Neural mechanisms of extinction generalization in human

项目总结/摘要 创伤后应激障碍（PTSD）是美国心理健康的严重损害， 终身患病率为6.8%。治疗PTSD最常用的临床技术是暴露 然而，这种策略是不完美的，并且在临床环境中暴露治疗期间获得的结果 一再未能概括到新的现实世界的情况。本申请的目的是表征 恐惧回归的神经机制，并测试一种新的策略来防止这种回归。巴甫洛夫恐惧 条件反射和消退分别作为PTSD和暴露疗法的有用的实验室模型。的 暴露疗法中观察到的失误可以用恐惧和消退学习中的背景作用来解释， 记得了灭绝是以特定的方式表达的，而恐惧很容易概括到新的环境中 一种叫做更新的现象。恐惧的更新和灭绝的特殊性解释了为什么许多 治疗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， 情景记忆研究的进展表明，心理背景在情景记忆中起着重要作用。 学习和记忆的能力。目前尚不清楚心理背景框架如何 应用于增强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定义复杂行为的机制，本提案的目标1 将研究恐惧和灭绝的神经机制，心理背景恢复在两个健康的 参与者和PTSD患者。先进的功能磁共振成像神经成像技术将用于量化 在更新测试期间重新激活心理环境。以前试图克服上下文特异性 灭绝的重点是上下文操纵，如熄灭在多种情况下，提示提醒，或 抑制上下文处理。这些技术的实施取得了不同程度的成功， 并且在药物治疗的情况下并不总是实用的解决方案。因此，目标2将测试 一种新的行为策略，旨在减少灭绝学习过程中的上下文处理，安全地促进 灭绝泛化这种被称为定向遗忘的简单操作，以前已经被证明可以 减少海马的活动。健康的受试者在消退学习期间会进行定向遗忘。我们 然后，我将测试，如果灭绝学习与定向遗忘增强的结果灭绝泛化到新的 contexts.该目标支持NIMH战略目标3，即通过以下方面的进步开发新的治疗方法： 神经科学和行为科学。该提案中提出的综合目标将大大加强 目前对恐惧学习后成功灭绝的神经和认知机制的认识， 将测试一种新的行为策略，以增加灭绝泛化。这些目标的实现将推动 情绪学习和记忆的神经科学知识，并有助于未来治疗创伤后应激障碍。

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.