Memory computations across hippocampal, entorhinal, and prefrontal circuits

海马、内嗅和前额叶回路的记忆计算

• 批准号: 10153897
• 负责人: Stefan Leutgeb
• 金额: $ 40.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10153897
• 关键词: Animals; Area; Award; Behavior; Brain; Brain Diseases; Brain region; Cells; Code; Data; Disease; Dorsal; Event; Foundations; Future; Hippocampus (Brain); Interruption; Knowledge; Medial; Memory; Memory impairment; Mental disorders; Neurodegenerative Disorders; Neurons; Pathology; Pattern; Population; Prefrontal Cortex; Role; Running; Short-Term Memory; Time; Variant; Work; cell cortex; cognitive function; entorhinal cortex; follow-up; improved; memory retention; nervous system disorder; relating to nervous system; way finding

PROJECT SUMMARY A combination of entorhinal, hippocampal, and prefrontal pathology has a pivotal role in most neurological and neurodegenerative diseases and in the emergence of memory impairments that are associated with these diseases. Despite the knowledge that these brain regions are particularly vulnerable, the diversity of neural computations within and across these brain regions is only beginning to be revealed. For example, a key function of the hippocampus and medial entorhinal cortex (mEC) is to bridge events that are discontinuous in time, and entorhinal and hippocampal cells that are sequentially active (‘time cells’) have been proposed to be pivotal for memory retention over delay intervals of many seconds. In our previous work, we therefore investigated the firing patterns over the delay interval in a spatial working memory (WM) task. We unexpectedly found that hippocampal time cells were not a general mechanism for WM retention in hippocampus-dependent tasks. Rather, preliminary data indicate that information about past and future choices during the delay interval is evident during brief population bursts in hippocampus, while mEC cells may show memory-related activity that persists irrespective of brain state. We therefore hypothesize that memory retention does not require time-varying activity over the delay interval but is rather evident in sporadic population bursts in hippocampus and medial prefrontal cortex (mPFC) throughout the delay period and in firing patterns of entorhinal cells that provide continuity irrespective of brain state. To record activity during the delay period with varying brain states, we will – within each animal – use two variants of a spatial WM task, one with and one without forced running throughout the delay such that either theta or non-theta states are predominant. Aim 1 will focus on population bursts in hippocampus and determine whether they are only informative in non-theta states, as shown in our preliminary data, or a general mechanism across brain states. In addition, we will selectively interrupt hippocampal activity within the delay period to determine whether coding of future choices by population bursts and behavior are perturbed. Aim 2 will then perform recordings across deep and superficial layers and along the dorso-ventral axis of entorhinal cortex to identify how mEC contributes to WM. Finally, Aim 3 will carry out large-scale combined single-unit and LFP recordings in hippocampus and mPFC and in mEC and mPFC to reveal the coordination of mechanisms for WM retention across brain regions and brain states. Taken together, we will identify whether neuronal activity during population bursts is a general mechanism for memory retention over delay intervals irrespective of brain state, whether mEC supports WM retention with persistent activity, and how subregions of mPFC are coordinated with hippocampal and entorhinal subareas along the dorso-ventral axis. Identifying these memory computations will be the foundation for treatment approaches to restore memory functions when brain circuits deteriorate in neurological and neurodegenerative diseases.

项目摘要 内嗅，海马和前额叶病理的结合在大多数神经系统中具有关键作用 和神经退行性疾病以及与这些相关的记忆障碍的出现 疾病。尽管知道这些大脑区域特别脆弱，但神经的多样性 这些大脑区域内部和整个大脑区域内的计算才刚刚开始揭示。例如，一个键 海马和内侧内嗅皮层（MEC）的功能是桥梁事件不连续的事件 已经提出了时间，以及依次活跃（“时间细胞”）的内嗅和海马细胞 超过许多秒的延迟间隔的记忆保持关键。因此，在我们以前的工作中，我们 在空间工作内存（WM）任务中研究了延迟间隔的射击模式。我们 出乎意料地发现，海马时间细胞不是WM保留的一般机制 海马依赖性任务。相反，初步数据表明有关过去和未来的信息 在延迟间隔期间的选择是海马短暂种群爆发期间的证据，而MEC细胞 无论大脑状态如何，都可能显示与内存有关的活动。因此，我们假设 保留记忆不需要时间变化的活动，而是在延迟间隔内进行的证据 在整个延迟期间 以及在内部细胞的发射模式中，可提供连续性，而与大脑状态无关。记录活动 在带有不同大脑状态的延迟期间，我们将在每只动物中使用两个空间变体 WM任务，其中一个没有强迫在整个延迟中奔跑 国家是主要的。 AIM 1将专注于海马中的人口爆发，并确定它们是否是 如我们的初步数据所示，仅在非态度状态或大脑的一般机制中所示 国家。此外，我们将在延迟期内有选择地中断海马活动以确定 是否会通过人口爆发和行为编码未来的选择。 AIM 2将执行 横跨深层和浅层层以及沿着内嗅皮层的dorso-central轴的记录以识别 MEC如何贡献WM。最后，AIM 3将进行大规模的单单元和LFP录音 在海马和MPFC以及MEC和MPFC中，以揭示WM保留机制的协调 跨大脑区域和大脑状态。综上所述，我们将确定是否在 人口爆发是保留记忆力超过延迟间隔的通用机制，无论大脑状态如何， WM保留持续活动，以及MPFC的子区域如何协调 沿着多索腹侧轴的海马和肠ham骨亚洲。识别这些记忆 计算将是脑电路时恢复记忆功能的治疗方法的基础 神经和神经退行性疾病的恶化。