Recall and Reconsolidation of Contextual Fear Memory: Differential Control by ERK and Zif268 Expression Dosage

Antoine Besnard,Jocelyne Caboche,Serge Laroche,Masuo Ohno

doi:10.1371/journal.pone.0072006

Antoine Besnard, Jocelyne Caboche + Show 2 more

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https://doi.org/10.1371/journal.pone.0072006

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Abstract

Compelling evidence points to the existence of independent cellular processes involved in the consolidation and reconsolidation of memory. For instance, a double dissociation has been reported between hippocampal Extracellular-Regulated Kinase-1/2 (ERK1/2) activity being necessary for contextual fear conditioning (CFC) consolidation but not reconsolidation. Conversely, hippocampal expression of the immediate early gene Zif268 is necessary for CFC reconsolidation but not consolidation. Since we previously reported that ERK1/2 controls the transcription of Zif268 in the hippocampus, we examined the precise role of ERK1/2 activity and Zif268 gene expression dosage in CFC memory processing. For this, we first assessed performance of Zif268 homozygous and heterozygous mutant mice in a CFC paradigm. Whereas Zif268−/− mice displayed a deficit of both consolidation and reconsolidation, Zif268+/− mice displayed a selective deficit of reconsolidation only, therefore pointing to the relationship between Zif268 gene expression dosage and CFC memory processing. Zif268 gene expression dosage interfered with the reconsolidation process if and only if CFC memory was relatively recently encoded and directly reactivated. Furthermore, CFC memory strengthening previously reported to involve Zif268 expression in the hippocampus was spared in Zif268+/− mice. Finally, blocking ERK1/2 activity prior to CFC retrieval prevented the deficit of reconsolidation observed in Zif268+/− mice. Collectively, these results highlight a tight relationship between Zif268 gene expression dosage and CFC memory processing. They also suggest that ERK1/2 activity upon CFC memory recall is necessary for its retrieval, a prerequisite for its reactivation and subsequent reconsolidation.

Highlights

Contextual fear conditioning (CFC) is a well-established paradigm to study the neural mechanisms of emotional learning and memory
In light of the complex relationship between Zif268 gene expression dosage and behavioral performance observed across distinct type of memories [24,25,26], we took advantage of Zif268 mutant mice to assess the relationship between Zif268 expression and CFC memory processing
Zif2682/2 mice, showed a clear deficit in freezing behavior 24 h after training (Fig. 1B). This consolidation deficit in CFC in Zif2682/2 mice, which display a complete loss of Zif268 expression in the whole brain are consistent with previous reports in as much as Zif268 expression in the amygdala was previously reported to be required for the consolidation of a contextual fear conditioning memory [27], albeit not the hippocampus [15]

Summary

Introduction

Contextual fear conditioning (CFC) is a well-established paradigm to study the neural mechanisms of emotional learning and memory. ERK1/2 activity [12,16] as well as Zif268 transcription [17] and protein expression [15,16] were shown to be increased in the hippocampus following CFC retrieval, a situation where memory reactivation initiate reconsolidation of CFC memory. Since ERK1/2 activity can control activity-dependent transcription of Zif268 [18], these observations raised the question of the precise role of ERK1/ 2 and Zif268 in CFC memory processing To investigate this issue, we trained wild-type, homozygous (Zif2682/2) and heterozygous (Zif268+/2) mutant mice in a trial unique CFC paradigm and examined post-learning and post-recall performance to investigate the relationship between Zif268 gene expression dosage and CFC memory processing. Blocking ERK1/2 activity prior to CFC retrieval prevented the deficit of reconsolidation observed in Zif268+/2 mice These results highlight a tight relationship between Zif268 gene expression dosage and CFC memory processing. We propose that upon CFC memory recall, ERK1/ 2 activation is an early molecular event required for CFC memory retrieval, followed by Zif268 regulation required for memory restabilization

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