NEURONS

对衰老恒河猴的行为研究清楚地表明， 与年龄相关的显著功能变化可能反映 皮质功能障碍 然而，该计划的观察结果表明， 这表明，无论是在大脑中还是大脑中， 皮质或海马结构也没有大的损失， 突触 因此，神经元和突触的丢失似乎不是一个主要的 与年龄相关的皮质功能障碍。 相比之下，定量 MRI图像分析显示皮质下白色物质丢失 我们和同事的EM研究表明， 与营养不良性髓鞘的增加有关。 后一种观察可以 反映了髓鞘的原发性损伤或对髓鞘变化的反应。 神经元及其轴突。 利用PET成像我们观察到一个年龄- 皮质血流量和代谢的相关减少以及随后的 用氧化酶标记物分析脑组织 细胞色素氧化酶显示这些标记物的年龄相关性减少 神经元代谢的过程。 根据这些发现， 这个项目的目的是观察皮层神经元， 确定年龄相关变化的类型和程度， 年龄相关的认知功能障碍发生在20岁以上的猴子身上， 岁的 这些研究将集中在海马/内嗅 皮质，视觉系统的17区和前额叶的46区 皮层具体的实验将进行：1）使用 组织化学和原位杂交方法，以确定 氧化代谢标志物的年龄相关变化程度。 （二） 使用载玻片上受体放射自显影来确定 和所选神经递质受体变化的分布。第三章 使用体外切片制备进行神经生理学检查， 突触反应研究，长时程增强，膜 特性和神经递质受体对选择的 激动剂和拮抗剂。 在这些实验过程中， 充满了生物胞素和它们的树突树 形态学分析。 4)用电子显微镜的方法 量化所选区域层中突触的类型和数量 17，46和内嗅皮层。 5)用电子显微镜 方法来量化轴突的数量和它们的形态在 穹窿、前连合和穿支通路。6）使用光学 分解器和分离器，以估计神经元数量并确定是否 在选定的区域有神经元缺失。 这些研究一起 将确定年龄相关变化的程度和一般性， 皮层神经元的功能和连接。

Behavioral studies of the aging rhesus monkey clearly demonstrate significant age-related functional changes that are likely to reflect cortical dysfunction. Yet observations from this program have demonstrated that there is no overt loss of neurons with age in either the cortex or the hippocampal formation nor is there a major loss of synapses. Thus it appears that neuron and synapse loss is not a major factor in age-related cortical dysfunction. In contrast, quantitative analysis of MRI images demonstrated a loss of subcortical white matter and EM studies by ourselves and colleagues have demonstrated an age- related increase in dystrophic myelin. This latter observation could reflect a primary damage to myelin or a response to changes in the neuron and its axon. Using PET imaging we have observed an age- related reduction in cortical blood flow and metabolism and subsequent analysis of brain tissue with markers for the oxidative enzyme cytochrome oxidase revealed an age-related reduction in these markers of neuronal metabolism. Based upon these findings, the overall objective of this project is to look at the cortical neuron to determine the type and extent of age-related changes that may underlie the age-related cognitive dysfunction that occurs in monkeys over 20 years of age. These studies will focus on the hippocampus/entorhinal cortex, area 17 of the visual system and area 46 of the prefrontal cortex. The specific experiments that will be conducted are: 1) To use histochemical and in situ hybridization methods to determine the extent of age-related changes in markers of oxidative metabolism. 2) To use on-the-slide receptor autoradiography to determine the extent and distribution of changes in selected neurotransmitter receptors. 3) To use the in vitro slice preparation for a neurophysiological investigation of synaptic responses, long term potentiation, membrane properties and neurotransmitter receptor responsivity to selected agonists and antagonists. In the course of these experiments neurons will be filled with biocytin and the extent of their dendritic tree analyzed morphologically. 4) To use electronmicroscopic methods to quantify the type and number of synapses in selected layers of areas 17, 46 and the entorhinal cortex. 5) To use electronmicroscopic methods to quantify the number of axons and their morphology in the fornix, anterior commissure and perforant path. 6) To use the optical disector and fractionator to estimate neuron number and determine if there is neuronal loss in selected areas. Together, these studies will establish the extent and generality of age-related changes in the function and connectivity of cortical neurons.