Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse

doi:10.1016/j.bbr.2010.05.009

Behavioural Brain Research

Volume 213, Issue 2, 1 December 2010, Pages 253-262

https://doi.org/10.1016/j.bbr.2010.05.009 Get rights and content

Abstract

This study used 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) in mice to determine if exercise improves behavior and dopamine (DA) and serotonin (5HT) content. Male C57BL/6 mice received MPTP (4 × 20 mg/kg) or saline. They remained sedentary or exercised by treadmill or voluntary running wheel for 6 weeks (n = 8/group). Saline-treated mice ran significantly faster on running wheels (22.8 ± 1.0 m/min) than on treadmill (8.5 ± 0.5 m/min), and MPTP lesion did not reduce voluntary exercise (19.3 ± 1.5 m/min, p > 0.05). There was a significant effect of both lesion and exercise on overall Rotarod performance (ORP): MPTP lesion reduced ORP, while treadmill exercise increased ORP vs sedentary mice (p < 0.05). MPTP increased anxiety in the marble-burying test: sedentary lesioned mice buried more marbles (74.0 ± 5.2%) than sedentary controls (34.8 ± 11.8%, p < 0.05). Conversely, exercise reduced anxiety on the elevated plus maze. Among saline-treated mice, those exposed to voluntary wheel-running showed an increased percent of open arm entries (49.8 ± 3.5%, p < 0.05) relative to sedentary controls (36.2 ± 4.0%, p < 0.05). Neither MPTP nor exercise altered symptoms of depression measured by sucrose preference or tail suspension. MPTP significantly reduced DA in striatum (in sedentary lesioned mice to 42.1 ± 3.0% of saline controls), and lowered 5HT in amygdala and striatum (in sedentary lesioned mice to 86.1 ± 4.1% and 66.5 ± 8.2% of saline controls, respectively); exercise had no effect. Thus, exercise improves behavior in a model of DA depletion, without changes in DA or 5HT.

Introduction

Parkinson's Disease (PD) is a progressive neurodegenerative disease with impaired motor function including slow execution of movement, rigidity, postural instability, and resting tremor [22]. However non-motor behavioral deficits are also common, occurring in approximately 60% of PD patients [1], [11], [50]. Depression affects ca. 25–40% of PD patients [46], [51], and anxiety affects approximately 40% [85]. The degree of psychiatric dysfunction does not appear to be related to the presence or extent of motor impairment [47], [61], [79]. In fact, affective disorders can be observed years before movement difficulties arise [72]. Understanding the neuropsychiatric contribution to PD symptoms will inform treatment options aimed at improving patient quality of life [11], [71].

The 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) mouse model replicates many neuropathologic and neurochemical features of PD [30], [38]. MPTP causes selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) leading to DA depletion in the caudate putamen (CPu [37]) and selective motor impairment [19], [66]. A recent study from our laboratories determined that MPTP also impairs cognitive function and elements of affective behavior [82]. C57BL/6 mice are highly susceptible to MPTP lesioning [77], and are commonly used in behavioral pharmacology research [15], [16], [52]. The present study applied MPTP lesioning in C57BL/6 mice to determine if nigrostriatal lesions induce anxiety and depression.

The second part of this study addressed the potential positive effects of exercise on symptoms of anxiety and depression in MPTP-lesioned mice. Recent studies have demonstrated that exercise improves motor function in PD patients and in animal models of PD [13], [25], [54], [59], [78]. Exercise also improves neuropsychiatric symptoms in non-PD patients and in mice [3], [5], [7], [20], [21], [56], [58]. Thus, it may similarly confer mental health benefits in PD patients.

Mice were subject to daily exercise for 30 days, either by running on a motorized treadmill or via exposure to a running wheel. Including voluntary exercise addresses the potential confounds of psychological stress imposed by forced exercise. We hypothesized that MPTP lesion would produce deficits in motor function and affective behavior, and that exercise would improve motor function and ameliorate anxiety and depression. Modulation of behavior would be accompanied by corresponding changes in brain levels of DA and serotonin (5HT), transmitters important for mood and motor function.

Section snippets

Animals

Forty-eight young adult male C57BL/6 mice (8–10 weeks of age, 22–26 g BW at the start of the study) were obtained from Charles River Laboratories (Wilmington, MA). Mice were group-housed 4/cage on a 12:12 reversed light–dark schedule (lights-off at 11 a.m.) in a temperature-controlled vivarium. Water and food were provided ad libitum. For 5 days before lesioning, all mice were handled daily for ca. 3 min. Half of the mice (n = 24) received 80 mg/kg MPTP (Sigma–Aldrich, St. Louis, MO) as 4 i.p.

Exercise

Fig. 1 depicts body weight and exercise measures for saline- and MPTP-lesioned mice. At the start of the study, there were no differences in body weight among treatment groups. MPTP lesion did not impair weight gain. Forty-five days after lesioning, MPTP-lesioned mice (all groups) gained an average of 3.3 ± 0.2 g to reach 27.5 ± 0.3 g BW, while BW in saline-treated mice increased by 2.8 ± 0.3 g to 27.0 ± 0.3 g (p > 0.05). Among saline-treated mice, exercise reduced final bodyweight (treadmill: 26.7 ± 0.3 g;

Discussion

The present study evaluated the ability of forced or voluntary exercise to overcome the inhibitory effects of MPTP lesions on motor and affective behavior, as well as dopamine and serotonin content in male C57BL/6 mice. Because exercise has been shown to enhance motor function in patients with PD [13], [26], [54] and also improves mood in non-PD patients [3], [5], [7], [20], [56], [58], the present study determined if exercise could manifest similar benefits in a mouse model of PD. For 6 weeks

Acknowledgements

We thank Drs. Satoru M. Sato and Eleni Antzoulatos for assistance with behavioral testing and tissue preparation. This work was supported by grants from the NIH (DC009125 to RIW, NS44327 to MWJ) and the US Army (NETRP W81XWH-04-1-0444 to MWJ).

References (88)

M. Al-Jarrah et al.
Endurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of parkinsonism with severe neurodegeneration
Neuroscience
(2007)
K.A. Barbour et al.
Exercise training and depression in older adults
Neurobiol Aging
(2005)
N.C. Berchtold et al.
Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus
Neuroscience
(2005)
K.R. Chaudhuri et al.
National institute for clinical excellence. Non-motor symptoms of Parkinson's disease: diagnosis and management
Lancet Neurol
(2006)
J.N. Crawley et al.
Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains
Brain Res Bull
(1982)
J.F. Cryan et al.
The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice
Neurosci Biobehav Rev
(2005)
M.F. Dallman et al.
Regulation of ACTH secretion: variations on a theme of B
Recent Prog Horm Res
(1987)
W. Dauer et al.
Parkinson's disease: mechanisms and models
Neuron
(2003)
M.H. De Moor et al.
Regular exercise, anxiety, depression and personality: a population-based study
Prev Med
(2006)
C.H. Duman et al.
Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice
Brain Res
(2008)

B.E. Fisher et al.

The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson's disease

Arch Phys Med Rehabil

(2008)

R.M. Hakvoort Schwerdtfeger et al.

The lateral hypothalamus and anterior hypothalamic nucleus differentially contribute to rats’ defensive responses in the elevated plus-maze and shock-probe burying tests

Physiol Behav

(2008)

R. Haobam et al.

Swim-test as a function of motor impairment in MPTP model of Parkinson's disease: a comparative study in two mouse strains

Behav Brain Res

(2005)

S. Hogg

A review of the validity and variability of the elevated plus-maze as an animal model of anxiety

Pharmacol Biochem Behav

(1996)

I. Irwin et al.

The relationships between aging, monoamine oxidase, striatal dopamine and the effects of MPTP in C57BL/6 mice: a critical reassessment

Brain Res

(1992)

V. Jackson-Lewis et al.

Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Neurodegeneration

(1995)

A. Leng et al.

Effects of blocking the dopamine biosynthesis and of neurotoxic dopamine depletion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on voluntary wheel running in mice

Behav Brain Res

(2004)

D. Liebetanz et al.

A highly sensitive automated complex running wheel test to detect latent motor deficits in the mouse MPTP model of Parkinson's disease

Exp Neurol

(2007)

N. Mitra et al.

Dissociation of serotoninergic and dopaminergic components in acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice

Brain Res Bull

(1992)

I. Miyai et al.

Treadmill training with body weight support: its effect on Parkinson's disease

Arch Phys Med Rehabil

(2000)

A. Mori et al.

Neural mechanisms underlying motor dysfunction as detected by the tail suspension test in MPTP-treated C57BL/6 mice

Neurosci Res

(2005)

K. Njung’e et al.

Evaluation of marble-burying behavior as a model of anxiety

Pharmacol Biochem Behav

(1991)

G. Rozas et al.

An automated Rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism

Brain Res Protoc

(1997)

G. Rozas et al.

Drug-free evaluation of rat models of parkinsonism and nigral grafts using a new automated Rotarod test

Brain Res

(1997)

G. Rozas et al.

Sprouting of the serotonergic afferents into the striatum after selective lesions of the dopaminergic system by MPTP in adult mice

Neurosci Lett

(1998)

G. Rozas et al.

The overall rod performance test in the MPTP-treated-mouse model of parkinsonism

J Neurosci Methods

(1998)

R. Rygula et al.

Anhedonia and motivational deficits in rats: impact of chronic social stress

Behav Brain Res

(2005)

J.L. Tillerson et al.

Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease

Neuroscience

(2003)

E. Tolosa et al.

The premotor phase of Parkinson's disease

Parkinsonism Relat Disord

(2007)

G. Uday et al.

LHRH antagonist attenuates the effect of fluoxetine on marble-burying behavior in mice

Eur J Pharmacol

(2007)

M.G. Vuckovic et al.

Memory, mood, dopamine, and serotonin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury

Neurobiol Dis

(2008)

H. Zheng et al.

Beneficial effects of exercise and its molecular mechanisms on depression in rats

Behav Brain Res

(2006)

D. Aarsland et al.

Range of neuropsychiatric disturbances in patients with Parkinson's disease

J Neurol Neurosurg Psychiatry

(1999)

M. Babyak et al.

Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months

Psychosom Med

(2000)

A.A. Bachmanov et al.

Positional cloning of the mouse saccharin preference (Sac) locus

Chem Senses

(2001)

J.A. Blumenthal et al.

Effects of exercise training on older patients with major depression

Arch Intern Med

(1999)

V. Brinks et al.

Strain specific fear behaviour and glucocorticoid response to aversive events: modelling PTSD in mice

Prog Brain Res

(2008)

M.R. Brown et al.

Central nervous system regulation of adrenocorticotropin secretion: role of somatostatins

Endocrinology

(1984)

D.S. Charney

Neuroanatomical circuits modulating fear and anxiety behaviors

Acta Psychiatr Scand

(2003)

H. Chen et al.

Physical activity and the risk of Parkinson disease

Neurology

(2005)

C.L. Comella et al.

Physical therapy and Parkinson's disease: a controlled clinical trial

Neurology

(1994)

J.N. Crawley

Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines

Pharmacol Biochem Behav

(1981)

J.N. Crawley et al.

Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies

Psychopharmacology (Berl)

(1997)

S. Fahn

Description of Parkinson's disease as a clinical syndrome

Ann N Y Acad Sci

(2003)

Cited by (103)

Effects of acute aerobic exercise with different intensities on cerebral dopamine/norepinephine/serotonin metabolites and executive-related oculomotor control in individuals with Parkinson's disease
2024, Mental Health and Physical Activity
The present study aimed to investigate the acute effects of aerobic exercise with different intensities on executive-related oculomotor control and cerebral dopamine/serotonin/norepinephrine metabolite concentrations in individuals with Parkinson's disease (PD). Twenty-eight PD individuals completed acute bouts of high-intensity interval exercise (HIIE), moderate-intensity continuous exercise (MICE), and REST sessions. The order of the three sessions was counterbalanced. We assessed the concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and methoxyhydroxyphenylglycol (MHPG), as well as neuropsychological and oculomotor performance indices in the saccade paradigm at baseline and following each session. The present study found that there was no significant effect of acute HIIE or MICE on the coefficient of variation of reaction time (RT) in individuals with PD. However, HIIE resulted in significantly shorter RTs in the antisaccade condition, and MICE achieved the same in both the prosaccade and antisaccade conditions. For oculomotor performance, we observed a change in saccade peak velocity only following MICE but not HIIE. Neither of the two aerobic exercise modes significantly affected saccade amplitude and latency. In addition, concentrations of HVA and MHPG, but not 5-HIAA, significantly increased following both MICE and HIIE in individuals with PD. Notably, MICE had a greater impact on HVA compared to HIIE. We also found significant correlations between the changes in MHPG concentration, but not HVA and 5-HIAA, and RTs before and after the two aerobic exercise interventions. These results suggest that although acute HIIE and MICE protocols could not improve oculomotor control, the two aerobic exercise modes induced distinct beneficial effects on executive function and cerebral neurotransmitter concentrations in individuals with PD.
Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction
2024, Pharmacology Biochemistry and Behavior
The Ndufs4 knockout (KO) mouse is a validated and robust preclinical model of mitochondrial diseases (specifically Leigh syndrome), that displays a narrow window of relative phenotypical normality, despite its inherent mitochondrial complex I dysfunction and severe phenotype. Preclinical observations related to psychiatric comorbidities that arise in patients with mitochondrial diseases and indeed in Leigh syndrome are, however, yet to be investigated in this model. Strengthening this narrative is the fact that major depression and bipolar disorder are known to present with deficits in mitochondrial function. We therefore screened the behavioural profile of male and female Ndufs4 KO mice (relative to heterozygous; HET and wildtype; WT mice) between postnatal days 28 and 35 for locomotor, depressive- and anxiety-like alterations and linked it with selected brain biomarkers, viz. serotonin, kynurenine, and redox status in brain areas relevant to psychiatric pathologies (i.e., prefrontal cortex, hippocampus, and striatum). The Ndufs4 KO mice initially displayed depressive-like behaviour in the tail suspension test on PND31 but not on PND35 in the forced swim test. In the mirror box test, increased risk resilience was observed. Serotonin levels of KO mice, compared to HET controls, were increased on PND36, together with increased tryptophan to serotonin and kynurenine turnover. Kynurenine to kynurenic acid turnover was however decreased, while reduced versus oxidized glutathione ratio (GSH/GSSG) was increased. When considering the comorbid psychiatric traits of patients with mitochondrial disorders, this work elaborates on the neuropsychiatric profile of the Ndufs KO mouse. Secondly, despite locomotor differences, Ndufs4 KO mice present with a behavioural profile not unlike rodent models of bipolar disorder, namely variable mood states and risk-taking behaviour. The model may elucidate the bio-energetic mechanisms underlying mood disorders, especially in the presence of mitochondrial disease. Studies are however required to further validate the model's translational relevance.
Investigating affective neuropsychiatric symptoms in rodent models of Parkinson's disease
2024, International Review of Neurobiology
Affective neuropsychiatric disorders such as depression, anxiety and apathy are among the most frequent non-motor symptoms observed in people with Parkinson’s disease (PD). These conditions often emerge during the prodromal phase of the disease and are generally considered to result from neurodegenerative processes in meso-corticolimbic structures, occurring in parallel to the loss of nigrostriatal dopaminergic neurons. Depression, anxiety, and apathy are often treated with conventional medications, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and dopaminergic agonists. The ability of these pharmacological interventions to consistently counteract such neuropsychiatric symptoms in PD is still relatively limited and the development of reliable experimental models represents an important tool to identify more effective treatments. This chapter provides information on rodent models of PD utilized to study these affective neuropsychiatric symptoms. Neurotoxin-based and genetic models are discussed, together with the main behavioral tests utilized to identify depression- and anxiety-like behaviors, anhedonia, and apathy. The ability of various therapeutic approaches to counteract the symptoms observed in the various models is also reviewed.
Mood disturbances in Parkinson's disease: From prodromal origins to application of animal models
2023, Neurobiology of Disease
Parkinson's disease (PD) is a complex illness with a constellation of environmental insults and genetic vulnerabilities being implicated. Strikingly, many studies only focus on the cardinal motor symptoms of the disease and fail to appreciate the major non-motor features which typically occur early in the disease process and are debilitating. Common comorbid psychiatric features, notably clinical depression, as well as anxiety and sleep disorders are thought to emerge before the onset of prominent motor deficits. In this review, we will delve into the prodromal stage of PD and how early neuropsychiatric pathology might unfold, followed by later motor disturbances. It is also of interest to discuss how animal models of PD capture the complexity of the illness, including depressive-like characteristics along with motor impairment. It remains to be determined how the underlying PD disease processes contributes to such comorbidity. But some of the environmental toxicants and microbial pathogens implicated in PD might instigate pro-inflammatory effects favoring α-synuclein accumulation and damage to brainstem neurons fueling the evolution of mood disturbances. We posit that comprehensive animal-based research approaches are needed to capture the complexity and time-dependent nature of the primary and co-morbid symptoms. This will allow for the possibility of early intervention with more novel and targeted treatments that fit with not only individual patient variability, but also with changes that occur over time with the evolution of the disease.
Reviewing the mitochondrial dysfunction paradigm in rodent models as platforms for neuropsychiatric disease research
2022, Mitochondrion
Neuropsychiatric disorders have complex pathophysiological constructs, requiring translational models to improve our understanding thereof. Mitochondrial dysfunction, generally associated with neurodegenerative disorders, is gaining interest as a key factor in the etiology of psychiatric conditions because of the often comorbid psychiatric symptoms observed. Although translational models of psychiatric disorders, support mitochondrial involvement, these models do not have a dysfunctional bio-energetic system as primary construct. Here, we consider the construct, face, and predictive validity of mitochondrial models from a neuropsychiatric perspective, to identify novel animal models that can improve our understanding of the underlying bio-energetic mechanisms of these conditions and treatments.
Metformin and fluoxetine improve depressive-like behavior in a murine model of Parkinsońs disease through the modulation of neuroinflammation, neurogenesis and neuroplasticity
2022, International Immunopharmacology
Thereabout 30–40% of patients with Parkinson's Disease (PD) also have depression contributing to the loss of quality of life. Among the patients who treat depression, about 50% do not show significant improvement due to the limited efficacy of the treatment. So far, there are no effective disease-modifying treatments that can impede its progression. The current clinical approach is based on symptom management. Nonetheless, the reuse of drugs with excellent safety profiles represents an attractive alternative strategy for treating of different clinical aspects of PD. In this study, we evaluated the effects of metformin separately and associated with fluoxetine on depressive like-behavior and motor alterations in experimental Parkinson's disease. C57BL6 mice were induced with rotenone (2.5 mg/kg/day) for 20 days and treated with metformin (200 mg/kg/day) and fluoxetine (10 mg/kg/day) from the 5th day of induction. The animals were submitted to Sucrose Preference, Tail Suspension, and rotarod tests. Hippocampus, prefrontal cortex, and substantia nigra were dissected for molecular and morphological analysis. Metformin and fluoxetine prevented depressive-like behavior and improved motor impairment and increased TH nigral positive cells. Metformin and fluoxetine also reduced IBA-1 and GFAP positive cells in the hippocampus. Moreover, metformin reduced the phospho-NF-kB, IL-1β in the prefrontal cortex and iNOS levels in the hippocampus. Both metformin and fluoxetine increased neurogenesis by increasing KI67, but only the combined treatment increased neuronal survival by NeuN positive cells in the hippocampus. In addition, fluoxetine reduced cell death, decreasing caspase-3 and PARP-1 levels. Lastly, metformin potentiated the effect of fluoxetine on neuroplasticity by increasing BDNF positive cells. Metformin has antidepressant and antiparkinsonian potential due to anti-inflammatory neurogenic, and neuroplasticity-inducing effects when combined with fluoxetine.

View all citing articles on Scopus

View full text

Research reportExercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse

Abstract

Introduction

Section snippets

Animals

Exercise

Discussion

Acknowledgements

Neuroscience

Neurobiol Aging

Neuroscience

Lancet Neurol

Brain Res Bull

Neurosci Biobehav Rev

Recent Prog Horm Res

Neuron

Prev Med

Brain Res

Arch Phys Med Rehabil

Physiol Behav

Behav Brain Res

Pharmacol Biochem Behav

Brain Res

Neurodegeneration

Behav Brain Res

Exp Neurol

Brain Res Bull

Arch Phys Med Rehabil

Neurosci Res

Pharmacol Biochem Behav

Brain Res Protoc

Brain Res

Neurosci Lett

J Neurosci Methods

Behav Brain Res

Neuroscience

Parkinsonism Relat Disord

Eur J Pharmacol

Neurobiol Dis

Behav Brain Res

Range of neuropsychiatric disturbances in patients with Parkinson's disease

J Neurol Neurosurg Psychiatry

Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months

Psychosom Med

Positional cloning of the mouse saccharin preference (Sac) locus

Chem Senses

Effects of exercise training on older patients with major depression

Arch Intern Med

Strain specific fear behaviour and glucocorticoid response to aversive events: modelling PTSD in mice

Prog Brain Res

Central nervous system regulation of adrenocorticotropin secretion: role of somatostatins

Endocrinology

Neuroanatomical circuits modulating fear and anxiety behaviors

Acta Psychiatr Scand

Physical activity and the risk of Parkinson disease

Neurology

Physical therapy and Parkinson's disease: a controlled clinical trial

Neurology

Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines

Pharmacol Biochem Behav

Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies

Psychopharmacology (Berl)

Description of Parkinson's disease as a clinical syndrome

Ann N Y Acad Sci

Research report
Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse