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Stress exacerbates experimental Parkinson’s disease

Molecular Psychiatry volume 19, pages 638–640 (2014)Cite this article

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The influence of life stress on the progression of Parkinson’s disease (PD) has received little attention. Here, we examined the effects of chronic variable stress (CVS), a widely used animal model that recapitulates core symptoms of depression, on the course of neuronal degeneration and behavioral deficits in a rat neurotoxin model of PD. Depression is highly correlated with PD and is suggested to contribute more to the lowered quality of patient life than the debilitating motor symptoms.1 Despite the high prevalence of depression in PD patients, preclinical research on the comorbidity of these neuropsychiatric and neurodegenerative disorders remains at an early stage. Dysregulation of the stress response is purported to have a large role in the etiology/progression of depression, and many of the brain regions involved in stress regulation are also linked to depression.2, 3 Experimental stress or depression can lead to neurodegeneration, cellular atrophy or increased susceptibility to subsequent injury in numerous brain regions.4 Stress was long ago hypothesized to contribute to the neuropathology of PD, possibly by increasing the vulnerability of midbrain dopamine cells to degeneration.5 Given the strong connection between PD and depression, it is imperative to understand if chronic stress can be a complicating factor in disease progression or severity.

To address this issue, we combined unilateral lesion of the nigrostriatal pathway via the neurotoxin 6-hydroxydopamine (6-OHDA) with exposure to multiple, random unpredictable stressors (CVS). This CVS regimen produces behavioral, physiological and hormonal correlates of depression in animals.3 Here we examined the effects of stress-induced depression on motor deficits, assessed using the forelimb asymmetry test, and on neurodegeneration of dopamine neurons in the substantia nigra par compacta (SNpc), assessed by stereological cell counts of tyrosine hydroxylase (TH, a marker for dopaminergic cells)-containing neurons. Rats were exposed to CVS 2 weeks prior to and 2 weeks after the lesion. Both vehicle-injected (sham-lesioned) and unstressed control groups were included. Behavior was evaluated 2 and 4 weeks after the lesion (Supplementary Figure 1a). The attenuated weight gain observed for each of the CVS treatment groups during each temporal iteration confirmed the effectiveness of the variable stress regimen (Supplementary Figure 2). The rats were killed at 4 weeks post-lesion, the brains dissected, sectioned through the midbrain, and processed for TH immunohistochemistry.

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Acknowledgements

This work was supported by NIH grant NS060114 (KBS), Udall Parkinson’s Disease Centers of Excellence grant NS058830 (KBS, JPH), by grants from the Sunflower Revolution/University of Cincinnati Neuroscience Institute, Gardner Family Center for Parkinson’s Disease and Movement Disorders, Davis Phinney Foundation, Morris Braun Foundation, and Parkinson’s Disease Support Network of Ohio, Kentucky and Indiana (all KBS), a Scottish Rite Schizophrenia Foundation Fellowship (JWD), and a University Research Council Fellowship (AMH). We are grateful to Dr Sheila Fleming for valuable discussions and comments on the manuscript.

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  1. J W Dickerson

    Present address: 4Current address: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA,

Authors and Affiliations

  1. Department of Neurology, The Selma Schottenstein Harris Laboratory for Research in Parkinson’s, Gardner Family Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    A M Hemmerle, J W Dickerson & K B Seroogy

  2. Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, USA

    A M Hemmerle, J W Dickerson, J P Herman & K B Seroogy

  3. Department of Psychiatry and Behavioral Neuroscience, Stress Neurobiology Laboratory, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    J P Herman

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  1. A M Hemmerle
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  2. J W Dickerson
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Correspondence to J P Herman or K B Seroogy.

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Hemmerle, A., Dickerson, J., Herman, J. et al. Stress exacerbates experimental Parkinson’s disease. Mol Psychiatry 19, 638–640 (2014). https://doi.org/10.1038/mp.2013.108

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