Spatial Analysis of Cerebral Cortex in Aging Monkeys

衰老猴子大脑皮层的空间分析

• 批准号: 7117220
• 负责人: H.Eugene STANLEY
• 金额: $ 32.82万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117220
• 关键词: Macaca mulatta; animal old age; behavior test; brain morphology; cerebral cortex; clinical research; cognition disorders; confocal scanning microscopy; immunocytochemistry; neurons; neuropsychology; psychological aspect of aging; short term memory; statistics /biometry

DESCRIPTION (provided by applicant): Quantitative methods for analyzing neuronal numbers have fueled advances in our knowledge of the brain but methods to study spatial organization have lagged. The microcolumn is a distinct vertical spatial organization that characterizes cerebral cortex. To quantitatively assess microcolumnar structure, we will adapt methods derived from statistical physics to analyze local spatial relationships among neurons as they are organized into microcolumns. Tissue for these studies will be obtained at no cost from young, middle aged and elderly rhesus monkeys that, as part of an NIA funded Program Project, have been behaviorally tested on tasks sensitive to age-related cognitive decline. Preliminary data confirms an age-related reduction in the strength of microcolumns in the prefrontal cortex. We will test the following hypotheses: (1) spatial organization of neurons into microcolumns is disrupted in normal aging despite of the lack of neuronal death; and (2) disruption of microcolumns will be associated with age-related cognitive decline. Hence, in Aim 1 we will develop a fully automated density map method to quantify the average "microcolumnar" structure across diverse interconnected cortical regions which are part of the circuitry of the pertinent cognitive functions. To do this efficiently we will apply our method to standard whole brain coronal series of 30 micron thick frozen sections stained with thionin. Because such sections shrink dramatically in the z plane, they only provide spatial neuronal locations in two dimensions (2D). In Aim 2 we will extend our analysis to 3D to validate the 2D density map method by acquiring x,y,z neuronal locations from thick celloidin sections that don't differentially shrink in the z dimension, as well as immunocytochemically stained sections analyzed with the confocal microscope. We will then extend our method to generate 3D density maps and determine if "correction" factors can be applied to the 2D density maps of Aim 1. In Aim 3 we will identify regions showing age-related changes in microcolumnar organization and then determine if these disruptions are associated with age-related cognitive decline. The importance of these investigations derives from two factors. First, currently available methods can only partially test the hypotheses proposed, so the methods we develop and validate will provide efficient and reliable new ways to quantify local spatial relationships. Second, the application of these methods to neuroanatomy of normal aging may allow us to detect subtle, sublethal, changes in cortical structure that reflect progressive neuronal dysfunction when neuronal loss is not a factor.

描述(申请人提供)：分析神经元数量的定量方法推动了我们对大脑知识的进步，但研究空间组织的方法却滞后了。微柱是大脑皮层独特的垂直空间组织。为了定量评估微柱结构，我们将采用来自统计物理的方法来分析神经元之间的局部空间关系，因为它们被组织成微柱。这些研究的组织将免费从年轻、中年和老年恒河猴身上获得，作为NIA资助的项目的一部分，这些恒河猴已经在对年龄相关认知能力下降敏感的任务中进行了行为测试。初步数据证实，与年龄相关的前额叶皮质微柱强度降低。我们将检验以下假设：(1)尽管没有神经元死亡，但正常衰老时，神经元微柱的空间组织被破坏；以及(2)微柱的破坏将与年龄相关的认知能力下降有关。因此，在目标1中，我们将开发一种全自动密度图方法来量化不同相互连接的皮质区域的平均“微柱状”结构，这些区域是相关认知功能回路的一部分。为了有效地做到这一点，我们将我们的方法应用于标准的全脑冠状序列，30微米厚的冰冻切片染有硫胺。因为这样的截面在z平面上急剧缩小，它们只提供了二维(2D)的空间神经元位置。在目标2中，我们将把我们的分析扩展到3D，以验证2D密度图方法，方法是从在z维度上没有差异收缩的厚纤维蛋白切片以及用共聚焦显微镜分析的免疫细胞化学染色的切片中获得x，y，z神经元的位置。然后，我们将扩展我们的方法来生成3D密度图，并确定是否可以将“校正”因子应用于目标1的2D密度图。在目标3中，我们将识别微柱组织中显示年龄相关变化的区域，然后确定这些干扰是否与年龄相关的认知能力下降有关。这些调查的重要性源于两个因素。首先，现有的方法只能部分验证所提出的假设，因此我们开发和验证的方法将提供有效和可靠的新方法来量化局部空间关系。其次，将这些方法应用于正常衰老的神经解剖学可能使我们能够发现皮质结构的细微、亚致命性变化，当神经元丢失不是一个因素时，这些变化反映了进行性神经元功能障碍。