title: An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear.
authors.affiliation: 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.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Yanxue
authors.initials: Y
authors.lastname: Xue
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Pharmacy, China MeiTan General Hospital, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Suo
authors.affiliation: 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.
authors.forename: Yixiao
authors.initials: Y
authors.lastname: Luo
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China; School of Pharmacy and Affiliated Hospital of Guiyang Medical University, Guiyang, China.
authors.forename: Baisheng
authors.initials: B
authors.lastname: Chai
authors.affiliation: Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, the Sixth Affiliated Hospital of Peking University, Beijing, China; School of Pharmacy and Affiliated Hospital of Guiyang Medical University, Guiyang, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Yang
authors.affiliation: School of Pharmacy and Affiliated Hospital of Guiyang Medical University, Guiyang, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Pickens
authors.affiliation: 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; Peking-Tsinghua Center for Life Sciences and Peking University-International Data Group-McGovern Institute for Brain Research, Peking University, Beijing, China. Electronic address: linlu@bjmu.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D003214:Conditioning, Classical; D003463:Cues; D004558:Electric Stimulation; D005108:Extinction, Psychological; D005239:Fear / Q000523:psychology*; D005260:Female; D006801:Humans; D008297:Male; D011939:Mental Recall; D051381:Rats; D012055:Reinforcement Schedule; D055815:Young Adult
keywords: Extinction; fear memory; hippocampus; reconsolidation; retrieval; unconditioned stimulus