NEURONS

对衰老恒河猴的行为研究清楚地表明 与年龄相关的重大功能变化可能反映 皮质功能障碍。然而，从这个项目中观察到的 结果表明，在这两种情况下，都没有明显的神经元随着年龄的增长而丧失。 大脑皮层或海马体结构也不存在重大的 突触。因此，神经元和突触的丧失似乎不是主要的 与年龄相关的皮质功能障碍的因素。相比之下，量化的 MRI图像分析显示皮质下白质丢失 我们和同事的EM研究已经证明了一个时代-- 营养不良的髓鞘相对增多。后一种观察结果可能 反映髓鞘的原发损伤或对 神经元及其轴突。使用正电子发射计算机断层扫描技术，我们观察到了一个年龄- 皮质血流量和代谢的相关减少以及随后的 用氧化酶标记物对脑组织进行分析 细胞色素氧化酶显示这些标记物随年龄增长而减少 神经新陈代谢的研究。根据这些调查结果，总体上 这个项目的目标是观察皮质神经元 确定与年龄相关的变化的类型和程度 发生在20岁以上猴子身上的年龄相关性认知功能障碍 几年前。这些研究将集中在海马体/内嗅觉 皮质，视觉系统的17区和前额叶的46区 大脑皮层。将进行的具体实验是：1)使用 组织化学和原位杂交方法测定 氧化代谢标志物随年龄变化的程度。2) 使用载玻片上的受体放射自显影来确定 以及选定的神经递质受体的变化的分布。3) 将体外切片制备用于神经生理学研究 突触反应、长时程增强、膜的研究 选择性神经递质受体的特性和反应性 激动剂和拮抗剂。在这些实验过程中，神经元 会充满生物细胞素和它们树突的范围 进行了形态分析。4)使用电子显微镜方法 量化选定区域层中突触的类型和数量 17、46和内嗅皮层。5)使用电子显微镜 方法定量测定大鼠脑内轴突的数量和形态 穹隆、前连合和穿通径。6)使用光驱 用于估计神经元数量并确定是否 在选定的区域有神经元丢失。总而言之，这些研究 将确定与年龄相关的变化的范围和一般性 大脑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.