Linking network activity and intracellular plasticity mechanisms during sleep-dep

描述(由申请人提供)：将近期经历巩固为长期记忆是大脑的基本功能，对生存至关重要。长期以来，睡眠一直被认为对巩固记忆很重要，而睡眠不足会对认知功能产生不利影响。最近的数据表明，睡眠促进了神经元之间连接的适应性变化，这被认为是记忆形成的基础。然而，由于睡眠大脑中同时发生的变化的数量和多样性，包括神经元放电模式、神经元之间的细胞间信号转导和神经元蛋白质合成的变化，理解睡眠如何促进这些过程的进展缓慢。这项研究的目的是确定睡眠的哪些特征对于一种简单形式的睡眠依赖记忆巩固是必要的和充分的--背景恐惧记忆。我们将使用最近开发的光遗传学和药物遗传学工具，以特定细胞类型的方式操纵睡眠中的大脑中的神经元活动。这将使我们能够测试睡眠大脑特有的网络活动(例如，海马体电路中的低频振荡)和神经传递(例如，去甲肾上腺素和乙酰胆碱释放的变化)是否在睡眠依赖记忆形成中起因果作用。我们还将使用新开发的分子工具来描述睡眠依赖记忆巩固期间海马体内特定细胞类型的活性蛋白翻译。最后，我们将结合这些工具首次确定与睡眠相关的神经元活动和神经传递的变化如何影响细胞内过程，如神经回路中的蛋白质翻译。

DESCRIPTION (provided by applicant): The consolidation of recent experiences into long-lasting memories is a fundamental function of the brain and essential for survival. Sleep has long been thought to be important for memory consolidation, and sleep deprivation has adverse consequences for cognitive function. Recent data suggest that sleep promotes the adaptive changes in connections between neurons which are thought to underlie memory formation. However, progress in understanding how sleep promotes these processes has been slow, due to the number and diversity of changes occurring simultaneously in the sleeping brain - including changes in neuronal firing patterns, intercellular signaling between neurons, and neuronal protein synthesis. The goal of the proposed research is to define which features of sleep are necessary and sufficient for a simple form of sleep-dependent memory consolidation - contextual fear memory. We will use recently-developed optogenetic and pharmacogenetic tools to manipulate neuronal activity in the sleeping brain in a cell type-specific manner. This will allow us to test whether features of network activity (e.g., low-frequency oscillations in hippocampal circuits) and neurotransmission (e.g., changes in noradrenaline and acetylcholine release) unique to the sleeping brain play a causal role in sleep-dependent memory formation. We will also use newly-developed molecular tools to profile active protein translation in specific cell types within the hippocampus during sleep- dependent memory consolidation. Finally, we will combine these tools to determine for the first time how sleep- associated changes in neuronal activity and neurotransmission impact intracellular processes such as protein translation in neural circuits.