The Role of Neuronal Ensembles Supporting Auditory Fear Conditioning (Engrams) in the Amygdala in Memory Formation, Generalization and Extinction

杏仁核中支持听觉恐惧调节（印迹）的神经元群在记忆形成、泛化和消退中的作用

• 批准号: 10553228
• 负责人: Sheena A Josselyn
• 金额: $ 33.78万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553228
• 关键词: Address; Amygdaloid structure; Anxiety; Anxiety Disorders; Architecture; Auditory; Behavior; Brain; Calcium; Cell Nucleus; Cells; Code; Dangerousness; Data; Development; Disease; Eligibility Determination; Endoscopes; Event; Extinction; Fluorescent in Situ Hybridization; Freezing; Fright; Future; Halorhodopsins; Hippocampus; Image; Immediate-Early Genes; Lateral; Light; Maps; Mediating; Memory; Mental disorders; Messenger RNA; Microscopy; Mus; Neurons; Nuclear; Opsin; Persons; Population; Post-Traumatic Stress Disorders; Prevention strategy; Process; Recurrence; Research Personnel; Retrieval; Role; Stimulus; System; Techniques; Testing; Time; Tissues; Training; Training Activity; Virus; Visualization; behavioral extinction; conditioned fear; data analysis pipeline; effective therapy; experience; fear memory; graph theory; in vivo calcium imaging; innovation; machine learning algorithm; memory consolidation; neuronal excitability; optogenetics; promoter; recruit; therapy development; treatment strategy

Project Summary/Abstract Memory may be defined as the retention over time of internal representations gained through experience, and the capacity to reconstruct these representations at later times (Dudai 2007). These internal representations are thought to be encoded by long-lasting physical brain changes (memory traces or `engrams') (Josselyn, Kohler & Frankland 2015, 2017; Tonegawa et al. 2015; Schacter 2001). Remembering fear-evoking events is adaptive; it helps one make future choices based on past experience. It may even be beneficial to generalize some fearful memories. However, excessive fear generalization or treating no-longer threatening stimuli as dangerous may be maladaptive. Indeed, recurrent or inappropriately expressed fearful memories are a major component of several psychiatric diseases, including post-traumatic stress disorder (PTSD) and anxiety. Therefore, understanding how memory traces for fearful events are formed, change over time, under what conditions they remain specific or generalize, and how they are impacted by behavioral extinction are critical questions to not only understanding how the brain uses information but also for informing the development of new treatment/prevention strategies for disorders characterized by inappropriate fear memories. Here two PIs (Drs. Josselyn and Frankland), both New Investigators, will combine their expertise to address these important questions. Because all techniques are associated with caveats and limitations, we will use a variety of techniques including optogenetic manipulation, brain-wide neuronal activity mapping and the use of graph-theory to produce “engram maps” and real time in vivo calcium imaging combined with behavior. Together, the ability to manipulate and observe an engram as it forms, changes over time and with behavioral extinction is innovative and may lead to a shift in the very definition of an engram, as well as increase our understanding for developing treatments aimed at resolving inappropriate fear memories.

项目概要/摘要 记忆可以定义为随着时间的推移，通过以下方式获得的内部表征的保留： 经验，以及以后重建这些表征的能力（Dudai 2007）。 这些内部表征被认为是由持久的物理大脑编码的 变化（记忆痕迹或“印迹”）（Josselyn、Kohler & Frankland 2015、2017；Tonekawa 等 等人。 2015年；沙克特 2001）。记住引起恐惧的事件是适应性的；它有助于一个人 未来的选择基于过去的经验。概括一些可怕的事情甚至可能是有益的 回忆。然而，过度的恐惧泛化或将不再具有威胁性的刺激视为 危险的可能是适应不良。事实上，经常或不恰当地表达恐惧 记忆是多种精神疾病的主要组成部分，包括创伤后疾病 应激障碍（PTSD）和焦虑。因此，了解记忆如何追踪恐惧 事件是形成的，随着时间的推移而变化，在什么条件下它们保持具体或概括， 以及它们如何受到行为灭绝的影响不仅是关键问题 了解大脑如何使用信息，同时也为新信息的开发提供信息 以不适当的恐惧记忆为特征的疾病的治疗/预防策略。 在这里，两位 PI（Josselyn 博士和 Frankland），都是新研究者，将结合他们的 解决这些重要问题的专业知识。因为所有技术都与 警告和限制，我们将使用各种技术，包括光遗传学操作， 全脑神经元活动映射以及使用图论生成“印迹图” 以及与行为相结合的实时体内钙成像。在一起，有能力 操纵和观察印迹的形成、随时间和行为的变化 灭绝是一种创新，可能会导致印迹定义的转变，以及 增加我们对开发旨在解决不适当恐惧的治疗方法的理解 回忆。

项目成果

Neuronal competition: microcircuit mechanisms define the sparsity of the engram.

神经元竞争：微电路机制定义了印迹的稀疏性。

• DOI: 10.1016/j.conb.2018.10.013
• 发表时间: 2019
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Rao-Ruiz,Priyanka;Yu,Julia;Kushner,StevenA;Josselyn,SheenaA
• 通讯作者: Josselyn,SheenaA

Exercise accelerates place cell representational drift.

运动会加速位置细胞表征漂移。

• DOI: 10.1016/j.cub.2022.12.033
• 发表时间: 2023
• 期刊: Current biology : CB
• 作者: deSnoo,MitchellL;Miller,AdamMP;Ramsaran,AdamI;Josselyn,SheenaA;Frankland,PaulW
• 通讯作者: Frankland,PaulW

Examining memory linking and generalization using scFLARE2, a temporally precise neuronal activity tagging system.

使用 scFLARE2（一种时间精确的神经元活动标记系统）检查记忆链接和泛化。

• DOI: 10.1016/j.celrep.2023.113592
• 发表时间: 2023
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Jung,JungHoon;Wang,Ying;Rashid,AsimJ;Zhang,Tao;Frankland,PaulW;Josselyn,SheenaA
• 通讯作者: Josselyn,SheenaA

Forgetting at biologically realistic levels of neurogenesis in a large-scale hippocampal model.

• DOI: 10.1016/j.bbr.2019.112180
• 发表时间: 2019-12-30
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Tran LM;Josselyn SA;Richards BA;Frankland PW
• 通讯作者: Frankland PW

Neurogenesis-dependent transformation of hippocampal engrams.

海马印迹的神经发生依赖性转化。

• DOI: 10.1016/j.neulet.2021.136176
• 发表时间: 2021
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Ko,SangyoonY;Frankland,PaulW
• 通讯作者: Frankland,PaulW