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: 10841900
• 负责人: Stefan Leutgeb
• 金额: $ 11.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10841900
• 关键词: Animals; Basal Ganglia; Behavior; Brain; Brain Diseases; Brain region; Cells; Code; Corpus striatum structure; Data; Deterioration; Disease; Dorsal; Event; Foundations; Future; Hippocampus; Interruption; Knowledge; Medial; Memory; Memory impairment; Mental disorders; Neurodegenerative Disorders; Neurons; Pathology; Pattern; Population; Prefrontal Cortex; Research; Role; Running; Short-Term Memory; Time; Variant; Work; cell cortex; cognitive function; entorhinal cortex; improved; memory retention; nervous system disorder; neural

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, mPFC and mEC to reveal the coordination of mechanisms for WM retention across brain regions. In a research supplement, we will also investigate the coordination between mEC and dorsal striatum. Taken together, we will identify whether neuronal activity during population bursts is a general mechanism for memory retention 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、海马和前额叶病变的组合在大多数神经系统疾病中具有关键作用。 和神经退行性疾病以及与这些疾病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，但神经系统的多样性仍然存在。 在这些大脑区域内和跨这些大脑区域的计算才刚刚开始被揭示。例如，一把钥匙 海马体和内侧内嗅皮层（mEC）的功能是桥接不连续的事件， 时间，内嗅和海马细胞是顺序活跃（'时间细胞'）已被提出， 关键是在几秒钟的延迟间隔内保持记忆。在我们以前的工作中，我们 研究了空间工作记忆（WM）任务中延迟间隔内的放电模式。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， 校园相关任务。相反，初步数据表明，关于过去和未来的信息 在海马短暂的群体爆发期间，延迟间隔期间的选择是明显的，而mEC细胞 可能显示出与记忆相关的活动，无论大脑状态如何，这种活动都会持续存在。因此，我们假设， 记忆保持不需要在延迟间隔上的时变活动， 在整个延迟期内，海马和内侧前额叶皮层（mPFC）中的零星群体爆发 以及内嗅细胞的放电模式，这些模式提供了与大脑状态无关的连续性。记录活动 在不同大脑状态的延迟期内，我们将在每只动物体内使用两种不同的空间 WM任务，一个有和一个没有强制运行整个延迟，这样无论是θ或非θ 国家占主导地位。目标1将集中在海马体的群体爆发，并确定它们是否是 只有在非θ状态下才能提供信息，正如我们的初步数据所示，或者是大脑的一般机制。 states.此外，我们将在延迟期内选择性地中断海马活动，以确定 种群爆发和行为对未来选择的编码是否受到干扰。目标2将执行 记录跨越深层和浅层和沿着背腹轴的内嗅皮层，以确定 mEC如何对WM做出贡献。最后，Aim3将进行大规模的组合单单元和LFP记录 在海马、mPFC和mEC中，以揭示WM在脑内滞留的协调机制 地区在研究补充中，我们还将研究mEC和背侧纹状体之间的协调。 总之，我们将确定群体爆发期间的神经元活动是否是一种普遍的机制， 不考虑大脑状态的记忆保留，mEC是否支持具有持续活动的WM保留，以及 mPFC的亚区如何与海马和内嗅亚区沿着背腹侧协调 轴线识别这些记忆计算将是恢复的治疗方法的基础 当神经系统和神经退行性疾病的大脑回路恶化时，记忆功能。

项目成果

Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons.

• DOI: 10.1038/s41593-017-0061-5
• 发表时间: 2018-03
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Sasaki T;Piatti VC;Hwaun E;Ahmadi S;Lisman JE;Leutgeb S;Leutgeb JK
• 通讯作者: Leutgeb JK

Hippocampal Neural Circuits Respond to Optogenetic Pacing of Theta Frequencies by Generating Accelerated Oscillation Frequencies.

海马神经回路通过产生加速振荡频率来响应theta频率的光遗传学起搏。

• DOI: 10.1016/j.cub.2018.02.061
• 发表时间: 2018-04-23
• 期刊: Current biology : CB
• 作者: Zutshi I;Brandon MP;Fu ML;Donegan ML;Leutgeb JK;Leutgeb S
• 通讯作者: Leutgeb S

Theta sequences of grid cell populations can provide a movement-direction signal.

• DOI: 10.1016/j.cobeha.2017.08.012
• 发表时间: 2017-10
• 期刊: Current opinion in behavioral sciences
• 影响因子: 5
• 作者: Zutshi I;Leutgeb JK;Leutgeb S
• 通讯作者: Leutgeb S

New and distinct hippocampal place codes are generated in a new environment during septal inactivation.

• DOI: 10.1016/j.neuron.2014.04.013
• 发表时间: 2014-05-21
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Brandon MP;Koenig J;Leutgeb JK;Leutgeb S
• 通讯作者: Leutgeb S

Precisely timed theta oscillations are selectively required during the encoding phase of memory.

• DOI: 10.1038/s41593-021-00919-0
• 发表时间: 2021-11
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Quirk CR;Zutshi I;Srikanth S;Fu ML;Devico Marciano N;Wright MK;Parsey DF;Liu S;Siretskiy RE;Huynh TL;Leutgeb JK;Leutgeb S
• 通讯作者: Leutgeb S