Inhibition of matrix metalloproteinase activity disrupts reconsolidation but not consolidation of a fear memory.
Inhibition of matrix metalloproteinase activity disrupts reconsolidation but not consolidation of a fear memory.
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DOI：
10.1016/j.nlm.2008.09.003
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发表时间：
2009-01
影响因子：
2.7
通讯作者：
Sorg, Barbara A.
中科院分区：
文献类型：
--
作者：
Brown, Travis E.;Wilson, Adrianne R.;Cocking, Davelle L.;Sorg, Barbara A.
再巩固假说认为，重新激活的记忆可以通过药物操作来增强或破坏。突触可塑性被认为是再巩固过程的基础。基质金属蛋白酶是一种调节参与可塑性事件的细胞外基质的蛋白质，这些蛋白质最近被证明影响学习和记忆。然而，所有关于基质金属蛋白酶在学习和记忆中的作用的研究都采用了依赖上下文线索的任务。本研究的目的是确定FN-439在多大程度上破坏与条件刺激相关的恐惧记忆的巩固和/或再巩固，这些条件刺激表明音调-休克配对，并且独立于上下文线索。雄性Sprague-Dawley大鼠在条件反射前30分钟或条件反射后24小时的单次再激活前30分钟注射FN-439 （35 μg）。当出现音调（条件刺激）时，给予FN-439不会破坏冻结反应的巩固。相反，FN-439输注以再激活依赖的方式破坏了恐惧记忆的再巩固。冻结行为的减少不是由于总体焦虑水平的降低，因为FN-439对在高强度迷宫任务中张开手臂的时间或张开手臂的进入的百分比没有影响。因此，我们首次证明了大脑中的基质金属蛋白酶抑制能够破坏不依赖于上下文线索的音调-休克关联记忆的重新巩固。对先前配对的条件刺激的恐惧反应可以通过MMP抑制剂在单次再激活过程中的治疗而中断，这一发现表明这类化合物可能具有治疗创伤后应激障碍和/或单纯恐惧症的潜力。
The reconsolidation hypothesis posits that memories that have been reactivated can be either enhanced or disrupted by pharmacological manipulation. Synaptic plasticity is presumed to underlie the reconsolidation process. Matrix metalloproteinases are proteins that regulate the extracellular matrix involved in plasticity events, and these proteins have recently been shown to influence learning and memory. However, all studies on the role of matrix metalloproteinases in learning and memory have employed tasks that rely on contextual cues. The goal of this study was to determine the extent to which FN-439 would disrupt the consolidation and/or reconsolidation of a fear memory associated with a conditioned stimulus that signaled tone-shock pairings and that was independent of contextual cues. Male Sprague-Dawley rats were given infusions of FN-439 (35 μg intracerebroventricular) 30 min prior to conditioning (tone-shock paired association) or 30 min prior to a single reactivation session given 24 hr after conditioning. Administration of FN-439 did not disrupt consolidation of the freezing response when the tone (conditioned stimulus) was presented. In contrast, FN-439 infusion disrupted reconsolidation of the fear memory in a reactivation-dependent manner. The reduced freezing behavior was not due to a decrease in general anxiety levels, since FN-439 had no effect on the percent of open-arm time or open-arm entries in an elevated-plus maze task. Thus, we demonstrated for the first time that matrix metalloproteinase inhibition in the brain is capable of disrupting the reconsolidation of a tone-shock association memory that does not depend on contextual cues. The finding that a fear response to a previously paired conditioned stimulus can be disrupted by treatment with an MMP inhibitor during a single reactivation session suggests that this class of compounds may have therapeutic potential for posttraumatic stress disorder and/or simple phobias.
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