Systems Genetic Analysis of Cognitive Resilience Using Multi-Parent Crosses

项目总结/摘要 认知复原力是一种现象，个体可以抵抗衰老的最具破坏性的影响 认知-尽管长寿但仍保持正常认知功能的个体（例如百岁老人） 根据概念上的定义，据说表现出高认知储备或弹性（见储备 和Resilience NIA Consortium）。因此，促进认知储备和恢复力的遗传因素可能会提供 治疗和预防一系列年龄相关性痴呆认知功能下降的关键目标 包括阿尔茨海默病（AD）和阿尔茨海默病相关痴呆（ADRD）。我们的整体目标 是通过使用网络方法整合数据来识别认知储备和弹性的驱动因素 从具有人类数据的多样性远交（DO）小鼠模型收集。作为父代的一部分生成的数据 一项研究表明，细胞类型组成的区域变化可能是一个重要的影响因素， 确定认知储备和复原力的个体差异。全脑空间神经元的研究进展 分析大脑储备和恢复力的相关性，特别是高通量平台的出现 对于大规模免疫组织化学（IHC）来标记遍及数百个小鼠脑的多种细胞类型， 现在可以评估认知储备和弹性的区域和细胞类型特异性标志， 用于评估认知、运动、睡眠和代谢的相同小鼠中的临床相关性状 症状，是对我们正在进行的工作的有力补充，并增加了一个新的信息层 关于区域和细胞类型的特异性，我们的多尺度网络模型。有了拟议的补充， 我们将能够识别与认知储备相关的特定大脑区域和细胞类型的变化， 以及它们与阿尔茨海默病和老年痴呆症之间的关系。该项目将 提供新的大脑区域和细胞类型，以促进健康的大脑衰老（储备）和抗衰老能力。 我们将注释，策划，并迅速传播数据到广泛的科学界之前， 出版物，以最大限度地利用这些数据的荟萃分析和系统生物学研究。

PROJECT SUMMARY/ABSTRACT Cognitive resilience is a phenomenon whereby individuals are resistant to the most damaging effects of aging on cognition – individuals that maintain normal cognitive function despite being long-lived (e.g. centenarians) are said to exhibit high cognitive reserve or resilience depending on the conceptual definitions (see Reserve and Resilience NIA Consortium). Genetic factors promoting cognitive reserve and resilience may thus provide key targets for treatment and prevention of cognitive decline across a spectrum of age-related dementias including Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). Our overall objective is to identify drivers of cognitive reserve and resilience by using network approaches to integrate data collected from Diversity Outbred (DO) mouse models with human data. Data generated as part of the parent award indicates that regional changes in cell-type composition may be a significant contributing factor in determining individual differences in cognitive reserve and resilience. Recent advances in brain-wide spatial analyses of correlates of brain reserve and resilience, and particularly the advent of high throughput platforms for large-scale immunohistochemistry (IHC) to label multiple cell types throughout hundreds of mouse brains, now make it feasible to assess region and cell type specific hallmarks of cognitive reserve and resilience and clinically relevant traits in the same mice as used for assessing cognition, motor, sleep, and metabolic symptoms, representing a powerful complement to our ongoing work and adding a new layer of information regarding regional and cell-type specificity to our multi-scale network model. With the proposed supplement, we will be able to identify changes in specific brain regions and cell types associated with cognitive reserve and their relationship to transition towards Alzheimer’s disease and age-related dementias. This project will deliver novel brain regions and cell types for promoting healthy brain aging (reserve) and resilience to aging. We will annotate, curate, and rapidly disseminate the data to the broad scientific community prior to publication to maximize the usability of these data for meta-analysis and systems biology research.