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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043441-02
Application #
6623469
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Project Start
2002-03-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
2
Fiscal Year
2003
Total Cost
$303,620
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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Wang, Jin-Yan; Chang, Jing-Yu; Woodward, Donald J et al. (2007) Corticofugal influences on thalamic neurons during nociceptive transmission in awake rats. Synapse 61:335-42
Chang, Jing-Yu; Shi, Li-Hong; Luo, Fei et al. (2007) Studies of the neural mechanisms of deep brain stimulation in rodent models of Parkinson's disease. Neurosci Biobehav Rev 31:643-57
Shi, Li-Hong; Luo, Fei; Woodward, Donald et al. (2006) Deep brain stimulation of the substantia nigra pars reticulata exerts long lasting suppression of amygdala-kindled seizures. Brain Res 1090:202-7
Shi, Li-Hong; Luo, Fei; Woodward, Donald J et al. (2006) Basal ganglia neural responses during behaviorally effective deep brain stimulation of the subthalamic nucleus in rats performing a treadmill locomotion test. Synapse 59:445-57
Chang, Jing-Yu; Shi, Li-Hong; Luo, Fei et al. (2006) Neural responses in multiple basal ganglia regions following unilateral dopamine depletion in behaving rats performing a treadmill locomotion task. Exp Brain Res 172:193-207
Yang, He; Chang, Jing-Yu; Woodward, Donald J et al. (2005) Coding of peripheral electrical stimulation frequency in thalamocortical pathways. Exp Neurol 196:138-52

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