Functional interactions of the entorhinal cortex during systems consolidation

系统整合过程中内嗅皮层的功能相互作用

• 批准号: 10565668
• 负责人: Andrew Toader
• 金额: $ 5.27万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565668
• 关键词: Alzheimer' s Disease; Animal Model; Animals; Anterior; Behavioral; Behavioral Paradigm; Brain; Brain region; Calcium; Cells; Chronic; Clinical; Clinical Treatment; Communication; Complex; Dementia; Disease; Dissection; Doctor of Philosophy; Fellowship; Fiber; Fiber Optics; Functional disorder; Goals; Head; Health; Hippocampus; Human; Image; Imaging Device; Impairment; Implant; Investigation; Learning; Life; Localized Lesion; Major Depressive Disorder; Memory; Mental disorders; Methods; Modeling; Monitor; Mus; Nature; Neocortex; Neurons; Neurosciences Research; Patients; Photometry; Physicians; Play; Post-Traumatic Stress Disorders; Process; Psychological reinforcement; Public Health; Research; Retrieval; Role; Scientist; Series; Stimulus; Symptoms; Synapses; System; Techniques; Technology; Testing; Time; Time Study; Training; Universities; Work; behavior measurement; career; cingulate cortex; cognitive function; design; disabling symptom; entorhinal cortex; insight; long term memory; medical schools; member; memory acquisition; memory consolidation; memory encoding; memory recall; memory retrieval; neocortical; neural; neural correlate; neuropsychiatric disorder; novel; optical fiber; optogenetics; programs; recruit; response; serial imaging; skills; theories; two-photon; virtual environment; virtual reality

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.

项目摘要 长期记忆稳定性的功能障碍是许多神经精神疾病的核心症状， 包括老年痴呆症、严重抑郁症和创伤后应激障碍。的过程 新形成的记忆被稳定到更永久的存储中被称为记忆巩固。的 海马体（HPC）在记忆的初始形成和储存中具有公认的作用。过程中 在几天到几个月的时间里，记忆回忆被认为越来越依赖于皮层区域，比如大脑皮层。 前扣带皮层（ACC）。如何在HPC和ACC之间在系统级别重新组织内存 仍然知之甚少。最近的研究涉及一个中间脑区，内嗅皮层（EC）， 有助于记忆的巩固破坏EC会损害新记忆的储存能力， 持续时间长。然而，目前还不清楚何时以及如何EC可能有助于记忆巩固。我们 假设EC在学习时被招募以稳定ACC中的神经元和神经系综， 代表着一种有学问的联想。本项目将通过利用监测和操纵方法来测试这一点 通过三个特定的目标，在很长一段时间内研究全脑回路的动力学。目标一，我们 将首先在头部固定的小鼠中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 在巩固期（数周至数月）内学习和回忆记忆。EC-ACC 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中 2，我们将使用长期植入的光纤（光纤）记录HPC、EC和ACC的大量神经活动。 光度学）来跟踪区域间的相互作用和记忆过程中记忆的神经相关物的出现 合并。在目标3中，我们将在整个记忆提取过程中对ACC进行双光子钙成像 包括最近和遥远的时间点。EC-ACC投射将被选择性地抑制， 在远程时间点对记忆的神经表征的回路将被量化。这项调查将填补一个 我们对系统整合的理解存在重大差距，并促进对分布式 精神健康和疾病中的记忆动力学。申请人的职业目标是成为一名学者 一位医生兼科学家，其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和 洛克菲勒大学，并将发展研究，科学交流和临床专业技能， 这个奖学金。