Linking memories through hippocampal ensemble reactivation

通过海马体整体重新激活连接记忆

• 批准号: 10370579
• 负责人: Yosif Zaki
• 金额: $ 4.52万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-08 至 2024-04-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370579
• 关键词: Address; Affect; Amygdaloid structure; Animals; Attention; Back; Behavioral; Behavioral Assay; Binding; Brain; Calcium; Cells; Cues; Data; Disease; Environment; Episodic memory; Etiology; Event; Exposure to; Fright; Functional disorder; Goals; Hippocampus (Brain); Hour; Image; Knowledge; Learning; Light; Link; Memory; Modeling; Mus; Neurons; Pattern; Population; Post-Traumatic Stress Disorders; Process; Rest; Retrieval; Shock; Sleep; Stimulus; Structure; Symptoms; Technology; Testing; Time; Trauma; Work; conditioned fear; experience; experimental study; in vivo calcium imaging; memory consolidation; memory encoding; novel; post-traumatic symptoms; prevent; sensory stimulus; time interval; tool; traumatic event

Project Summary Post-traumatic stress disorder (PTSD) is a debilitating condition characterized by persistent and intrusive memories of a traumatic event. Understanding the mnemonic processes through which fear is triggered by environmental stimuli is therefore paramount to PTSD treatment. That said, the most widely employed models of associative fear conditioning used to study PTSD only assess cues directly paired with an aversive event and do not capture the spread of fear beyond these stimuli. This represents a critical gap in our knowledge of the etiology of the disorder. This proposal seeks to increase our understanding of how aversive memories propagate to other memories and could fundamentally change our view of how fear spreads in PTSD. We recently demonstrated that when animals are exposed to two neutral environments within several hours of each other they are capable of being linked in memory (they activate overlapping cell populations), providing a tool for understanding how events across time come to be related. Moreover, we found that when one of these environments was subsequently paired with an aversive event, fear spread to the linked (neutral) environment as well, providing a novel mechanism for the spread of fear. However, it is unknown how strength of an aversive experience affects the propensity for memories to be linked. Moreover, it is unknown how neuronal activity after learning supports the integration of distinct episodic memories. I have collected extensive preliminary data suggesting that aversive events are able to extend the window of linking, such that fear is transferred from an aversive event to a neutral memory formed days before. These findings are remarkable because they could potentially explain how so many stimuli come to trigger PTSD symptoms. The unifying goal of this proposal is to understand how aversive experience links distinct memories encoded across days, and to identify a circuit mechanism that explains how this occurs. In the first aim, I will examine how the strength of aversive experience modifies the ability of stimuli to be linked across time, while simultaneously imaging calcium dynamics in the hippocampus, a brain structure known to be altered in PTSD. I will record during learning, the period directly following learning, and retrieval of neutral and aversive experiences. In the second aim, I will selectively inhibit the hippocampal ensemble of the neutral memory after learning of the aversive experience. This will enable me to test whether co-reactivation of the neutral- and aversive-encoding ensembles in the hippocampus after learning is necessary for the two experiences to become linked in memory. Integrating advanced behavioral assays, in vivo calcium imaging, and cell-specific neuronal manipulation strategies, this work promises to shed light on how fear spreads in PTSD, and how this spread might be prevented.

项目概要 创伤后应激障碍 (PTSD) 是一种使人衰弱的疾病，其特征是持续且持续的 创伤事件的侵入性记忆。了解恐惧的记忆过程 因此，创伤后应激障碍是由环境刺激引发的，对于创伤后应激障碍（PTSD）治疗至关重要。也就是说，最 用于研究创伤后应激障碍（PTSD）的广泛采用的联想恐惧调节模型仅评估线索 直接与厌恶事件配对，并且没有捕捉到这些刺激之外的恐惧传播。这 代表了我们对该疾病病因学知识的一个关键差距。该提案旨在 增加我们对厌恶记忆如何传播到其他记忆的理解，并且可以 从根本上改变我们对恐惧如何在创伤后应激障碍中传播的看法。我们最近证明了当 动物在几个小时内暴露在两个中性环境中，它们有能力 在记忆中被链接（它们激活重叠的细胞群），提供了一种工具 了解不同时间的事件如何相互关联。此外，我们发现当其中之一 这些环境随后伴随着令人厌恶的事件，恐惧蔓延到相关的地方 （中性）环境也是如此，为恐惧的传播提供了一种新颖的机制。然而，它是 目前尚不清楚厌恶经历的强度如何影响记忆关联的倾向。 此外，尚不清楚学习后的神经元活动如何支持不同的整合 情景记忆。我收集了广泛的初步数据，表明厌恶事件是 能够延长链接的窗口，使恐惧从厌恶事件转移到中性事件 记忆是几天前形成的。这些发现非常引人注目，因为它们可以潜在地解释 如此多的刺激是如何引发创伤后应激障碍症状的。该提案的统一目标是 了解厌恶体验如何将不同天编码的不同记忆联系起来，并识别 电路机制解释了这是如何发生的。在第一个目标中，我将检查 厌恶体验改变了刺激跨时间联系的能力，同时 对海马体中的钙动态进行成像，海马体是一种已知在 PTSD 中会发生改变的大脑结构。我会 记录学习期间、学习后的时期以及中性和厌恶的检索 经验。在第二个目标中，我将选择性地抑制中性的海马体 得知厌恶经历后的记忆。这将使我能够测试是否共同重新激活 学习后海马体中的中性和厌恶编码集合对于 两种经历在记忆中联系在一起。整合先进的体内行为分析 钙成像和细胞特异性神经元操作策略，这项工作有望揭示 关于恐惧如何在创伤后应激障碍中传播，以及如何预防这种传播。