Fear memory attenuation: testing reconsolidation-extinction boundaries

描述(由申请者提供)：夸大或持续的恐惧是精神障碍的常见现象。虽然巴甫洛夫条件反射的研究在揭示恐惧学习的神经基础方面取得了很大的进展，但对于如何减少或消除病理性病例中的创伤记忆却知之甚少，这是临床上非常关注的问题。我们最近设计了一种新的行为范式，可以减弱和防止恐惧记忆的回归。我们的结果表明，对常用的临床治疗(暴露疗法)进行细微的修改可以极大地改善结果，并降低患有创伤后应激障碍或特定恐惧症的个人复发的可能性。与此同时，我们的合作者实验室(普林斯顿大学的雅尔·尼夫博士)开发的一个新的计算模型为我们的结果提供了一个原则性的解释，并将有助于生成可测试的预测，以完善我们的方案，并更好地理解持续更新恐惧记忆的机制。在拟议的研究中，我们将首先使用计算得出的预测来改进我们的协议。接下来，我们将测试这一优化方案的局限性，并研究它是否可能被用于针对更强、更老、更复杂的恐惧记忆，希望它最终可能被用于减弱临床人群的创伤记忆。 与公共卫生相关：夸大或持续的恐惧在精神障碍中是常见的。实验室环境中使用了两种模式(阻止重新巩固和消除)来减少获得性恐惧；然而，这些技术的临床效果有限。我们最近提出了一种新的行为范式，通过结合再巩固和消退原则(Ret+Ext)来减弱和防止恐惧记忆的回归。我们的发现表明，对常用的临床治疗(暴露疗法)进行细微的修改可以极大地改善结果，并降低患有创伤后应激障碍或特定恐惧症的个人复发的可能性。在这里，我们建议扩展这些发现，以分离我们减少恐惧治疗的神经机制，并仔细检查使用Ret+Ext范式的优势、弱点和可能的后果。

DESCRIPTION (provided by applicant): Exaggerated or persistent fear is a common occurrence in psychiatric disorders. Although much progress has been made in uncovering the neural basis of fear learning through studies of Pavlovian conditioning, little is known about how to reduce or eliminate traumatic memories in pathological cases, which is of great clinical concern. We have recently devised a novel behavioral paradigm that attenuates and prevents the return of fear memories. Our results indicate that subtle modifications to a commonly employed clinical treatment (exposure therapy) could greatly improve outcome, and reduce the potential for relapse in individuals suffering from post-traumatic stress disorder or specific phobias. In parallel, a new computational model developed in our collaborator's lab (Dr. Yael Niv, at Princeton University) provides a principled explanation for our results, and will help generate testable predictions to refine our protocol, and better understand the mechanisms that underlie the persistent updating of fear memories. In the proposed studies, we will first refine our protocol using computationally-derived predictions. Next, we will test the limits of this optimized protocol, and examine whether it may be used to target stronger, older, and more complex fear memories, with the hopes that it may eventually be employed to attenuate traumatic memories in clinical populations. PUBLIC HEALTH RELEVANCE: Exaggerated or persistent fear is a common occurrence in psychiatric disorders. Two paradigms (blockade of reconsolidation and extinction) have been used in the laboratory setting to reduce acquired fear; however, the clinical efficacy of these techniques has been limited. We have recently presented a novel behavioral paradigm that attenuates and prevents the return of fear memories by combining reconsolidation and extinction principles (Ret+Ext). Our findings suggest that subtle modifications to a commonly employed clinical treatment (exposure therapy) could greatly improve outcome, and reduce the potential for relapse in individuals suffering from post-traumatic stress disorder or specific phobias. Here, we propose to extend these findings to isolate the neural mechanisms that underlie our fear-reducing treatment, and to closely examine the strengths, weaknesses, and possible consequences of using this Ret+Ext paradigm.