Modifying age-related changes in mouse neuroinflammation & functional behaviors

在接下来的几十年里，美国人口将出现“老龄化”。最快的 这个国家不断增长的人口群体是老年人，而在这一群体中，最年长的人 这些趋势对我们目前的医疗实践构成了重大挑战。例如，潜在的 与年龄相关的行为变化的原因仍不确定。此应用程序将检查 通过测试衰老与功能行为(吃、喝、活动)变化之间的关系 假设(1)小鼠功能行为的年龄相关变化与 调控炎症和免疫介质的基因表达，以及(2)运动和环境 富集素通过延缓或减少中枢神经系统功能储备的差异表达 调节免疫和炎症过程的基因。我们建议对年轻的， 中年、老年小鼠。将使用一种最先进的系统对行为进行监控，该系统可以对 以可靠和自动化的方式传输大量行为数据流。衡量整体行为的标准，包括 昼夜节律、时间预算和属性(持续时间、频率等)移动，进食，和 将对饮酒比赛进行分析。初步数据发现，这些指标的变化类似于 老龄化的人类人口。此外，下丘脑和额叶皮质的基因表达将 采用基因芯片和QT-PCR方法进行检测。差异表达的基因产品将被分类 通过基因的目的。这将使我们能够测试观察到的行为是否与基因变化有关 调节免疫反应，而不是调节活动、运动和摄食行为的基因。我们 还将使用图论方法来确定特定的代谢途径(例如，ATF3-Mapk8-TLR2)改变 在老化的下丘脑中。我们还建议进行一项纵向研究，以测试生活方式的改变 包括运动和环境丰富，增加中枢神经系统功能储备。我们将使用类似的 这项研究的结果是测量小鼠的行为和基因表达。最终，我们预计 这些数据将为了解大脑衰老过程的性质提供重要的见解，并可能表明 治疗操作的重要基因靶点。

The coming decades will be marked by a "graying" of the United States population. The most rapidly growing demographic group in the country is that of elderly persons, and within this group, that of the "oldest old." These trends pose significant challenges to our current medical practice. For example, the underlying causes of age-related behavioral changes remain undetermined. This application will examine the relationship between aging and changes in functional behaviors (eating, drinking, activity) by testing the hypotheses that (1) Age-related changes in mouse functional behaviors correlate with changes in gene expression regulating inflammatory & immune mediators, and (2) Exercise & environmental enrichment improve CNS functional reserve by delaying or diminishing differential expression of genes regulating immune & inflammatory processes. We propose a cross-sectional study of young, middle-aged, & aged mice. Behaviors will be monitored using a state-of-the-art system that finely classifies large behavioral data streams in a reliable and automated fashion. Measures of overall behavior, including those of circadian rhythm, time budget, & properties (duration, frequency, etc.) of movement, feeding, and drinking bouts will be analyzed. Preliminary data finds alterations in these measures similar to those seen in aging human populations. Additionally, gene expression in the hypothalamus and frontal cortex will be assessed using microarray and QT-PCR methods. Differentially expressed gene products will be classified by gene purpose. This will allow us to test whether observed behaviors correlate with changes in genes regulating immune responses rather than genes regulating activity, movement, & ingestive behaviors. We will also use graph-theory approaches to identify specific metabolic pathways (e.g., Atf3-Mapk8-Tlr2) altered in the aging hypothalamus. We also propose a longitudinal study to test whether lifestyle modifications including exercise & environmental enrichment increase CNS functional reserve. We will use similar measures of mouse behavior & gene expression as outcomes in this study. Ultimately, we anticipate that these data will provide important insight regarding the nature of aging processes in the brain, & may suggest important genetic targets for therapeutic manipulation.