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.

项目概要/摘要 该项目涉及理解情境相关恐惧（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，其中最近的 经验转化为稳定、长期的记忆。对动物和人类进行了大量研究 研究表明，快速眼动睡眠和与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，包括情感记忆。情绪记忆巩固缺陷 与许多神经精神疾病中快速眼动睡眠迹象的调节受损有关， 包括阿尔茨海默病和焦虑症。尽管与快速眼动睡眠相关的影响很大 记忆巩固的生理迹象，对于细胞、分子和/或 快速眼动睡眠相关情绪记忆处理的网络机制。 PI 的近期工作 实验室重点关注快速眼动睡眠的一个显着生理标志——相性脑桥波（P 波）——即 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。中央 假设训练后：1) REM 睡眠期间相位 P 波发生器 (SubCD) 的激发是 对于巩固记忆至关重要，并且 2) 激活 P 波发生器需要激活输入 从 PPT 胆碱能细胞到 SubCD。设计了三个具体目标来系统地测试 这些假设： 1. 确定负责激活纵波发生器的机制如下 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 - CFC 和 CFE 内存的关联整合。额外的实验将确定是否失活 即使有足够的快速眼动睡眠，P 波发生器的功能也会损害记忆巩固。 3. 通过以下方式确定 P 波发生器的激活是 CFC 内存整合的因果因素 杏仁核-海马 theta 同步以及背海马 BDNF 和 Arc 基因表达 （DH）。实验将以成年雄性和雌性大鼠为受试者。与情境相关的恐惧和恐惧 老鼠的消退学习已被证明是研究情绪记忆机制的绝佳模型 在人类。分子技术将用于阻断局部 BDNF 合成和神经元活动，以及双重 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。颈部肌肉肌电图和脑电图活动记录 额叶皮层、海马体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、内侧前额皮质和脑桥记录，以分析杏仁核-海马 西塔波同步。我们相信，这些研究结果将扩展该领域的领先优势 关于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大进步。