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.

项目总结

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