two weeks before induction of MI (EX-MI-EX). Sham operated mice served as controls. EX after MI had no effect on survival, infarct size, LV hypertrophy or dilation (Table ). However, EX improved LV function, reflected in enhanced LV fractional shortening (FS), rate of rise in LV pressure at 30 mmHg (LVdP/dt P30 ), and decreased pulmonary congestion and right ventricular weight (RVW). When EX was started prior to MI, post-MI survival nearly doubled and mice ran an average post-MI distance of ~7km/d compared to ~5km/d in MI-EX mice. Infarct cross-sectional area was larger, which was principally due to an increased infarct thickness (0.15±0.02mm EX-MI-EX vs 0.11±0.01mm MI; P =0.06). Surprisingly, however, LV hypertrophy and dysfunction were aggravated in the EX-MI-EX group compared to MI-EX. Conclusion: In line with our hypothesis, EX started prior to MI improved survival. However, contrary to our hypothesis, the improved survival was associated with a deterioration of LV dysfunction. The latter may have been the result of survival and hence inclusion of mice with the most severe LV dysfunction.

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Animals with Endometriosis Experience Beneficial Effects and Localized Modulation of Cytokine Levels when Exposed to Voluntary Wheel Running

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.04695 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Myrella L Cruz ◽

Johnathan Velazquez-Cruz ◽

Gladys Chompre ◽

Luis A Rivera ◽

Merie M Reyes-Bonilla ◽

...

Keyword(s):

Wheel Running ◽

Voluntary Wheel Running ◽

Beneficial Effects ◽

Cytokine Levels ◽

Voluntary Wheel

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Modifications in dietary self-selection specifically attributable to voluntary wheel running and exercise training in the rat

Physiology & Behavior ◽

10.1016/0031-9384(95)02175-2 ◽

1996 ◽

Vol 59 (6) ◽

pp. 1123-1128 ◽

Cited By ~ 22

Author(s):

Fabien Oudot ◽

Christiane Larue-Achagiotis ◽

Guy Anton ◽

Philippe Verger

Keyword(s):

Exercise Training ◽

Wheel Running ◽

Voluntary Wheel Running ◽

Self Selection ◽

Voluntary Wheel

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Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes

Physiology & Behavior ◽

10.1016/j.physbeh.2016.11.041 ◽

2017 ◽

Vol 170 ◽

pp. 141-150 ◽

Cited By ~ 19

Author(s):

Zoe Thompson ◽

Donovan Argueta ◽

Theodore Garland ◽

Nicholas DiPatrizio

Keyword(s):

Wheel Running ◽

Voluntary Exercise ◽

Voluntary Wheel Running ◽

Circulating Levels ◽

Voluntary Wheel

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Examination of nucleus accumbens mechanisms underlying the motivation for physical activity

10.32469/10355/63870 ◽

2017 ◽

Author(s):

◽

Gregory Neal Ruegsegger

Keyword(s):

Physical Activity ◽

Nucleus Accumbens ◽

Molecular Mechanisms ◽

Leptin Receptor ◽

Wheel Running ◽

Receptor Expression ◽

Voluntary Wheel Running ◽

Age Related ◽

Voluntary Physical Activity ◽

Voluntary Wheel

Physical inactivity, a primary contributor to numerous diseases including obesity, type 2 diabetes, depression, and dementia, has reached pandemic levels worldwide. Alarmingly, the percentage of individuals engaging in physical activity is low and decreasing. Accelerometry data shows that > 90% of adults fail to meet the U.S. Physical Activity Guidelines despite the excess of knowledge suggesting exercise improves health. Therefore, beginning to understand the molecular mechanisms which influence physical activity levels is imperative for the development of therapies to reduce sedentary behavior. The work presented in this dissertation made use of three independent experimental paradigms in rats to test the hypothesis that differences in the mesolimbic dopamine system associate with/cause changes in voluntary physical activity. In the first study, rats selectively bred for high (HVR) or low (LVR) voluntary wheel running distance were used to assess inherent differences in opioidergic signaling between HVR and LVR, as well as the influence of dopamine on opioid-induced changes in voluntary wheel running. Mu-opioid receptor expression and function was increased in the nucleus accumbens (NAc) of HVR compared to LVR. Likewise, naltrexone injection decreased dopamine-related mRNA expression in mesolimbic brain regions and reduced wheel running in HVR, but not LVR. Finally, lesion of dopaminergic neurons in the NAc prevented the decrease in running following naltrexone administration in HVR, suggesting opioidergic signaling requires downstream dopaminergic activity to influence voluntary running. In the second study, the transgenerational effect of maternal Western diet (WD) on offspring voluntary wheel running was assessed. Wheel running was increased in female WD offspring from 4-7 weeks of age, but decreased running from 16-19 weeks of age, compared to offspring from chow fed dams. These age-specific changes in wheel running are associated with the up- and down-regulation of dopamine receptor 1 in the NAc at 6 and 18 weeks of age, respectively, in WD female offspring, which in turn was negatively associated with leptin receptor mRNA in the ventral tegmental area. In the third study, age-related influences on wheel running were assessed in 8 and 14 week-old rats. In addition to a [about]60% reduction in running, RNA-sequencing revealed down-regulations in networks related to cAMP-mediated signaling and synaptic plasticity in the NAc from 8 to 14 weeks-old. The down-regulations of these networks was mirrored by reductions in dendritic spine density in the NAc from 8 to 14 weeks-old. Additionally, intra-NAc injection of the Cdk5 inhibitor roscovitine, a known modulator of dendritic density and dopamine signaling, dose-dependently decreased wheel running. Despite the varying experimental models used in this dissertation, these findings collectively suggest that alterations in dopaminergic signaling in the NAc associate with, and influence, voluntary physical activity.

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