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: 10475683
• 负责人: Christine Ann Denny
• 金额: $ 75.36万
• 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/10475683
• 关键词: Address; Age-associated memory impairment; Alzheimer' s Disease; Area; Atlases; Behavior; Behavioral; Behavioral Assay; 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 Projection; Positive Lymph Node; Post-Traumatic Stress Disorders; Problem Solving; Research; Research Personnel; Resolution; Retrieval; Role; Structure; System; Techniques; Technology; Time; Transgenic Organisms; United States National Institutes of Health; Viral; Virus; Work; base; biological systems; combinatorial; experience; experimental study; genetic approach; in vivo; in vivo imaging; innovation; insight; memory encoding; memory retrieval; network models; neural network; neuromechanism; novel; optogenetics; programs; relating to nervous system; 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.

项目概要/摘要 大量研究使我们了解神经元如何协同工作 在个人记忆的形成和检索过程中。虽然我们了解记忆是如何存储在 由于大脑区域数量有限，我们还不了解多个记忆痕迹是如何跨区域存储的 全脑神经网络，以及它们的实时生理动态、遗传景观和 优先布线。现在需要的是技术来弥合我们之间的理解差距 神经元层面的微观相互作用和跨区域执行计算的宏观结构 涉及学习和记忆的网络。使用两个依赖于活动的标记系统的组合 利用立即早期基因 (IEG) Arc 和 c-fos，该提案的目的是解决 获取多个记忆的地图并提供行为背景下大脑的动态状态 表现和记忆表达。我们将首先利用行为分析和全脑成像来 提供关于如何存储多个记忆（例如积极和消极记忆）的前所未有的见解 以全脑方式进行单细胞分辨率。识别之间的相似点和差异 正面和负面记忆整体的数量和预测将被量化并与 通过使用丹尼实验室开发的神经元模型来表现行为。标记的细胞也将 被拉下来并测序以描绘区分阳性和阴性的遗传景观 回忆。然后，我们将使用体内 Ca2+ 成像来解析神经元的实时动态（例如 Ca2+ 活动） 整体，因为它们参与积极和消极的记忆编码和检索。此外，我们将使用 光遗传学调制以在受试者内的方式操纵正或负系综 行为表现来识别参与记忆表达的关键节点。最后，我们将使用病毒追踪 确定这些集合如何在大脑中结构连接的策略，从而提供连接 大脑中多种体验的图表。综上所述，综合分子生物学， 将利用免疫组织化学、网络建模、Ca2+ 成像和光遗传学技术。正如大多数 研究已将分析范围缩小到单一大脑结构，这些研究将扩大这一范围 通过分析介导多个记忆的全脑记忆痕迹，呈指数级增长。这个组合系统 将产生个人记忆的全脑图谱，包括积极和消极的记忆， 细胞分辨率。