Histone acetylation and cognitive aging

描述（由申请人提供）：随着寿命的延长，发病率的降低，以及老年人期望过上具有智力挑战性的生活，认知老化已成为一个主要的社会问题。衰老不会引起弥漫性脑功能障碍，而是针对特定的脑区域，特别是额叶和海马结构。海马结构本身由独立但相互连接的子区域组成。广泛的研究已经确定，海马亚区是不同的功能障碍的机制脆弱。每个子区域都有一个分子上不同的神经元群体，为观察到的差异脆弱性提供了分子基础。一系列体内功能成像和死后研究表明：A）与阿尔茨海默病的早期阶段相比，正常衰老不同地靶向齿状回; B）齿状回对血糖升高的敏感性不同;以及C）齿状回不同地受益于体育锻炼。此外，初步数据表明，D）年龄相关的齿状回功能障碍与组蛋白修饰相关分子表达的变化有关。在这个建议中，我们将这些观察结果链接到一个自上而下的模型中，提出病因，分子机制和改善年龄相关的海马功能障碍的方法。本提案的总体目标是测试模型的假设要素。一般的方法是使用功能性磁共振成像的高分辨率变体，可以随着时间的推移纵向评估小鼠海马结构。通过绘制各种操作对活体齿状回的影响，这种方法将使我们能够测试模型的特定假设。通过确认或修改自上而下的模型，这一提议具有潜在的意义，因为它将扩大我们对机制的理解，但更重要的是，它将直接导致改善年龄相关的海马功能障碍的方法。 公共卫生相关性：随着寿命的延长和发病率的降低，认知老化已成为一个主要的社会问题。这项提案的短期目标是依靠以前的发现来测试有关导致认知老化的病因学和分子机制的假设。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大脑。不仅仅是了解功能障碍的机制，这项提案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.