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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS058830-04
Application #
8382677
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$218,832
Indirect Cost
$79,448
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Fischer, D Luke; Manfredsson, Fredric P; Kemp, Christopher J et al. (2017) Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal ?-Synuclein Overexpression. Sci Rep 7:16356
Fischer, D Luke; Kemp, Christopher J; Cole-Strauss, Allyson et al. (2017) Subthalamic Nucleus Deep Brain Stimulation Employs trkB Signaling for Neuroprotection and Functional Restoration. J Neurosci 37:6786-6796
Collier, Timothy J; Srivastava, Kinshuk R; Justman, Craig et al. (2017) Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form. Neurobiol Dis 106:191-204
Kneynsberg, Andrew; Collier, Timothy J; Manfredsson, Fredric P et al. (2016) Quantitative and semi-quantitative measurements of axonal degeneration in tissue and primary neuron cultures. J Neurosci Methods 266:32-41
Polinski, Nicole K; Manfredsson, Fredric P; Benskey, Matthew J et al. (2016) Impact of age and vector construct on striatal and nigral transgene expression. Mol Ther Methods Clin Dev 3:16082
Madhavan, Lalitha; Daley, Brian F; Davidson, Beverly L et al. (2015) Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration. PLoS One 10:e0137136
Grabinski, Tessa M; Kneynsberg, Andrew; Manfredsson, Fredric P et al. (2015) A method for combining RNAscope in situ hybridization with immunohistochemistry in thick free-floating brain sections and primary neuronal cultures. PLoS One 10:e0120120
Paumier, Katrina L; Luk, Kelvin C; Manfredsson, Fredric P et al. (2015) Intrastriatal injection of pre-formed mouse ?-synuclein fibrils into rats triggers ?-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185-199
Polinski, Nicole K; Gombash, Sara E; Manfredsson, Fredric P et al. (2015) Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging 36:1110-20
Fischer, D Luke; Collier, Timothy J; Cole-Strauss, Allyson et al. (2015) High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine. PLoS One 10:e0133957

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