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: 7923266
• 负责人: PHILIP W. LANDFIELD
• 金额: $ 57.8万
• 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/7923266
• 关键词: Address; Age; Age-Months; Aging; Anemia; Animal Feed; Animal Model; Animals; Arts; 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; Figs - dietary; 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）：本申请提出解决认知老化领域中的基本未解决的问题，即区分健康认知老化（HCA）个体与不健康认知老化（UCA）个体的神经生物学因素的性质。研究的重点将是在不健康认知衰老与健康认知衰老分化年龄附近发展的生物标志物，因为这些生物标志物似乎特别有可能为因果机制提供重要见解。该项目的一个主要重点也将是测试假设，即海马体中髓鞘生成程序的中年激活是将HCA转化为UCA的重要因素。这一观点源于我们最近的工作与微阵列和免疫组织化学技术表明，髓鞘生成增加中年大鼠，在同一年龄段，不健康的认知老化开始出现。拟议的研究将包括一个大型的多学科项目，旨在获得一个独特的综合角度对神经生物学相关的认知老化在一个既定的大鼠模型的老化。它将涉及海马切片中最先进的细胞内电生理学，记录的神经元中伴随的Ca 2+成像，用一系列染色剂进行广泛的免疫组织化学，扩散张量成像（MRI/DTI），对每只大鼠进行单独的微阵列分析，以及对每只动物进行大量的行为测试。将在每只动物中应用多种技术。这些研究的目的是在同一动物中将认知老化的电生理学和基因组标志物相关联，并将认知功能与横截面和纵向分析中的髓鞘结构和密度相关联。此外，髓鞘形成的过程将在操纵膳食铁和/或用cuprizone治疗的长期研究中改变。将对髓鞘发生改变的动物进行一系列行为、电生理、微阵列和免疫组织化学分析，以测试向UCA转化已经减慢的命题，如果已经减慢，则确定这是通过哪些海马通路发生的。总的来说，这些研究应该充分阐明区分UCA和HCA的神经生物学标志物，并且应该重要地确定髓鞘生成程序在认知老化中的作用。此外，拟议的纵向研究应该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已建立的大鼠衰老模型中进行，该模型显示出与人类衰老的相关性。这些研究将阐明影响健康和不健康认知老化差异的神经生物学标志物和过程。因此，拟议的研究应该在确定人类认知老化的过程中具有预测和治疗价值。