The Role of Homer in Maintenance of Wakefulness

衰老过程涉及许多生理功能随着时间的推移而逐渐退化。睡哪 恢复功能也会随着年龄的增长而被破坏。睡眠和清醒都是碎片化的， 日间困倦是长者的常见问题。白天嗜睡增加可能是一种 夜间睡眠质量差或保持清醒的能力受损的后果。不成体系 觉醒的发生主要是由于不能维持长时间的觉醒。这种机制 变化及其后果尚不清楚。我们已经发现， 在突触后密度调节的稳定性维持状态。缺乏显性阴性的小鼠 Homer 1的短形式Homer 1a在活跃期无法保持清醒，就像 老了我们假设，尾流的维持需要Homer 1a，而Homer 1a的下降或丧失， 这一机制导致在衰老过程中观察到的行为状态不稳定。这项建议将力求 确定Homer 1a有助于维持唤醒的分子机制以及如何 这些随年龄而变化，以了解随年龄的尾迹碎裂的分子基础。我们提出的 研究将确定Homer 1a依赖性控制持续觉醒的细胞基础， 在大脑中荷马是必需的（特定目标1）。使用代谢型谷氨酸受体（mGluR） 转基因敲入小鼠，我们将探索一种新的信号通路来确定其背后的机制 Homeria在保持清醒方面的作用（具体目标2）。在第三章中，我们将研究 在大脑中，Homeria随着年龄的增长而减少，研究与年龄相关的分子变化， Homer 1a-mGluR信号通路并最终确定Homer 1a表达下降是如何发生的 与无法保持清醒有关。

The aging process involves progressive deterioration of many physiological functions over time. Sleep which serves a restorative function is also disrupted with aging. There is fragmentation of both sleep and wake and daytime sleepiness is a common problem in the elderly. Increased daytime sleepiness may be a consequence of poor nighttime sleep quality or an impaired ability to maintain wakefulness. Fragmentation of wake occurs largely as a result of an inability to sustain long bouts of wakefulness. The mechanisms for this change and its consequences are unknown. We have found that Homerl scaffolding proteins that are found in the post-synaptic density modulate the stability of sustaining state. Mice lacking the dominant negative short form of Homer1, Homer1a, are unable to maintain wakefulness during the active period much like the aged. We hypothesize that the maintenance of wake requires Homer1a and that declines in or loss of this mechanism leads to behavioral state instability that is observed during aging. This proposal will seek to determine the molecular mechanisms by which Homer1a contributes to the maintenance of wake and how these change with age to understand the molecular basis of wake fragmentation with age. Our proposed studies will determine the cellular basis of Homer1a-dependent control of sustained wake by mapping where in the brain Homeria is required (Specific Aim1). Using metabotropic glutamate receptor (mGluR) transgenic knockin mice we will explore a novel signaling pathway to determine the mechanism underlying Homeria action in the maintenance of wakefulness (Specific Aim 2). In Specific Aim 3 we will examine where in the brain Homeria is reduced with aging, investigate age-related molecular changes in the Homer1a-mGluR signaling pathway and finally determine how declining Homer1a expression that occurs with aging correlates with the inability to maintain wakefulness.