Behavioural and Clinical Neuroscience Institute and
Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom.
J Neurosci. 2018 Mar 28;38(13):3199-3207. doi: 10.1523/JNEUROSCI.3273-17.2018. Epub 2018 Feb 23.
Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation, and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analyzed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate conditioned stimulus (CS) exposure events. We show that an intermediate re-exposure (four CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signaling pathway in conjunction with four CS presentations had no effect on fear expression, and the NMDA receptor partial agonist d-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (seven CSs), had no behavioral or molecular effect when given in association with four CS presentations. These molecular and behavioral data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CS-dependent molecular events in the BLA may arrest reconsolidation intracellular signaling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease. Consolidated fear memories can be altered by retrieval-dependent mechanisms. Whereas a brief conditioned stimulus (CS) exposure promotes fear memory maintenance through reconsolidation, a prolonged exposure engages extinction and fear inhibition. The nature of this transition and whether an intermediate degree of CS exposure engages reconsolidation or extinction is unknown. We show that an intermediate cue exposure session (four CSs) produces the arrest of ERK1/2 activation in the basolateral amygdala, a common mechanism for reconsolidation and extinction. Amnestic or hypermnestic treatments given in association with four CSs had no behavioral or molecular effects, respectively. This evidence reveals a novel retrieval-dependent memory phase. Intermediate degrees of CS exposure fail to trigger reconsolidation or extinction, leaving the original memory in an insensitive state.
完全巩固的恐惧记忆可以通过检索依赖的机制来维持或抑制，具体取决于重新暴露于恐惧线索的程度。短暂的暴露会通过再巩固来促进记忆的维持，而长时间的暴露会通过消退来促进抑制。目前对于增加线索暴露如何克服再巩固并转而引发消退的神经机制知之甚少。我们在雄性大鼠中使用听觉恐惧条件反射，分析了在中间条件刺激（CS）暴露事件后，普遍存在于恐惧再巩固和消退中的分子机制——外侧杏仁核（BLA）中的 ERK1/2 激活，在中间 CS 暴露事件中的作用。我们发现，中间重新暴露（四次 CS 呈现）未能激活 BLA 中的 ERK1/2，表明不存在再巩固或消退机制。这一假设得到了支持，在四次 CS 呈现的同时，抑制 BLA 中的 ERK1/2 依赖性信号通路没有对恐惧表达产生影响，而 NMDA 受体部分激动剂 d-环丝氨酸，在部分消退方案（七次 CS）中增强了消退和 ERK1/2 激活，当与四次 CS 呈现相关联时，对行为或分子没有影响。这些分子和行为数据揭示了一个新的检索依赖记忆阶段，发生在条件性恐惧维持和抑制的转变过程中。BLA 中的 CS 依赖性分子事件可能以非依赖于消退的方式阻止再巩固的细胞内信号机制。这些发现对于理解检索后健康和疾病中恐惧记忆持久性的分子基础至关重要。记忆可以通过检索依赖的机制来改变。短暂的条件刺激（CS）暴露会通过再巩固来促进恐惧记忆的维持，而长时间的暴露则会引发消退和恐惧抑制。这种转变的性质以及中间程度的 CS 暴露是否会引发再巩固或消退尚不清楚。我们发现，中间线索暴露（四次 CS）会导致外侧杏仁核中 ERK1/2 激活的停止，这是再巩固和消退的共同机制。在与四次 CS 呈现相关联时，遗忘或超忆治疗分别没有行为或分子作用。这一证据揭示了一个新的检索依赖记忆阶段。中间程度的 CS 暴露既不能触发再巩固也不能触发消退，而是使原始记忆处于不敏感状态。
