REM Sleep and Memory

描述(由申请人提供)：一系列综合证据支持快速眼动睡眠在学习和记忆巩固中的作用。在第一次授予期间，我们显示了REM期间海马神经活动的变化，这种变化与经验相关，并遵循记忆巩固(SA1)的过程，即从theta节律峰值到低谷的放电阶段的逆转。在一项新的行为任务中，我们用REM剥夺(SA2)和增强(SA3)改变了学习速度和表现策略，并用这些操作测量了theta从峰到谷反转的变化。这项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，这些事件对于海马体依赖任务中的记忆巩固非常重要。我们推测，在海马体睡眠恢复过程中，去甲肾上腺素和5-羟色胺的缺失提供了一种环境，在这种环境中，内嗅觉到CA1的直接突触可能被加强，而CA3到CA1的突触可能被削弱(去增强)。理论上，去增强对于清除海马体临时的、可修改的联想记忆网络是必要的，以允许记忆代码随着新信息的到来而改变。在具体目标1中，我们将测试睡眠期间海马体重新激活对去增强的必要性，并测试在转换任务中成功修改记忆的去增强的必要性。通过在海马体暂时失活的同时让睡眠正常进行，我们将分离出在记忆巩固过程中固定时间点的海马体重新激活的贡献。我们预计，当海马体在巩固完成之前被灭活时，睡眠的助记益处将不会在海马体依赖的任务中实现。当我们释放睡眠重新激活时，我们希望在清醒和REM睡眠中看到神经活动模式，这表明巩固过程已经停止，从峰到谷的相位反转被推迟。我们还预计，从行为表现恢复改善所表明的那样，整合将从停止的点正常继续进行。在特定的目标2和3中，我们将测试两个神经递质系统在快速眼动睡眠期间通常不会出现的助记必要性。我们将允许发生快速眼动睡眠，但在睡眠期间在海马体中引入去甲肾上腺素和5-羟色胺能激动剂，测量学习和睡眠/清醒状态下细胞活动的变化，作为第一个特定目标。这些结果应该提示不同的抗抑郁药对单胺能轴有不同的助记力影响。此外，这一努力将有助于建立记忆巩固机制的知识库，最终指明改善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.