The role of dentate gyrus input-output computations in episodic memory

齿状回输入输出计算在情景记忆中的作用

• 批准号: 10481838
• 负责人: Antoine David Madar
• 金额: $ 7.41万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481838
• 关键词: Address; Alzheimer' s Disease; Anatomy; Animals; Anxiety; Anxiety Disorders; Area; Axon; Behavioral; Brain; Brain region; Calcium; Cells; Code; Cognition Disorders; Computer Models; Confusion; Data Set; Dendrites; Discrimination; Disease; Doctor of Philosophy; Environment; Episodic memory; Event; Familiarity; Freezing; Fright; Goals; Hippocampus; Image; Impairment; Individual; Inherited; Investigation; Knowledge; Learning; Major Depressive Disorder; Measures; Memory; Memory impairment; Mental Depression; Methods; Mus; Neocortex; Neurologic; Neurons; Output; Parahippocampal Gyrus; Pathologic; Pattern; Phase; Physiology; Play; Population; Post-Traumatic Stress Disorders; Process; Reporting; Research; Research Project Grants; Research Proposals; Resolution; Retrieval; Role; Schizophrenia; Slice; Source; Specificity; Stimulus; Stressful Event; Symptoms; Temporal Lobe Epilepsy; Testing; Training; Transfection; Transgenic Mice; Viral; Work; autism spectrum disorder; cognitive function; conditioned fear; dentate gyrus; entorhinal cortex; experience; experimental study; in vivo; in vivo evaluation; mathematical model; memory consolidation; memory encoding; memory recall; memory retrieval; neocortical; nervous system disorder; neural; neuronal cell body; novel; post-traumatic stress; prevent; spatiotemporal; theories; therapy design; two-photon; virtual environment

PROJECT SUMMARY A critical feature of memory is mnemonic discrimination, the ability to distinguish between similar events in our past and prevent confusion between similar situations. The dentate gyrus (DG) of the hippocampus is a brain region known to play a central part in this cognitive function. For thirty years, the DG neuronal network has been hypothesized to support mnemonic discrimination by performing a computation called "pattern separation" during memory encoding. In this view, the role of the DG is to disambiguate upstream cortical representations of similar events, transforming similar patterns of incoming activity into dissimilar output patterns, before they reach downstream hippocampal areas to be stored as memories. Computational modelling suggests that the anatomy and physiology of the DG network could allow DG to perform pattern separation, and recent experimental studies demonstrated that the isolated DG is able to perform some forms of pattern separation. However, a direct demonstration that DG performs such computation in vivo remains elusive. Consequently, the central tenet that pattern separation in DG during memory encoding is the mechanism underlying mnemonic discrimination has never been directly tested. Moreover, the role of DG during memory retrieval or consolidation is also unclear. The general goals of this research project are thus to 1) test in vivo whether DG performs pattern separation or other computations and 2) determine how DG computations during encoding and retrieval support mnemonic discrimination. Measuring the computations of a network like DG requires knowledge about its simultaneous inputs and outputs, which has never been achieved in vivo at a single-cell resolution. To resolve this difficulty, I will use multiplane two-photon calcium imaging in behaving mice in order to simultaneously record activity dynamics of a large population of DG output neurons and the activity of the cortical axons that target their dendrites. To investigate the basis of mnemonic discrimination, one needs to compare neuronal representations of different but similar experiences. To this end, mice trained to navigate in a virtual environment will be placed in several novel environments of parametrically varied similarity. Experiment-1 will consist of recording DG inputs and outputs while mice explore a sequence of environments, repeated over several days to determine how computations evolve as familiarity increases. In experiment-2, an explicit mnemonic component will be added: a new environment will be associated to a fearful stimulus and the ability of individual mice to discriminate this context from another similar but neutral one will be measured. This will allow to determine what computations are performed by DG during encoding and recall and how they relate to context discrimination: if the theory is correct, the degree of pattern separation during encoding should correlate to the amount of discrimination. Finally, the analysis of this rich dataset will help constrain more detailed theories of episodic memory, an instrumental step towards understanding memory impairments symptomatic of numerous cognitive disorders.

项目摘要 记忆的一个重要特征是记忆辨别力，即区分记忆中相似事件的能力。 避免混淆类似情况。海马体的齿状回（DG）是一个大脑 这一区域在认知功能中起着核心作用。三十年来，DG神经元网络一直是 假设通过执行称为"模式分离"的计算来支持记忆辨别， 存储器编码在这种观点中，DG的作用是消除类似的上游皮质表征的歧义。 事件，将类似的传入活动模式转换为不同的输出模式，然后再到达 下游的海马区被储存为记忆。计算模型表明， DG网络的生理学可以允许DG执行模式分离，最近的实验研究 证明了孤立的DG能够执行某些形式的模式分离。然而，一个直接 DG在体内进行这种计算的证明仍然是难以捉摸的。因此，中心原则， 在记忆编码过程中DG中的模式分离是记忆辨别的潜在机制， 从未直接测试过。此外，DG在记忆提取或巩固过程中的作用也不清楚。 因此，本研究项目的总体目标是：1）在体内测试DG是否执行模式分离， 2）确定在编码和检索期间DG计算如何支持助记符 歧视测量像DG这样的网络的计算需要了解其同时 输入和输出，这在单细胞分辨率下从未在体内实现。为了解决这个难题，我 将使用多平面双光子钙成像在行为小鼠，以同时记录活动 大量DG输出神经元的动力学和靶向它们的皮质轴突的活动 树突为了研究记忆辨别的基础，需要比较神经元的表征 不同但相似的经历。为此，将放置经过训练在虚拟环境中导航的老鼠 在几个参数变化相似的新环境中。实验1将包括记录DG输入 当老鼠探索一系列环境时，重复几天，以确定如何 计算随着熟悉度的增加而发展。在实验2中，将添加一个明确的助记成分： 新的环境将与可怕的刺激和个体小鼠区分这种刺激的能力相关联。 将测量来自另一个类似但中立的上下文的上下文。这将允许确定哪些计算 是由DG在编码和回忆过程中执行的，以及它们如何与上下文区分相关：如果理论是 正确的，在编码过程中模式分离的程度应该与辨别力的大小相关。 最后，对这个丰富的数据集的分析将有助于限制更详细的情景记忆理论， 这是理解许多认知障碍的记忆障碍症状的重要一步。