Mechanisms of Cognitive Decline During Aging

描述（由申请人提供）：本项目的总体目标是阐明认知能力随年龄增长而下降的机制。为了实现这一目标，我们组织了一个研究计划，其中包括4个研究项目，三个必要的核心设施和一组有才华的研究人员。该研究计划是由现在强烈支持的假设驱动的，即大脑中的氧化应激导致与年龄相关的氧化损伤，并且是认知老化速度的主要决定因素。 解决这个问题的一个重要方法是定义认知老化中动物间的差异，将这些动物间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将确定C57 BL/6小鼠认知和精神老化的速率和动物间差异，并确定这些行为与大脑中区域、细胞、亚细胞和分子氧化损伤之间的关系，以及热量限制影响这些事件的能力。 项目2将确定雌激素减弱NF κ B激活的机制，NF κ B是一种主要的氧化信号通路，从而减少衰老过程中神经元的脆弱性。项目3将确定认知老化和氧化应激对细胞内Ca 2+通道及其相关信号蛋白的影响以及对细胞内Ca 2+稳态的影响。项目4将评估另一种重要的卵巢类固醇孕酮对认知衰老和大脑健康的影响，基于初步数据表明孕酮是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、组织和使用行为特征小鼠方面都是互动的，这些小鼠根据其对整个人群行为多样性的介绍而被分配给项目。 这是通过一个管理核心（核心A）来实现的，该核心将监督该项目，一个动物护理行为和评估核心（核心B）将提供所有小鼠的护理和行为表征，一个生物统计学核心（核心C）将提供统计设计、动物随机化和生成的所有数据分析。这一基于统计学的多学科研究计划旨在表征认知老化，将增强我们对氧化应激在认知老化中的作用，介导这些影响的机制以及有效干预的潜在目标的理解。

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.