Gene Regulation and Synaptic Plasticity in Sleep

描述(申请人提供)：大量证据表明 睡眠对巩固白天的记忆起着重要作用 事件。例如，正在积极学习特定范例的动物 表现出增强的REM睡眠，而被剥夺REM的动物 在重测中，学习表现出记忆缺陷。然而，人们对此知之甚少 睡眠在巩固记忆中所起作用的大脑机制。我们 最近发现与即刻早期基因(IEG)连锁的ZIF-268 神经可塑性，在暴露于辐射的动物的特定脑区被激活 丰富的环境，然后在随后的快速眼动睡眠中重新激活 与饲养在家中笼子里的动物相比。来自我们实验室的初步数据 表明这种重新激活也发生在随后的REM睡眠中 强烈的嗅觉刺激，或海马区的诱导 长时程增强(LTP)是突触可塑性的模型。 我们推测，快速眼动睡眠期间的基因重新激活可能参与了 REM在记忆巩固中扮演的角色。本提案的目的是 测试这种可能性。在目标I中，我们将参考我们的初步观察结果 通过确定睡眠中的基因重新激活是否也发生在动物身上 暴露于特定的学习范式(例如，空间记忆；运动学习， 嗅觉刺激)清醒时；时序和大脑 具有代表性的IEG电池的分布，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体验；他们应该 导致更多受限的基因重新激活模式，这可能更容易 与清醒时刺激的性质有关。目标2是 海马区诱导后睡眠中基因重新激活的特征 LTP。这将使我们能够非常精确地控制位置、强度和 刺激的时机。在目标3中，我们将评估封闭基因的效果。 在睡眠中重新激活(通过脑内注射RNA和蛋白质合成 阻滞剂)对长时程增强的空间记忆保持和维持。在目标4中，我们将 利用分子、药理学和电生理学的组合 研究边缘皮质和新皮质之间可能相互作用的技术 睡眠中的结构。这些研究应该会产生重要的见解 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.