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.

行为放缓是人类衰老的基本特征之一，导致运动功能在衰老中的恶化。我们的主要假设是，中央多巴胺能途径的功能变化对运动功能的年龄相关下降显着贡献。我们未来五年的实验计划旨在进一步了解行为放缓的中枢神经系统过程，并分析干预的治疗方法。具体而言，我们的研究集中于多巴胺（DA）神经元 在基底尼格拉（SN）及其对基底神经节的尾状核，壳核和苍白球的投影。拟议的研究将使用行为表征的女性恒河猴作为人类衰老的模型来分析调节基底神经节运动功能的神经回路的关键连接。 该项目中的研究和方法旨在量化5 -25岁以上恒河猴的志愿和认知功能的相关性下降。将测试特定的DA受体激动剂和GDNF提高年龄动物运动和认知性能水平的能力。该行为结果对于分析Gerhardt和Zhang Project的fMRI和解剖学MRI研究的功能性神经化学研究至关重要。此外，该项目将分析四个重要的mRNA表达水平 DA神经元，TH，DAT，GFRALPHA-1和RET的标记。 Gfralpha-1和RET形成了GRNF的受体复合物，在SN中很高。还将评估DA神经元靶位点，尾状核和壳肌的GDNF mRNA的表达水平。这些数据将通过Gerhardt在项目中相同标记的蛋白质水平的平行蛋白质印迹分析进行整理，以更好地理解中央DA神经元功能变化的分子变化。