研究背景:记忆修饰是生物个体的记忆信息随着自身条件或外部环境的改变而产生记忆更新的过程。它是个体不断适应机体内外环境变化的重要保证。由负性刺激带来的负性记忆，对于个体及时规避危险环境、保护个体安全有着积极的作用和意义。然而，并非所有的负性记忆对于个体的生存都有着积极的影响。例如，在物质成瘾的过程中，当个体处于戒断期时，戒断症状产生的负性记忆往往是个体戒除物质成瘾的重要障碍并且强烈的负性记忆很难被修饰;当个体再次暴露于成瘾相关线索时，由负性记忆的唤醒带来的负面情绪体验是个体重新觅药而引发复吸的重要因素之一。因此，无论是在物质成瘾的研究还是治疗过程中，如何有效地消除由戒断症状产生的负性记忆己逐渐成为重要的关注点。虽然口前记忆消退的行为范式有多种，包括单纯消退训练和“提取一消退”训练等，但其消退效果依旧不令人满意。并且记忆消退相关的神经机制研究至今也没有一个明确的结论。因此，进一步探究记忆消退背后的神经生物学基础，有利于充分了解记忆修饰的神经机制，并为指导建立更加有效的记忆消退行为模式或临床干预手段提供理论依据。
研究方法:本研究以小鼠纳洛酮诱导吗啡急性戒断条件性位置仄恶(conditioned place preference, CPA)行为模型为基础，结合Fos免疫组织化学染色和化学遗传学方法，验证参与CPA记忆提取的相关脑区和神经通路;采用电生理膜片钳技术结合光遗传方法，验证该神经通路的活化对于下游脑区细胞活性的影响;此外，采用“提取一消退”行为模式，并在记忆提取前给予光遗传干预，检验对记忆消退效果的影响;采用Fos标定激活细胞群体基因重组策略(Fos targeted recombination in activated populations, FosTRAP }，结合Fos免疫组织化学染色方法，实现记忆形成、记忆提取和记忆消退三个阶段过程中的每两个过程被激活细胞的双标共染，以验证记忆消退所修改记忆信息的主要来源;最后，采用FosTRAP策略结合光遗传技术，以实时CPA训练为行为模式，进一步验证记忆提取阶段激活的细胞群所包含记忆信息的性质。
研究结果(1)蓝斑一背侧齿状回(LC-dDG)神经通路参与小鼠纳洛酮诱导吗啡戒断CPA记忆提取过程，抑制该通路活性能够抑制小鼠CPA行为表达;(2)光 遗传激活LC-dDG神经通路能够活化齿状回脑区细胞的活性，使其更容易被外界刺激所激活;(3)“提取一消退”行为模式前激活LC-dDG神经通路，相对“提取一消退”和“单纯消退”行为模式，能够促进消退效果;(4)在dDG脑区中，记忆提取阶段激活的细胞，在记忆消退阶段被再次激活的数量占消退阶段激活细胞数量的比例，与消退效果呈显著正相关性，并且记忆提取前激活LC-dDG神经通路能够提升该比例;然而，消退效果及背侧齿状回细胞再激活的程度与记忆形成阶段的神经元活性无相关性;(4)在dDG脑区，记忆提取过程中激活的细胞群包含了原始的记忆信息(与记忆学习阶段的记忆信息相同)，但与记忆学习阶段区分为两群不同的细胞群体。
研究结论:记忆消退过程主要修改了记忆提取过程而非记忆形成过程所包含的记忆信息，LC-dDG神经通路的激活能够促进记忆提取信息在消退过程中的重新改写。
其他摘要
Background: Memory modification is a process of memory information updating with an individual internal or external environment change, that is an important guarantee for the individual adaptive survival. Aversive memory that guides individual remember aversive things and avoid them has a positive meaning for both human and animals.
However, the role of aversive memory is not always positive. For example, in substance addiction, aversive memory brought by withdrawal period is one of the important obstacles for the extinction of the addiction memory. Once addiction related cues emerging, aversive emotion evoked by aversive memory can generate a motivational sate leading to drug seeking and taking, and finally relapse occurs. Thereby, how to extinct aversive memory effectively has become a focus in both addiction researches and treatments. Although some extinction patterns have been engaged in practice, like "pure extinction" and "recall一extinction", the efficacies of extinction are not satisfactory enough. Besides of that, it still remains unclear on the mechanism of memory extinction. Altogether, approaching to the neurobiological basis of extinction benefits the understanding for the mechanism of the memory modification and provides theoretical support for establishing a more effective behavioral pattern for memory extinction or a clinical intervention.
Methods: Naloxone-induced conditioned place aversion (CPA) in morphine dependence mice was engaged in this study. The brain regions and neuronal pathway was identified by using Fos immunofluorescent staining and chemogenetic tools. Using patch clamp combined with optogenetics, it was clarified how the cell sensitivity of downstream brain region was affected by the activation of the neuronal pathway. Based on "recall-extinction" pattern, the efficacy of extinction was tested by optogenetics intervention prior to memory recall. To test the origin of the memory information modified in the extinction stage, Fos-targeted recombination in activated populations (FosTRAP) strategy combined with Fos immunofluorescent was used to clarify the colocalization between activated cells groups in each two memory stages, among learning, recall and extinction. At last, the information contained in recall一and acquisition- activated cell group was tested by real time CPA training using FosTRAP strategy with optogenetical approach.
Results: 1)Locus coeruleus-dentate gyrus (LC) and dentate gyrus (DG) were engaged in the memory recall of naloxone一induced CPA behavior in morphine-dependent mice, and CPA expression was inhibited by suppressing the LC-DG pathway; 2) The sensitivity of DG cells was elevated by optogenetically activating LC-DG pathway; (3) Extinction was facilitated by activating LC-DG pathway prior to recall found on "recall-extinction" pattern; (4) The extinction progress promoted by LC-DG pathway activation was correlated with the population size of reactivated recall-tagged DG cells in extinction session, but not with that of acquisition-tagged cell group; (5) Although recall一activated cells contained the aversive information similar to acquisition-activated cells, they showed almost separated cell ensembles in DG.
Conclusion: Extinction process mainly modifies the memory information contained in the retrieval process rather than the acquisition process. The activation of the LC-DG pathway can promote the rewriting of the retrieval information during the extinction process.
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