Linking memories through hippocampal ensemble reactivation

通过海马体整体重新激活连接记忆

• 批准号: 10592250
• 负责人: Yosif Zaki
• 金额: $ 4.61万
• 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/10592250
• 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; Hour; Image; Knowledge; Learning; 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; genetic approach; in vivo calcium imaging; memory consolidation; memory encoding; neuronal excitability; 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.

项目摘要 创伤后应激障碍(PTSD)是一种令人衰弱的疾病，其特征是持续性和 对创伤性事件的侵入性记忆。理解恐惧的助记过程 因此，由环境刺激触发的信号对创伤后应激障碍的治疗至关重要。也就是说，最多的 用于研究创伤后应激障碍的广泛使用的关联恐惧条件作用模型只评估线索 与令人厌恶的事件直接配对，而不会捕捉到这些刺激之外的恐惧传播。这 代表着我们对这种疾病的病因学知识的严重差距。这项建议旨在 增加我们对厌恶记忆如何传播到其他记忆的理解，并可能 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。我们最近展示了，当 动物在几个小时内被暴露在两个中性的环境中，它们有能力 在记忆中联系在一起(它们激活重叠的细胞群)，为 理解跨越时间的事件是如何联系在一起的。此外，我们发现当其中一个 这些环境随后伴随着一种令人厌恶的事件，恐惧蔓延到 (中性)环境，为恐惧的传播提供了一种新的机制。然而，它是 不知道厌恶经历的强度如何影响记忆联系的倾向。 此外，尚不清楚学习后的神经元活动如何支持不同的整合 情节记忆。我已经收集了大量的初步数据，表明厌恶事件是 能够延长链接的窗口，从而将恐惧从厌恶事件转移到中性事件 记忆是几天前形成的。这些发现之所以引人注目，是因为它们可能解释了 为什么有这么多刺激会引发创伤后应激障碍症状。这项提案的统一目标是 了解厌恶体验如何将跨天编码的不同记忆联系在一起，并确定 解释这一现象如何发生的电路机制。在第一个目标中，我将考察 厌恶体验改变了刺激跨越时间联系的能力，同时 在海马体中进行钙动力学成像，这是一种已知在创伤后应激障碍中改变的大脑结构。这就做 在学习过程中记录，紧跟学习之后的时期，以及中性和厌恶的提取 经历。在第二个目标中，我将选择性地抑制中性神经元的海马区 学习后记忆中的厌恶经历。这将使我能够测试联合重新激活 学习后在海马区的中性和厌恶编码集合的研究对于 这两次经历在记忆中联系在一起。集成先进的行为分析，在体内 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，以及如何防止这种传播。