REM Sleep and Memory

描述（由申请人提供）：许多证据支持快速眼动睡眠在学习和记忆巩固中的作用。在第一个实验阶段，我们发现快速眼动期间海马神经活动的变化与经验相关，并遵循记忆巩固（SA1）的过程，即从θ节律高峰到低谷的放电阶段的逆转。我们通过快速眼动剥夺（SA2）和增强（SA3）改变了新的行为任务的学习速率和表现策略，并测量了这些操作下theta峰谷反转的变化。与操纵快速眼动睡眠不同，该研究旨在确定快速眼动睡眠的生理事件，这些事件对海马体依赖性任务中的记忆巩固很重要。我们假设，在海马睡眠再激活过程中，去甲肾上腺素和血清素的缺乏提供了一个环境，在这个环境中，直接的内啡肽到ca1通路上的突触可能会加强，而ca3到ca1通路上的突触可能会减弱（去增强）。从理论上讲，为了清除海马体中临时的、可修改的联想记忆网络，使记忆代码随着新信息的到来而发生变化，去强化是必要的。在具体目标1中，我们将测试睡眠期间海马体再激活对去强化的必要性，并测试去强化对转换任务中成功修改记忆的必要性。通过让睡眠在海马体暂时失活的情况下正常发生，我们将在记忆巩固过程的固定时间点分离海马体再激活的贡献。我们预计，当海马体在巩固完成前失活时，睡眠的记忆益处将不会在海马体依赖性任务中实现。当我们释放睡眠再激活时，我们期望在清醒和快速眼动睡眠中看到神经活动模式，表明巩固过程已经被阻止，波峰到波谷的θ相位反转被延迟。我们也期望巩固从它被停止的点正常继续，正如行为表现的恢复改善所显示的那样。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助记必要性。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血清素能激动剂，测量学习和睡眠/清醒时细胞活动的变化，如第一个具体目标。这些结果表明，不同的抗抑郁药对单胺能轴有不同的助记作用。此外，这一努力将有助于建立记忆巩固机制的知识库，最终指出提高受损个体记忆和学习能力的有效方法。

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.