Liu Jianfeng, Zhao Liyan, Xue Yanxue, Shi Jie, Suo Lin, Luo Yixiao, Chai Baisheng, Yang Chang, Fang Qin, Zhang Yan, Bao Yanping, Pickens Charles L, Lu Lin
Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, the Sixth Affiliated Hospital of Peking University, Beijing, China; National Institute on Drug Dependence, Peking University, Beijing, China.
National Institute on Drug Dependence, Peking University, Beijing, China.
Biol Psychiatry. 2014 Dec 1;76(11):895-901. doi: 10.1016/j.biopsych.2014.03.027. Epub 2014 Apr 3.
Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear.
In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats.
Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats.
These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear.
条件性恐惧记忆可在重新巩固过程中通过消退进行更新，且这种效应特定于重新激活的条件刺激（CS）。然而，创伤性事件可能与多个线索相关联，且每个线索都可能触发对该事件的回忆。我们引入了一种技术，以针对与引起恐惧的厌恶事件相关的所有不同线索。
在人体实验中，161名受试者接受了改良的恐惧条件反射，在此过程中，他们暴露于无条件刺激（US）或未强化的CS以重新激活记忆，然后进行消退、自发恢复和恢复。在动物实验中，343只大鼠按照与人体实验相似的方案接受情境恐惧条件反射。我们还探究了大鼠中US重新激活后的分子变化。
在消退前呈现较低强度的US破坏了人类和大鼠中不同CS与重新激活的US之间的关联。这种效应在人类中持续至少6个月，且对重新激活的US具有选择性。该程序对人类和大鼠的远期记忆也有效。与CS相比，US在大鼠背侧海马中诱导更强的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸谷氨酸受体1和2的内吞作用以及更强的蛋白激酶A、p70S6激酶和环磷酸腺苷反应元件结合蛋白的激活。
这些发现表明，改良的US提取消退策略可能对预防恐惧复发的治疗方法具有潜在影响。
