MOTORIC DECLINES IN AGING: MRI STUDIES OF NIGROSTRIATAL DOPAMINERGIC SYSTEM

这项资助的中心假设是，与年龄相关的运动功能下降是由于动物和人类黑质纹状体多巴胺能系统的功能变化造成的。为了解决这个问题，我们团队开发了一种技术，使用功能磁共振成像(FMRI)来测量MRI适应的清醒恒河猴基底节中药物诱发的血氧水平依赖(BOLD)的变化。在为该项目提出的研究中，我们将利用功能磁共振成像来测量对各种DA激动剂的大胆反应中与年龄相关的变化。具体地说，我们计划比较阿朴吗啡与多巴胺受体特异性激动剂SKF-81297(D1激动剂)和LY17155(奎比罗，D2激动剂)的作用。然后，我们将通过使用多个单单位电生理记录来确定药物诱发的BOLD反应与特定感兴趣区(Rod)潜在神经活动之间的关系。我们还将利用解剖MRI来确定关键基底节结构的体积随年龄的变化。我们还将测量苍白球和黑质中铁的积聚。这些解剖学测量将被用来检验我们的假设，即这些核团中与年龄相关的功能变化对 行为缺陷比结构变化更重要。我们将评估GDNF对这些功能和形态指标的影响，以确定强大的DA神经营养因子是否在基底节具有修复特性。这些研究将补充Gash和Berhardt项目的行为、神经化学和组织病理学/生物化学研究。

The central hypothesis of this grant is that age-related declines in motor function result from functional changes in the nigrostriatal dopaminergic system in animals and humans. To address this issue, our group has developed techniques to measure pharmacologically-evoked blood oxygen level-dependent (BOLD) changes in the basal ganglia of MRI-adapted, awake rhesus monkeys using functional magnetic resonance imaging (fMRI). In the studies proposed for this project, we will utilize fMRI to measure age-related changes in the BOLD response to various DA agonists. Specifically, we plan to compare the effects of apomorphine with the DA receptor-specific agonists SKF-81297 (D1 agonist) and LY17155 (quinpirole, a D2 agonist). We will then determine the relationship between pharmacologically evoked BOLD responses and underlying neural activity in specific regions of interest (ROD by using multiple single-unit electrophysiological recording. We will also utilize anatomical MRI to determine age-related changes in the volume of key basal ganglia structures. We will also measure iron accumulation in the globus pallidus and the substantia nigra. These anatomical measures will be conducted to test our hypothesis that age-related functional changes in these nuclei contribute more to behavioral deficits than do structural changes. We will assess the effects of GDNF on these functional and morphological measures in order to determine whether the potent DA neurotrophic factor possesses restorative properties in the basal ganglia. These studies will complement the behavioral, neurochemical and histopathological/biochemieal studies of Projects by Gash and Berhardt.