Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging

描述(由申请人提供)：本申请旨在解决认知老化领域中一个尚未解决的基本问题，即区分健康认知老化(HCA)和不健康认知老化(UCA)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老化背离的年龄附近发展的生物标记物，因为这些似乎特别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检验这一假设，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通过微阵列和免疫组织化学技术所做的工作，表明大鼠在中年前后髓鞘生成增加，而不健康的认知衰老开始出现在同一个年龄段。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，研究认知衰老的神经生物学相关性。它将涉及最先进的海马片细胞内电生理学、记录的神经元中伴随的钙离子成像、广泛的免疫组织化学和一组染色、扩散张量成像(MRI/DTI)、每只大鼠的单独微阵列分析，以及每种动物的实质性行为测试。将在每只动物身上应用多种技术。这些研究将追求在同一动物中将认知老化的电生理和基因组标记联系起来的目标，并将在横断面和纵向分析中将认知功能与髓鞘结构和密度联系起来。此外，髓鞘形成的过程将在长期研究中改变，即操纵膳食铁和/或使用铜试剂治疗。遭受髓鞘生成改变的动物将接受一系列行为、电生理、微阵列和免疫组织化学分析的测试，以测试向UCA的转换已经放缓的命题，如果确实如此，则确定这是通过哪些海马体途径发生的。总体而言，这些研究应该实质上阐明区别UCA和HCA的神经生物学标记物，并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已建立的大鼠衰老模型中进行，该模型显示了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记物和过程。因此，所提出的研究在确定人类认知老化的过程中应该具有预测和治疗价值。

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.