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

项目摘要/摘要 这个项目关注于理解与背景相关的恐惧(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，通过这个过程 经验会转化为稳定的、长期的记忆。在动物和人类身上的大量研究 已经表明，快速眼动睡眠和快速眼动睡眠相关的生理体征有助于巩固许多 不同类别的记忆，包括情绪记忆。情绪记忆巩固方面的缺陷 与许多神经精神障碍患者的快速眼动睡眠信号调节受损有关， 包括阿尔茨海默氏症和焦虑症。尽管与快速眼动睡眠相关的主要影响 记忆巩固的生理迹象，对细胞、分子和/或 REM睡眠相关情绪记忆处理的网络机制。国际和平研究所最近的工作 Lab专注于REM睡眠的一个显著的生理迹象--脑桥波(P波)--也就是 非常适合在快速眼动睡眠期间促进记忆巩固和神经元可塑性。中环 假设在训练后：1)在REM睡眠期间，相位P波发生器(SubCD)的兴奋是 对于巩固记忆至关重要，以及2)激活P波发生器需要激活输入 从PPT胆碱能细胞到亚CD细胞。设计了三个具体的目标来系统地测试 这些假设：1.确定以下P波发生器激活的机制 氟氯化碳和CFE培训。2.确定P波发生器的激活是否足以使REM睡眠- 氟氯化碳和CFE内存的关联整合。更多的实验将确定灭活 纵然有充足的快速眼动睡眠，P波发生器的失灵也会损害记忆的巩固。3. 通过以下方法确定P波发生器的激活是CFC记忆巩固的一个原因 杏仁核-海马theta同步化与BDNF和Arc基因在背侧海马区的表达 (Dh)。实验将以成年雄性和雌性大鼠为实验对象。与环境相关的恐惧和恐惧 大鼠的消亡学习已被证明是研究情绪记忆机制的一个很好的模型 在人类身上。分子技术将被用来阻断局部的BDNF合成和神经元活性，以及双重 病毒DREADD以及兴奋性和抑制性DREADD将被用于操纵P波的活动 产生神经网络和P波活动。老年人颈部肌肉肌电和脑电活动的记录 额叶皮质、海马体和脑桥将被用来识别睡眠-觉醒阶段。局域场势(LFP) 将记录于杏仁核、内侧前额叶皮质和脑桥，以分析杏仁核-海马体 Theta波同步。我们相信，这些研究的结果将扩大领先优势 关于睡眠依赖情绪记忆处理的基本神经生物学机制的知识， 将促进认知神经科学和睡眠功能领域的重要进步。

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.