Aging of Central Dopaminergic Systems in Primates

描述(申请人提供)：行为减慢是人类衰老的基本特征之一，导致衰老过程中运动功能的衰弱。在过去五年的研究中，我们对这个项目的主要假设是，中枢多巴胺能通路的变化构成了与年龄相关的运动功能下降的基本组成部分。我们的研究和其他研究提供了强有力的证据支持这一假说。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，我们的研究集中在黑质(SN)中的多巴胺(DA)神经元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。总的来说，本计划中的三个项目和三个支持核心将批判性地检验以下假设： 假设1-虽然多巴胺能功能的变化发生在整个基底节，但SN内神经加工的变化是年龄相关运动下降的主要组成部分。 假设2-基底节多巴胺能系统的功能变化，包括酪氨酸羟化酶(TH)、多巴胺转运体(DAT)和DA受体，与年龄相关的运动性衰退密切相关。 假设3--与与年龄相关的运动能力下降的功能变化相比，基底节正常衰老的解剖学变化更难预测。 假设4-在黑质内局部应用有效的多巴胺能营养因子GDNF(胶质细胞系衍生神经营养因子)，可显著修复和恢复与年龄相关的黑质多巴胺能功能的下降。

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.