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: 7489250
• 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/7489250
• 关键词: Affect; Amygdaloid structure; Animal Model; Aversive Stimulus; Behavior; Behavioral; Biochemical; Characteristics; Clinical; Disruption; 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; Traumatic Stress Disorders; Up-Regulation; Western Blotting; base; conditioned fear; experience; inhibitor/antagonist; 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）的特征性症状是创伤经历的反复出现的侵入性记忆。目前项目的长期目标是使用动物模型来寻找临床工具，以治疗具有不必要的创伤记忆的人。该项目在大鼠中探索了这样的想法：在创伤经历后破坏恐惧记忆的形成可能是减轻创伤后应激障碍症状的一种有用方法。这种方法来源于巩固理论，该理论认为新获得的记忆最初是不稳定的，并随着时间的推移而稳定下来。我们实验室的最新研究结果表明，在恐惧条件反射（短间隔消退）后10分钟进行消退训练，会以一种难以恢复的方式破坏恐惧记忆，这种恢复方式包括恢复、更新和自发恢复--这三种动物模型与临床复发相关。相反，所有三种形式的复发都是明显的恐惧记忆破坏后，由灭绝训练后72小时的恐惧条件反射（长时间间隔灭绝）。基于这些和支持的生化研究结果，有人假设，不像长间隔灭绝，短间隔灭绝破坏恐惧记忆巩固通过擦除或“遗忘”机制。因此，短间隔消退可能是临床上破坏创伤记忆的一种有前途的工具。然而，在创伤后立即进行干预并不总是可行的，这种方法对现存的PTSD患者没有帮助。然而，一种被称为再巩固阻滞的现象，即稳定的恐惧记忆如果在重新激活后立即受到干扰，可能会被破坏，这可能有助于消除长期的恐惧记忆。具体目标是：1.提供行为和生物化学支持的想法，短时间间隔灭绝破坏记忆巩固通过擦除机制。使用蛋白质印迹分析，杏仁核神经元将在恐惧训练后和短间隔消退后的不同时间点检查特定的生化变化。据预测，短间隔灭绝将逆转训练后观察到的某些与学习相关的生化变化。2.将联合收割机再巩固阻断与短间隔消退结合成一种新的行为方案，即成熟的恐惧记忆的重新激活后立即消退。使用蛋白质印迹分析，将在记忆再激活后和再激活后短间隔消退后的不同时间点检查杏仁核神经元的特异性生化变化。据预测，复活后看到的生化变化将被逆转后立即复活短时间间隔灭绝。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）相关的不必要的，持久的和侵入性的记忆。创伤后应激障碍是一种使人衰弱和昂贵的高发病率疾病，是主要的公共卫生问题。因此，寻找减轻PTSD症状的工具对心理健康研究至关重要。