Functional Reorganization of Motor and Limbic Circuits after Exercise Training in a Rat Model of Bilateral Parkinsonism

Abstract

Exercise training is widely used for neurorehabilitation of Parkinson’s disease (PD). However, little is known about the functional reorganization of the injured brain after long-term aerobic exercise. We examined the effects of 4 weeks of forced running wheel exercise in a rat model of dopaminergic deafferentation (bilateral, dorsal striatal 6-hydroxydopamine lesions). One week after training, cerebral perfusion was mapped during treadmill walking or at rest using [14C]-iodoantipyrine autoradiography. Regional cerebral blood flow-related tissue radioactivity (rCBF) was analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. In non-exercised rats, lesions resulted in persistent motor deficits. Compared to sham-lesioned rats, lesioned rats showed altered functional brain activation during walking, including: 1. hypoactivation of the striatum and motor cortex; 2. hyperactivation of non-lesioned areas in the basal ganglia-thalamocortical circuit; 3. functional recruitment of the red nucleus, superior colliculus and somatosensory cortex; 4. hyperactivation of the ventrolateral thalamus, cerebellar vermis and deep nuclei, suggesting recruitment of the cerebellar-thalamocortical circuit; 5. hyperactivation of limbic areas (amygdala, hippocampus, ventral striatum, septum, raphe, insula). These findings show remarkable similarities to imaging findings reported in PD patients. Exercise progressively improved motor deficits in lesioned rats, while increasing activation in dorsal striatum and rostral secondary motor cortex, attenuating a hyperemia of the zona incerta and eliciting a functional reorganization of regions participating in the cerebellar-thalamocortical circuit. Both lesions and exercise increased activation in mesolimbic areas (amygdala, hippocampus, ventral striatum, laterodorsal tegmental n., ventral pallidum), as well as in related paralimbic regions (septum, raphe, insula). Exercise, but not lesioning, resulted in decreases in rCBF in the medial prefrontal cortex (cingulate, prelimbic, infralimbic). Our results in this PD rat model uniquely highlight the breadth of functional reorganizations in motor and limbic circuits following lesion and long-term, aerobic exercise, and provide a framework for understanding the neural substrates underlying exercise-based neurorehabilitation.

Exercise intensity modulates the change in cerebral blood flow following aerobic exercise in chronic stroke

“…Transient changes in perfusion during and immediately following exercise, however, are not well understood in the context of stroke rehabilitation. The basis for mesolimbic activation in motor deficit retraining was demonstrated in an animal model (Wang et al 2013), thereby advocating an important role in stroke recovery.…”

Exercise alters resting-state functional connectivity of motor circuits in parkinsonian rats

“…The experimental protocol has been previously reported and the reader is referred to our publication for additional details (Wang, et al, 2013). This study was carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research and was approved by the Institutional Animal Care and Use Committee at the University of Southern California.…”

“…No-exercise animals were handled and left in a stationary running wheel for 30 min/day. Animals were trained for 4 weeks using an individually adjusted, performance-based speed adaptation paradigm as described (Wang, et al, 2013). Thereafter rats received implantation of the right external jugular vein cannula that was externalized dorsally in the suprascapular region.…”

“…The current resting-state functional connectivity analysis was based on data from 3 of the 6 groups we reported earlier, with subjects and tissue sections being identical (Wang, et al, 2013). We applied inter-regional correlation analysis to investigate rsFC (Wang, et al, 2012).…”

“…We recently demonstrated in a rat model of 6-OHDA-induced Parkinsonism that 4 weeks of forced running wheel exercise improved motor deficits and resulted in altered regional brain activation (Wang, et al, 2013), including the motor cortex, caudate putamen, globus pallidus, zona incerta, and cerebellum. Our earlier study presented histochemical, behavioral, and regional cerebral blood flow (rCBF) findings.…”