Neural Mechanisms of Cognitive Decline in Aging

衰老过程中认知能力下降的神经机制

• 批准号: 9250037
• 负责人: JENNIFER Lynn BIZON
• 金额: $ 30.36万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250037
• 关键词: Adaptive Behaviors; Affect; Aging; Anatomy; Attention; Attenuated; Behavior; Behavioral; Behavioral Assay; Cognition; Cognitive; Complex; Data; Decision Making; Electrophysiology (science); Evaluation; Executive Dysfunction; Foundations; Gene Expression; Goals; Immediate-Early Genes; Impaired cognition; Impairment; Inbred F344 Rats; Individual; Individual Differences; Interneurons; Intervention; Knowledge; Link; Longevity; Methodology; Molecular; Neurons; Pathologic; Pattern; Pharmacology; Pharmacology Study; Play; Population; Positioning Attribute; Prefrontal Cortex; Process; Prosencephalon; Publishing; Quality of life; Rattus; Regulation; Research; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Signaling Protein; System; Techniques; Testing; Work; age related; aged; basal forebrain; cognitive ability; cognitive disability; cognitive testing; executive function; experimental study; flexibility; gamma-Aminobutyric Acid; improved; individualized medicine; innovation; neuromechanism; normal aging; novel; programs; public health relevance; response; therapeutic target

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.

描述（由申请人提供）：积累证据表明，在正常老化期间，前额叶皮层支持的执行功能是最早，最严重受损的认知能力。高管功能（包括注意力，工作记忆和认知灵活性）对于成功指导适应性行为以及对认知（例如决策）的高阶方面至关重要。皮质脂质G-氨基丁酸（GABA）ERGIC抑制回路可能会对执行功能产生深远的后果，并且初步数据表明，在正常老化中，前额叶皮质GABA能系统失调。我们的长期目标是了解前脑抑制作用与年龄相关的变化如何影响执行功能，并确定可以利用的潜在治疗靶标，以改善老年人的认知。对这个目标很重要，我们发现正常衰老对执行功能的影响存在牢固的个体差异，因此某些老年受试者在注意力集合测试的认知灵活性测试中受到了损害，而其他受试者在工作记忆的延迟响应测试中受到了损害。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，该提案的目的是确定前额叶皮层内的GABA能信号如何影响执行功能以及是否可以操纵该信号以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能信号传导的个体差异是老化人群中不同形式的执行功能障碍的基础。拟议工作的基本原理是，通过了解前额叶皮层中的抑制性信号改变如何导致不同形式的执行功能障碍，我们将有充分的位置开始制定干预策略，从而允许量身定制，更有效的治疗方法，以伴随着伴随着衰老的行政衰落。使用一种综合方法，我们在Fischer 344大鼠中将行为测定与分子，电生理，解剖学和药理研究结合在一起，我们将通过以下方式测试我们的中心假设：1）确定前额叶皮质GABAERGIC信号的个体差异是否有助于不同形式的年龄降低的执行良性降低的降低造成的， 2）确定前额叶皮质中间神经元的调节和激活是否导致与年龄相关的执行功能障碍； 3）确定衰老中的GABA能信号传导和执行功能障碍是否有助于决策损害。我们将采用一种创新的方法，既考虑个体差异，又采用了对执行功能的多个子组件的评估。拟议研究的发现将是重要的，因为所获得的信息将为开发量身定制的治疗方法提供基本知识，以弥补行政人员的衰落并促进整个生命周期的生活质量和独立性。