Quantitative Analysis of Cerebral Cortex in Aging Monkeys

项目总结/摘要 在与年龄相关的神经退行性疾病中，如阿尔茨海默病，皮层神经元的丧失是 很可能是导致认知障碍的原因相比之下，在正常老化，相对温和的原因 由于皮层神经元没有丢失，因此发展的认知障碍仍然不清楚。然而，皮质 神经元已经被证明在许多方面变得功能失调， 有髓轴突，其将皮层区域与索马处的动作电位产生的变化互连。一 皮层信息处理的关键功能成分是微柱，一种垂直排列的神经元 它们紧密相连，共同处理基本信息。一个经典的例子 是视觉皮层的方向柱。越来越多的证据表明， 微柱状组织可能是年龄相关的皮质功能障碍的重要标志。 微柱中与脑相关的改变将使用可从 对恒河猴的研究，其中对所有动物进行行为测试以表征认知状态， 大脑被收获用于神经生物学研究。第一个目标是获得整个大脑的照片蒙太奇， 定量评估男性和女性整个大脑皮层的微柱结构 恒河猴的整个成年期。这将确定与年龄有关的最大的地区 微柱中的中断发生，并且这些变化与认知最密切相关 损伤这将检验微柱状结构和相关的区域变化的假设， 皮质功能障碍导致与年龄相关的认知障碍。根据受影响最严重的国家的确定， Aim 2将利用免疫组织化学方法标记皮质区的细胞内细胞骨架成分， 皮层神经元的树突。这些将被分析，以测试假设，在树突状结构的改变， 与微柱状结构的破坏有关。同样，Aim 3将使用NeuN 免疫组化以独特地将神经元与神经胶质分开，从而允许单独分析神经胶质变化。 这一目标将检验胶质细胞分布的破坏与年龄相关的破坏有关的假设 微柱。对于树突和神经胶质两者，将使用交叉相关方法来量化树突和神经胶质细胞之间的相互作用。 与微柱变化的关系，对于所有三个目标，多变量方法将评估关系 有认知障碍 这些数据将产生关于微柱形成原因的可检验的机制假说。 功能障碍，并将提供深入了解与年龄相关的皮质功能障碍和认知障碍的基础。 这项研究的未来方向将包括分析小但功能重要的人群， GABA能神经元和将皮质结合在一起的细胞间粘附分子的分布。项目叙述 在正常的衰老过程中，认知功能障碍的发生并没有皮层神经元的损失，但有证据表明， 大脑皮层神经元垂直排列的结构被破坏，这些神经元被组织成微柱。这些 微柱是大脑皮层的基本计算单元， 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 并与树突结构和神经胶质细胞的变化进行比较，以确定年龄背后的过程- 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.