Cellular, molecular, and network interactions promoting emotional memory consolidation during sleep

项目总结/摘要 本研究旨在了解情境相关恐惧（CFC）和恐惧消退的机制 (CFE)快速眼动睡眠期间的记忆巩固记忆巩固是一个过程， 经验转化为稳定的长期记忆。大量的动物和人类研究 已经表明，REM睡眠和REM睡眠相关的生理信号促进了许多疾病的巩固。 不同种类的记忆，包括情绪记忆。情感记忆巩固的缺陷 在许多神经精神疾病中与REM睡眠信号调节受损有关， 包括老年痴呆症和焦虑症。尽管快速眼动睡眠的主要影响， 关于记忆巩固的生理标志，对细胞，分子和/或 REM睡眠相关情绪记忆处理的网络机制。最近在PI的工作 一个实验室专注于快速眼动睡眠的一个突出的生理标志-相位桥脑波（P波）-也就是说， 理想地适合于在REM睡眠期间促进记忆巩固和神经元可塑性。中央 假设在训练后：1）在REM睡眠期间相位P波发生器（SubCD）的激发是 对于记忆的巩固至关重要，以及2）P波发生器的激活需要激活输入 从PPT胆碱能细胞到SubCD。设计了三个具体目标，以系统地测试 这些假设：1.确定负责激活P波发生器的机制， CFC和CFE培训。2.确定P波发生器的激活是否足以进行REM睡眠- 相关的CFC和CFE记忆巩固。其他实验将确定灭活是否 P波发生器的振荡会损害记忆的巩固，即使是在有足够的REM睡眠的情况下。3. 确定P波发生器的激活是CFC记忆巩固的因果因素， 杏仁核-海马Theta同步化与背侧海马BDNF和Arc基因表达 （DH）。实验将包括成年雄性和雌性大鼠作为受试者。情境关联恐惧和恐惧 大鼠的消退学习被证明是研究情绪记忆机制的一个很好的模型 在人类中。分子技术将用于阻断局部BDNF合成和神经元活性， 病毒性DREADD以及兴奋性和抑制性DREADD将用于操纵P波活动 产生神经元网络和P波活动。记录颈部肌肉肌电图和脑电图活动， 额叶皮层、海马和脑桥将用于识别睡眠-觉醒阶段。局部场电位（LFP） 将从DH、杏仁核、内侧前额叶皮层和脑桥记录，以分析杏仁核-海马 θ波同步我们相信，这些研究的结果将扩大领先优势， 了解睡眠依赖性情绪记忆处理的基本神经生物学机制， 将促进认知神经科学和睡眠功能领域的重要进展。

Project Summary/Abstract This project is concerned with understanding mechanisms of context-associated fear (CFC) and fear extinction (CFE) memory consolidation during REM sleep. Memory consolidation is a process whereby a recent experience transforms into stable, long-term memories. A large number of studies in both animals and humans have shown that REM sleep and REM sleep-associated physiological signs facilitate consolidation of many different categories of memories, including emotional memory. Deficits in emotional memory consolidation have been associated with impaired regulation of REM sleep signs in a number of neuro-psychiatric disorders, including Alzheimer's disease and anxiety disorders. Despite the major impact of REM sleep-associated physiological signs on memory consolidation, remarkably little is known about the cellular, molecular and/or network mechanisms underlying REM sleep-associated emotional memory processing. Recent work in the PI's lab has focused on a prominent physiological sign of REM sleep - phasic pontine-wave (P-wave) - that is ideally suited to promote memory consolidation and neuronal plasticity during REM sleep. The central hypotheses are that after training: 1) excitation of the phasic P-wave generator (SubCD) during REM sleep is critical for the consolidation of memory, and 2) activation of the P-wave generator requires activating inputs from the PPT cholinergic cells to the SubCD. Three specific aims have been designed to systematically test these hypotheses: 1. Identify the mechanism responsible for the activation of the P-wave generator following CFC and CFE training. 2. Determine if the activation of the P-wave generator is sufficient for REM sleep- associated consolidation of CFC and CFE memory. Additional experiments will determine whether inactivation of the P-wave generator impairs memory consolidation, even in the presence of sufficient REM sleep. 3. Determine that the activation of the P-wave generator is a causal factor for CFC memory consolidation through amygdala-hippocampal theta synchronization and BDNF and Arc gene expressions in the dorsal hippocampus (DH). The experiments will involve adult male and female rats as subjects. Context-associated fear and fear extinction learning in the rats have proven to be an excellent model to study mechanisms of emotional memory in human. Molecular techniques will be used to block localized BDNF synthesis and neuronal activity, and dual viral DREADD as well as excitatory and inhibitory DREADDs will be used to manipulate activities of P-wave generating neuronal network and P-wave activity. Recordings of neck muscle EMG and EEG activities from frontal cortex, hippocampus, and pons will be used to identify sleep-wake stages. Local field potentials (LFP) will be recorded from the DH, amygdala, medial prefrontal cortex, and pons to analyze amygdala-hippocampal theta wave synchronization. We believe that the results of these studies will extend the leading edge of knowledge on the basic neurobiological mechanisms of sleep-dependent emotional memory processing, which will facilitate vital advancement in the areas of cognitive neuroscience and sleep functionality.