Circuit Mechanisms Encoding Homeostatic Sleep Drive

项目摘要 动态平衡是一种基本的生理属性，将关键的状态变量保持在特定范围内 为了动物的生存和健康。动态平衡机制对动机行为也很重要， 比如进食或睡觉。例如，长时间的清醒会增加睡眠动力(睡眠压力)，从而导致 增加睡眠时间和/或深度(睡眠反弹)。细胞和分子机制 睡眠的动态平衡调节的基础仍然不清楚，我们最近发现了一种新的神经 对休眠驱动进行编码的电路。尽管人们普遍认为睡眠驱动力不可避免地会随着更多的 觉醒，这一规则的例外在自然界中是存在的，特别是在高度唤醒的条件下。我们 假设特定的信号机制作用于这个体内平衡回路以抑制积聚 和/或释放睡眠驱动力。这项提案的总体目标是利用这些新的发现来揭示 睡眠动态平衡的分子和细胞机制。此外，新出现的数据表明， 神经胶质细胞在睡眠动态平衡调节中的重要作用。因此，我们建议实现以下目标： 1)表征作用于该新电路以调节睡眠驱动的信号通路；2)表征 作用于睡眠平衡回路下游以促进睡眠的回路机制；以及3)研究 神经胶质细胞在睡眠动态平衡调节中的特殊作用。为了进行这些研究，我们将使用各种不同的 方法，包括行为分析、分子遗传分析、免疫组织化学、功能 成像和膜片钳电生理学。这些研究应该会揭示睡眠是如何变化的 自我平衡调节的。失眠和病理性嗜睡障碍是常见的，而且常常与之相关。 有相当高的发病率。更好地理解睡眠稳态的潜在机制可能会有所帮助 我们正在寻找治疗病理性嗜睡和失眠的新疗法。

Project Summary Homeostasis is a fundamental physiological property, maintaining crucial state variables within a specific range for the viability and fitness of animals. Homeostatic mechanisms are also important for motivated behaviors, such as feeding or sleep. For example, prolonged wakefulness increases sleep drive (sleep pressure), leading to an increase in sleep amount and/or depth (sleep rebound). The cellular and molecular mechanisms underlying the homeostatic regulation of sleep remain unclear, and we have recently identified a novel neural circuit that encodes sleep drive. Although sleep drive is widely assumed to inevitably increase with greater wakefulness, exceptions to this rule exist in nature, particularly under conditions of high arousal. We hypothesize that specific signaling mechanisms act on this homeostatic circuit to suppress the accumulation and/or release of sleep drive. The overall goal of this proposal is to leverage these new findings to unravel the molecular and cellular mechanisms underlying sleep homeostasis. In addition, emerging data suggest an important role for glia in the homeostatic regulation of sleep. Thus, we propose to carry out the following aims: 1) characterize the signaling pathways acting on this novel circuit to regulate sleep drive; 2) characterize the circuit mechanisms acting downstream of this sleep homeostatic circuit to promote sleep; and 3) investigate a specific role for glia in the homeostatic regulation of sleep. To carry out these studies, we will use a variety of approaches, including behavioral assays, molecular genetic analyses, immunohistochemistry, functional imaging, and patch-clamp electrophysiology. These studies should reveal new insights into how sleep is homeostatically regulated. Insomnia and disorders of pathologic sleepiness are common and often associated with substantial morbidity. A better understanding of the mechanisms underlying sleep homeostasis may help in our search for novel treatments for both pathologic sleepiness and insomnia.