Aging and Parkinson's disease: Models of therapeutics and neurologic comorbidity. This is an A2 application for a Udall Parkinson's Disease Center of Excellence from the University of Cincinnati directed by Timothy J. Collier, Ph.D. Two less studied aspects of Parkinson's disease (PD) are the neural mechanisms associated with development of adverse consequences of disease and treatment (such as depression and therapy-induced dyskinesias) and mechanisms associated with translational therapeutics (such as subthalamic nucleus DBS and progenitor ceU transplantation). In addition, it long has been appreciated that advancing age is a primary risk factor for PD, yet aging rarely is incorporated into experimental studies. Thus, the present proposal groups these topics under the rubric of """"""""adaptive and maladaptive plasticity""""""""and examines their expression in the context of advancing chronological age. The proposal consists of four projects and two cores that interconnect and serve the projects. Project 1 examines the roles of maladaptive changes in spine morphology in suboptimal recovery provided by grafted dopamine (DA) neurons and the development of therapy-induced dyskinesias. Project 2 will determine the degree and mechanism of neuroprotection for the DA system conferred by high frequency electrical stimulation of the subthalamic nucleus. In particular, stimulation effects on neurotrophic mechanisms wUl be examined. Project 3 tests the hypothesis that preservation of the structure and function of the injured nigrostriatal system following engraftment of undifferentiated neural progenitor ceUs is not a product of replacement of DA neurons by grafted cells, but is mediated by graft-induced protection and/or regeneration of mature host DA neurons. The goal of Project 4 is to gain insight into the co-mingling of PD, stress, anxiety and depression. It will test the hypothesis that comorbid depression exacerbates the behavioral deficits, neurochemical abnormalities, and neurodegeneration associated with PD via deleterious glucocorticoid mechanisms. AH projects will utilize well-established rat models and examine differences and similarities of mechanisms and outcomes in the context of advancing chronological age. To the extent that plasticity is characteristic of PD, it provides points of access to harness its therapeutic effects and curtail its negative effects.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Sieber, Beth-Anne
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Michigan State University
Schools of Medicine
East Lansing
United States
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Ventorp, Filip; Bay-Richter, Cecilie; Nagendra, Analise Sauro et al. (2017) Exendin-4 Treatment Improves LPS-Induced Depressive-Like Behavior Without Affecting Pro-Inflammatory Cytokines. J Parkinsons Dis 7:263-273
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
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
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
Kanaan, Nicholas M; Collier, Timothy J; Cole-Strauss, Allyson et al. (2015) The longitudinal transcriptomic response of the substantia nigra to intrastriatal 6-hydroxydopamine reveals significant upregulation of regeneration-associated genes. PLoS One 10:e0127768
Collier, Timothy J; O'Malley, Jennifer; Rademacher, David J et al. (2015) Interrogating the aged striatum: robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration. Neurobiol Dis 77:191-203
Paumier, Katrina L; Sortwell, Caryl E; Madhavan, Lalitha et al. (2015) Tricyclic antidepressant treatment evokes regional changes in neurotrophic factors over time within the intact and degenerating nigrostriatal system. Exp Neurol 266:11-21
Nordströma, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra et al. (2015) Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease. Neurobiol Dis 73:70-82

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