Recruitment of the prefrontal cortex and cerebellum in Parkinsonian rats following skilled aerobic exercise

Abstract

Exercise modality and complexity play a key role in determining neurorehabilitative outcome in Parkinson’s disease (PD). Exercise training (ET) that incorporates both motor skill training and aerobic exercise has been proposed to synergistically improve cognitive and automatic components of motor control in PD patients. Here we introduced such a skilled aerobic ET paradigm in a rat model of dopaminergic deafferentation. Rats with bilateral, intra-striatal 6-hydroxydopamine lesions were exposed to forced ET for 4 weeks, either on a simple running wheel (non-skilled aerobic exercise, NSAE) or on a complex wheel with irregularly spaced rungs (skilled aerobic exercise, SAE). Cerebral perfusion was mapped during horizontal treadmill walking or at rest using [14C]-iodoantipyrine 1 week after the completion of ET. Regional cerebral blood flow (rCBF) was quantified by autoradiography and analyzed in 3-dimensionally reconstructed brains by statistical parametric mapping. SAE compared to NSAE resulted in equal or greater recovery in motor deficits, as well as greater increases in rCBF during walking in the prelimbic area of the prefrontal cortex, broad areas of the somatosensory cortex, and the cerebellum. NSAE compared to SAE animals showed greater activation in the dorsal caudate-putamen and dorsal hippocampus. Seed correlation analysis revealed enhanced functional connectivity in SAE compared to NSAE animals between the prelimbic cortex and motor areas, as well as altered functional connectivity between midline cerebellum and sensorimotor regions. Our study provides the first evidence for functional brain reorganization following skilled aerobic exercise in Parkinsonian rats, and suggests that SAE compared to NSAE results in enhancement of prefrontal cortex- and cerebellum-mediated control of motor function.

Recruitment of prefrontal-striatal circuit in response to skilled motor challenge

“…Unique about our paradigm was the ability to apply whole brain imaging in awake, unrestrained animals during a task that required quadrupedal motion. Walking compared to the resting condition increased rCBF in regions within the basal ganglia thalamocortical motor circuit and in somatosensory regions, as previously reported [10,15]. These activations were greater during walking in the complex wheel than in the simple wheel, suggesting greater functional activation of these regions.…”

“…Our results in agreement with our earlier work in a rat model of Parkinsonism (bilateral partial dopaminergic deafferentation of the dorsal striatum). In the lesioned animals, 4 weeks of daily motor training resulted in greater functional connectivity of the PFC to the striatum and motor cortex when rats were trained in a complex versus a simple wheel [10]. This increase in functional connectivity was observed when animals were imaged during horizontal walking, suggesting a carry-over effect from their training in the running wheels.…”

“…These motor challenges differ by the level of motor complexity, rather than by differences in physical expenditure. Our group has introduced the complex wheel as a means of delivering skilled motor training that is standardized and more quantifiable than exposure to an enriched environment [10]. In these wheels, a pseudo random pattern of rung spacing is achieved by repeating a pattern OOOOXOX (O indicates a rung, X indicates a missing rung) (Fig.…”

“…Data was analyzed in 3-dimensionally (3-D) reconstructed brains by statistical parametric mapping (SPM 5) [16] and seed-based functional connectivity using our prior methods [10,17]. Significance changes in regional cerebral blood flow (rCBF) were determined at p < 0.05 at the voxel level with an extent threshold of 100 contiguous voxels, which reflects a balanced approach to control Type I and Type II errors.…”

What and How Can Physical Activity Prevention Function on Parkinson’s Disease?

“…In previous studies, physical exercise was found to have a positive effect on neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, and PD [75][76][77]. Physical exercise could reduce the loss of dopaminergic neurons, increase synaptic connections, and upregulate neurotrophic factor levels to improve PD dyskinesia [78][79][80]. Physical exercise could downregulate α-Syn protein levels and neuronal apoptosis [70,[81][82][83], which could reduce inflammation and mitochondrial dysfunction to restore the motor function in PD patients.…”