Prediction error in contextual fear memory reconsolidation

描述（由申请人提供）：在过去的15年中，神经生物学家已经挑战了记忆通过巩固过程随时间稳定的观点;最近的研究表明，记忆在重新激活/检索后经历了一段时间的重新稳定，这与最初的巩固不同。这个过程被称为“再巩固”，它似乎是进化上保守的和动态的--维持、加强和/或更新现有的记忆，以保持它们的预测相关性。重新整合是研究人员和临床医生感兴趣的，部分原因是它为那些遭受侵入性和经常使人衰弱的记忆的人带来了巨大的希望，例如创伤后应激障碍（PTSD）患者。重新巩固研究有可能为认知行为治疗提供信息和促进，从而为PTSD患者带来更好的结果。不幸的是，再巩固的基本行为和神经生物学机制知之甚少。然而，我们实验室和其他人的初步调查表明预测误差的重要作用（即，惊喜，或违反预期），在记忆重新巩固过程的启动。如果重新整合提供了一种更新现有记忆的机制，那么新的（即，尚未预测的）信息，以便启动重新合并过程。使用行为，解剖学和药理学的方法相结合，我们提出了一个系统的分析负责的预测错误信号，触发上下文的恐惧记忆的重新巩固的神经回路。在目标1中，我们将检查意外提取后的背景恐惧记忆再巩固。我们假设，在一个意想不到的方式重新激活的背景下的恐惧记忆将启动恐惧记忆再巩固过程中的基底外侧杏仁核（BLA）。无论是遗漏一个预期的结果，还是用一个不同的令人厌恶的刺激来替代一个预期的结果，都会引发重新整合。此外，我们假设，BLA表达的zif 268和Arc/Arg3.1将升高后，一个意想不到的再激活会话。在目标2中，我们将定义腹外侧中脑导水管周围灰质（vlPAG）阿片受体在触发情境恐惧记忆再巩固意外检索后的作用。我们假设，vlPAG阿片受体触发杏仁核的恐惧记忆的再巩固过程中的记忆再激活，违反了预期。在目标3中，我们将定义眶额皮层（OFC）在触发情境恐惧记忆重新巩固后意外提取的作用。我们假设，OFC将发挥关键作用，在信号的结果预期，从而触发BLA重新巩固过程时，重新激活会话违反了预期的结果。我们的应用程序代表了一个重大的概念创新，因为它是第一个看在重新整合的产品的相互作用的组件集成纠错电路。

DESCRIPTION (provided by applicant): In the past 15 years, neurobiologists have challenged the view that memories stabilize over time through a process of consolidation; recent research indicates that memories undergo a period of restabilization following reactivation/retrieval that i distinct from initial consolidation. Termed "reconsolidation," this process appears to be evolutionarily conserved and dynamic - maintaining, strengthening, and/or updating existing memories in order to preserve their predictive relevance. Reconsolidation is of interest to researchers and clinicians, in part because it holds tremendous promise for those who suffer from intrusive and often debilitating memories, such as patients with post-traumatic stress disorder (PTSD). Reconsolidation research has the potential to inform and facilitate cognitive-behavioral therapy, resulting in better outcomes for PTSD sufferers. Unfortunately, the basic behavioral and neurobiological mechanisms of reconsolidation are poorly understood. However, preliminary investigations by our lab and others suggest an important role for prediction error (i.e., surprise, or the violation of expectation), in the initiation of memory reconsolidation processes. If reconsolidation provides a mechanism for the updating of existing memories, then new (i.e., not already predicted) information must be present in order for reconsolidation processes to be initiated. Using a combination of behavioral, anatomical and pharmacological approaches, we propose a systematic analysis of the neural circuits responsible for the prediction error signal that triggers reconsolidation of contextual fear memories. In Aim 1, we wil examine contextual fear memory reconsolidation following an unexpected retrieval. We hypothesize that reactivation of a contextual fear memory in an unexpected manner will initiate fear memory reconsolidation processes in the basolateral amygdala (BLA). Either the omission of an expected outcome or the substitution of an expected outcome with a different aversive stimulus will initiate reconsolidation. Further, we hypothesize that BLA expression of both zif268 and Arc/Arg3.1 will be elevated following an unexpected reactivation session. In Aim 2, we will define the role of ventrolateral periaqueductal gray (vlPAG) opioid receptors in triggering contextual fear memory reconsolidation following an unexpected retrieval. We hypothesize that vlPAG opioid receptors trigger amygdalar reconsolidation of fear memories during memory reactivation that violates an expectation. In Aim 3, we will define the role of the orbitofrontal cortex (OFC) in triggering contextual fear memory reconsolidation following an unexpected retrieval. We hypothesize that the OFC will play a critical role in signaling outcome expectancy and thereby triggering BLA reconsolidation processes when the reactivation session violates an expected outcome. Our application represents a major conceptual innovation, as it is the first to look at reconsolidation as the product of interacting components of an integrated error-correction circuit.