Quantitative Analysis of Cerebral Cortex in Aging Monkeys

描述（由申请人提供）：在与年龄相关的神经退行性疾病中，如阿尔茨海默病，皮质神经元的丧失是进行性认知障碍的可能原因。相比之下，在正常的衰老过程中，由于皮质神经元没有丢失，导致相对轻微的认知障碍的原因尚不清楚。然而，皮层神经元已被证明以多种方式变得功能失调，从连接皮层区域的髓鞘轴突的退化到体细胞动作电位产生的改变。皮层信息处理的一个关键功能组成部分是微柱，这是一个由神经元组成的垂直阵列，它们紧密相连，共同处理基本信息。典型的例子是视觉皮层的方向柱。越来越多的证据表明，与年龄相关的微柱组织变化可能是与年龄相关的皮层功能障碍的重要标志。微柱中与年龄相关的变化将利用一项恒河猴研究中提供的存档大脑材料来解决，在这项研究中，所有动物都进行了行为测试，以表征认知状态，大脑被采集用于神经生物学研究。第一个目标是获取全脑照片蒙太奇，以定量评估覆盖整个成年寿命的雄性和雌性恒河猴整个大脑皮层的微柱结构。这将确定与年龄相关的微柱破坏最严重的区域，以及这些变化与认知障碍最密切相关的区域。这将验证微柱结构的区域改变和相关的皮质功能障碍是与年龄相关的认知障碍的假说。在确定最受影响的皮质区域的基础上，Aim 2将利用免疫组织化学方法标记皮质神经元树突的细胞内细胞骨架元件。这些将被分析以检验树突结构的改变与微柱结构的破坏有关的假设。同样，Aim 3将利用NeuN免疫组织化学将神经元从胶质细胞中分离出来，从而单独分析胶质细胞的变化。这一目的将检验神经胶质分布的破坏与微柱的年龄相关破坏有关的假设。对于树突和胶质细胞，交叉相关方法将用于量化与微柱变化的关系，对于所有三个目标，多元方法将评估与认知障碍的关系。这些数据将产生关于微柱功能障碍原因的可测试的机制假设，并将深入了解与年龄相关的皮层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gaba能神经元群体和将皮层结合在一起的细胞间粘附分子的分布。公共卫生相关性：在正常的衰老过程中，认知功能障碍的发生并不会导致皮层神经元的丢失，但有证据表明，作为微柱组织的皮层神经元垂直排列的结构被破坏。这些微柱是大脑皮层的基本计算单元，它们与年龄相关的退化与年龄相关的认知障碍有关。研究人员将使用先进的定量方法，并将其与树突结构和神经胶质细胞的变化进行比较，以确定与年龄相关的认知障碍的潜在过程。

DESCRIPTION (provided by applicant): 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 the 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. PUBLIC HEALTH RELEVANCE: 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.