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为对过去和未来可能的行为进行精神探索提供了基础 来指导行为。由于严重的记忆障碍普遍存在于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。最近记忆的回忆依赖于完整的海马体 (HPC)和周围的鼻腔皮质，并假设依赖于一个特定的机制：空间调谐 HPC中的“place”单元格索引空间关联的表示，使得激活特定序列 定位细胞的活动可以使大脑皮层中原有的情景活动模式重新活跃起来。这些空间 在HPC中观察到了位置细胞的相干序列，特别是以离散的爆发形式出现 网络振荡中的活动，称为尖波涟漪（SWR）。尽管越来越多的证据表明 SWR非常适合传播记忆信息，但关键问题仍然存在， 进一步确立它们在记忆中的机械作用是必要的。首先，为了确定这些 事件协调了整个大脑中连贯记忆痕迹的重新激活，证实了 清醒状态下SWR-重放的表征内容在大脑皮层回路中是忠实协调的 必须建立。第二，不知道在多大程度上唤醒记忆序列， 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 神经可塑性来巩固情景关联。为了直接解决这些关键问题，我们 我建议调查HPC和其主要神经元之间清醒时SWR相关活动的确切性质。 空间信息的目标，内侧内嗅皮层（MEC）。我们假设清醒状态下的SWR回放 直接驱动大脑皮层协调的再激活，以指导决策和记忆 合并。我们将用多点电生理记录HPC中的神经活动来验证这一假设 和大鼠学习空间记忆任务的MEC（目的1、2和3）。我们还将使用双极微刺激 电极在腹侧海马连合选择性地破坏SWR，并建立其因果关系的作用， 大脑皮层活动模式和决策（目标3）。我们的具体目标是： 目的1：验证MEC活动与海马SWR-重放活动相对应的假设。 目的2：检验MEC中与SWR相关的活动对行为表现有预测作用的假设。 目的3：验证清醒状态下记忆巩固与睡眠反应启动序列关联的假设. 验证这些假设将是将神经活动与记忆功能联系起来的关键进展， 其潜在影响通过记录的序列再激活模型中的损伤来强调， 神经精神障碍，如精神分裂症和痴呆。作为大脑记忆的重要组成部分 系统，HPC和MEC是科学探究的优先事项和临床干预的有希望的目标。

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.