Mechanisms of Cognitive Decline During Aging

描述(申请人提供)：本项目的总体目标是阐明认知衰退的机制(S)随年龄增长。为了实现这一目标，我们组织了一个研究计划，包括4个研究项目，3个必要的核心设施和一批有才华的调查人员。这项研究计划是由一个现在得到有力支持的假设推动的，即大脑中的氧化应激会导致与年龄相关的氧化损伤，是认知衰老速度的主要决定因素。 解决这一问题的一个基本方法是定义认知衰老中动物之间的可变性，将这些动物间的差异与特定脑区的氧化损伤联系起来，并确定将氧化事件传递给细胞反应的信号通路。因此，这四个研究项目侧重于对这些问题进行系统评估。 项目1将定义C57BL/6小鼠认知和精神运动衰老的速度和动物间的差异，并定义这些行为与大脑中局部、细胞、亚细胞和分子氧化损伤之间的关系，以及限制热量影响这些事件的能力。项目2将确定雌激素减弱NFKB激活的机制，NFKB是一种主要的氧化信号通路，从而减少神经元在衰老过程中的脆弱性。项目3将确定认知老化和氧化应激对细胞内钙通道的影响，它们相关的信号蛋白，以及由此产生的对细胞内钙稳态的影响。项目4将根据初步数据评估另一种重要的卵巢类固醇黄体酮对认知老化和大脑健康的影响，初步数据表明，黄体酮是GABAA受体的有效抑制剂和有效的神经保护剂。所有这些研究项目在分享想法、组织和使用具有行为特征的小鼠方面都是互动的，这些小鼠基于它们对整个种群行为多样性的呈现而被分配到项目中。 这是通过一个将监督该计划的行政核心(核心A)、一个将提供所有老鼠的护理和行为特征的动物关爱行为和评估核心(核心B)和一个将提供统计设计、动物随机化和产生的所有数据分析的生物统计核心(核心C)来实现的。这项以统计学为基础的多学科研究计划，旨在描述认知老化的特征，将增强我们对氧化应激在认知老化中的作用、调节这些影响的机制以及有效干预的潜在靶点的理解。

DESCRIPTION (provided by applicant): The present program project has the overall goal of elucidating the mechanism(s) underlying cognitive decline with aging. To achieve this goal, we have organized a program of research that includes 4 research projects, three essential core facilities and a group of talented investigators. The research program is driven by the now strongly supported hypothesis that oxidative stress in the brain leads to age-related oxidative damage and is a major determinant of the rate of cognitive aging. An essential approach to this problem is to define the animal-to-animal variability in cognitive aging, relate these inter-animal differences to oxidative damage in specific brain regions and to determine the signaling pathways that communicate oxidative events to cellular responses. As such, the four research projects focus on a systematic assessment of these issues. Project 1 will define the rate and inter-animal differences in cognitive and psychomotor aging in C57BL/6 mice and define the relationship between these behaviors and regional, cellular, subcellular and molecular oxidative damage in the brain as well as the ability of caloric restriction to affect these events. Project 2 will determine the mechanism by which estrogens attenuate the activation of NFKB, a major oxidative signaling pathway, and thereby reduce neuronal vulnerability during aging. Project 3 will determine the effects of cognitive aging and oxidative stress on intracellular Ca 2+ channels, their associated signaling proteins and the resulting effects on intracellular Ca 2+ homeostasis. Project 4 will assess the other important ovarian steroid, progesterone, for its effects on cognitive aging and brain health, based upon preliminary data that indicate that progesterone is a potent inhibitor of the GABAA receptor and a potent neuroprotectant. All of these research projects are interactive in the sharing of ideas, tissues, and the use of behaviorally characterized mice that are distributed to projects based upon their presentation of the behavioral diversity of the population as a whole. This is achieved through an Administrative Core (Core A) that will oversee the program, a Animal Care Behavioral and Assessment Core (Core B) that will provide care for and behavioral characterization of all mice and a Biostatistics Core (Core C) that will provide statistical design, animal randomization and analysis of all data generated. This statistically based, multidisciplinary program of research, aimed at the characterization of cognitive aging, will enhance our understanding of the role of oxidative stress in cognitive aging, the mechanisms mediating these effects and potential targets for effective intervention.