MOTORIC DECLINES IN AGING: BEHAVIOR AND QUANTITATIVE MORPHOLOGY

行为减慢是人类衰老的基本特征之一，在衰老过程中会导致运动功能的衰弱。我们的主要假设是，中枢多巴胺能通路的功能变化显著地导致了与年龄相关的运动功能的下降。我们未来五年的实验计划旨在加深我们对行为减慢背后的中枢神经系统过程的理解，并分析干预的治疗方法。具体地说，我们的研究重点是多巴胺(DA)神经元 黑质(SN)及其向基底节的尾状核、壳核和苍白球的投射。这项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连接，使用行为特征的雌性恒河猴作为人类衰老的模型，年龄从年轻到老年(5-25岁以上)不等。 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随年龄的下降。将测试特定的DA受体激动剂和GDNF改善老年动物运动和认知能力的能力。行为学研究结果对分析Gerhardt项目中的功能神经化学研究和张项目中的功能磁共振成像和解剖MRI研究具有重要意义。此外，该项目还将分析四个重要基因的mRNA表达水平 多巴胺能神经元标记物TH、DAT、GFRα-1和Ret。GFRpha-1和Ret形成GRNF的受体复合体，在SN中发现高水平的GRNF。此外，还将评估多巴胺能神经元靶点、尾状核和壳核中GDNF mRNA的表达水平。这些数据将与Gerhardt对该项目中相同标记物的蛋白质水平进行平行的蛋白质印迹分析进行核对，以更好地了解中枢DA神经元功能变化背后的分子变化。

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.