Neural mechanisms of extinction generalization in human

项目摘要/摘要 创伤后应激障碍(PTSD)在美国是一种严重损害心理健康的疾病，有 终生患病率为6.8%。治疗创伤后应激障碍最常用的临床技术是暴露。 治疗，然而，这一策略是不完美的，在临床环境中暴露治疗所获得的结果 一次次地无法概括到新的现实世界的情况。这个应用程序的目的是描述 研究恐惧回归的神经机制，并测试防止恐惧回归的新策略。巴甫洛夫式的恐惧 条件反射和消退分别是创伤后应激障碍和暴露疗法的有用的实验室模型。这个 暴露疗法中观察到的失误可以用情境在恐惧和消退学习中的作用来解释 召回。灭绝是以特定的语境表达的，而恐惧很容易概括为新的语境 在一种被称为更新的现象中。恐惧的重生和灭绝的特殊性解释了为什么许多人 治疗方法不能产生持久的益处。在实验室环境中，上下文通常被定义为物理空间，但 情景记忆研究的进展表明，心理环境在记忆过程中起着重要作用。 学习和回忆人类的记忆。目前尚不清楚心理语境框架如何 应用于提高对情绪学习和记忆的神经和认知机制的理解。 根据NIMH战略目标1，以定义复杂行为的机制，本提案的目标1 将研究恐惧和消亡心理情境恢复的神经机制 参与者和创伤后应激障碍患者。先进的fMRI神经成像技术将被用来量化 在更新测试期间重新激活心理情境。先前试图克服上下文特殊性的尝试 消亡的重点是上下文操作，如在多个上下文中熄灭、提示提醒或 从药物上抑制上下文处理。这些技术的实施取得了好坏参半的结果， 在药物治疗的情况下，并不总是切实可行的解决方案。因此，目标2将测试一个 新的行为策略旨在减少灭绝学习过程中的上下文处理，安全地促进 灭绝泛化。这种简单的操作，称为定向遗忘，以前已经被证明是 减少海马区的活动。健康的受试者在消亡学习过程中会进行定向遗忘。我们 然后将测试灭绝学习与定向遗忘的增强是否导致灭绝泛化为新的 上下文。这一目标支持NIMH战略目标3通过在以下方面的进展开发新的治疗方法 神经科学和行为科学。这项提案中列出的综合目标将显著支持 恐惧学习后成功消亡的神经和认知机制的最新知识 将测试一种新的行为策略，以增加灭绝泛化。这些目标的实现将会向前推进 了解有关情绪学习和记忆的神经科学知识，并为未来的创伤后应激障碍的治疗做出贡献。

PROJECT SUMMARY/ABSTRACT Post-Traumatic Stress Disorder (PTSD) is a serious detriment to mental health in the United States, with a lifetime prevalence of 6.8%. The most commonly used clinical technique in the treatment of PTSD is exposure therapy, however this strategy is imperfect, and the results obtained during exposure therapy in a clinical setting repeatedly fail to generalize to novel real-world situations. The Aims of this application are to characterize the neural mechanisms of the return of fear and to test a novel strategy to prevent this return. Pavlovian fear conditioning and extinction serve as useful laboratory models of PTSD and exposure therapy respectively. The observed lapses in exposure therapy can be explained by the role of context in fear and extinction learning and recall. Extinction is expressed in a contextually specific manner, while fear readily generalizes to new contexts in a phenomenon called renewal. The renewal of fear and the specificity of extinction explain why many treatments fail to produce lasting benefits. In laboratory settings, context is often defined as physical space, but advancements in episodic memory research have shown that mental context plays a significant role in the learning and recall of memories in humans. It is currently unknown how a mental context framework can be applied to enhance understanding of the neural and cognitive mechanisms of emotional learning and memory. In line with NIMH Strategic Objective 1 to define the mechanism of complex behaviors, Aim 1 of this proposal will investigate the neural mechanisms of fear and extinction mental context reinstatement in both healthy participants and patients with PTSD. Advanced fMRI neuroimaging techniques will be used to quantify the reactivation of mental contexts during a renewal test. Previous attempts to overcome the contextual specificity of extinction focus on contextual manipulations such as extinguishing in multiple contexts, cue reminders, or pharmacologically inhibiting contextual processing. These techniques have been implemented to mixed success, and in the case of pharmacological treatments are not always practical solutions. Accordingly, Aim 2 will test a novel behavioral strategy designed to diminish contextual processing during extinction learning, safely facilitating extinction generalization. This simple manipulation, known as directed forgetting, has previously been shown to diminish hippocampal activity. Healthy subjects will engage in directed forgetting during extinction learning. We will then test if extinction learning augmented with directed forgetting results in extinction generalization to new contexts. This Aim supports NIMH Strategic Objective 3 to develop new treatments through advancements in neuroscience and behavioral sciences. The combined Aims laid out in this proposal will significantly bolster current knowledge of the neural and cognitive mechanisms of successful extinction following fear learning and will test a novel behavioral strategy to increase extinction generalization. Completion of these Aims will advance knowledge of neuroscience of emotional learning and memory and contribute to the future treatments of PTSD.