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      Chronic behavioral stress exaggerates motor deficit and neuroinflammation in the MPTP mouse model of Parkinson's disease

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      1 , 1 , 2 , 1 , *
      Translational Psychiatry
      Nature Publishing Group

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          Abstract

          Environmental stressor exposure is associated with a variety of age-related diseases including neurodegeneration. Although the initial events of sporadic Parkinson's disease (PD) are not known, consistent evidence supports the hypothesis that the disease results from the combined effect of genetic and environmental risk factors. Among them, behavioral stress has been shown to cause damage and neuronal loss in different areas of the brain, however, its effect on the dopaminergic system and PD pathogenesis remains to be characterized. The C57BL/6 mice underwent chronic restraint/isolation (RI) stress and were then treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whereas the control mice were treated only with MPTP and the effect on the PD-like phenotype was evaluated. The mice that underwent RI before the administration of MPTP manifested an exaggerated motor deficit and impairment in the acquisition of motor skills, which were associated with a greater loss of neuronal tyrosine hydroxylase and astrocytes activation. By showing that RI influences the onset and progression of the PD-like phenotype, our study underlines the novel pathogenetic role that chronic behavioral stressor has in the disease process by triggering neuroinflammation and degeneration of the nigral dopaminergic system.

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          Most cited references16

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          Tests to assess motor phenotype in mice: a user's guide.

          The characterization of mouse models of human disease is essential for understanding the underlying pathophysiology and developing new therapeutics. Many diseases are often associated with more than one model, and so there is a need to determine which model most closely represents the disease state or is most suited to the therapeutic approach under investigation. In the case of neurological disease, motor tests provide a good read-out of neurological function. This overview of available motor tasks aims to aid researchers in making the correct choice of test when attempting to tease out a transgenic phenotype or when assessing the recovery of motor function following therapeutic intervention.
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            A rotarod test for evaluation of motor skill learning.

            The rotarod test is widely used to evaluate the motor coordination of rodents, and is especially sensitive in detecting cerebellar dysfunction. However, mice with striatal dopamine depletion show only mild or no motor deficit on the typical accelerating rotarod. This suggests that dopamine-depleted mice are useful as animal models for non-motor symptoms, because the influence of motor deficit is minimum and easy to discriminate from cognitive aspects of the behavioral change. The typical accelerating rotarod test is designed to evaluate maximal motor performance and is not optimized to detect motor skill learning. In an attempt to make the test more selective to motor skill learning rather than maximal gait performance, we modified the rotarod test by using a slowly rotating large drum to obtain a steep learning curve. Furthermore, administration of nomifensine, a dopamine uptake inhibitor, improved the learning. On the other hand, apomorphine, an agonist of dopamine autoreceptor, a dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) impaired the learning. These pharmacological profiles fit the involvement of the so-called phasic dopamine neurotransmission. Using our modified procedure, we found impaired learning of Parkin-deficit mice, which has not been detected in typical accelerating rotarod. The modified rotarod test would be useful for evaluation of dopamine involvement in the acquisition of motor skill learning. Copyright (c) 2010 Elsevier B.V. All rights reserved.
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              A guide to neurotoxic animal models of Parkinson's disease.

              Kim Tieu (2011)
              Parkinson's disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechanisms of cell death, and to evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. The primary objectives of this article are twofold: First, to assist new investigators who are contemplating embarking on PD research to navigate through the available animal models. Emphasis will be placed on common neurotoxic murine models in which toxic molecules are used to lesion the nigrostriatal dopaminergic system. And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                February 2016
                09 February 2016
                1 February 2016
                : 6
                : 2
                : e733
                Affiliations
                [1 ]Department of Pharmacology and Center for Translational Medicine, School of Medicine, Temple University , Philadelphia, PA, USA
                [2 ]Department of Pharmaceutical Sciences, School of Pharmacy, Temple University , Philadelphia, PA, USA
                Author notes
                [* ]Department of Pharmacology and Center for Translational Medicine, School of Medicine, Temple University, 947 Medical Education and Research Building , 3500 North Broad Street, Philadelphia, PA 19140, USA. E-mail: praticod@ 123456temple.edu
                Article
                tp20161
                10.1038/tp.2016.1
                4872430
                26859816
                beeb2ade-0efa-4af3-9e1d-4152d3172520
                Copyright © 2016 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 29 June 2015
                : 25 August 2015
                : 19 September 2015
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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