Quantitative Analysis of Cerebral Cortex in Aging Monkeys

项目摘要/摘要 在阿尔茨海默病等与年龄相关的神经退行性疾病中，皮质神经元的丢失是 可能是进行性认知障碍的原因。相比之下，在正常衰老中，病因相对较轻 由于大脑皮层神经元没有丢失，导致认知障碍的原因尚不清楚。然而，皮质 神经元已经被证明在许多方面变得功能失调，从退化到 有髓轴突将皮质区域与胞体动作电位产生的变化相互连接。一个 皮层信息处理的关键功能组件是微柱，即神经元的垂直阵列 它们紧密联系在一起，共同处理基本信息。经典的例子 是视皮层的定向柱。越来越多的证据表明，与年龄相关的变化 微柱状结构可能是年龄相关性皮质功能障碍的重要标志。 微柱中与年龄相关的改变将使用可从 对恒河猴的研究，对所有动物进行行为测试，以表征认知状态和 大脑是用来进行神经生物学研究的。第一个目标是获取整个大脑的照片图像以 定量评估男性和女性整个大脑皮层的微柱状结构 覆盖整个成年生命的恒河猴。这将确定与年龄关系最密切的地区 微柱的中断发生，并且这些变化与认知最密切相关 减损。这将检验这样一种假设，即微柱状结构和相关的区域变化 皮质功能障碍是与年龄相关的认知障碍的原因。根据受影响最大的 皮质区域，AIM 2将利用免疫组织化学方法标记细胞内细胞骨架元素 皮质神经元的树突。将对这些进行分析，以检验树突结构的变化 与微柱状建筑的破坏有关。同样，Aim 3将使用Neun 免疫组织化学以独特的方式将神经元从胶质细胞中分离出来，从而可以单独分析胶质细胞的变化。 这一目标将检验这样的假设，即神经胶质分布的中断与年龄相关的中断有关 微柱。对于树突和胶质细胞，将使用互相关方法来量化 与微柱变化的关系，对于所有三个目标，多变量方法将评估这种关系 有认知障碍。 这些数据将产生关于微柱状的原因的可测试的机械假说 并将提供对与年龄相关的皮质功能障碍和认知障碍的基础的洞察。 这项研究的未来方向将包括分析少数但具有重要功能的人群 GABA能神经元和将皮质结合在一起的细胞间黏附分子的分布。项目叙事 在正常衰老中，认知功能障碍的发生没有皮质神经元的损失，但有证据表明 破坏组织成微柱的皮质神经元垂直阵列的结构。这些 微柱是大脑皮层的基本计算单位，它们与年龄相关的退化 与年龄相关的认知障碍有关。这些将使用先进的定量方法进行研究。 并与树突状结构和胶质细胞的变化进行比较，以确定年龄- 相关的认知障碍。

Project Summary/Abstract In age-related neurodegenerative disorders like Alzheimer's disease, the loss of cortical neurons is the likely cause of progressive cognitive impairments. In contrast, in normal aging, the cause of the relatively mild cognitive impairments that develops remains unclear as cortical neurons are not lost. However, cortical neurons have been shown to become dysfunctional in a number of ways ranging from deterioration of myelinated axons that interconnect cortical areas to changes in action potential generation at the soma. A critical functional component of cortical information processing is the microcolumn, a vertical array of neurons that are tightly interconnected and that work together to process fundamental information. The classic example is the orientation column of visual cortex. Accumulating evidence suggests that age-related changes in microcolumnar organization may be an important marker of age-related cortical dysfunction. Age-related alterations in microcolumns will be addressed using archival brain material available from a study of rhesus monkeys in which all animals are behaviorally tested to characterize cognitive status and the brains are harvested for neurobiological study. The first aim is to acquire whole brain photomontages to quantitatively assess microcolumnar structure throughout the entire cerebral cortex of both male and female rhesus monkeys that cover the entire adult life span. This will identify regions where the greatest age-related disruptions in microcolumns occur and where those changes are most strongly related to cognitive impairments. This will test the hypothesis that regional alterations in microcolumnar structure and associated cortical dysfunction account for age-related cognitive impairments. Based on the identification of most affected cortical areas, Aim 2 will utilize immunohistochemical methods to label intracellular cytoskeletal elements of dendrites of cortical neurons. These will be analyzed to test the hypothesis that alterations in dendritic structure are associated with the disruption of microcolumnar architecture. Similarly, Aim 3 will utilize NeuN immunohistochemistry to uniquely separate neurons from glia allowing for separate analysis of glia changes. This aim will test the hypothesis that disruptions in glial distribution are associated with age-related disruption of microcolumns. For both dendrites and glia, cross correlation methods will be used to quantify the relationship to microcolumn changes and for all three aims multivariate methods will assess the relationship with cognitive impairments. These data will generate testable mechanistic hypotheses regarding the causes of microcolumnar dysfunction and will provide insight into the basis of age-related cortical dysfunction and cognitive impairment. Future directions for this study will include analysis of the small but functionally significant population of GABAergic neurons and the distribution of intercellular adhesion molecules that bind the cortex together. Project Narrative In normal aging, cognitive dysfunction occurs without the loss of cortical neurons yet evidence indicates disruption of the architecture of vertical arrays of cortical neurons that are organized as microcolumns. These microcolumns are a fundamental computational unit of the cerebral cortex, and their age-related degradation correlates with age-related cognitive impairment. These will be studied using advanced quantitative methods and compared with changes in dendritic structure and glia cells to determine the processes underlying age- related cognitive impairments.