Coordinated reactivation in hippocampus and entorhinal cortex during awake sharp-wave ripple events

项目摘要 清醒状态下的记忆回忆提供了对过去和未来可能采取的行动进行心理探索的基础 引导人们的行为。随着严重的记忆障碍弥漫在广泛的神经精神障碍中， 研究大脑记忆系统背后的未知神经机制对于 制定有针对性的临床干预措施。对最近记忆的回忆依赖于完整的海马体 (HPC)和周围的鼻皮质，并假设依赖于一种特定的机制：空间调谐 HPC索引空间关联表示中的‘Place’单元，从而激活特定序列 位置细胞可以使大脑皮层原有的间歇性活动模式重新活跃起来。这些在空间上 已经在HPC中观察到位置单元的相干序列，特别是以离散突发的形式出现 网络振荡中的活动，称为尖锐波纹(SWR)。尽管越来越多的证据表明 SWR非常适合于传播助记信息，关键问题仍然悬而未决 有必要进一步确立它们在记忆中的机械性作用。首先，为了确定这些是否 这些事件协调了整个大脑连贯的记忆轨迹的重新激活，证实了 清醒的SWR重播的代表性内容在整个海马-皮质回路中被忠实地协调 必须被确立。第二，还不清楚助记序列在多大程度上被唤醒 HPC有助于两个重要的记忆过程：对潜在未来行动的想象，或归纳 神经可塑性来巩固间歇性联系。为了直接解决这些关键问题，我们 建议调查HPC和其初级HPC之间清醒的SWR相关活动的确切性质 空间信息的目标是内侧内嗅皮层(MEC)。我们假设苏醒的SWR重播 直接驱动海马区-大脑皮层的协调重新激活以指导决策和记忆 整合。我们将通过对HPC神经活动的多点电生理记录来验证这一假说 和学习空间记忆任务的大鼠的MEC(目标1、2和3)。我们还将使用双极微刺激 选择性阻断海马区腹侧连合部电极及其致病作用的研究 海马区-皮质活动模式和决策(目标3)。我们的具体目标是： 目的1：验证MEC活性与海马SWR-Replay活性相对应的假设。 目的2：验证MEC中SWR相关活动预测行为绩效的假设。 目的3：检验觉醒短波相关素数序列与记忆巩固的关系。 测试这些假说将是将神经活动与记忆功能联系起来的关键进展， 它的潜在影响被记录在案的序列重新激活的损伤所突显 精神分裂症和痴呆症等神经精神障碍。作为大脑记忆的关键组成部分 HPC和MEC是科学研究的重点和临床干预的有希望的靶点。

Project Abstract Memory recall in the waking state provides the basis for mental exploration of past and possible future actions to guide behavior. As severe memory impairments pervade widespread neuropsychiatric disorders, investigation of the unknown neural mechanisms that underlie the brain's memory system is crucial for developing targeted clinical interventions. The recall of recent memory is dependent on the intact hippocampus (HPC) and surrounding rhinal cortices, and is hypothesized to rely on a specific mechanism: spatially tuned `place' cells in the HPC index spatially-associated representations, such that activating a particular sequence of place cells can reanimate a trace of the original episodic activity patterns across the cortex. These spatially coherent sequences of place cells have been observed in the HPC, and in particular occur as discrete bursts of activity within network oscillations, called sharp wave ripples (SWRs). Although mounting evidence suggests that SWR's are ideally suited to propagate mnemonic information, critical questions remain open that are necessary to further establish their mechanistic role in memory. First, in order to determine whether these events orchestrate the reactivation of a coherent memory trace throughout the brain, confirmation that the representational content of awake SWR-replay is faithfully coordinated across the hippocampal-cortical circuit must be established. Second, it is unknown to what extent awake reactivation of mnemonic sequences from the HPC contributes to two important memory processes: imagination of potential future action, or the induction of neural plasticity to consolidate episodic associations. In order to directly address these critical questions, we propose to investigate the precise nature of awake SWR-related activity between the HPC and its primary target for spatial information, the medial entorhinal cortex (MEC). We hypothesize that awake SWR-replay directly drives hippocampal-cortical coordinated reactivation to guide both decision-making and memory consolidation. We will test this hypothesis with multi-site electrophysiological recording of neural activity in HPC and MEC of rats learning a spatial memory task (Aims 1, 2, and 3). We will also use a bipolar microstimulation electrode in the ventral hippocampal commissure to selectively disrupt SWRs and establish their causal role in hippocampal-cortical activity patterns and decision-making (Aim 3). Our specific aims are: Aim 1: To test the hypothesis that the MEC activity corresponds to that of hippocampal SWR-replay. Aim 2: To test the hypothesis that SWR-related activity in MEC is predictive of behavioral performance. Aim 3: To test the hypothesis that awake SWRs prime sequence association for memory consolidation. Testing these hypotheses would be a critical advance in linking neural activity to memory functions, the potential impact of which is underscored by documented impairments of sequence reactivation in models of neuropsychiatric disorders such as schizophrenia and dementia. As critical components of the brain's memory system, the HPC and MEC are priorities for scientific inquiry and promising targets for clinical intervention.