Defining Astrocyte Engram Ensembles During Memory Formation

定义记忆形成过程中的星形胶质细胞印迹整体

• 批准号: 10722056
• 负责人: Benjamin Deneen
• 金额: $ 44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722056
• 关键词: 3-Dimensional; Ablation; Acute; Alzheimer' s Disease; Amnesia; Anxiety; Astrocytes; Behavior; Behavioral; Brain; Calcium; Cell Separation; Cells; Clozapine; Cognition; Data; Dementia; Diphtheria Toxin; Disease; Event; Exhibits; Experimental Designs; Exposure to; FOS gene; Freezing; Gene Expression; Goals; Hippocampus; Image; Immediate-Early Genes; Impairment; Label; Learning; Ligands; Maps; Measures; Memory; Memory impairment; Molecular; Molecular Analysis; Morphology; Mus; Nature; Neurons; Output; Oxides; Physiological; Play; Population; Post-Traumatic Stress Disorders; Process; Property; Resolution; Retrieval; Role; Signal Transduction; Slice; Specificity; Synapses; Synaptic plasticity; System; Testing; Trauma; Viral; Virus; calcium indicator; conditioned fear; dentate gyrus; experimental study; inducible gene expression; insight; memory encoding; memory process; memory recall; memory retrieval; nervous system disorder; neuronal circuitry; prospective; reconstruction; tool; transcriptome sequencing; two-photon

Summary Astrocytes play diverse and indispensable roles in brain function. Participating as a component of the ‘tripartite synapse’, a single astrocyte is estimated to contact up to 100,000 neuronal synapses in the hippocampus. Notably, studies have identified essential functions of astrocytes in hippocampal circuits, where astrocytes are required for regulating synaptic plasticity including LTP, a key process associated with learning and memory. Recent studies have shown that enhancing Gq-signaling in astrocytes promotes LTP and enhances acute memory, while impairing astrocyte function suppresses LTP and memory, highlighting central roles for astrocytes in memory-dependent tasks. Learning events invoke activity and plasticity among a discrete ensemble of cells. Activation of these ensembles by learning and reactivated during memory recall constitute the physical substrate of memory and are referred to as engrams. Despite the critical involvement of astrocytes in learning and memory processes, the study of memory engrams has been limited exclusively to neuronal ensembles. The goal of this proposal is to study the potential of astrocyte engrams as a substrate of memory and to understand the nature and function of hippocampal astrocyte ensembles. We have created a host of mouse lines and associated AAV-viral tools the enable us to label and manipulate astrocytes during learning events in the hippocampus. Preliminary studies with these tools indicate that we can label ensembles of astrocytes after learning and that reactivation of these same astrocytes promotes memory recall. Based on the strength of these preliminary data and the associated tools we have built, we propose the following specific aims. In specific aim1, we will label astrocyte ensembles after learning and characterize whether they exhibit engram properties. In specific aim2, we will manipulate the prospective engram astrocyte populations and determine whether they encode memory storage and recall. In specific aim3, we will characterize the cellular and molecular properties of these labeled astrocyte engram populations.

摘要 星形胶质细胞在脑功能中发挥着多种不可或缺的作用。作为“三方”的一部分参与 据估计，一个星形细胞可以接触到海马体中多达100,000个神经元突触。值得注意的是， 研究已经确定了星形胶质细胞在海马环路中的基本功能，在那里星形胶质细胞是 调节突触的可塑性，包括LTP，一个与学习和记忆相关的关键过程。最新研究 研究表明，增强星形胶质细胞中的GQ信号可促进长时程增强和增强敏锐记忆，而损害 星形胶质细胞功能抑制LTP和记忆，突显星形胶质细胞在记忆依赖中的中心作用 任务。学习事件会在离散的细胞集合中激发活性和可塑性。激活这些 通过学习和在记忆回忆过程中重新激活的集合构成了记忆的物理底物，并 被称为雕刻字。尽管星形胶质细胞在学习和记忆过程中起着至关重要的作用，但这项研究 记忆印记的研究仅限于神经元集合。这项建议的目标是研究 星形胶质细胞纹状体作为记忆底物和了解海马区性质和功能的潜力 星形细胞群体。 我们已经创造了一系列小鼠品系和相关的AAV病毒工具，使我们能够标记和 在学习活动期间操纵海马体中的星形胶质细胞。对这些工具的初步研究表明， 我们可以在学习后标记星形胶质细胞的集合，这些星形胶质细胞的重新激活促进了 回忆回忆。基于这些初步数据和我们建立的相关工具的力量，我们建议 以下是具体目标。在特定的目标1中，我们将在学习后对星形胶质细胞群进行标记和表征 它们是否表现出压痕特性。在特定的AIM2中，我们将操纵预期的印迹星形胶质细胞 并确定它们是否对记忆存储和回忆进行编码。在具体的目标3中，我们将描述 这些标记的星形胶质细胞印迹群体的细胞和分子特性。