Neurotransmitters in memory destabilization: An integrative perspective framed by prediction error and novelty.

Abstract

Memory destabilization is a critical phase in memory reconsolidation, during which the transient disruption of consolidated memory traces allows for the incorporation of new information, supporting memory updating and adaptive behavioral modification. While neurotransmitter release and receptor signaling during memory reactivation are known to trigger memory destabilization, the underlying regulatory networks and dynamic interactions remain unclear. Existing studies often examine neurotransmitters in isolation, lacking a unified framework. This review introduces a novel integrative framework that organizes existing evidence on neurotransmitter-mediated memory destabilization around novelty and prediction error (PE) signaling. By synthesizing experimental findings across dopamine (DA), norepinephrine (NE), acetylcholine (ACh), the glutamatergic/GABAergic systems, and the endocannabinoid system, we analyze how PE and novelty engage distinct yet interacting neural pathways. Integrating experimental data and theoretical concepts from multiple systems, we propose the PE-Novelty-Neurotransmitter Network-a unified framework explaining how multimodal neurotransmitter co-release across the midbrain-locus coeruleus-cortex circuit dynamically regulates the balance between memory stability and flexibility. This review addresses diverse memory types, with a focus on maladaptive memories, while also discussing emotional and nonemotional memories. It further discusses potential clinical implications, particularly how neuromodulatory process related to PE and novelty may inform strategies for modifying maladaptive memories and enhancing cognitive flexibility. By bridging mechanistic insights with translational considerations, this work establishes a unified framework for understanding memory plasticity and informs future efforts to translate basic neuroscience into therapeutic contexts. 中文摘要: 记忆去稳定 (Memory destabilization) 是记忆再巩固过程中的关键阶段。在此期间，已巩固记忆痕迹的暂时性破坏允许了新信息的整合，从而支持记忆更新和适应性的行为改变。虽然已知记忆提取激活期间的神经递质释放和受体信号转导会引发记忆去稳定，但其潜在的调节网络和神经递质间的动态交互仍不明确。现有研究通常孤立地考察单一神经递质的作用，缺乏统一的理论框架。据此，本综述提出了一种新的整合框架，围绕新异性 (Novelty) 和预期错误 (Prediction Error, PE) 信号，对现有的神经递质介导的记忆去稳定证据进行了系统评述。通过综合多巴胺 (DA)、去甲肾上腺素 (NE)、乙酰胆碱 (ACh)、谷氨酸能/GABA能系统以及内源性大麻素系统的实验发现，我们分析了预期错误和新异性如何募集不同但又相互作用的神经通路。结合多系统的实验数据和理论概念，我们提出了“预期错误-新异性-神经递质网络”模型 (PE–Novelty–Neurotransmitter Network) ——这是一个解释中脑-蓝斑-皮层环路中多模态神经递质共释放如何动态调节记忆稳定性与灵活性平衡的统一框架。本综述涵盖了多种记忆类型，以非适应性记忆为重点，并兼顾情绪性和非情绪性记忆。此外，本文还分析了潜在的临床启示，特别是如何利用与预期错误和新异性相关的神经调节过程优化再巩固干预策略，进而为修改非适应性记忆并增强认知灵活性提供参考。通过将底层机制研究与临床转化考量有机结合，本研究构建了一个理解记忆可塑性的统一理论框架，从而为未来将基础神经科学向临床治疗应用的转化研究提供了重要启示。 关键词：记忆；去稳定；预期错误；新异性；神经递质.