Assessing the Dynamics of Hippocampal Neuronal Engrams in Memory Formation and Aging

评估海马神经元印迹在记忆形成和衰老中的动态

• 批准号: 10829020
• 负责人: Amy Monasterio
• 金额: $ 4.87万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10829020
• 关键词: Address; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Area; Behavior; Brain; Brain region; Calcium; Cells; Computer Models; Cues; Data; Disease; Educational process of instructing; Environment; Episodic memory; FOS gene; Faculty; Fellowship; Fostering; Functional disorder; Future; Genetic; Genetic Techniques; Goals; Grant; Health; Healthcare Systems; Hippocampus; Image; Immediate-Early Genes; Impaired cognition; Impairment; Individual; Intervention; Job Application; Knowledge; Label; Learning; Life; Longevity; Memory; Memory Loss; Memory impairment; Mentors; Methods; Modeling; Mus; Neurodegenerative Disorders; Neurons; Neurosciences; Pattern; Phase; Physiology; Population; Postdoctoral Fellow; Preparation; Process; Professional Competence; Prosencephalon; Research; Research Personnel; Research Project Grants; Retrieval; Rodent; Role; Scientist; Societies; Structure; Synapses; Techniques; Technology; Testing; Time; Training; age related; awake; career; cell type; cognitive function; experience; experimental study; genetic approach; imaging approach; imaging genetics; in vivo; insight; memory recall; memory retrieval; mouse model; negative affect; novel; novel strategies; optical imaging; recruit; success; treatment strategy; two-photon; virus genetics

PROJECT SUMMARY/ABSTRACT Defining how we form, store, and retrieve memories is one of neuroscience’s most researched areas. The hippocampus is a well-characterized forebrain structure with a crucial role in the formation and retrieval of episodic memory, and is known to be vulnerable to age-related memory dysfunction. Cognitive decline in age and neurodegenerative disease is an increasing burden on healthcare systems and society at large. To treat the causes of memory decline in age and age-related disease, the mechanisms by which hippocampal cell populations form and maintain individual memories over time must be characterized. Decades of research have shown that new learning results in strengthened synaptic connections between networks of hippocampal neurons. These distributed connections between cells are believed to make up the physical basis for memories, often defined as an engram. Significant progress has been made in finding the engram in the brain with the application of activity-dependent genetic strategies, which isolate populations of cells expressing immediate- early genes (IEGs), to identify the neurons activated by learning. Subpopulations of neurons expressing the IEG c-Fos are activated during learning and reactivated during memory recall, so they are often referred to as engram neurons. Previous studies demonstrated the crucial role of hippocampal engram neurons in memory recall behavior, and artificial reactivation of these cells in mouse models of aging and Alzheimer’s disease rescued memory retrieval deficits, pointing to engram cells as a promising target for future interventions to treat memory deficits. However, the in vivo mechanisms by which these cells store associations, and how their reactivation drives memory retrieval, have yet to be explored. To address this gap in knowledge, this project will utilize novel two-photon imaging to combine an inducible c-Fos tagging strategy with large-scale calcium imaging, to investigate how these cell populations contribute to memory formation. Aim 1 of this project is to characterize the dynamics of engram cell populations across learning in order to inform our understanding of circuit mechanisms underlying memory formation in healthy states. This mechanistic understanding will then be utilized in Aim 2 to define how these processes are negatively impacted by aging. Overall, the aims of this proposal will contribute to the advancement of our understanding of the circuit mechanisms of hippocampal memory formation in health and disease, with the potential to inform current treatment strategies for cognitive decline.

项目摘要/摘要 定义我们如何形成，存储和检索记忆是神经科学研究最多的领域之一。 海马是一种特征良好的前脑结构，在形成和检索中起着至关重要的作用 情节记忆，众所周知，容易受到与年龄相关的记忆功能障碍的影响。年龄认知能力下降 神经退行性疾病在医疗系统和整个社会上的燃烧越来越大。治疗 年龄和年龄相关疾病记忆下降的原因，海马细胞的机制 人口随着时间的推移形成并保持个人记忆必须表征。数十年的研究已经 表明新的学习会导致海马网络之间加强突触连接 神经元。据信，这些细胞之间的这些分布式连接构成了记忆的物理基础， 通常被定义为引擎。在大脑中找到发动机的取得了重大进展 活性依赖性遗传策略的应用，该策略分离了表达立即表达细胞的种群 早期基因（IEG），以识别通过学习激活的神经元。表达IEG的神经元的亚群 在记忆回忆中学习和重新激活C-FOS，因此通常将其称为engram 神经元。先前的研究表明，海马Engram神经元在记忆回忆中的关键作用 这些细胞在衰老和阿尔茨海默氏病小鼠模型中的行为和人工重新激活 内存检索定义，指出Engram单元格是未来干预措施以治疗记忆的有望的目标 缺陷。但是，这些细胞储存关联的体内机制及其重新激活方式 驱动记忆检索，尚未探索。为了解决知识的差距，该项目将利用新颖 两光子成像将诱导型C-FOS标签策略与大型钙成像结合在一起 研究这些细胞种群如何促进记忆形成。该项目的目标1是表征 为了告知我们对电路的理解，器官细胞种群的动力学 健康状态下记忆形成的机制。然后将使用这种机械理解 在AIM 2中，以定义这些过程如何受到衰老的负面影响。总体而言，该提议的目标将 有助于提高我们对海马记忆形成电路机制的理解 在健康和疾病中，有可能为当前的治疗策略提供认知能力下降的可能性。