Neural and Behavioral Profiles of Cognitive Aging

描述(申请人提供)：随着寿命的增加，发病率的下降，以及老年人希望过上具有智力挑战的生活，认知老化已经成为一个主要的社会问题。衰老不会导致弥漫性大脑功能障碍，而是针对选定的大脑区域，特别是额叶和海马结构。海马体结构本身由独立但相互关联的亚区组成。广泛的研究已经证实，海马亚区对功能障碍的机制具有不同的易感性。每个分区域都有一个分子上不同的神经元群体，为观察到的不同脆弱性提供了分子基础。一系列体内功能成像和尸检研究表明：A)与阿尔茨海默病的早期阶段不同，正常衰老主要针对齿状回；B)齿状回特别容易受到血糖升高的影响；以及C)齿状回从体育锻炼中受益不同。此外，初步数据表明，D)与年龄相关的齿状回功能障碍与组蛋白修饰相关分子的表达变化有关。在这项建议中，我们将这些观察结果联系到一个一般的自上而下的模型中，提出了病因、分子机制和改善年龄相关海马区功能障碍的方法。这项提议的总体目标是测试模型的假设元素。一般的方法是使用功能磁共振成像的高分辨率变体，可以随时间纵向评估小鼠的海马体结构。通过映射各种操作对活的齿状回的影响，这种方法将允许我们测试模型的特定假设。通过确认或修改自上而下的模型，这一建议具有潜在的重要意义，因为它将扩大我们对机制的理解，但更重要的是，它将直接导致改善与年龄相关的海马区功能障碍的方法。 公共卫生相关性：随着寿命的延长和发病率的下降，认知老龄化已成为一个主要的社会问题。这项提议的短期目标是依靠之前的发现来测试关于导致认知老化的病因和分子机制的假说。一般的方法是使用一种高分辨率的功能成像变体，可以随着时间的推移纵向评估小鼠的大脑。除了了解功能障碍的机制外，这项建议的最终目标是学习如何改善认知老化。

DESCRIPTION (provided by applicant): With increasing longevity, decreasing morbidity, and as older individuals expect to live intellectually challenging lives, cognitive aging has emerged as a major societal problem. Aging does not cause diffuse brain dysfunction but rather targets select brain areas, in particular the frontal lobes and the hippocampal formation. The hippocampal formation itself is made up of separate but interconnected subregions. A wide range of studies have established that hippocampal subregions are differentially vulnerable to mechanisms of dysfunction. Each subregion houses a molecularly-distinct population of neurons, providing a molecular basis for the observed differential vulnerability. A range of in vivo functional imaging and post-mortem studies suggest that: A) In contrast to early stages of Alzheimer's disease, normal aging differentially targets the dentate gyrus; B) the dentate gyrus is differentially vulnerable to elevations in blood glucose; and, C) the dentate gyrus differentially benefits from physical exercise. Additionally, preliminary data suggest that, D) age-related dentate gyrus dysfunction is linked to changes in the expression of molecules related to histone modification. In this proposal we link these observations into a general top-down model, suggesting etiologies, molecular mechanisms, and ways to ameliorate age-related hippocampal dysfunction. The general goal of this proposal is to test hypothesized elements of the model. The general approach is to use a high-resolution variant of functional magnetic resonance imaging that can assess the mouse hippocampal formation longitudinally over time. By mapping the effects various manipulations have on the living dentate gyrus, this approach will allow us to test specific hypotheses of the model. By confirming or modifying the top-down model, this proposal is potentially significant as it will expand our mechanistic understanding, but more importantly, it will directly lead to ways to ameliorate age-related hippocampal dysfunction. PUBLIC HEALTH RELEVANCE: With increasing longevity and decreasing morbidity, cognitive aging has emerged as a major societal problem. The short term goal of this proposal is to rely on previous findings to test hypotheses about etiologies and molecular mechanisms that contribute to cognitive aging. The general approach is to use a high-resolution variant of functional imaging that can assess the mouse brain longitudinally over time. More than just understanding mechanisms of dysfunction, the ultimate goal of this proposal is learn how to ameliorate cognitive aging.