Hippocampal Network Dynamics during Sleep

描述（由申请人提供）：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：记忆在活动时在海马体中编码，然后在睡眠时在新皮层回路中巩固。在神经元集合的层面上，支持这一猜想的主要证据是，海马体在快速眼动和慢波睡眠（SWS）期间都会重播部分特定于体验的清醒活动，尽管这两个阶段的电和化学特征截然不同。这就提出了几个关键问题：这两个睡眠阶段在记忆巩固中有什么不同的作用（如果有的话）？SWS和REM的神经活动模式是如何支持这些角色的？可塑性是如何影响这些模式的形成的呢？我们将在自由活动的大鼠身上结合大规模电生理学、计算模型和药理学操作来验证REM和SWS以经验依赖的方式不同地改变海马体的协调放电的假设。特别是，我们的初步数据强烈表明，快速眼动增加了海马体的协调放电（Aim 1），而SWS具有相反的效果（Aim 2）。基于对海马体细胞表现出位置特异性放电（位置细胞）的观察，我们将使用重复的线性轨迹遍历来产生一致的海马体模式激活。通过改变环境和遍历次数，我们将创建多个参数变化强度的体验特定轨迹，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目标和参与可塑性机制的能力方面起着关键作用。在目标3中，我们将通过以下方式来描述突触可塑性在控制海马体内协调放电水平方面的作用：(1)开发一个计算框架来测试可塑性规则是否可以解释REM和SWS产生的相关放电变化；(2)通过药物阻断NMDA受体后重复Aims 1、2的实验测量；(3)利用电刺激探测CA3循环连接的平均突触重量，并追踪其在睡眠过程中的演变。拟议的研究将实验和计算方法结合起来，量化同步如何改变睡眠期间的海马活动模式，以及这些变化如何依赖于清醒经验。在许多精神疾病中都观察到睡眠活动的失调，如精神分裂症和抑郁症。拟议的研究可能为理解这种监管不当的起源和后果提供一个框架。此外，我们还研究了循环神经网络中突发放电和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状态（如癫痫发作）的基础。

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.