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Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior

Fischer, A; Radulovic, M; Schrick, C; Sananbenesi, F; Godovac-Zimmermann, J; Radulovic, J; (2007) Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior. Neurobiology of Learning and Memory , 87 (1) 149 - 158. 10.1016/j.nlm.2006.08.003. Green open access

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Abstract

Fear memories elicit multiple behavioral responses, encompassing avoidance, or behavioral inhibition in response to threatening contexts. Context-specific freezing, reflecting fear-induced behavioral inhibition, has been proposed as one of the main risks factors for the development of anxiety disorders. We attempted to define the key hippocampal mediators of extinction in a mouse model of contextdependent freezing. Nine-week-old male C57BL/6J mice were trained and tested for contextual fear conditioning and extinction. Freezing behavior scored by unbiased sampling, was used as an index of fear. Proteomic, immunoblot, and immunohistochemical approaches were employed to identify, verify, and analyze the alterations of the hippocampal extracellular signal-regulated kinases 1 and 2 (Erk-1/2). Targeted pharmacological inhibition of the Erk-1/2 activating kinase, the mitogen activated and extracellular signal-regulated kinase (Mek), served to establish the role of Nlek/Erk signaling in extinction. When compared to acquisition, extinction of contextual freezing triggered a rapid activation of Erk-1/2 showing a distinctive time-course, nuclear localization, and subcellular isoform distribution. These differences suggested that the upstream regulation and downstream effects of this pathway might be specific for each process. Dorsohippocampat injections of the Mek inhibitors U0126 (0.5 mu g/site) and PD98059 (1.5 mu g/site) immediately after the nonreinforced trials prevented Erk-1/2 activation and significantly impaired extinction. This effect was dissociable from potential actions on memory retrieval or reconsolidation. On the basis of these findings, we propose that hippocampal Mek/Erk signaling might serve as one of the key mediators of contextual fear extinction. (c) 2006 Elsevier Inc. All rights reserved.

Type: Article
Title: Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.nlm.2006.08.003
Publisher version: http://dx.doi.org/10.1016/j.nlm.2006.08.003
Language: English
Additional information: Copyright © 2006 Elsevier Inc. This manuscript is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at http://creativecommons.org/ licenses/by/4.0. Access may be initially restricted by the publisher.
Keywords: Extinction, erk, proteome, context, freezing, hippocampus, mice, fear-potentiated startle, prefrontal cortex, conditioned fear, protein-synthesis, nuclear translocation, synaptic plasticity, recognition memory, regulated kinase, consolidation, amygdala
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/147891
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