Hippocampal Network Dynamics during Sleep

描述(申请人提供)：长期记忆是如何形成的？一个著名的理论提出了一个两阶段的过程：在活跃的行为中，记忆在海马体中编码，然后在睡眠时，通过新皮质回路巩固记忆。在神经元组装的水平上，支持这一猜测的主要证据是，海马体在REM和慢波睡眠(SWS)期间重复其特定于经验的清醒活动的一部分，尽管这两个阶段的电和化学特征截然不同。这引出了几个关键问题：这两个睡眠阶段在记忆巩固中扮演了什么不同的角色？SWS和REM的神经活动模式如何支持这些角色？可塑性是如何影响这些模式的呢？我们将结合行为自由的大鼠的大规模电生理学、计算建模和药理学操作来测试REM和SWS以经验依赖的方式不同地改变海马区协调放电的假设。特别是，我们的初步数据强烈表明，REM增加了海马区的协调放电(目标1)，而SWS具有相反的效果(目标2)。基于观察到的海马细胞表现出特定位置的放电(位置细胞)，我们将使用重复的线性轨迹遍历来产生一致的海马区模式激活。通过改变环境和穿越次数，我们将创建参数不同的强度的多个特定经验轨迹，并测量它们在几个SWS/REM睡眠阶段的演变。协调放电的变化在控制海马体驱动突触后靶点和参与可塑性机制的能力方面发挥着关键作用。在目标3中，我们将通过以下方式来表征突触可塑性在控制海马区协调放电水平中的作用：(1)建立一个计算框架，用于测试可塑性规则是否可以解释REM和SWS产生的相关放电的变化；(2)通过重复药物阻断NMDA受体后对AIMS 1、2的实验测量；以及(3)通过使用电刺激来探测CA3反复连接的平均突触重量并跟踪其在睡眠中的演变。公共健康相关性拟议的研究结合了实验和计算方法，以量化同步如何改变睡眠期间的海马体活动模式，以及这些变化如何依赖于醒着的经验。睡眠活动的失调在许多精神疾病中都能观察到，例如精神分裂症和抑郁症。拟议的研究可能为理解这种不当监管的根源和后果提供一个框架。此外，我们还研究了循环网络中突发发射与可塑性之间的相互作用。这些过程之间的异常相互作用可能是海马体发作性状态的基础，如癫痫发作。

DESCRIPTION (provided by applicant): How are long-term memories formed? One prominent theory proposes a two-stage process: memories are encoded in the hippocampus during active behavior and then consolidated across neocortical circuits during sleep. At the level of neuronal assemblies, the main evidence for this conjecture is that the hippocampus replays portions of its experience-specific awake activity during both REM and slow-wave sleep (SWS), even though the electrical and chemical profiles of these stages differ drastically. This raises several key questions: What differential roles, if any, do these two sleep stages play in memory consolidation? How are these roles supported by the neural activity patterns of SWS and REM? And how does plasticity contribute to shaping these patterns? We will employ a combination of large-scale electrophysiology in freely behaving rats, computational modeling, and pharmacological manipulations to test the hypothesis that REM and SWS differentially alter coordinated firing in the hippocampus in an experience-dependent manner. In particular, our preliminary data strongly suggest that REM increases coordinated firing in the hippocampus (Aim 1), while SWS has the opposite effect (Aim 2). Building on the observation that hippocampal cells exhibit place specific firing (place cells), we will use repeated linear track traversals to generate consistent activation of hippocampal patterns. By changing the environment and the number of traversals, we will create multiple experience-specific traces of parametrically varying strengths and measure their evolution over several SWS/REM sleep stages. Changes in coordinated firing play a critical role in controlling the ability of the hippocampus to drive its post-synaptic targets and engage plasticity mechanisms. In Aim 3, we will characterize the role of synaptic plasticity in controlling the level of coordinated firing within the hippocampus by: (1) developing a computational framework for testing whether plasticity rules can account for changes in correlated firing produced by REM and SWS; (2) by repeating the experimental measurements of Aims 1,2 after pharmacological blockade of NMDA receptors; and (3) by using electrical stimulation to probe the mean synaptic weight of CA3 recurrent connections and track its evolution during sleep. PUBLIC HEALTH RELEVANCE The proposed studies integrate experimental and computational approaches to quantify how synchrony alters hippocampal activity patterns during sleep, and how these changes depend on waking experience. Misregulation of sleep activity is observed in many psychiatric disorders, such as schizophrenia and depression. The proposed studies may provide a framework for understanding the origins and consequences of such misregulation. In addition, we investigate the interactions between burst firing and plasticity in recurrent networks. Abnormal interactions between these processes may underlie paroxysmal states in the hippocampus such as epileptic seizures.