NEUROCHEMICAL STUDIES OF THE AGING BASAL GANGLIA

我们的中心假设是多巴胺（DA）神经元功能特性的变化 中枢神经系统基底神经节中的神经递质参与老年动物和人类中与年龄相关的运动功能下降。我们实验室和其他人的先前研究支持这一假设，即与年龄相关的运动功能下降与DA神经元的强烈下降无关。相反，DA调节和释放的功能特性在含DA的区域受到影响。从我们最近的研究中一个惊人的发现是，体树突释放DA，诱发的d-安非他明和测量在体内微透析，大大减少了老年猴子的黑质。 利用MRI引导的立体定位手术，本项目将使用最近开发的方法，允许在麻醉猴中重复进行体内微透析测量。本方法与死后Western blot免疫分析和HPLC-EC法相结合，对幼龄（5-9岁）、成年（13-16岁）和中晚期/老年（20-25岁）恒河猴的壳核、尾状核、GPe和SN进行了研究。本项目将结合Gash项目的行为学、组织学和免疫组化研究以及Zhang项目的解剖学和功能MRI成像研究，对猴基底神经节在衰老过程中的神经化学变化进行功能研究。此外，我们实验室最近的结果支持胶质细胞源性神经营养因子（GDNF）可能能够恢复老年DA神经元的功能。我们的第二个系列的神经化学研究将在中年晚期/老年猴子中进行，这些猴子接受了慢性黑质内输注载体或GDNF，试图恢复或增强 老年DA神经元的功能。这些研究解决了DA在衰老中运动行为下降的作用，以及非人灵长类动物中老年多巴胺能神经元的神经化学性质。

It is our central hypothesis that changes in the functional properties of dopamine (DA) neurons in the basal ganglia of the CNS contribute to age-related declines in motoric function in aged animals and humans. Prior studies from our laboratory and others support the hypothesis that age-related declines in motoric function are not associated with a robust decline in DA neurons. Rather, functional properties of DA regulation and release are affected in DA-containing areas. A striking finding from our recent studies is that somatodendritic release of DA, evoked by d-amphetamine and measured with in vivo microdialysis, is greatly decreased in the substantia nigra of aged monkeys. Using MRI guided stereotaxic surgery, this Project will use recently developed methods that allow for repeated in vivo microdialysis measures in anesthetized monkeys. This method has been combined with postmortem Western blot immunoassays and HPLC-EC methods for studies of the putamen, caudate nucleus, GPe and SN of young adult (5-9 year old), adult (13-16 year old) and late middleage/aged (20-25 year old) rhesus monkeys. This project will perform functional studies of neurochemical changes to the monkey basal ganglia during aging in conjunction with the behavioral, histological and immunohistochemical studies of Project by Gash and anatomical and functional MRIimaging studies in Project by Zhang. In addition, recent results from our laboratory support that glial cell linederived neurotrophic factor (GDNF) may be capable of restoring function to aged DA neurons. Our second series of neurochemical studies will be performed in late middle-aged/aged monkeys that have received chronic intranigral infusions of vehicle or GDNF, in an attempt to restore or enhance the function of aged DA neurons. These studies address the role of DA in decreased motor behavior in aging and the neurochemical properties of aged dopaminergic neurons in nonhuman primates.