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

项目总结/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。的 海马体是一种特征明显的前脑结构，在大脑皮层的形成和恢复中起着至关重要的作用。 情景记忆，并且已知易受年龄相关的记忆功能障碍的影响。老年认知能力下降 并且神经变性疾病是卫生保健系统和整个社会日益增加的负担。治疗 老年记忆力下降的原因和与年龄有关的疾病，海马细胞 人口形成和维持个人的记忆随着时间的推移必须加以表征。几十年的研究 表明新的学习导致海马神经网络之间的突触连接加强， 神经元细胞之间的这些分布式连接被认为构成了记忆的物理基础， 通常被定义为印迹。在寻找大脑中的记忆印迹方面已经取得了重大进展， 活性依赖性遗传策略的应用，该策略分离表达直接- 早期基因（IEG），以识别由学习激活的神经元。表达IEG的神经元亚群 c-Fos在学习过程中被激活，在记忆回忆过程中被重新激活，因此它们通常被称为印迹 神经元以往的研究表明海马神经元在记忆回忆中起着重要作用 行为，并人工重新激活这些细胞在小鼠模型的老化和阿尔茨海默氏病获救 记忆提取缺陷，指出记忆印迹细胞是未来治疗记忆干预的有希望的靶点 赤字然而，这些细胞储存关联的体内机制，以及它们的重新激活 驱动记忆提取，还有待探索为了解决这一知识差距，该项目将利用新的 双光子成像将诱导型c-Fos标记策略与大规模钙成像结合联合收割机， 研究这些细胞群如何促进记忆形成。该项目的目标1是表征 记忆印迹细胞群在学习过程中的动态变化，以告知我们对电路的理解。 健康状态下记忆形成的机制。这种机械的理解将被利用 目标2中定义这些过程如何受到老化的负面影响。总的来说，本提案的目标将 有助于我们进一步了解海马记忆形成的电路机制 在健康和疾病方面，有可能为当前的认知能力下降治疗策略提供信息。

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.