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: 8318674
• 负责人: PHILIP W. LANDFIELD
• 金额: $ 57.17万
• 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/8318674
• 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; Health; 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; iron deficiency; middle age; morris water maze; multidisciplinary; myelination; programs; protein degradation; 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）：本申请旨在解决认知衰老领域的一个根本未解决的问题，即区分健康认知衰老（HCA）个体和不健康认知衰老（UCA）个体的神经生物学因素的本质。这些研究的重点将放在不健康认知衰老与健康认知衰老分化年龄附近的生物标志物上，因为这些标志物似乎特别有可能为因果机制提供重要的见解。该项目的一个主要重点还将是验证一个假设，即中年激活海马体中的髓鞘生成程序是将HCA转化为UCA的重要因素。这一观点来源于我们最近用微阵列和免疫组织化学技术进行的研究，研究表明大鼠的髓鞘生成在中年前后增加，而在这个年龄段，不健康的认知衰老开始出现。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视角，在一个已建立的大鼠衰老模型中，认知衰老的神经生物学相关因素。它将涉及最先进的海马体切片细胞内电生理学，记录神经元的伴随Ca2+成像，广泛的免疫组织化学与一系列染色，扩散张量成像（MRI/DTI），每只大鼠的单独微阵列分析，以及每只动物的大量行为测试。每只动物将采用多种技术。这些研究将追求在同一动物中关联认知衰老的电生理和基因组标记的目标，并将在横断面和纵向分析中将认知功能与髓磷脂结构和密度联系起来。此外，在长期研究中，控制饮食铁和/或用铜酮治疗将改变髓鞘形成的过程。接受髓鞘发生改变的动物将接受一系列行为学、电生理学、微阵列和免疫组织化学分析的测试，以检验向UCA的转化是否减慢，如果确实如此，则确定这种转变是通过哪条海马通路发生的。总的来说，这些研究应该从本质上阐明区分UCA和HCA的神经生物学标记，并应该重要地确定髓鞘生成程序在认知衰老中的作用。此外，提出的纵向研究应具有直接的翻译相关性。