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

细胞、分子和网络相互作用促进睡眠期间情绪记忆巩固

• 批准号: 9453365
• 负责人: Subimal Datta
• 金额: $ 34.23万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453365
• 关键词: Adult; Affect; Alzheimer' s Disease; Amygdaloid structure; Anatomy; Animals; Anxiety Disorders; Area; Behavioral; Binding; Brain-Derived Neurotrophic Factor; Categories; Cell Nucleus; Cells; Chemosensitization; Cognitive deficits; Data; Development; Disease; Dorsal; Drug usage; EKG P Wave; Electroencephalography; Emotional; Extinction (Psychology); Female; Fright; Gene Expression; Generations; Glutamates; Goals; Hippocampus (Brain); Human; Huntington Disease; Impaired cognition; Impairment; Intervention; Knowledge; Learning; Medial; Mediating; Memory; Memory impairment; Mental Depression; Modeling; Molecular; Neurologic; Neuronal Plasticity; Neurons; Outcome; Parkinson Disease; Pharmacology; Phase; Physiological; Pontine structure; Population; Prefrontal Cortex; Process; Prosencephalon; REM Sleep; REM Sleep Deprivations; Rattus; Regulation; Research; Schizophrenia; Skeletal muscle structure of neck; Sleep; Sprague-Dawley Rats; Stroke; Techniques; Testing; Therapeutic Uses; Training; Viral; Work; addiction; age related; aging population; base; cholinergic; cognitive function; cognitive neuroscience; design; designer receptors exclusively activated by designer drugs; experience; experimental study; fear memory; frontal lobe; heart rate variability; homologous recombination; learning extinction; long term memory; male; memory consolidation; memory process; neurobiological mechanism; neurochemistry; neuropsychiatric disorder; normal aging; novel; novel strategies; novel therapeutic intervention; pedunculopontine tegmentum; rapid eye movement; translational impact

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.

项目摘要/摘要 该项目与理解与上下文相关的恐惧（CFC）和恐惧灭绝的机制有关 （CFE）REM睡眠期间的记忆合并。记忆整合是一个最近的过程 经验转变为稳定的长期记忆。对动物和人类的大量研究 已经表明，REM睡眠和与睡眠相关的生理体征有助于巩固许多 不同类别的记忆，包括情感记忆。情绪记忆巩固的缺陷 与许多神经精神疾病中的REM睡眠标志调节受损有关， 包括阿尔茨海默氏病和焦虑症。尽管REM睡眠相关产生了重大影响 关于记忆巩固的生理迹象，关于细胞，分子和/或 REM睡眠相关的情绪记忆处理的基础网络机制。 PI的最新工作 实验室专注于REM睡眠的突出生理迹象 - 阶段pontine -Wave（P -Wave） - 理想情况下适合在REM睡眠期间促进记忆巩固和神经元可塑性。中央 假设是在训练之后：1）在REM睡眠期间的Phasic P-波发电机（SUBCD）的激发是 对于存储器的合并至关重要，2）激活P波生成器需要激活输入 从PPT胆碱能细胞到SUBCD。已经设计了三个特定目标来系统测试 这些假设：1。确定负责p波发生器激活的机制 CFC和CFE培训。 2。确定P波发生器的激活是否足以使REM睡眠 - CFC和CFE内存的关联合并。其他实验将确定是否失活 即使在有足够的REM睡眠的情况下，P-波发电机也会损害记忆巩固。 3。 确定P波生成器的激活是CFC存储器合并的因素 背侧海马中的杏仁核 - 海马theta同步和BDNF和ARC基因表达 （DH）。实验将涉及成年男性和雌性大鼠作为受试者。与上下文相关的恐惧和恐惧 事实证明，老鼠的灭绝学习是研究情绪记忆机制的绝佳模型 在人类中。分子技术将用于阻断局部的BDNF合成和神经元活性，并且双重 病毒dreadd以及兴奋性和抑制性恐怖将用于操纵P波的活动 生成神经元网络和P波活动。颈部肌肉EMG和EEG活动的记录 额叶皮层，海马和pon将用于识别睡眠效果阶段。本地现场电位（LFP） 将从DH，Amygdala，内侧前额叶皮层和PON中记录以分析杏仁核-HAPPOCAMPAL theta波同步。我们认为这些研究的结果将扩大 有关睡眠依赖性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。