Prediction error in contextual fear memory reconsolidation

描述(申请人提供)：在过去的15年里，神经生物学家对记忆通过巩固过程随着时间的推移而稳定的观点提出了质疑；最近的研究表明，记忆在重新激活/提取后经历了一段不同于最初巩固的重新稳定时期。这个过程被称为“再巩固”，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，以保持它们的预测性相关性。研究人员和临床医生对重新巩固很感兴趣，部分原因是它对那些患有侵入性和经常使人衰弱的记忆的人有巨大的希望，例如创伤后应激障碍(PTSD)患者。再巩固研究有可能提供信息并促进认知行为治疗，从而为创伤后应激障碍患者带来更好的结果。不幸的是，人们对再巩固的基本行为和神经生物学机制知之甚少。然而，我们实验室和其他实验室的初步研究表明，预测误差(即意外或违反预期)在启动记忆重新巩固过程中起着重要作用。如果重新合并提供了用于更新现有存储器的机制，则必须存在新的(即，尚未预测的)信息，以便启动重新合并过程。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分析方法，对触发情景恐惧记忆重新巩固的预测误差信号负责的神经回路进行分析。在目标1中，我们将研究意外提取后背景恐惧记忆的重新巩固。我们假设，背景恐惧记忆以一种意想不到的方式重新激活，将启动杏仁基底外侧核(BLA)的恐惧记忆再巩固过程。要么省略一个预期结果，要么用一个不同的令人厌恶的刺激方案取代一个预期结果，都将引发重新整合。此外，我们假设Zif268和Arc/Arg3.1的BLA表达在意外的重新激活过程后将上调。在目标2中，我们将确定腹外侧导水管周围灰质(VlPAG)阿片受体在意外提取后触发情景恐惧记忆再巩固中的作用。我们假设vlPAG阿片受体在违反预期的记忆重新激活过程中触发杏仁核恐惧记忆的重新巩固。在目标3中，我们将定义眼眶额叶皮质(OFC)在意外提取后触发情景恐惧记忆重新巩固中的作用。我们假设，OFC将在发出预期结果信号，从而在重新激活会话违反预期结果时触发BLA重新整合过程中发挥关键作用。我们的应用代表了一项重大的概念创新，因为它是第一次将重新合并视为集成纠错电路的交互组件的产物。

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.