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.
We found in the behavioral tests that at both 2 and 4 weeks post-6-OHDA injection, the two lesion groups demonstrated significant reduction in the usage of the impaired (contralateral, left) forelimb relative to the vehicle-injected groups (Figure 1a), as expected. However, by 4 weeks the lesioned rats that were subjected to CVS demonstrated greater disuse of the impaired limb compared with the 6-OHDA-lesioned, unstressed rats (F3,19=23.89, P<0.01; Figure 1a). Stereological cells counts of surviving TH+ neurons in the SNpc, in contrast to findings using a milder (habituating) stress regimen,6 demonstrated that significantly greater cell loss was observed in the stressed, lesioned rats compared with the unstressed, lesioned animals (F3,19=69.18, P<0.01; Figures 1b and c). NeuN+ cell counts confirmed that the exacerbated loss of TH+ neurons was due to frank neuronal degeneration rather than downregulation of TH phenotype (Supplementary Figure 3).
Epidemiological studies variably suggest that depression predisposes individuals for PD or, in contrast, that PD predisposes for depression.7, 8 Therefore, to evaluate the temporal effects of chronic stress-induced depression in our present combined model, we subjected rats to the CVS regimen either only preceding or only after a 6-OHDA-induced nigrostriatal lesion (Supplementary Figures 1b and c). We found that CVS neither solely prior to the lesion nor solely following the lesion affected the motor deficits or the neurodegeneration of TH+ neurons normally seen in the 6-OHDA model (Supplementary Figures 4 and 5).
The present study demonstrates that chronic stress-induced depression concurrent with, rather than preceding or following, neurotoxin-induced neurodegeneration exacerbates the behavioral dysfunction and degeneration of the dopaminergic nigrostriatal system. Thus, stress-induced exacerbation of Parkinsonian symptoms is dependent on cellular changes affecting both resistance and reactivity to toxic challenge. Our finding of increased PD deficits with our combined model underlies the importance of screening and treating PD patients for depression to lessen any possible worsening of motor (as well as non-motor) deficits.
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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.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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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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