Preventing the return of fear in humans: Reconsolidation and control

描述（由申请人提供）：焦虑症的患病率估计高达美国成年人口的18%。焦虑症的主要治疗方法是暴露疗法，它基于恐惧消退的原则。尽管基于消退的疗法可能是有效的，但它们的功效是有限的，部分原因是消退学习本身的性质。有大量证据表明，灭绝学习不会导致原始恐惧记忆的显著改变，而是导致新的学习，即以前害怕的事件现在是安全的。结果之一是，最初的恐惧记忆和消退记忆可能会竞争表达。一系列的情况，如时间的推移（自发恢复），环境的改变（更新）和压力（恢复），都可能导致恐惧的回归。 这种恐惧记忆恢复的潜力，即使在广泛的灭绝训练之后，也突出了发现更持久和强大的技术来减少恐惧的必要性。使用简单的经典恐惧条件反射范式，对非人类动物的研究已经确定了两种防止恐惧回归的潜在机制。第一种是操纵原始恐惧记忆的重新巩固或重新储存。第二种方法是让动物体验对压力源的控制，这已经被证明对减少恐惧恢复的可能性有持久的影响。 拟议研究的目标是在人类中评估已被证明可防止非人类动物恐惧回归的技术的功效、特异性和潜在神经机制。目标1下的研究审查了破坏或改变人类条件性恐惧再巩固的技术。具体而言是 探讨了再巩固的药理学破坏，并检查了用于改变条件性恐惧的再巩固的行为干扰技术的特异性和心理和神经后果。目标2检验了控制压力源的经验是否可以减少恐惧记忆恢复的可能性。最后，目标3下的研究检查了这些技术在PTSD患者中的成功，以确定这种焦虑症的神经后果是否会改变这些程序的有效性。所有拟议研究的总体目标是发现我们如何以及何时能够防止人类恐惧的回归，这有可能导致新的和更有效的治疗焦虑症的方法。

DESCRIPTION (provided by applicant): The prevalence of anxiety disorders is estimated to be up to 18% of the US adult population. A primary treatment for anxiety disorders is exposure therapy, which is based on the principles of fear extinction. Although extinction based therapies can be effective, their efficacy is limited, in part due to the nature of extinction learning itsel. There is abundant evidence that extinction learning does not result in a significant alteration of the original fear memory, but rather results in new learning that the previously feared event is now safe. One consequence is that the original fear memory and the extinction memory may compete for expression. A range of circumstances, such as the passage of time (spontaneous recovery), alterations in context (renewal), and stress (reinstatement), can result in the fear returning. This potential for fear memory recovery even after extensive extinction training highlights the need to discover more persistent and robust techniques to diminish fear. Using simple classical fear conditioning paradigms, research in non-human animals has identified two potential mechanisms to prevent the return of fear. The first is by manipulating the reconsolidation or re-storage of the original fear memory. The second is by allowing the animal experience with control over the stressor, which has been shown to have lasting effects on reducing the likelihood of fear recovery. The goal of the proposed research is to assess in humans the efficacy, specificity, and underlying neural mechanisms of techniques that have been shown to prevent the return of fear in non- human animals. Studies under Aim 1 examine techniques to disrupt or alter the reconsolidation of conditioned fear in humans. Specifically, the pharmacological disruption of reconsolidation is explored and the specificity and the psychological and neural consequences of behavioral interference techniques used to alter the reconsolidation of conditioned fear are examined. Aim 2 examines whether experience with control over a stressor can diminish the likelihood that a fear memory returns. Finally, the studies under Aim 3 examine the success of these techniques in patients who suffer from PTSD to determine if the neural consequences of this anxiety disorder alters the effectiveness of these procedures. The overarching goal of all the proposed studies is to discover how and when we might be able to prevent the return of fear in humans, which has the potential to lead to novel and more effective treatments for anxiety disorders.