Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior

Andre Fischer, Marko Radulovic, Christina Schrick, Farahnaz Sananbenesi, Jasminka Godovac-Zimmermann, Jelena Radulovic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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 context-dependent 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 Mek/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. Dorsohippocampal injections of the Mek inhibitors U0126 (0.5 μg/site) and PD98059 (1.5 μg/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.

Original languageEnglish (US)
Pages (from-to)149-158
Number of pages10
JournalNeurobiology of Learning and Memory
Volume87
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Context
  • Erk
  • Extinction
  • Freezing
  • Hippocampus
  • Mice
  • Proteome

ASJC Scopus subject areas

  • Experimental and Cognitive Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

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