Quantitative Analysis of Cerebral Cortex in Aging Monkeys

衰老猴子大脑皮层的定量分析

基本信息

批准号：
7919022
负责人：
Luis R Cruz Cruz
金额：
$ 20.51万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919022
关键词：
5 year old Accounting Action Potentials Address Adult Affect Age Age-Years Age-associated memory impairment Aging Aging-Related Process Algorithms Alzheimer&apos s Disease Anatomy Animal Model Animals Apical Architecture Area Astrocytes Atrophic Axon Behavioral Binding Boston Brain Cells Cerebral cortex Cognition Cognitive Computer Simulation Data Dendrites Deterioration Digital Photography Elements Female Fiber Frozen Sections Functional disorder Funding Future Generations Harvest Human Image Analysis Immunohistochemistry Impaired cognition Impairment Indium Individual Inflammation Intercellular Adhesion Molecules Interdisciplinary Study Label Learning Length Longevity Macaca mulatta Maps Measures Memory Methods Microglia Modeling Monkeys Myelin Neocortex Neurobiology Neurodegenerative Disorders Neuroglia Neurons Neuropil Outcome Pathology Periodicity Physics Population Positioning Attribute Prefrontal Cortex Process Program Research Project Grants Progress Reports Protocols documentation Proxy Publications Publishing Quantitative Evaluations Ranvier&apos s Nodes Research Personnel Series Staging Staining method Stains Structure Study Subject Study models Synapses System Testing Tissues Uncertainty Universities Visual Cortex Width Work age effect age related base case-based cognitive function density digital executive function information processing insight male mild neurocognitive impairment myelination neuronal cell body neuronal excitability normal aging orientation columns public health relevance spatial relationship young adult

项目摘要

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.

描述（由申请人提供）：在与年龄相关的神经退行性疾病中，如阿尔茨海默氏病，皮质神经元的丧失可能是进行性认知障碍的原因。相反，在正常衰老中，由于皮质神经元不会丢失，因此相对温和的认知障碍的原因尚不清楚。然而，皮质神经元已被证明会以多种方式变得功能失调，从髓鞘轴突的恶化，这些骨髓轴突相互连接的皮质区域到SOMA的动作电位产生变化。皮质信息处理的关键功能组成部分是MicroColumn，这是紧密互连的神经元的垂直阵列，并共同使用以处理基本信息。经典的示例是视觉皮层的方向列。积累的证据表明，与年龄相关的组织组织的变化可能是与年龄相关的皮质功能障碍的重要标志。通过对恒河猴的研究可用的档案脑材料来解决与年龄相关的变化，其中所有动物均经过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。第一个目的是获取整个脑光官，以定量评估覆盖整个成人寿命的男性和雌性恒河猴的整个大脑皮层的微柱结构。这将确定在微柱中发生与年龄相关的最大干扰以及这些变化与认知障碍最密切相关的区域。这将检验以下假设：微柱结构中的区域变化和相关的皮质功能障碍会导致与年龄相关的认知障碍。基于对大多数受影响的皮质区域的鉴定，AIM 2将利用免疫组织化学方法来标记皮质神经元树突的细胞内细胞骨架元素。这些将进行分析，以检验以下假设：树突结构的改变与微柱结构的破坏有关。同样，AIM 3将利用Neun免疫组织化学将神经元与神经胶质分开，从而可以单独分析神经胶质变化。该目的将检验以下假设：胶质分布的破坏与年龄相关的小colt虫的破坏有关。对于树突和神经胶质，将使用跨相关方法来量化与微柱变化的关系，对于所有三种目标，多元方法将评估与认知障碍的关系。这些数据将产生有关微船员功能障碍原因的可检验的机械假设，并将提供有关与年龄相关的皮质功能障碍和认知障碍的基础的见解。这项研究的未来方向将包括对少量但功能上重要的GABA能神经元的分析以及将皮质结合在一起的细胞间粘附分子的分布。公共卫生相关性：在正常衰老中，认知功能障碍发生而不会丧失皮质神经元，但证据表明破坏了被组织为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元，它们与年龄相关的降解与与年龄相关的认知障碍相关。这些将使用先进的定量方法研究，并将其与树突结构和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基础过程。