title: Delayed noradrenergic activation in the dorsal hippocampus promotes the long-term persistence of extinguished fear.
abstract: Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM.
authors.affiliation: 1] Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Beijing, China [2] Institute of Mental Health and Hebei Brain Ageing and Cognitive Neuroscience Laboratory, Hebei Medical University, Shijiazhuang, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Chai
authors.affiliation: 1] Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Beijing, China [2] National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Liu
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Yan-Xue
authors.initials: YX
authors.lastname: Xue
authors.affiliation: Affiliated Hospital and School of Pharmacy of Guiyang Medical University, Guiyang, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Yang
authors.affiliation: 1] Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Beijing, China [2] National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: 1] Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Beijing, China [2] National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Wang
authors.affiliation: 1] Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Beijing, China [2] National Institute on Drug Dependence, Peking University, Beijing, 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, China.
authors.forename: Hai-Shui
authors.initials: HS
authors.lastname: Shi
authors.affiliation: Affiliated Hospital and School of Pharmacy of Guiyang Medical University, Guiyang, China.
authors.forename: Ji-Shi
authors.initials: JS
authors.lastname: Wang
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Bao
authors.affiliation: 1] Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Beijing, China [2] National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Shi-Qiu
authors.initials: SQ
authors.lastname: Meng
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing, China.
authors.forename: Zeng-Bo
authors.initials: ZB
authors.lastname: Ding
authors.affiliation: Institute of Mental Health and Hebei Brain Ageing and Cognitive Neuroscience Laboratory, Hebei Medical University, Shijiazhuang, China.
authors.forename: Xue-Yi
authors.initials: XY
authors.lastname: Wang
authors.affiliation: 1] Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Beijing, China [2] National Institute on Drug Dependence, Peking University, Beijing, China [3] Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011943:Receptors, Adrenergic, beta; D009638:Norepinephrine