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

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 [(14)C]-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.