Acquisition and Consolidation of Contextual Fear Memory in Engram Cell Pathways

印迹细胞通路中情境恐惧记忆的获取和巩固

• 批准号: 10297838
• 负责人: Jun-Hyeong Cho
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297838
• 关键词: Affect; Amygdaloid structure; Animals; Area; Attenuated; Aversive Stimulus; Behavior; Brain; Cells; Chronic; Dangerousness; Data; Detection; Electrophysiology (science); Emotional; Event; Exposure to; Fright; Hippocampus; Knowledge; Label; Learning; Medial; Memory; Mental disorders; Mission; National Institute of Mental Health; Neocortex; Neurons; Output; Pathogenicity; Pathologic; Pathway interactions; Play; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Public Health; Publishing; Random Allocation; Reporting; Research; Role; Signal Transduction; Specificity; Synapses; System; Techniques; Testing; Theoretical model; Viral; Work; conditioned fear; fear memory; innovation; insight; memory encoding; neocortical; neural circuit; neural correlate; neuromechanism; neuroregulation; novel; novel strategies; novel therapeutic intervention; optogenetics; prevent; recruit; response; tool

PROJECT SUMMARY/ABSTRACT In order to survive, animals develop fear responses to dangerous situations. The neural mechanism of learned fear has great survival value for animals, who must predict danger from seemingly neutral contexts. For adaptive fear, the brain discriminates between different contexts and associates only relevant contexts with aversive events. Dysregulation of this process leads to maladaptive overgeneralized fear in PTSD, which affects 7 percent of the U.S. population. A fundamental gap in understanding the mechanism underlying the specificity and persistence of contextual fear memory limits research on developing effective neuromodulatory strategies to prevent long-lasting maladaptive fear in PTSD. The overall objective in this application is to determine the mechanism by which specific contextual fear memory is encoded and consolidated in a network of the hippocampus, neocortex, and amygdala. The rationale for the proposed studies is to fill a critical void in the understanding of fundamental principles of adaptive fear responses to relevant contexts and to provide new insight into developing strategies to attenuate persistent pathological fear in PTSD. The central hypothesis, based on the applicant’s preliminary data, is that (1) the acquisition and consolidation of contextual fear memory require strengthening of engram cell pathways, which connect populations of memory engram cells in a distributed network, and (2) selective weakening of the engram cell pathways prevents conditioned fear responses to a context that predicts danger. This hypothesis will be tested by pursuing three specific aims: (A) Determine how contextual fear memory is encoded in the hippocampal–amygdala circuit and how it is consolidated for permanent storage in prefrontal neocortical circuits (Aims 1 and 2), and (B) Determine input- output connectivity of memory engram cells for contextual fear memory (Aim 3). The first and second aims will investigate synaptic changes in the context-specific hippocampal–amygdala pathway as well as excitatory connections between prefrontal neocortical engram cells during the acquisition and consolidation of contextual fear memory. To accomplish this, the applicant recently developed a novel approach by combining engram cells labeling, optogenetic, and electrophysiological techniques. Under the third aim, engram cells labeling and trans- synaptic tracing will be used to determine how memory engram cells are connected to neurons conveying contextual and aversive signals and neurons generating defensive behavior. The proposed research is innovative because it will use novel combined approaches to efficiently identify the neural correlates of associative memory encoded in functionally heterogeneous neural circuits, which has been unattainable through conventional approaches. The proposed research is significant because it will elucidate how fear memory for a relevant context is encoded and consolidated in a distributed network of memory engram cells and provide insight into developing a novel approach to attenuate chronic maladaptive fear in PTSD without affecting adaptive emotional memories.

项目总结/摘要 为了生存，动物会对危险情况产生恐惧反应。的神经机制 习得性恐惧对动物有很大的生存价值，它们必须从看似中性的环境中预测危险。为 在适应性恐惧中，大脑区分不同的背景，只将相关的背景与 令人厌恶的事件这一过程的失调导致PTSD中适应不良的过度恐惧， 占美国人口的7%。在理解特异性的机制方面存在根本性的差距， 背景恐惧记忆的持续性限制了开发有效的神经调节策略的研究 以防止创伤后应激障碍中的长期适应不良恐惧。本申请的总体目标是确定 特定的背景恐惧记忆被编码和巩固在网络中的机制。 海马体、新皮层和杏仁核。拟议研究的基本原理是填补 理解适应性恐惧反应的基本原则，并提供新的 深入了解发展战略，以减轻持续的病理性恐惧创伤后应激障碍。中心假设， 基于申请人的初步数据，（1）情境恐惧记忆的获得和巩固 需要加强记忆印迹细胞通路，它连接记忆印迹细胞的群体， 分布式网络，（2）选择性削弱记忆印迹细胞通路，防止条件性恐惧 对预测危险的情境的反应。这一假设将通过追求三个具体目标来检验：（A） 确定背景恐惧记忆是如何编码在海马-杏仁核回路中的，以及它是如何 巩固以永久存储在前额叶新皮层回路中（目的1和2），以及（B）确定输入- 背景恐惧记忆的记忆印迹细胞的输出连接性（Aim 3）。第一和第二个目标将 研究特定环境下海马-杏仁核通路的突触变化以及兴奋性 在获取和巩固背景信息期间前额叶新皮质印记细胞之间的连接 恐惧记忆为了实现这一点，申请人最近开发了一种新的方法， 标记、光遗传学和电生理学技术。在第三个目标下，记忆印迹细胞标记和trans-RNA-RNA-RNA-RNA-RNA。 突触追踪将用于确定记忆印迹细胞如何连接到神经元， 情境和厌恶信号以及产生防御行为的神经元。拟议的研究是 创新，因为它将使用新的组合方法来有效地识别神经相关性， 联想记忆编码在功能异构的神经回路中，这是通过 传统的方法。这项拟议中的研究意义重大，因为它将阐明恐惧记忆是如何影响一个人的， 相关上下文被编码并合并在存储器印迹单元的分布式网络中， 深入研究开发一种新方法来减轻PTSD中的慢性适应不良恐惧， 适应性情绪记忆

项目成果

Neocortical synaptic engrams for remote contextual memories.

• DOI: 10.1038/s41593-022-01223-1
• 发表时间: 2023-02
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Lee, Ji-Hye;Kim, Woong Bin;Park, Eui Ho;Cho, Jun-Hyeong
• 通讯作者: Cho, Jun-Hyeong