Sleep Homeostasis, Plasticity and Memory

描述（由申请人提供）：睡眠不足困扰着超过5000万美国人，导致认知功能下降和精神疾病。在睡眠障碍和精神疾病中，潜在的睡眠机制是如何出错以破坏认知功能的，在分子水平上还没有很好的理解。研究表明，精神疾病、睡眠稳态、突触可塑性和学习记忆之间存在密切联系。为了解决连接这些神经过程的细胞和分子机制，我们一直在使用一个简单的模式生物，果蝇。值得注意的是，果蝇表现出睡眠的许多核心特征。事实上，遗传分析表明，许多参与调节睡眠水平的基因在果蝇和哺乳动物之间是保守的。作为我们研究果蝇睡眠调节的一部分，我们确定了特定神经位点（称为蘑菇体（MB））在促进恢复性睡眠中的作用。值得注意的是，MB也是学习和记忆的核心。为了进一步了解连接睡眠、觉醒和神经可塑性的神经和分子基础，我们建议进一步细化在睡眠稳态中发挥特定作用的MB神经元。此外，我们将评估睡眠剥夺对MB依赖性学习和记忆以及MB突触的影响。我们还将研究学习和记忆基因与睡眠稳态之间的联系，包括关注它们在介导睡眠不足对学习和记忆的影响中的作用。这些研究利用了果蝇系统的许多方面，包括睡眠、觉醒和记忆的保守机制，以有针对性的方式操纵体内神经回路功能的能力，以及轻松操纵基因功能以阐明睡眠、记忆和可塑性之间的联系机制的能力。鉴于睡眠和记忆通路的遗传保守性，这些研究可能揭示睡眠障碍的潜在机制及其与人类学习和记忆以及精神疾病的关系。 公共卫生相关性：睡眠不足困扰着数百万美国人，并导致精神疾病。在这里，我们使用一个简单的模型来阐明连接睡眠和记忆的基本分子和神经机制。

DESCRIPTION (provided by applicant): Inadequate sleep afflicts over 50 million Americans, contributing to reduced cognitive function and psychiatric disorders. How underlying sleep mechanisms go awry in sleep disorders and mental illness to disrupt cognitive function is not well understood at the molecular level. Studies suggest an intimate link between mental illness, sleep homeostasis, synaptic plasticity, and learning and memory. To address the cellular and molecular mechanisms linking these neural processes, we have been using a simple model organism, the fruit fly Drosophila. Remarkably, the fruit fly exhibits many of the core features of sleep. In fact, genetic analysis suggests that many genes involved in regulating sleep levels are conserved between Drosophila and mammals. As part of our studies to understand sleep regulation in Drosophila, we identified a role for specific neural loci, termed the mushroom bodies (MBs), in promoting restorative sleep. Of note, the MBs are also central to learning and memory. To further understand the neural and molecular basis linking sleep, arousal, and neuroplasticity, we propose to further refine MB neurons playing specific roles in sleep homeostasis. In addition, we will assess the effects of sleep deprivation on MB-dependent learning and memory and MB synapses. We will also examine the link between learning and memory genes and sleep homeostasis, including a focus on their role in mediating the effects of sleep loss on learning and memory. These studies take advantage of many aspects of the Drosophila system, including conserved mechanisms of sleep, arousal, and memory, the ability to manipulate in a targeted manner the function of neural circuits in vivo and to easily manipulate gene function to elucidate mechanisms linking sleep, memory and plasticity. Given the genetic conservation of sleep and memory pathways, these studies may shed light on underlying mechanisms of disordered sleep and its relationship to learning and memory as well as mental illness in humans. PUBLIC HEALTH RELEVANCE: Inadequate sleep afflicts millions of Americans and contributes to mental illness. Here we use a simple model to elucidate the fundamental molecular and neural mechanisms linking sleep and memory.