Temporal factors in extinction and spontaneous recovery

描述(由申请人提供)：在许多精神障碍中，包括抑郁症和创伤后应激障碍，普遍存在的一个问题是未能抑制某些环境线索引发的强烈情绪反应。行为干预通常试图通过消退技术来消除这些反应，这些技术旨在通过切断环境线索和反应之间的关系来削弱环境线索触发问题反应的能力。然而，这种干预长期成功的挑战是，在灭绝过程中被抑制的行为会随着时间的推移自发恢复，表明原始记忆在灭绝后保持不变。这项提案中概述的实验旨在研究一些可能导致物种灭绝持续存在的情况，从而削弱任何自发的恢复效应。具体地说，该提案的目的是围绕时间在老鼠恐惧的发展和长期维持中的作用。首先，我们将研究灭绝经历之间的时间的作用，以检查不同的灭绝时间模式可能抑制恐惧记忆的条件。其次，我们将考察自习得以来的时间函数的消亡，以了解在习得后的间隔时间中，恐惧记忆是否特别容易受到消亡的抑制特性的影响。第三，我们将探索自灭绝以来的时间对药物操纵敏感性的影响。我们的药理学研究将重点放在蛋白激酶A和蛋白质合成上，这是涉及记忆的两个关键分子过程。这些药理学研究将检验海马体在背景恐惧条件作用后消亡记忆形成中的作用。在基本层面上，确定这些不同处理后的灭绝过程和持续时间，将对当前的灭绝理论和总体上的研究具有重要意义。在临床层面上，探索使消亡记忆持久的行为和药物干预将提出治疗组合，这些治疗组合可能被用来持久抑制导致许多精神疾病的衰弱环境触发反应。

DESCRIPTION (provided by applicant): A pervasive problem in many psychiatric disorders, including depression and post-traumatic stress disorder, is the failure to inhibit intense emotional reactions elicited by certain environmental cues. Behavioral interventions often attempt to eliminate these reactions through extinction techniques designed to weaken the ability of environmental cues to trigger problematic responses by severing the relation between the cues and responses. A challenge for the long-term success of this kind of intervention, however, is that the behavior that is suppressed during extinction spontaneously recovers with time, demonstrating that the original memory remains intact after extinction. The experiments outlined in this proposal are designed to examine some circumstances that may lead to the persistence of extinction, thereby weakening any spontaneous recovery effect. Specifically, the aims of the proposal are centered around the role of time in the development and long-term maintenance of extinction of fear in mice. First, we will examine the role of time between extinction experiences to examine the conditions under which different temporal patterns of extinction may suppress fearful memories. Second, we will examine extinction as a function of time since acquisition to see if there are intervals after acquisition in which the fearful memory is particularly vulnerable to the suppressive properties of extinction. Third, we will explore the effects of time since extinction on sensitivity to pharmacological manipulations. Our pharmacological studies will focus on protein kinase A and protein synthesis, two critical molecular processes involved in memory. These pharmacological studies will examine the contribution of the hippocampus to the formation of extinction memories after contextual fear conditioning. At a basic level, determining the course and persistence of extinction after these different treatments will have important implications for current theories of extinction and learning in general. At a clinical level, exploring the behavioral and pharmacological interventions that make the extinction memory long lasting will suggest treatment combinations that may be used to cause lasting suppression of debilitating environmentally triggered responses that underlie many psychiatric disorders.