MOTORIC DECLINES IN AGING: BEHAVIOR AND QUANTITATIVE MORPHOLOGY

衰老过程中运动能力的下降：行为和定量形态学

• 批准号: 7371006
• 负责人: Don Marshall Gash
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371006
• 关键词: Age; Aging; Animals; Basal Ganglia; Behavior; Behavioral; CNS processing; Cell Nucleus; Cognitive; Complex; Data; Deterioration; Dopamine; Dopamine Agonists; Dopamine Receptor; Female; Functional Magnetic Resonance Imaging; Globus Pallidus; Human; Intervention; Laboratories; Macaca mulatta; Magnetic Resonance Imaging; Messenger RNA; Methodology; Modeling; Molecular; Morphology; Motor; Pathway interactions; Performance; Process; Proteins; Range; Site; Substantia nigra structure; System; Testing; Therapeutic; Tyrosine 3-Monooxygenase; Western Blotting; age group; aged; caudate nucleus; cognitive function; design; dopamine transporter; dopaminergic neuron; glial cell-line derived neurotrophic factor; improved; mRNA Expression; neural circuit; neurochemistry; normal aging; programs; putamen; receptor; relating to nervous system; repaired; senescence

Behavioral slowing is one of the cardinal features of human aging, contributing to the debilitating deterioration of motor functions in senescence. Our principal hypothesis is that functional changes in central dopaminergic pathways contribute significantly to age-associated declines in motor functions. Our experimental plan for the next five years is designed to further our understanding of CNS processes underlying behavioral slowing and analyze therapeutic approaches for intervention. Specifically, our studies focus on the dopamine (DA) neurons in the substantia nigra (SN) and their projections to the caudate nucleus, putamen and globus pallidus of the basal ganglia. The proposed studies will analyze key junctions in the neural circuitry regulating motor functions in the basal ganglia, using behaviorally characterized female rhesus monkeys ranging in age from young adulthood to old age (5-25years+) as a model of human aging. The studies and methodology in this Project are designed to quantify age-associated declines in motoric and cognitive functions in rhesus monkeys from 5 -25+ years old. The ability of specific DA receptor agonists and GDNF to improve motor and cognitive performance levels of aged animals will be tested. The behavioral results are crucial for analyzing the functional neurochemical studies in Project by Gerhardt and the fMRI and anatomical MRI studies in Project by Zhang. In addition, this Project will analyze mRNA expression levels of four important markers of DA neurons, TH, DAT, GFRalpha-1 and Ret. GFRalpha-1 and Ret form a receptor complex for GRNF that is found at high levels in the SN. Expression levels of GDNF mRNA in DA neuron target sites, the caudate nucleus and putamen, will also be evaluated. These data will be collated with parallel Western blot analyses of protein levels of the same markers in the Project by Gerhardt to better understand molecular changes underlying functional changes in central DA neurons.

行为减缓是人类衰老的主要特征之一，导致衰老过程中运动功能的衰弱退化。我们的主要假设是，中枢多巴胺能通路的功能变化有助于显着的年龄相关的运动功能下降。我们未来五年的实验计划旨在进一步了解行为减缓的中枢神经系统过程，并分析干预的治疗方法。具体来说，我们的研究集中在多巴胺（DA）神经元 在黑质（SN）及其向基底节尾状核、壳核和苍白球的投射。拟议的研究将分析调节基底神经节运动功能的神经回路中的关键接头，使用行为特征的雌性恒河猴，年龄从青年到老年（5- 25岁以上）作为人类衰老的模型。 本项目中的研究和方法旨在量化5 - 25岁以上恒河猴运动和认知功能的年龄相关性下降。将测试特异性DA受体激动剂和GDNF改善老年动物的运动和认知表现水平的能力。行为结果对于分析Gerhardt项目中的功能神经化学研究以及Zhang项目中的fMRI和解剖MRI研究至关重要。此外，本项目将分析四个重要的mRNA表达水平， DA神经元标记物、TH、DAT、GFR α-1和Ret. GFR α-1和Ret形成GRNF的受体复合物，其在SN中以高水平存在。还将评估DA神经元靶位点、尾状核和壳核中GDNF mRNA的表达水平。这些数据将与Gerhardt项目中相同标记物的蛋白质水平的平行蛋白质印迹分析进行整理，以更好地了解中枢DA神经元功能变化的分子变化。