Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model of Parkinson's disease

Abstract

The causes of most cases of Parkinson's disease (PD) are still poorly understood. Here we show that chronic stress and elevated corticosterone levels exaggerate motor deficits and neurodegenerative events in a Parkinson's disease rat model. Animals were tested in skilled and non-skilled movement while being exposed to daily restraint stress or oral corticosterone treatment. Stress and corticosterone compromised normal motor function and exaggerated motor deficits caused by unilateral 6-hydroxydopamine lesion of the nigrostriatal bundle. Moreover, stress and corticosterone treatments diminished the ability to acquire compensatory strategies in limb use during skilled reaching and skilled walking. In contrast, lesion control animals were able to significantly improve in the ability of skilled limb use during the repeated test sessions. The exaggerated motor impairments in stress-treated animals were related to accelerated loss of midbrain dopamine-producing neurons during the first week postlesion. Correlation analysis revealed a significant connection between loss of tyrosine hydroxylase-positive cells and increase in Fluoro-Jade-positive cells only in stress-and corticosterone-treated animals. Furthermore, stress and elevated corticosterone levels caused greater permanent loss of midbrain neurons than found in non-treated lesion animals. These findings demonstrate that stress and elevated corticosterone levels can exaggerate nigral neuronal loss and motor symptoms in a rat analogue of PD. It is therefore possible that stress represents a key factor in the pathogenesis of human PD by impeding functional and structural compensation and exaggerating neurodegenerative processes.

Blockade of Mineralocorticoid and Glucocorticoid Receptors Reverses Stress-Induced Motor Impairments

“…The stress- and CORT-induced motor deficits shown here confirm previous studies of diminished reaching success and movement scores [20,22,23]. Appropriate changes in plasma CORT and glucose also confirm the salience of the present manipulations.…”

“…Indeed, systemic administration of CORT or stress disturbs skilled and non-skilled movement at both acute and long-term intervals [19,20]. Moreover, motor function seems to be equally impaired by treatment with either stress or CORT [20,21,22,23]. These observations also apply to studies of brain damage.…”

“…These observations also apply to studies of brain damage. In rat models of stroke and Parkinson’s disease, both stress and CORT can impair motor recovery [21,24] and exaggerate loss of movement [22], respectively. Notably, the motor system shows sexual dimorphism in response to stress [25].…”

Synergistic effects of age and stress in a rodent model of stroke

“…Although animals may show gradual habituation to daily restraint in physiological measures, it nevertheless causes chronically diminished motor deficits [19,22,35]. Similar findings were made in the young animals that displayed a modest increase in circulating CORT levels after three days of restraint and return to baseline levels at chronic time points.…”

Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism

“…Several reports have suggested that the GC-GR responses might be crucially linked to PD pathogenesis. Thus, chronically high levels of GCs were shown to exacerbate motor deficits in 6-hydroxy-DA-treated rats (11). This experimental observation corroborates clinical data showing that stress can trigger or worsen motor symptoms in PD patients (12).…”