Post-retrieval extinction as reconsolidation interference: methodological issues or boundary conditions?

Abstract

Memories that are emotionally arousing generally promote the survival of species; however, the systems that modulate emotional learning can go awry, resulting in pathological conditions such as post-traumatic stress disorders, phobias, and addiction. Understanding the conditions under which emotional memories can be targeted is a major research focus as the potential to translate these methods into clinical populations carries important implications. It has been demonstrated that both fear and drug-related memories can be destabilised at their retrieval and require reconsolidation to be maintained. Therefore, memory reconsolidation offers a potential target period during which the aberrant memories underlying psychiatric disorders can be disrupted. Monfils et al. (Science 324:951-955, 2009) have shown for the first time that safe information provided through an extinction session after retrieval (during the reconsolidation window) may update the original memory trace and prevent the return of fear in rats. In recent years, several authors have then tested the effect of post-retrieval extinction on reconsolidation of either fear or drug-related memories in both laboratory animals and humans. In this article, we review the literature on post-reactivation extinction, discuss the differences across studies on the methodological ground, and review the potential boundary conditions that may explain existing discrepancies and limit the potential application of post-reactivation extinction approaches.

Fig. 1

Molecular pathways of memory reconsolidation. Molecular signalling cascades downstream of β-adrenergic receptors (βAR), dopamine D1 receptor (D1) and N-methyl-d-aspartate receptors (NMDAR) have been shown to be implicated in reconsolidation. The mammalian target of rapamycin (mTOR), influenced by the activities of neuronal surface receptors and channels including NMDAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and dopaminergic and metabotropic glutamate receptors (mGluR), also seems to play a key role in reconsolidation through the phosphorylation of kinase p70S6 (p70S6K) and ribosomal protein S6 (rpS6P). βAR and D1 activate adenylyl cyclase (AC) leading to protein kinase A (PKA) phosphorylation and gene expression. PKA also phosphorylates AMPAR after memory retrieval. Ca⁺⁺ influx from NMDAR and AMPAR activates the extracellular signal-regulated kinase pathway (ERK), by rat sarcoma (RAS) and mitogen- activated protein kinase (MEK), and phosphatidylinositide 3-kinases (PI3K). Phosphorylation of ERK increases the levels of the transcription factors ets-like gene-1 (Elk-1), phosphorylated cAMP response element binding (pCREB), known to be involved in reconsolidation. PI3K activation leads to mTOR activation resulting in p70S6K and rpS6 phosphorylation and synaptic protein translation. mGluR1 receptor activation is requested after post-retrieval extinction leading to the selective removal of synaptic calcium-permeable AMPAR (X symbol in the Figure). Although the molecular details are not yet known the mGluR1-induced internalization of AMPAR may distinguish reconsolidation update from conventional extinction