REM Sleep and Memory

描述（由申请人提供）：大量证据支持REM睡眠在学习和记忆巩固中的作用。在第一个授权期，我们显示了快速眼动期间海马神经活动的变化，这些变化与经验相关，并遵循记忆巩固（SA 1）的过程，即从θ节律峰到谷的放电相位逆转。我们改变了学习率和性能策略与REM剥夺（SA 2）和增强（SA 3）的一个新的行为任务，并测量的变化，θ峰谷逆转与这些操作。这个建议不是操纵快速眼动睡眠，而是试图确定快速眼动睡眠的生理事件，这些事件对记忆巩固在一个依赖于记忆的任务中很重要。我们假设，在海马睡眠再激活过程中去甲肾上腺素和5-羟色胺的缺乏提供了一个环境，其中直接内鼻-CA 1通路中的突触可能会加强，CA 3-CA 1突触可能会减弱（去增强）。从理论上讲，去增强作用对于清除海马体的临时的、可修改的关联记忆网络是必要的，以允许随着新信息的到来而改变记忆代码。在具体目标1中，我们将测试睡眠期间海马再激活对去电位的必要性，并测试在转换任务中成功修改记忆的去电位的必要性。通过让睡眠正常发生，同时暂时使海马失活，我们将在记忆巩固过程中的固定时间点分离海马重新激活的贡献。我们预计，当海马在巩固完成之前失活时，睡眠对记忆的好处将不会在海马依赖性任务中实现。当我们解除睡眠再激活时，我们希望看到清醒和REM睡眠中的神经活动模式，这表明巩固过程已经被阻止，峰谷θ相位反转延迟。我们还预计，从行为表现恢复改善所显示的停止点开始，整合将继续正常进行。在具体目标2和3中，我们将测试在快速眼动睡眠期间通常沉默的两种神经递质系统缺失的记忆必要性。我们将允许快速眼动睡眠发生，但在睡眠期间在海马体中引入去甲肾上腺素能和肾上腺素能激动剂，测量学习和睡眠/觉醒细胞活动的变化。这些结果表明，不同的抗抑郁药对单胺能轴有不同的疗效，对记忆的影响。此外，这项工作将有助于记忆巩固机制的知识基础，最终表明有效的方法来提高受损个体的记忆和学习能力。

DESCRIPTION (provided by applicant): A number of confluent lines of evidence support a role for REM sleep in learning and memory consolidation. In the first grant period we showed changes in hippocampal neural activity during REM that correlate with experience and follow the course of memory consolidation (SA1), namely a reversal in phase of firing from theta rhythm peaks to troughs. We altered learning rates and performance strategies with REM deprivation (SA2) and enhancement (SA3) on a new behavioral task and measured the changes in the theta peak-to-trough reversal with these manipulations. Instead of manipulating REM sleep, this proposal seeks to determine the physiological events of REM sleep that are important for memory consolidation in a hippocampus-dependent task. We hypothesize that the absence of norepinephrine and serotonin during hippocampal sleep reactivation provides an environment wherein synapses in the direct entorhinal-to-CA1 path may be strengthened and CA3-to-CA1 synapses may be weakened (depotentiated). Depotentiation is theoretically necessary for clearing the temporary, modifiable associative memory network of the hippocampus to allow changes in the memory code with the arrival of new information. In Specific Aim 1 we will test the necessity of hippocampal reactivation during sleep for depotentiation and test the necessity of depotentiation for successful modification of memory in a switching task. By allowing sleep to occur normally while temporarily inactivating the hippocampus, we will isolate the contribution of hippocampal reactivation at fixed time points in the memory consolidation process. We expect that the mnemonic benefits of sleep will not be realized in hippocampal-dependent tasks when the hippocampus is inactivated before consolidation is complete. When we release sleep reactivation, we expect to see neural activity patterns in waking and in REM sleep that indicate the consolidation process had been arrested and the peak-to-trough theta phase reversal delayed. We also expect consolidation to continue normally from the point at which it had been stopped as shown by resumed improvement in behavioral performance. In Specific Aims 2 and 3 we will test the mnemonic necessity of the absence of the two neurotransmitter systems normally silent during REM sleep. We will allow REM sleep to occur, but introduce noradrenergic and serotoniergic agonists in the hippocampus during sleep, measuring the changes in learning and in the sleep/waking profile of cellular activity as in the first specific aim. These results should suggest mnemonic influences of different antidepressants which act with varying efficacy on the monoaminergic axis. In addition, this effort will contribute to the knowledge base of memory consolidation mechanisms to ultimately indicate effective ways to improve the memory and learning capabilities of impaired individuals.