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

描述(申请人提供)：拟议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Schaffer侧支和海马CA1区的临时氨基输入在记忆处理中的特殊作用，以及NE和5-羟色胺如何在清醒和快速眼动(REM)睡眠中启动这些通路。在REM睡眠期间，我们发现，随着动物熟悉环境，海马细胞的重新激活在几天的过程中发生变化。在一个最初新颖的环境中，具有位置场的细胞在快速眼动过程中从theta节律峰值附近的放电切换到theta谷附近的放电，同时在清醒探索期间保持theta峰值活动。快速眼动过程中的Theta槽放电可能独特地促进与现在熟悉的皮质巩固记忆相关的海马区内突触的去增强，并允许学习新信息和新信息与旧记忆的整合。这项建议旨在测试独特的REM抑制的神经递质去甲肾上腺素(NE)和5-羟色胺(5-HT)在theta相逆转、TA-CA1输入的增强、SC-CA1突触的去增强和海马区依赖的学习和记忆中的作用。具体地说，实验和模型研究旨在探讨这样一种假设，即在REM重新激活过程中，NE和5-HT的缺失提供了一个环境，其中TA-CA1突触可能被加强，SC-CA1突触可能被削弱，从而表明REM睡眠在学习和记忆中具有独特的作用。了解睡眠期间记忆巩固的机制应该会导致针对学习障碍者和老年人的睡眠治疗。结果还将表明常用的抗抑郁药物，如选择性去甲肾上腺素(SNRIs)和5-羟色胺(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.