Quantitative Analysis of Cerebral Cortex in Aging Monkeys

描述(申请人提供)：在阿尔茨海默病等与年龄相关的神经退行性疾病中，皮质神经元的丧失可能是进行性认知障碍的原因。相比之下，在正常衰老中，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，皮质神经元已经被证明在许多方面变得功能失调，从连接皮质区域的有髓轴突的恶化到胞体动作电位产生的变化。皮层信息处理的一个关键功能组件是微柱，这是一个紧密相连的垂直神经元阵列，它们一起工作来处理基本信息。经典的例子是视觉皮质的方位栏。越来越多的证据表明，微柱组织的年龄相关性变化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变化将使用从恒河猴研究中获得的大脑档案材料来解决，在该研究中，所有动物都接受行为测试，以表征认知状态，并收集大脑进行神经生物学研究。第一个目标是获取全脑照片，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状结构。这将确定微柱中与年龄相关的干扰发生最严重的区域，以及这些变化与认知障碍最密切相关的区域。这将检验这样一种假设，即微柱结构的区域变化和相关的皮质功能障碍是年龄相关认知障碍的原因。在确定受影响最严重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素。这些都将被分析，以检验树突结构的变化与微柱状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与胶质细胞独特地分离出来，从而单独分析胶质细胞的变化。这一目标将检验这样一种假设，即胶质细胞分布的中断与年龄相关的微柱中断有关。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，将使用多变量方法来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说，并将为年龄相关性皮质功能障碍和认知障碍的基础提供洞察力。这项研究的未来方向将包括分析GABA能神经元的数量较少但功能显著的群体，以及将皮质结合在一起的细胞间黏附分子的分布。与公共健康相关：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，组织成微柱的皮质神经元垂直阵列的结构被破坏。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与年龄相关的认知损害相关。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.