CRCNS - Neuromodulation of Hippocampal Synaptic Plasticity in Waking & REM Sleep

描述（由申请人提供）：拟议的实验和模拟研究探讨了睡眠期间记忆巩固的第一个可行机制之一。研究结果将阐明海马CA1区的Schaffer侧叶和时间氨输入在记忆加工中的特殊作用，以及NE和5-HT在清醒和快速眼动（REM）睡眠期间如何控制这些通路。在快速眼动睡眠期间，我们发现海马细胞的再激活会随着动物对环境的熟悉而在几天内发生变化。在最初的新环境中，具有位置场的细胞在快速眼动期间从靠近θ节律峰的放电切换到靠近θ波谷的放电，同时在清醒探索期间保持其θ峰活动。快速眼动期间的θ波波谷放电可能会特别促进海马体内突触的失联，这些突触与现在熟悉的、皮层巩固的记忆有关，并允许学习新信息以及将新信息与旧记忆整合。本研究旨在测试快速眼动期抑制的神经递质去甲肾上腺素（NE）和血清素（5-HT）在θ相逆转、TA-CA1输入增强、SC-CA1突触去增强和海马依赖性学习和记忆中的作用。具体来说，我们提出了实验和模型研究，以探讨REM再激活期间NE和5-HT的缺失提供了TA-CA1突触可能增强而SC-CA1突触可能减弱的环境，从而表明REM睡眠在学习和记忆中的独特作用。了解睡眠过程中记忆巩固的机制将有助于针对学习障碍人士和老年人的睡眠特异性治疗。研究结果还将表明常用的抗抑郁药，如选择性去甲肾上腺素能（SNRIs）和血清素能（SSRIs）再摄取抑制剂对学习和记忆的影响。

DESCRIPTION (provided by applicant): The proposed experiments and simulation studies investigate one of the first feasible mechanisms for memory consolidation during sleep. The results will elucidate particular roles for the Schaffer Collateral and temporo-ammonic inputs to the hippocampal CA1 region in memory processing and how NE and 5-HT gate these pathways during waking and Rapid Eye Movement (REM) sleep. During REM sleep, we have found that reactivation of hippocampal cells changes over the course of several days as the animals became familiar with an environment. Cells with place fields in an initially novel environment switch from firing near the theta rhythm peaks to firing near the theta troughs during REM, while maintaining their theta peak activity during waking exploration. Theta trough firing during REM may uniquely facilitate depotentiation of intra-hippocampal synapses which are associated with now familiar, cortically-consolidated memories and allow for learning of new information and the integration of novel information with old memories. This proposal seeks to test the role of the uniquely REM-suppressed neurotransmitters norepinephrine (NE) and serotonin (5-HT) in theta phase reversal, potentiation of TA-CA1 inputs, depotentiation of SC-CA1 synapses and hippocampus-dependent learning and memory. Specifically, experimental and modeling studies are proposed to investigate the hypothesis that the absence of NE and 5-HT during REM reactivation provides an environment wherein TA-CA1 synapses may be strengthened and SC-CA1 synapses may be weakened, thus indicating a unique role for REM sleep in learning and memory. Understanding the mechanisms underlying memory consolidation during sleep should lead to sleep-specific treatments for learning disabled persons and the elderly. The results will also indicate effects of commonly prescribed anti-depressants, such as selective noradrenergic (SNRIs) and serotonergic (SSRIs) re-uptake inhibitors, on learning and memory.