Neural Mechanisms of Cognitive Decline in Aging

描述(申请人提供)：越来越多的证据表明，在正常衰老过程中，由前额叶皮质支持的执行功能是认知能力最早和最严重的损害之一。执行功能，包括注意力、工作记忆和认知灵活性，对于成功引导适应性行为和认知的更高层次方面(如决策)至关重要。皮质边缘g-氨基丁酸(GABA)能抑制回路的破坏可能会对执行功能产生深远的影响，初步数据表明，在正常衰老过程中，前额叶皮质GABA能系统调节失调。我们的长期目标是了解与年龄相关的前脑抑制电路的变化如何影响执行功能，并确定可以用来改善老年人认知的潜在治疗靶点。重要的是，我们发现在正常衰老对执行功能的影响上存在显著的个体差异，例如，一些老年人在认知灵活性的注意定势转移测试中受损，而另一些老年人在工作记忆的延迟反应测试中受损。此外，我们的初步数据表明，这些不同形式的执行功能障碍与GABA能信号模式的差异有关。在我们广泛的初步数据的基础上，这项提议的目标是确定前额叶皮质内改变的GABA能信号如何影响执行功能，以及这种信号是否可以被操纵来减轻与年龄相关的执行障碍。我们的中心假设是，前额叶皮质GABA能信号的个体差异是老年人口中不同形式的执行功能障碍的基础。这项拟议工作的基本原理是，通过了解前额叶皮质中抑制信号的变化如何导致不同形式的执行功能障碍，我们将处于有利地位，开始开发干预策略，从而为随着年龄增长而出现的执行能力下降提供量身定制的、更有效的治疗方法。我们将采用综合方法，将行为分析与分子、电生理学、解剖学和药理学研究结合起来，对我们的中心假设进行验证，方法包括：1)确定前额叶皮质GABA能信号的个体差异是否导致不同形式的增龄相关执行功能障碍；2)确定额叶皮质间神经元的调节和激活受损是否导致增龄相关的执行功能障碍；以及3)确定增龄过程中GABA能信号的改变和执行功能障碍是否有助于决策障碍。我们将采用一种创新的方法，既考虑个体差异，又使用执行功能的多个子组成部分的评估。拟议研究的结果将具有重要意义，因为所获得的信息将提供必要的基础知识，以开发针对高管衰退的量身定做的治疗方法，并在整个生命周期内提高生活质量和独立性。

DESCRIPTION (provided by applicant): Accumulating evidence indicates that during normal aging, executive functions supported by the prefrontal cortex are among the earliest and most severely impaired cognitive abilities. Executive functions, which include attention, working memory, and cognitive flexibility, are essential to the successful guidance of adaptive behavior and to higher-order aspects of cognition such as decision making. Disruption of corticolimbic g- aminobutyric acid (GABA)ergic inhibitory circuits can have profound consequences for executive function, and preliminary data indicate that prefrontal cortical GABAergic systems are dysregulated in normal aging. Our long term goal is to understand how age-related alterations in forebrain inhibitory circuitry affect executive functions, and to identify potential therapeutic targets that can be exploited to improve cognition in aged individuals. Important to this goal, we have found that there are robust individual differences in the effects of normal aging on executive function, such that some aged subjects are impaired on an attentional set shifting test of cognitive flexibility whereas others are impaired on a delayed response test of working memory. Moreover, our preliminary data suggest that these distinct forms of executive dysfunction are linked to differences in patterns of GABAergic signaling. Building on our extensive preliminary data, the objective of this proposal is to determine how altered GABAergic signaling within the prefrontal cortex affects executive function and whether this signaling can be manipulated to attenuate age-related executive impairments. Our central hypothesis is that individual differences in prefrontal cortical GABAergic signaling underlie distinct forms of executive dysfunction within aging populations. The rationale for the proposed work is that by understanding how altered inhibitory signaling in prefrontal cortex contributes to different forms of executive dysfunction, we will be well-positioned to begin to develop intervention strategies that will allow tailored and more efficacious treatments for executive decline that accompanies aging. Using an integrative approach in which we combine behavioral assays with molecular, electrophysiological, anatomical, and pharmacological studies in Fischer 344 rats, we will test our central hypothesis by: 1) determining if individual differences in prefrontal cortical GABAergic signaling contribute to different forms of age-related executive dysfunction; 2) determining if compromised regulation and activation of prefrontal cortical interneurons contributes to age-related executive dysfunction; and 3) determining if altered GABAergic signaling and executive dysfunction in aging contribute to impairments in decision making. We will employ an innovative approach which both considers individual differences and employs the evaluation of multiple subcomponents of executive function. The findings from the proposed studies will be significant because the information gained will provide foundational knowledge necessary to develop tailored treatments for remediating executive decline and promoting quality of life and independence across the full lifespan.