Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging

健康认知衰老中的海马电生理学和髓磷脂生成

• 批准号: 8132938
• 负责人: PHILIP W. LANDFIELD
• 金额: $ 57.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132938
• 关键词: Address; Age; Age-Months; Aging; Anemia; Animal Feed; Animal Model; Animals; Astrocytes; Behavioral; Binding; Bioenergetics; Bioinformatics; Biological Markers; Brain; Cholesterol; Cognition; Cognitive; Cognitive aging; Corpus Callosum; Cuprizone; Data; Diet; Dietary Iron; Diffusion Magnetic Resonance Imaging; Elderly; Electrophysiology (science); Event; Exhibits; Fostering; Gene Expression; Genes; Genomics; Guanosine Triphosphate Phosphohydrolases; Hemochromatosis; Hippocampus (Brain); Human; Image; Immune; Immunohistochemistry; Impaired cognition; Individual; Inflammation; Inflammatory; Intake; Intervention; Investigation; Iron; Left; Link; Lipids; Liver; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Memory; Methods; Microarray Analysis; Modeling; Monkeys; Myelin; Nature; Neurites; Neurobiology; Neurons; Oligodendroglia; Oxidative Stress; Pathway interactions; Performance; Phase; Play; Process; Protocols documentation; Rattus; Regulation; Research; Resources; Role; Sampling; Serum; Signal Transduction; Slice; Staining method; Stains; Stimulus; Structure; Techniques; Testing; Therapeutic; Translating; Up-Regulation; Validation; Work; age related; aged; aging brain; base; behavior test; biological adaptation to stress; cognitive function; density; indexing; insight; interest; middle age; morris water maze; multidisciplinary; myelination; programs; protein degradation; public health relevance; response; trafficking; young adult

DESCRIPTION (provided by applicant): This application proposes to address a fundamental unresolved question in the field of cognitive aging, the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging, as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased around midlife in rats, the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices, concomitant Ca2+ imaging in recorded neurons, extensive immunohistochemistry with a battery of stains, diffusion tensor imaging (MRI/DTI), separate microarray analysis of each individual rat, and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further, the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral, electrophysiological, microarray and immunohistochemical analyses, to test the proposition that conversion to UCA has been slowed and, if it has, to determine through which hippocampal pathways this occurred. Overall, these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA, and should importantly determine the role of myelinogenic programs in cognitive aging. Further, the proposed longitudinal studies should have direct translational relevance. PUBLIC HEALTH RELEVANCE: This proposed research will be conducted in an established rat model of aging, which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore, the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.

描述（由申请人提供）：本申请提议解决认知衰老领域的基本未解决的问题，即神经生物学因素的性质，这些因素将健康认知衰老（HCA）与不健康认知衰老（UCA）（UCA）的人区分开来。研究的重点将放在生物标志物与健康认知衰老不健康的差异时代发展的生物标志物上，因为这些似乎特别有可能提供有关因果机制的重要见解。该项目的主要重点还将检验以下假设：海马中髓源原理的中年激活是将HCA转化为UCA的重要因素。这种观点源于我们最近对微阵列和免疫组织化学技术的工作，表明大鼠中期周围的髓质生成增加了，与不健康的认知衰老开始出现相同的年龄范围。拟议的研究将包括一个大型的多学科项目，旨在在既定的大鼠衰老模型中就认知衰老的神经生物学相关性获得独特的综合观点。它将涉及海马切片中的最新细胞内电生理学，记录神经元中的Ca2+成像，广泛的免疫组织化学和一系列污渍，扩散量张量成像（MRI/DTI），每种单独的老鼠的单独微阵列分析和每种动物的实质性行为测试。每只动物将应用多种技术。这些研究将追求与同一动物认知衰老的电生理学和基因组标记相关联的目的，并将认知功能与乳糖结构和横截面和纵向分析中的密度联系起来。此外，在操纵饮食铁和/或用丘比特治疗的长期研究中，脊髓纤维发生的过程将改变。经过改变脊髓纤维化的动物将在一系列行为，电生理学，微阵列和免疫组织化学分析上进行测试，以测试以下主张，即转化为UCA的人已减慢，并且（如果有）确定这是哪种发生的海马途径。总体而言，这些研究应实质性地阐明将UCA与HCA区分开的神经生物学标志物，并应重要地确定骨髓生成程序在认知衰老中的作用。此外，拟议的纵向研究应具有直接的翻译相关性。 公共卫生相关性：这项拟议的研究将在既定的老化衰老模型中进行，该模型表明与人类衰老相关。这些研究将阐明影响健康和不健康认知衰老的差异的过程和过程。因此，拟议的研究在确定人类认知衰老的过程中应具有预测性和治疗价值。