MANIPULATION OF BASAL GANGLIA AGING BY DIET AND DOPAMINE

本研究将探讨啮齿类动物基底神经节老化的操作 重点是GFAP的转录变化，GFAP是一种中间体， 星形胶质细胞的细丝，显示在 衰老 除了GFAP，其他老化的星形胶质细胞标志物（apoE和apoJ） 也增加对病变的反应，这表明假设 一些自发的老化变化代表了星形胶质细胞对 与对损伤的急性反应相同的刺激。 作为一个理由， 这些研究操纵老化，慢性饮食限制（DR） 减少纹状体多巴胺D2受体的年龄相关损失， 多巴胺受体激动剂培高利特（pergolide，PERG）减少黑质纹状体的损失， terminals. 此外，DR减弱了星形胶质细胞的年龄相关性增加， 纹状体中的GFAP mRNA（初步数据），正如我们在 海马体和下丘脑。 我们假设操纵衰老 慢性DR或PERG在基底神经节中的作用机制相同， 减轻刺激神经胶质过度活跃的氧化损伤。 在 特别是，我们将研究DR和PERG如何影响神经胶质细胞的年龄变化， 为了验证激活的小胶质细胞增加 TGF-β 1和其他细胞因子反过来激活星形胶质细胞， 增加GFAP和apoJ（丛生蛋白）产生。 我们亦会研究 D2受体mRNA，一种在衰老过程中减少的神经元标记物。 氧化损伤将在蛋白质和脂质中直接测定。 我们 还将研究GFAP对以下反应的转录机制： 损伤和老化。 这些研究探索了基底节细胞中的机制， 在正常衰老过程中，衰老会影响运动功能的变化， 可能增加物质灾难性损失风险的变化 黑质神经元导致帕金森病（PD）。

This study will examine manipulations of basal ganglia aging in rodents with an emphasis on transcriptional changes in GFAP, an intermediate filament of astrocytes that shows a general increase in prevalence during aging. Besides GFAP, other astrocyte markers of aging (apoE and apoJ) also increase in response to lesioning, which suggests the hypothesis that some spontaneous aging changes represent responses of astrocytes to the same stimuli as in acute responses to lesions. As a rationale for these studies on the manipulation of aging, chronic diet restriction (DR) reduced the age-related loss of striatal dopaminergic D2-receptors, while the DA agonist pergolide (PERG) reduced the loss of nigrostriatal terminals. Moreover, DR attenuated age-related increase of astrocyte GFAP mRNA in the striatum (preliminary data), as we have found in hippocampus and hypothalamus. We hypothesize that manipulation of aging in the basal ganglia by chronic DR or PERG share common mechanisms by attenuating oxidative damage that stimulates glial hyperactivity. In particular, we will examine how DR and PERG influence age changes in glia to test the hypothesis that activated microglia increase production of TGF-Beta1 and other cytokines that, in turn, activate astrocytes to increase production of GFAP and apoJ (clusterin). We will also examine the D2-receptor mRNA, a neuronal marker which decreases during aging. Oxidative damage will be directly assayed in proteins and lipids. We will also examine transcriptional mechanisms in the responses of GFAP to lesions and aging. These studies probe mechanisms in basal gangliar aging that bear on changes in motor functions during normal aging and changes that may increase the risk of catastrophic loss of substantia nigra neurons that lead to Parkinson disease (PD).