Prediction error in contextual fear memory reconsolidation

描述（由申请人提供）：在过去的15年里，神经生物学家对记忆随着时间的推移通过巩固过程稳定下来的观点提出了挑战；最近的研究表明，记忆在再激活/提取之后会经历一段重新稳定的时期，这与最初的巩固不同。这个过程被称为“再巩固”，似乎是进化上保守和动态的——维持、加强和/或更新现有的记忆，以保持它们的预测相关性。研究人员和临床医生对重新巩固感兴趣，部分原因是它为那些遭受侵入性记忆和经常衰弱的人带来了巨大的希望，比如创伤后应激障碍（PTSD）患者。再巩固研究有可能为认知行为疗法提供信息和促进，从而为创伤后应激障碍患者带来更好的结果。不幸的是，重新巩固的基本行为和神经生物学机制尚不清楚。然而，我们的实验室和其他人的初步调查表明，预测错误（即意外或违反预期）在记忆再巩固过程的启动中起着重要作用。如果再巩固提供了一种更新现有记忆的机制，那么新的（即尚未预测到的）信息必须存在，才能启动再巩固过程。结合行为学、解剖学和药理学的方法，我们提出了一种系统的神经回路分析，该神经回路负责触发情境恐惧记忆重新巩固的预测错误信号。在目标1中，我们将研究意外检索后情境恐惧记忆的再巩固。我们假设情境恐惧记忆以一种意想不到的方式重新激活将启动基底外侧杏仁核（BLA）的恐惧记忆再巩固过程。要么是预期结果的缺失，要么是预期结果被不同的厌恶刺激替代，都会引发再巩固。此外，我们假设在意外的再激活过程后，zif268和Arc/Arg3.1的BLA表达都会升高。在目的2中，我们将定义腹外侧导水管周围灰色（vlPAG）阿片受体在意外检索后触发情境恐惧记忆再巩固中的作用。我们假设vlPAG阿片受体在违背预期的记忆再激活过程中触发杏仁核对恐惧记忆的重新巩固。在目标3中，我们将定义眼窝前额皮质（OFC）在意外检索后触发情境恐惧记忆再巩固中的作用。我们假设OFC将在结果预期信号中发挥关键作用，从而在再激活会话违反预期结果时触发BLA再巩固过程。我们的应用程序代表了一个主要的概念创新，因为它是第一个将重新整合视为集成纠错电路的相互作用组件的产物。

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.