Functional interactions of the entorhinal cortex during systems consolidation

项目总结 长期记忆稳定性障碍是许多神经精神障碍的核心症状， 包括阿尔茨海默氏症、严重抑郁症和创伤后应激障碍。这一过程中， 新形成的记忆被稳定到更持久的存储中，这称为记忆巩固。这个 海马体(HPC)在记忆的初始形成和存储中具有公认的作用。在整个过程中 从几天到几个月，记忆回忆被认为变得越来越依赖于皮质区域，例如 前扣带回皮质(ACC)。在HPC和Access之间如何在系统级别重新组织内存 人们对此仍然知之甚少。最近的研究表明，大脑的中间区域--内嗅皮层(EC)， 以促进记忆的巩固。干扰EC会损害新记忆的存储能力 持续时间长。然而，EC何时以及如何促进记忆巩固仍不清楚。我们 假设EC在学习时被招募来稳定ACC中的神经元和神经丛 表示已学习的关联。这个项目将通过使用监控和操纵的方法来测试这一点 通过三个特定的目标在延长的时间段内的全脑回路的动力学。在目标一号中，我们 将首先在头部固定的老鼠身上开发一种新的基于虚拟现实的情境学习任务，使我们能够探索 在巩固过程中(几周到几个月)对记忆的学习和回忆。欧共体-Access 投射将在不同的时间点被选择性地抑制，以量化其在远程记忆回忆中的作用。在AIM 2，我们将使用长期植入的光纤(光纤)记录HPC、EC和ACC的整体神经活动 光度学)来追踪记忆过程中区域间的相互作用和记忆的神经关联的出现 整合。在目标3中，我们将在整个记忆提取过程中在ACC中进行双光子钙成像 包括最近时间点和远程时间点。EC-ACC投射将被选择性地抑制，其影响 远程时间点记忆的神经表示电路将被量化。这项调查将填补一个 在我们对系统整合的理解上存在很大差距，并促进对分布式 心理健康和疾病中的记忆动力学。申请者的职业目标是成为一名学者 内科医生-科学家，研究项目旨在弥合基础系统神经科学之间的差距 研究和临床治疗。他正在威尔·康奈尔医学院接受医学博士培训， ，并将在期间培养研究、科学交流和临床专业技能 这份团契。

PROJECT SUMMARY Dysfunction in the stability of long-term memories is a core symptom of many neuropsychiatric disorders, including Alzheimer’s disease, major depression, and post-traumatic stress disorder. The process by which newly formed memories are stabilized into more permanent storage is known as memory consolidation. The hippocampus (HPC) has a well-established role in the initial formation and storage of memory. Over the course of days-to-months, memory recall is thought to become increasingly dependent on cortical regions, such as the anterior cingulate cortex (ACC). How memory is reorganized at the systems level between HPC and ACC remains poorly understood. Recent studies implicate an intermediate brain region, the entorhinal cortex (EC), as facilitating consolidation of memories. Disrupting the EC impairs the ability of new memories to be stored over long durations. However, it remains unclear when and how EC may contribute to memory consolidation. We hypothesize that EC is recruited at the time of learning to stabilize neurons and neural ensembles in ACC that represent a learned association. This project will test this by utilizing methods of monitoring and manipulating the dynamics of brain-wide circuits over extended periods of time through three specific aims. In aim one, we will first develop a novel virtual-reality based contextual learning task in head-fixed mice, allowing us to probe the learning and recall of memories throughout the duration of consolidation (weeks-to-months). The EC-ACC projection will be selectively inhibited at various time points to quantify its role in remote memory recall. In aim 2, we will record bulk neural activity from HPC, EC, and ACC using chronically implanted optical fibers (fiber photometry) to track interregional interactions and the emergence of neural correlates of memory during memory consolidation. In aim 3, we will perform two photon calcium imaging in ACC throughout memory retrieval including recent and remote time points. The EC-ACC projection will be selectively inhibited and the effect of this circuit on neural representations of memory at remote time points will be quantified. This investigation will fill a substantial gap in our understanding of systems consolidation and facilitate new insights into the distributed dynamics of memory in psychiatric health and disease. The applicant’s career goal is to be an academic physician-scientist with a research program aimed at bridging the gap between basic systems neuroscience research and clinical treatments. He is pursuing MD-PhD training at Weill Cornell Medical College and The Rockefeller University, and will develop research, scientific communication, and clinical expertise skills during this fellowship.