Aging of Central Dopaminergic Systems in Primates

描述（由申请人提供）：行为减缓是人类衰老的主要特征之一，导致衰老时运动功能的衰弱性恶化。在过去五年的研究中，我们的主要假设是，中枢多巴胺能通路的变化构成了与年龄相关的运动衰退的基本组成部分。来自我们研究和其他研究的越来越多的证据为这一假设提供了强有力的支持。我们未来五年的实验计划旨在进一步了解中枢神经系统行为减缓背后的过程，并分析干预的治疗方法。具体而言，我们的研究重点是黑质（SN）内的多巴胺（DA）神经元及其对基底节区尾状核、壳核和苍白球的投射。本研究将分析调节基底节区运动功能的神经回路中的关键节点，并以具有行为特征的雌性恒河猴作为人类衰老的模型，这些雌性恒河猴的年龄范围从青年到老年（5-25岁以上）。总的来说，该计划的三个项目和三个支持核心将严格检验以下假设：

DESCRIPTION (provided by applicant): Behavioral slowing is one of the cardinal features of human aging, contributing to the debilitating deterioration of motor functions in senescence. Our principal hypothesis for the past five years of research on this Program Project has been that changes in central dopaminergic pathways constitute a fundamental component of age-associated motoric declines. Converging evidence from our studies and others are providing strong support for this hypothesis. 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. Collectively, the three Projects and three supporting Cores in this Program will critically test the following hypotheses: Hypothesis 1 - That while changes in dopaminergic functions occur throughout the basal ganglia, alterations in neural processing in the SN is a principal component of age-associated motor declines. Hypothesis 2 - That functional changes in the basal ganglia dopaminergic system, including in tyrosine hydroxylase (TH), dopamine transporters (DAT) and DA receptors, are closely associated with age-associated motoric declines. Hypothesis 3 - That anatomical changes in normal aging in the basal ganglia are less predictive than functional changes of age-associated declines in motoric performance. Hypothesis 4 - That local administration of the potent dopaminergic trophic factor GDNF (glial cell line-derived neurotrophic factor) into the SN significantly repairs and restores age-associated declines in SN dopaminergic functions.