The Effect of Short-Interval Extinction on Consolidation and Reconsolidation of F

短间隔消光对F固结和再固结的影响

• 批准号: 7615746
• 负责人: Ebony M Glover
• 金额: $ 3.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-21 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615746
• 关键词: Affect; Amygdaloid structure; Animal Model; Aversive Stimulus; Behavior; Behavioral; Biochemical; Characteristics; Clinical; Extinction (Psychology); Fright; Goals; Hour; Injection of therapeutic agent; Laboratories; Learning; Mediating; Memory; Mental Health; Modeling; Morbidity - disease rate; Neurons; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Post-Traumatic Stress Disorders; Proteins; Protocols documentation; Public Health; Rattus; Recovery; Recurrence; Relapse; Research; Resistance; Retrieval; Sirolimus; Stimulus; Symptoms; Testing; Time; Training; Trauma; Up-Regulation; Western Blotting; base; conditioned fear; experience; inhibitor/antagonist; mTOR protein; theories; tool

DESCRIPTION (provided by applicant): A characteristic symptom of posttraumatic stress disorder (PTSD) is recurrent, intrusive memories of a traumatic experience. The long-term goal of the current project is to use animal models to find clinical tools to treat people with unwanted traumatic memories. This project explores in the rat the idea that disrupting fear memory formation in the aftermath of a traumatic experience may be a useful approach for mitigating PTSD symptoms. This approach derives from consolidation theory, which holds that newly acquired memories are initially labile and stabilize over time into enduring traces. Recent findings from our laboratory show that extinction training given 10 min after fear conditioning (short-interval extinction) disrupts fear memory in a manner that is resistant to recovery by reinstatement, renewal, and spontaneous recovery - three animal model correlates of clinical relapse. Conversely, all three forms of relapse are evident following fear memory disruption by extinction training given 72 hrs after fear conditioning (long-interval extinction). Based on these and supporting biochemical findings it is hypothesized that, unlike long-interval extinction, short-interval extinction disrupts fear memory consolidation via an erasure or "unlearning" mechanism. Thus, short-interval extinction may serve as a clinically promising tool to disrupt traumatic memories. Yet, it is not always practical to intervene in the immediate aftermath of a trauma, and this approach does not help extant PTSD patients. However, a phenomenon called reconsolidation blockade, whereby stable fear memories may be disrupted if perturbed immediately after reactivation, may prove useful for eliminating long-term fear memories. The specific aims are to: 1. Provide behavioral and biochemical support for the idea that short-interval extinction disrupts memory consolidation via an erasure mechanism. Using western blot analysis, amygdala neurons will be examined for specific biochemical changes at various time points after fear training and after short-interval extinction. It is predicted that short-interval extinction will reverse certain learning-related biochemical changes observed after training. 2. Combine reconsolidation blockade with short-interval extinction into a new behavioral protocol whereby the reactivation of a mature fear memory is immediately followed by extinction. Using western blot analysis, amygdala neurons will be examined for specific biochemical changes at various time points after memory reactivation and after post-reactivation short-interval extinction. It is predicted that the biochemical changes seen after reactivation will be reversed by immediate post-reactivation short-interval extinction. The long-term goal of this project is to use animal models of fear memory to develop clinical tools to treat unwanted, persistent, and intrusive memories associated with posttraumatic stress disorder (PTSD). PTSD is a debilitating and costly illness of high morbidity, and is major public health concern. Thus, finding tools to mitigate PTSD symptoms is of vital importance to mental health research.

描述(由申请人提供)：创伤后应激障碍(PTSD)的一个特征症状是对创伤经历的反复、侵入性记忆。目前这个项目的长期目标是使用动物模型来寻找临床工具来治疗有不想要的创伤记忆的人。这个项目在大鼠身上探索了这样的想法，即在创伤经历后扰乱恐惧记忆的形成可能是缓解创伤后应激障碍症状的有用方法。这种方法源于巩固理论，该理论认为，新获得的记忆最初是不稳定的，并随着时间的推移稳定下来，形成持久的痕迹。我们实验室最近的发现表明，在恐惧条件作用后10分钟进行的消退训练(短时间消退)以一种通过恢复、更新和自发恢复的方式扰乱恐惧记忆，这三种动物模型与临床复发相关。相反，在恐惧条件作用72小时后进行消退训练(长时间间隔消退)，所有三种形式的复发都明显发生在恐惧记忆中断之后。基于这些和支持生化研究的发现，我们假设，与长时间间隔消亡不同，短时间间隔消退通过一种擦除或“忘却”机制来破坏恐惧记忆的巩固。因此，短时间间隔消退可以作为一种有临床前景的工具来扰乱创伤记忆。然而，在创伤后立即进行干预并不总是可行的，而且这种方法对现有的创伤后应激障碍患者没有帮助。然而，一种被称为重新巩固封锁的现象，即稳定的恐惧记忆如果在重新激活后立即被扰乱，可能会被证明对消除长期恐惧记忆有用。其具体目的是：1。为短时间间隔消失通过擦除机制破坏记忆巩固的观点提供行为学和生物化学支持。利用蛋白质印迹分析，杏仁核神经元将在恐惧训练后和短时间间隔消退后的不同时间点检测特定的生化变化。据预测，短时间的消退将逆转训练后观察到的某些与学习有关的生化变化。2.将重新巩固封锁和短时间的消退结合起来，形成一种新的行为模式，即在重新激活成熟的恐惧记忆之后，立即消退。利用蛋白质印迹分析，检测杏仁核神经元在记忆重新激活后和重新激活后短时间间隔消退后的不同时间点的特定生化变化。据预测，重新激活后的生化变化将被重新激活后的即刻短时间间隔消退逆转。该项目的长期目标是使用恐惧记忆的动物模型来开发临床工具，以治疗与创伤后应激障碍(PTSD)相关的不受欢迎的、持久的和侵入性记忆。创伤后应激障碍是一种发病率高、耗资巨大、使人衰弱的疾病，也是主要的公共卫生问题。因此，找到缓解创伤后应激障碍症状的工具对心理健康研究至关重要。