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 在中枢神经系统的基底节，老年动物和人类的运动功能随着年龄的增长而下降。我们实验室和其他人之前的研究支持这样的假设，即与年龄相关的运动功能下降与DA神经元的强劲下降无关。相反，DA调节和释放的功能特性在含有DA的区域受到影响。我们最近研究的一个惊人发现是，由d-苯丙胺诱发的、用体内微透析测量的DA的躯体树突释放，在老年猴子的黑质中大大减少。利用MRI引导的立体定向手术，该项目将使用最近开发的方法，允许在麻醉猴子身上重复进行体内微透析措施。本方法与死后Western印迹免疫分析和高效液相-电化学法相结合，对幼年(5~9岁)、成年(13~16岁)和中老年晚期(20~25岁)恒河猴的壳核、尾状核、GPE和SN进行了研究。该项目将结合Gash项目的行为、组织学和免疫组织化学研究以及张项目的解剖和功能磁共振成像研究，对猴子基底节在衰老过程中的神经化学变化进行功能研究。此外，我们实验室最近的研究结果支持，胶质细胞源性神经营养因子(GDNF)可能能够恢复老化的DA神经元的功能。我们的第二系列神经化学研究将在中年后期/老年猴子身上进行，这些猴子接受了慢性黑质内注射Vehicle或GDNF，试图恢复或增强 衰老DA神经元的功能。这些研究涉及DA在衰老过程中运动行为减少中的作用，以及非人类灵长类动物中衰老的多巴胺能神经元的神经化学特性。

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.