Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson's disease (PD) during the past decade. The neuronal mechanisms underlying the therapeutic effects of DBS, however, are yet to be clarified. DBS methods have been developed based on the experiments performed exclusively on primate model. Many critical issues regarding the therapeutic effects of DBS need to be addressed using a rodent model. This proposal is aimed at three objectives: first is to establish a rodent model of DBS for Parkinsonian conditions. The rat will be subjected to unilateral 6-hydroxydopamine injection to destroy nigrostriatal dopamine system and thus develop a Parkinsonian motor deficit revealed by treadmill locomotion task. Treadmill will be turned on and off 20 seconds alternatively. Array of ten stimulation electrodes will be implanted in the subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr). High frequency stimulation (HFS) will be applied during the treadmill walking phase. The improvement on locomotion by HFS will be measured and the effects will be compared between STN and SNr stimulations using different stimulation parameters. Second objective is to understand the dynamic neural activity responses in the basal ganglia system during the development of motor deficit by monitoring and comparing the activities from same neurons cross 10 day dopamine depletion period. Chronic multi- channel, single-unit recording technique will be used in this experiment. Sixty-four electrodes will be implanted in the striatum, globus pallidus, STN, and SNr. Extracellular spike activity will be recorded simultaneously in the behavioral rat. This study will test the hypothesis that direct and indirect pathways of basal ganglia will respond in different yet correlated manners during dopamine depletion. Third objective is to study the neuronal mechanisms mediating therapeutic effects of DBS in the behavioral model described above. In addition to the 64 electrodes implanted in the basal ganglia regions mentioned above, eight more stimulation electrodes will be added to target the STN and SNr. The neuronal responses in all four basal ganglia regions during behavioral effective HFS will be recorded and analyzed to reveal the effects of HFS on motor behavioral and associated changes in basal ganglia neuronal activity. This study is designed to address the fundamental mechanisms regarding the effects of DBS on treating PD and the information obtained from this experiment will have direct impact on improving the effects of DBS on PD and other movement disorders.
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