Modifying age-related changes in mouse neuroinflammation & functional behaviors

描述(由申请者提供)：未来几十年，美国人口将“老龄化”。该国增长最快的人口群体是老年人，在这一群体中，“高龄老人”。这些趋势给我们目前的医疗实践带来了巨大的挑战。例如，与年龄相关的行为变化的根本原因仍未确定。这项应用将通过检验以下假设来检验衰老与功能行为(吃、喝、活动)变化之间的关系：(1)与年龄相关的小鼠功能行为的变化与调节炎症和免疫介质的基因表达的变化相关；(2)运动和环境丰富通过延迟或减少调节免疫和炎症过程的基因的差异表达来改善中枢神经系统的功能储备。我们建议对年轻、中年和老年小鼠进行横断面研究。将使用最先进的系统对行为进行监控，该系统以可靠和自动化的方式对大型行为数据流进行精细分类。对整体行为的衡量，包括昼夜节律、时间分配和属性(持续时间、频率等)。将对运动、进食和饮酒的回合进行分析。初步数据发现，这些指标的变化与老龄化人口中的变化相似。此外，下丘脑和额叶皮质的基因表达将使用微阵列和QT-PCR方法进行评估。差异表达的基因产物将根据基因目的进行分类。这将使我们能够测试观察到的行为是否与调节免疫反应的基因的变化有关，而不是与调节活动、运动和摄食行为的基因相关。我们还将使用图论方法来确定在老化的下丘脑中改变的特定代谢途径(例如，ATF3-Mapk8-TLR2)。我们还建议进行一项纵向研究，以测试包括锻炼和丰富环境在内的生活方式改变是否会增加中枢神经系统功能储备。在这项研究中，我们将使用类似的老鼠行为和基因表达的测量方法。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，并可能为治疗操作提供重要的基因靶点。公共卫生相关性：最终，预计这些数据将提供有关大脑衰老过程性质的重要见解，并可能为治疗操作提供重要的基因靶点。

DESCRIPTION (provided by applicant): 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 and immune mediators, and (2) exercise and environmental enrichment improve CNS functional reserve by delaying or diminishing differential expression of genes regulating immune and inflammatory processes. We propose a cross-sectional study of young, middle-aged, and 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, and properties (duration, frequency, etc.) of movement, feeding, and drinking bouts will be analyzed. Preliminary data find 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, and 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 and environmental enrichment increase CNS functional reserve. We will use similar measures of mouse behavior and 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, and may suggest important genetic targets for therapeutic manipulation. PUBLIC HEALTH RELEVANCE: Ultimately, it is anticipated that these data will provide important insight regarding the nature of aging processes in the brain, and may suggest important genetic targets for therapeutic manipulation.