Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear

Abstract

Aversive associative memories formed by the association between a neutral conditioned stimulus (CS+) and an aversive unconditioned stimulus (US+) are progressively made permanent by a process of consolidation 1 . However upon retrieval, intervention by amnestic agents [2][3][4][5][6][7] , either prior to or immediately after retrieval, results in disruption of the previously consolidated fear memory. This suggests that a consolidated memory returns to a transient destabilized state shortly after reactivation necessitating a dynamic time-dependent process of reconsolidation in order to persist further. During this reconstruction, a memory is vulnerable to experimental intervention [8][9][10] leading to amnesia, but can also be enhanced [11][12][13] or modified on the long-term [14][15][16] , thereby updating the previous memory with new information [14][15][16][17] . In clinical terms, the bidirectional and adaptive nature of reconsolidation is ideally placed to mediate both the modification of memory strength 12 , as well as memory content 16,18 , rendering this process a promising therapeutical target to counteract the hyper-responsive fear system. In order to fully exploit reconsolidation-based therapies that adapt the content of fear memories, leading to a loss of fear response on the long term, it is crucial to elucidate the molecular underpinnings of reconsolidation, which to this date remain obscure.3 Long-lasting changes in synaptic efficacy brought about by gene transcription, protein synthesis and changes in strength of hippocampal glutamatergic synapses via AMPA receptor trafficking are believed to be the cellular substrates of learning and memory [19][20][21] . Although reconsolidation is not merely a recapitulation of the initial consolidation process 22 , it has been shown that transcription, de novo protein synthesis and synaptic protein degradation in the hippocampus are also necessary for memory remodeling after retrieval 4,7,17,[23][24][25] . Here, we investigated whether the temporal profile of reconsolidation that is hypothesized to be limited to a 6 h time window 5,8 actuates a sequential profile of defined dorsohippocampal AMPA receptor synaptic plasticity that is crucial to the synaptic remodeling that underlies subsequent fear expression (changes in memory strength) and reinterpretation of fear memory after retrieval (changes in memory content). Results Memory recall induces acute hippocampal AMPAR-endocytosisIn order to analyze whether glutamate receptors are regulated during reconsolidation in animals receiving the US+ and retrieval (US-R), we dissected the dorsal hippocampus at 1 and 4 h post-retrieval, and analyzed the synaptic membrane fraction, including membrane-bound proteins and associated proteins 26,27 , by immunoblotting for subunits of AMPA receptors. A no-shock group experiencing retrieval (NS-R) was used to control for the specificity of an aversive-associative memory (Supplementary Fig. S1). These two time points were chosen as they fall within the 6-h time window after ret...

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits

“…Further, some studies have shown similar effects to those of Monfils et al (2009) using contextual fear preparations in mice (Rao-Ruiz et al 2011) while others show findings like ours in contextual paradigms (Ishii et al 2012). Although important to study, it is unlikely that the discrepant findings in the literature are simply due to procedural differences, such as the type of fear conditioning (cued or contextual), the postsession delay (immediate or 10 min), or differences in species.…”

The Extracellular Matrix Protein Brevican Limits Time-Dependent Enhancement of Cocaine Conditioned Place Preference

“…The dorsal half of the hippocampus was dissected from fresh brains and stored at − 80°C (Rao-Ruiz et al, 2011). For the mPFC, brains were removed, rapidly frozen, and the area was dissected freehand from~1 mm coronal sections in a cryostat.…”

“…Contextual FC was performed as described previously (Rao-Ruiz et al, 2011), with small modifications. In short, conditioning and testing was performed in a Plexiglas chamber with a stainless steel grid floor (Ugo Basil).…”

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

“…Recently, it has been shown in mice (10,11), rats (12), and humans (13)(14)(15)(16)) that precisely timing behavioral extinction to coincide with memory reconsolidation can persistently inhibit the return of defensive reactions (but see refs. 17-19 for a discussion of boundary conditions).…”