Temporal factors in extinction and spontaneous recovery

描述（由申请人提供）：在许多精神疾病中，包括抑郁症和创伤后应激障碍，一个普遍存在的问题是无法抑制由某些环境线索引起的强烈情绪反应。行为干预通常试图通过消除技术来消除这些反应，这些技术旨在通过切断线索和反应之间的关系来削弱环境线索引发问题反应的能力。然而，这种干预长期成功的挑战是，在灭绝过程中受到抑制的行为会随着时间的推移而自发恢复，这表明原始记忆在灭绝后仍然完好无损。本提案中概述的实验旨在研究可能导致灭绝持续存在的某些情况，从而削弱任何自发恢复效应。具体来说，该提案的目的是围绕时间在小鼠恐惧消退的发展和长期维持中的作用。首先，我们将研究灭绝经验之间的时间的作用，以研究不同的灭绝时间模式可能抑制恐惧记忆的条件。第二，我们将研究消退作为获得后时间的函数，看看在获得后是否存在恐惧记忆特别容易受到消退抑制特性影响的时间间隔。第三，我们将探讨灭绝后的时间对药物操作敏感性的影响。我们的药理学研究将集中在蛋白激酶A和蛋白质合成，两个关键的分子过程参与记忆。这些药理学研究将检查海马体在情境恐惧条件反射后对消退记忆形成的贡献。在基本层面上，确定这些不同治疗后灭绝的过程和持续性将对目前的灭绝理论和一般学习产生重要影响。在临床水平上，探索使消退记忆持久的行为和药理学干预将建议治疗组合，可用于引起持久抑制许多精神疾病的基础上的衰弱环境触发的反应。

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.