Deep brain Stimulation (DBS) of the subthalamic nucleus (STN) has become the most often practiced neurosurgery for treatment of the cardinal motor features of Parkinson's disease (PD). Preclinical evidence indicates that high frequency stimulation (HFS) of the STN protects substantia nigra pars compacta (SNc) dopamine (DA) neurons from DA-depleting lesions. However, none of these studies examined the impact of STN HFS on DA terminal density or neurochemistry in the striatum and thus our understanding of the entire scope of protection is incomplete. Further, these studies did not examine the ability of STN HFS to provide neuroprotection in the face of previous large scale DA neuron loss. Growing evidence suggests that STN HFS drives and synchronizes the STN making it unlikely that decreased excitotoxicity is involved in STN HFS-mediated neuroprotection. We therefore propose to systematically examine the magnitude and mechanism of neuroprotection conferred by STN HFS in rats made parkinsonian by intrastriatal 6-hydroxydopamine (6-OHDA). We will examine the impact of STN HFS on nigrostriatal morphology and dopamine biochemistry. Our findings suggest that initiation of long-term HFS of the STN two weeks after lesion completely halts nigral DA neuron degeneration. We will test the hypothesis that HFS of the STN elicits upregulation of brain-derived neurotrophic factor (BDNF) mRNA and protein in primary and secondary STN target structures. Indeed, our findings demonstrate that long-term unilateral STN DBS upregulates the expression of BDNF protein and mRNA in the striatum and external pallidum, respectively. Lastly, we will examine the impact of STN HFS on the aged nigrostriatal system and test the hypothesis that STN HFS will provide little to no neuroprotection in the aged brain. We speculate that STN HFS may not be neuroprotective due to limited trophic plasticity of the aged brain. The proposed studies will determine whether STN DBS can slow the progression of DA neuron degeneration and whether this outcome is compromised by advancing age. The results of these studies may inform optimal therapeutic timing for intervention with STN DBS as well as identify a neuroprotective mechanism to be harnessed via this therapy. RELEVANCE (See Instmctions): The purpose of this project is to determine whether the surgical treatment for Parkinson's disease, deep brain stimulation, can potentially slow the progression of the disease. The mechanism of action of deep brain stimulation will also be investigated.