MOTORIC DECLINES IN AGING: MRI STUDIES OF NIGROSTRIATAL DOPAMINERGIC SYSTEM

这项研究的中心假设是，与年龄相关的运动功能下降是由动物和人类黑质纹状体多巴胺能系统的功能变化引起的。为了解决这个问题，我们的小组已经开发了技术来测量药理学诱发的血氧水平依赖（BOLD）的变化，在基底神经节的MRI适应，清醒的恒河猴使用功能性磁共振成像（fMRI）。在本项目的研究中，我们将利用fMRI来测量BOLD对各种DA激动剂反应的年龄相关变化。具体而言，我们计划比较阿扑吗啡与DA受体特异性激动剂SKF-81297（D1激动剂）和LY 17155（quinpirole，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在特定感兴趣区域（ROD）中的诱发BOLD反应和潜在神经活动之间的关系。我们还将利用解剖MRI来确定关键基底神经节结构体积的年龄相关变化。我们还将测量苍白球和黑质中的铁积累。这些解剖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更有助于 行为缺陷比结构变化更重要。我们将评估GDNF对这些功能和形态学措施的影响，以确定是否有效的DA神经营养因子具有恢复性质的基底神经节。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.