Gene Regulation and Synaptic Plasticity in Sleep

描述（由申请人提供）：大量证据表明， 睡眠在巩固白天的记忆方面起着重要的作用 事件例如，动物积极学习特定的范式， 显示出增强的REM睡眠，而在以下情况下被剥夺REM睡眠的动物 在重新测试时显示记忆缺陷。然而，人们对它知之甚少。 睡眠在记忆巩固中的作用的大脑机制。我们 最近发现，Zif-268，一个立即早期基因（IEG）与 神经元可塑性，在暴露于 一个丰富的环境，然后在随后的快速眼动睡眠中重新激活， 与关在笼子里的动物相比。我们实验室的初步数据 表明这种再激活也发生在随后REM睡眠中 呈现强有力的嗅觉刺激，或诱导海马 长时程增强（LTP），后者是突触可塑性的模型。 我们推测，在REM睡眠期间基因的重新激活可能与 快速眼动在记忆巩固中的作用。本建议旨在 测试这种可能性。在目标I中，我们将重新考虑我们的初步观察结果 通过确定睡眠中的基因再激活是否也发生在动物身上， 暴露于特定的学习范例（例如，空间记忆;运动学习， 嗅觉刺激）;时间进程和大脑 一组代表性综合环境小组的分布情况，以及 不同的睡眠阶段，将被检查。这些特定的范例代表了 比丰富的环境暴露更受限制的经验;他们应该 导致更受限制的基因再激活模式， 与清醒时刺激的性质有关。目标二是 表征海马神经元诱导后睡眠中的基因再激活 LTP这将使我们能够非常精确地控制网站，强度和 刺激的时机。在目标3中，我们将评估阻断基因的效果。 在睡眠中重新激活（通过大脑注射RNA和蛋白质合成 阻断剂）对空间记忆保持和LTP维持的影响。在目标4中，我们 利用分子、药理学和电生理学的组合， 研究边缘系统和新皮层之间可能相互作用的技术 睡眠时的结构这些研究应该产生重要的见解， 与睡眠在学习和记忆中的作用有关的基本机制。

DESCRIPTION (provided by applicant): A large body of evidence suggests that sleep plays a significant role in the consolidation of memories of day-time events. For example, animals that are actively learning a particular paradigm display enhanced REM sleep, while animals which are REM deprived following learning display memory deficits on retest. Little is known, however, about the brain mechanisms that underlie the role of sleep in memory consolidation. We recently discovered that Zif-268, an immediate early gene (IEG) linked with neuronal plasticity, is activated in certain brain areas in animals exposed to an enriched environment, and then reactivated in the ensuing REM sleep-in comparison to animals kept in their home cages. Preliminary data from our lab indicate that such reactivation also occurs in REM sleep that follows presentation of a potent olfactory stimulus, or induction of hippocampal long-term potentiation (LTP), the latter being a model of synaptic plasticity. We hypothesize that gene reactivation during REM sleep may be involved in the role that REM plays in memory consolidation. The present proposal is aimed at testing this possibility. In Aim I we will ref1ne our preliminary observations by determining whether gene reactivation in sleep also occurs in animals exposed to specific learning paradigms (e.g., spatial memory; motor learning, olfactory stimulation) during wakefulness; the timecourse and brain distribution of a battery of representative IEGs, as well as the influence of different sleep phases, will be examined. These specific paradigms represent more restricted experiences than the enriched environment exposure; they should result in more restricted gene reactivation patterns that can be more easily correlated with the nature of the stimulation during wakefulness. Aim 2 is to characterize gene reactivation in sleep that follows induction of hippocampal LTP. This will allow us to very precisely control the site, intensity and timing of the stimulation. In Aim 3, we will assess the effect of blocking gene reactivation during sleep (with brain injections of RNA and protein synthesis blockers) on spatial memory retention and maintenance of LTP. In Aim 4, we will utilize a combination of molecular, pharmacological and electrophysiological techniques to investigate possible interactions between limbic and neocortical structures during sleep. These studies should yield significant insights into basic mechanisms related to the role of sleep in learning and memory.