Single-cell and target-specific resolution of multiple memories across the brain

大脑中多个记忆的单细胞和目标特异性分辨率

• 批准号: 10689742
• 负责人: Christine Ann Denny
• 金额: $ 75.82万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689742
• 关键词: Address; Age-associated memory impairment; Alzheimer' s Disease; Area; Atlases; Behavior; Behavioral; Behavioral Assay; Biological; Brain; Brain Mapping; Brain imaging; Brain region; Catalogs; Cells; Cognition; Cognition Disorders; Development; Disease; Documentation; FOS gene; Fluorescence-Activated Cell Sorting; Funding; Genetic; Genetically Engineered Mouse; Goals; Histologic; Image; Immediate-Early Genes; Immunohistochemistry; Individual; Label; Laboratories; Lead; Learning; Maps; Mediating; Memory; Mental Depression; Mental disorders; Microscopic; Modeling; Molecular; Molecular Biology; Mus; National Institute of Mental Health; Neurons; Neurosciences; Optics; Organism; Performance; Physiological; Play; Population; Positive Lymph Node; Post-Traumatic Stress Disorders; Research; Research Personnel; Resolution; Retrieval; Role; Structure; System; Techniques; Technology; Time; Transgenic Organisms; United States National Institutes of Health; Viral; Virus; Visualization; Work; biological systems; combinatorial; experience; experimental study; genetic approach; in vivo; innovation; insight; memory encoding; memory retrieval; network models; neural; neural network; neuromechanism; novel; optogenetics; programs; tool

PROJECT SUMMARY / ABSTRACT A tremendous amount of research has provided us with an understanding of how neurons work in concert during the formation and retrieval of individual memories. While we understand how memories are stored in a limited number of brain regions, we do not yet understand how multiple memory traces are stored across whole-brain neural networks, as well as their real-time physiological dynamics, genetic landscape, and preferential wiring. What is needed now is technology to bridge the gap in our understanding between microscopic interactions at the neuronal level and macroscopic structures that perform computations across networks involved in learning and memory. Using a combination of two activity-dependent tagging systems that utilize the immediate early genes (IEG) Arc and c-fos, the aim of this proposal is to address the critical need for obtaining a map of multiple memories and provide the dynamic states of the brain in the context of behavioral performance and memory expression. We will first utilize behavioral assays and whole-brain imaging to provide unprecedented insight on how multiple memories (e.g., positive and negative memories) are stored with single-cell resolution in a brain-wide manner. Identification of similarities and differences between populations and projections of positive and negative memory ensembles will be quantified and correlated with behavioral performance by using neuronal modeling developed in the Denny laboratory. Tagged cells will also be pulled down and sequenced to delineate the genetic landscape differentiating positive and negative memories. We will then use in vivo Ca2+ imaging to resolve the real-time dynamics (e.g., Ca2+ activity) of neural ensembles as they participate in positive and negative memory encoding and retrieval. Moreover, we will use optogenetic modulation to manipulate the positive or negative ensembles in a within-subject manner during behavioral performance to identify key nodes involved in memory expression. Finally, we will use viral tracing strategies to determine how these ensembles are structurally wired across brain, thereby providing a wiring diagram for multiple experiences in the brain. In summary, comprehensive molecular biology, immunohistochemistry, network modeling, Ca2+ imaging, and optogenetic techniques will be utilized. As most studies have narrowed their analyses to a single brain structure, these studies will expand this scope exponentially by analyzing whole-brain memory traces mediating multiple memories. This combinatory system will result in a whole-brain atlas for individual memories, including positive and negative memories, with single- cell resolution.

项目摘要/摘要 大量的研究为我们提供了对神经元如何协同工作的理解 在个体记忆的形成和提取过程中。当我们了解记忆是如何存储在 有限的大脑区域，我们还不知道多个记忆痕迹是如何存储在 全脑神经网络，以及它们的实时生理动力学、遗传格局和 优先布线。现在需要的是技术来弥合我们在理解上的鸿沟 神经元水平的微观相互作用和执行计算的宏观结构 参与学习和记忆的网络。使用两个依赖于活动的标记系统的组合， 利用即刻早期基因(IEG)Arc和c-fos，本提案的目的是解决以下关键需求 获得多个记忆的地图，并在行为背景下提供大脑的动态状态 性能和内存表达式。我们将首先利用行为分析和全脑成像来 对多重记忆(例如，积极记忆和消极记忆)的存储方式提供前所未有的洞察力 以全脑的方式实现单细胞分辨率。找出两者之间的异同 正面和负面记忆集合的群体和投射将被量化并与 使用丹尼实验室开发的神经元模型进行的行为表现。标记的单元格还将 被拉下并测序，以描绘区分阳性和阴性的遗传格局 回忆。然后，我们将使用体内的钙离子成像来解决神经的实时动力学(例如，钙活动) 当他们参与积极和消极记忆的编码和提取时。此外，我们将使用 光遗传调制以在受试者内的方式操纵积极或消极的合奏 行为性能，用于识别内存表达式中涉及的关键节点。最后，我们将使用病毒跟踪 确定这些集合如何在结构上连接整个大脑的策略，从而提供一个连接 大脑中多个体验的示意图。总而言之，综合分子生物学， 将利用免疫组织化学、网络建模、钙离子成像和光遗传技术。就像大多数 研究已经将他们的分析缩小到单一的大脑结构，这些研究将扩大这一范围 通过分析调节多个记忆的全脑记忆轨迹呈指数级增长。这种组合系统 将产生一个关于个人记忆的全脑图谱，包括积极和消极的记忆，具有单一的- 单元格分辨率。

项目成果

Social reactivation of fear engrams enhances memory recall.

• DOI: 10.1073/pnas.2114230119
• 发表时间: 2022-03-22
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Finkelstein AB;Leblanc H;Cole RH;Gallerani T;Vieira A;Zaki Y;Ramirez S
• 通讯作者: Ramirez S

Hippocampal fear engrams modulate ethanol-induced maladaptive contextual generalization in mice.

海马恐惧印迹调节小鼠乙醇诱导的适应不良情境泛化。

• DOI: 10.1002/hipo.23463
• 发表时间: 2022
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Cincotta,Christine;Ruesch,Evan;Senne,Ryan;Ramirez,Steve
• 通讯作者: Ramirez,Steve

Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice.

• DOI: 10.1002/hipo.23263
• 发表时间: 2021-01
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Cincotta C;Murawski NJ;Grella SL;McKissick O;Doucette E;Ramirez S
• 通讯作者: Ramirez S