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

描述（由申请人提供）：所提出的实验和模拟研究调查了睡眠期间记忆巩固的第一个可行机制之一。这些结果将阐明海马CA 1区的Schaffer侧支和颞-氨输入在记忆处理中的特殊作用，以及NE和5-HT如何在清醒和快速眼动（REM）睡眠期间门控这些通路。在REM睡眠期间，我们发现海马细胞的重新激活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，位置场的细胞在REM期间从θ节律峰附近的放电切换到θ谷附近的放电，同时在清醒探索期间保持它们的θ峰活动。在REM期间的θ谷放电可能独特地促进海马内突触的去增强作用，海马内突触与现在熟悉的皮质巩固的记忆相关联，并允许学习新信息以及将新信息与旧记忆整合。该提议旨在测试独特的REM抑制的神经递质去甲肾上腺素（NE）和5-羟色胺（5-HT）在θ相逆转、TA-CA 1输入的增强、SC-CA 1突触的去增强和海马依赖性学习和记忆中的作用。特别是，实验和建模研究提出了调查的假设，NE和5-HT的情况下，在REM再激活提供了一个环境，其中TA-CA 1突触可能会被加强和SC-CA 1突触可能会被削弱，从而表明REM睡眠在学习和记忆中的独特作用。了解睡眠中记忆巩固的机制，将有助于对学习障碍者和老年人进行睡眠特异性治疗。结果还将表明常用抗抑郁药，如选择性去甲肾上腺素能（SNRIs）和选择性去甲肾上腺素能（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.