Mechanisms of expression and relationship between two distinct types of internally generated hippocampal sequences

项目摘要/摘要 大脑表达几种不同类型的内部产生的神经元活动序列 独立于外部感觉刺激，以及这种在时间上精确的、自组织的序列起着至关重要的作用 在信息处理和记忆形成/检索中的作用。特别是，海马体产生两个 独立的、定义明确的神经元序列：与尖波/涟漪(SWR)相关的序列 在“离线”状态下观察到，如休息或睡眠，以及与theta相关的序列 “上线”等状态积极探索。先前的工作已经证明了SWR序列和 工作记忆、长期记忆和未来计划，而theta序列与 决策和近期行为。然而，关于这两个序列是如何排列的，人们知之甚少 类型与经验或彼此相互作用，以促进助记过程。此外，电路机制 允许在内部产生的序列中表达特定的神经元活动模式的是 很大程度上是未知的。本研究的中心目标是利用超高密度、大规模的体内 电生理学结合复杂的空间导航任务深入研究这两种形式的 顺序活动以确定其生成、功能和关系所依据的基本原则 为了彼此。在大量初步数据的支持下，我们建议通过三个步骤来实现这一目标 具体目标：(1)定义内部产生的序列和正在进行的行为之间的关系 在记忆形成阶段与记忆提取/使用阶段；(2)确定潜在的机制 睡眠中内部生成的序列的发展、持久性和功能；(3)确定 海马区内连通性的模式和权重有助于表达和传播 内部生成的序列。总而言之，这项研究有望有意义地推进我们的理解 通过揭示允许精确的活动模式的基本原理来研究电路水平的大脑功能 动态生成并在整个海马区网络中传播，以支持学习。

PROJECT SUMMARY/ABSTRACT The brain expresses several distinct types of internally generated sequences of neuronal activity independent of external sensory stimuli, and such temporally precise, self-organized sequences play a crucial role in information processing and memory formation/retrieval. In particular, the hippocampus generates two separate, well-defined forms of neuronal sequences: sharp-wave/ripple (SWR)-associated sequences which are observed during “off-line” states such as rest or sleep, and theta-associated sequences which occur during “on-line” states such as active exploration. Prior work has demonstrated a link between SWR sequences and working memory, long-term memory, and future planning, while theta sequences have been associated with decision-making and immediate future behaviors. However, little is known regarding how these two sequence types interact with experience or each other to facilitate mnemonic processes. Further, the circuit mechanisms which allow specific neuronal activity patterns to be expressed within internally generated sequences are largely unknown. The central objective of this study is to utilize ultra-high density, large-scale in vivo electrophysiology coupled with complex spatial navigational tasks to examine in depth these two forms of sequential activity to identify fundamental principles which underlie their generation, function, and relationship to each other. Supported by considerable preliminary data, we propose to pursue this objective through three specific aims: (1) To define the relationship between internally generated sequences and ongoing behavior during periods of memory formation vs. memory retrieval/use; (2) To determine the mechanisms underlying development, persistence, and function of internally generated sequences in sleep; (3) To identify how the patterns and weights of connectivity within the hippocampus contribute to the expression and propagation of internally generated sequences. Together, this study is expected to meaningfully advance our understanding of circuit-level brain function by revealing the fundamental principles which allow precise patterns of activity to be dynamically generated and propagated throughout the hippocampal network in support of learning.