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: 10018072
• 负责人: Christine Ann Denny
• 金额: $ 76.13万
• 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/10018072
• 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 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.

项目摘要 /摘要 大量的研究使我们了解了神经元如何共同起作用 在单个记忆的形成和检索期间。虽然我们了解记忆如何存储在 有限数量的大脑区域，我们尚不了解如何将多个内存轨迹存储在跨越 全脑神经网络及其实时生理动态，遗传景观和 优先接线。现在需要的是弥合我们在理解之间的差距的技术 在神经元水平和宏观结构上进行计算的微观相互作用 与学习和记忆有关的网络。使用两个与活动有关的标记系统的组合 利用早期基因（IEG）弧和C-Fos，该提议的目的是满足至关重要的需求 获得多个记忆的图，并在行为上提供大脑的动态状态 性能和记忆表达。我们将首先利用行为测定和全脑成像 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 以脑部整个方式分辨出单细胞分辨率。识别相似性和差异 积极和负记忆集成的人群和预测将被量化并与 通过使用丹尼实验室中开发的神经元建模的行为性能。标记的单元也将 被拉下并测序描绘遗传景观区分阳性和阴性 回忆。然后，我们将使用体内Ca2+成像来解决神经的实时动力学（例如Ca2+活动） 当他们参与编码和检索的正面和负记忆时，合奏。而且，我们将使用 光遗传学调制以在受试者内部的方式操纵正聚合物或负面合奏。 行为性能以识别与内存表达相关的关键节点。最后，我们将使用病毒追踪 确定这些集团在结构上如何跨大脑的策略，从而提供接线 大脑多种经历的图。总之，综合分子生物学， 将利用免疫组织化学，网络建模，CA2+成像和光遗传技术。大多数 研究将分析范围缩小到单个大脑结构，这些研究将扩大此范围 通过分析全脑记忆痕迹介导多个记忆，以指数级。这个组合系统 将为单个记忆（包括积极记忆和负记忆）带来一个全脑图集的全脑图集 细胞分辨率。