title: Role of hippocampal β-adrenergic and glucocorticoid receptors in the novelty-induced enhancement of fear extinction.
abstract: Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the β-adrenergic receptor (βAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal βAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not βAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal βAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction.
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and.
authors.forename: Chang
authors.initials: C
authors.lastname: Yang
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Deng
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Yi-Xiao
authors.initials: YX
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, Basic Medical College, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Hai-Shui
authors.initials: HS
authors.lastname: Shi
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Shi-Qiu
authors.initials: SQ
authors.lastname: Meng
authors.affiliation: Affiliated Hospital and School of Pharmacy, Guiyang Medical University, Guiyang 550004, China.
authors.forename: Bai-Sheng
authors.initials: BS
authors.lastname: Chai
authors.affiliation: Affiliated Hospital and School of Pharmacy, Guiyang Medical University, Guiyang 550004, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Institute of Mental Health and Hebei Brain Ageing and Cognitive Neuroscience Laboratory, Hebei Medical University, Shijiazhuang 050031, China, and.
authors.forename: Ning
authors.initials: N
authors.lastname: Chai
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Yan-Xue
authors.initials: YX
authors.lastname: Xue
authors.affiliation: Affiliated Hospital and School of Pharmacy, Guiyang Medical University, Guiyang 550004, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Mental Health and Hebei Brain Ageing and Cognitive Neuroscience Laboratory, Hebei Medical University, Shijiazhuang 050031, China, and.
authors.forename: Xue-Yi
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Affiliated Hospital and School of Pharmacy, Guiyang Medical University, Guiyang 550004, China, linlu@bjmu.edu.cn jswang_yg@yahoo.com.
authors.forename: Ji-Shi
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, National Clinical Research Center for Mental Disorders and National Institute on Drug Dependence, Peking University, Beijing 100191, China, Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China linlu@bjmu.edu.cn jswang_yg@yahoo.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011965:Receptors, Glucocorticoid
keywords: behavioral tag; extinction; glucocorticoid receptors; hippocampus; β-adrenergic receptors