Systems Reconsolidation Reveals a Selective Role for the Anterior Cingulate Cortex in Generalized Contextual Fear Memory Expression

Abstract

After acquisition, hippocampus-dependent memories undergo a systems consolidation process, during which they become independent of the hippocampus and dependent on the anterior cingulate cortex (ACC) for memory expression. However, consolidated remote memories can become transiently hippocampus-dependent again following memory reactivation. How this systems reconsolidation affects the role of the ACC in remote memory expression is not known. Using contextual fear conditioning, we show that the expression of 30-day-old remote memory can transiently be supported by either the ACC or the dorsal hippocampus following memory reactivation, and that the ACC specifically mediates expression of remote generalized contextual fear memory. We found that suppression of neural activity in the ACC with the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) impaired the expression of remote, but not recent, contextual fear memory. Fear expression was not affected by this treatment if preceded by memory reactivation 6 h earlier, nor was it affected by suppression of neural activity in the dorsal hippocampus with the GABA-receptor agonist muscimol. However, simultaneous targeting of both the ACC and the dorsal hippocampus 6 h after memory reactivation disrupted contextual fear memory expression. Second, we observed that expression of a 30-day-old generalized contextual fear memory in a novel context was not affected by memory reactivation 6 h earlier. However, intra-ACC CNQX infusion before testing impaired contextual fear expression in the novel context, but not the original training context. Together, these data suggest that although the dorsal hippocampus may be recruited during systems reconsolidation, the ACC remains necessary for the expression of generalized contextual fear memory.

Changes in patterns of neural activity underlie a time‐dependent transformation of memory in rats and humans

“…We first set out to replicate our previous behavioral findings to demonstrate the reliability of contextual fear generalization over time (Einarsson, Pors, & Nader, ; Wiltgen & Silva, ; Winocur et al, ). Freezing behavior, the measure of fear memory, was assessed in the original conditioning context (CXT‐A), or in a novel context (CXT‐B) following a short delay (SD; 1 day) or a long delay (LD; 30 days).…”

Dissociation of the Role of Infralimbic Cortex in Learning and Consolidation of Extinction of Recent and Remote Aversion Memory

“…Major differences between the two paradigms concern the dependency on hippocampus and amygdala. Although CFC clearly relies on hippocampus even at remote time points (Debiec et al, 2002;Einarsson et al, 2014;Einarsson and Nader, 2012;Goshen et al, 2011), cue-based (taste and odor) food aversion memory is considered hippocampal independent (Ballarini, et al, 2009;Cui et al, 2005;Ding et al, 2008;Gusev et al, 2005;Josselyn et al, 2004). However, this assumption was recently challenged for conditioned taste aversion (Chinnakkaruppan et al, 2014) and long time ago for COA (Bermudez-Rattoni et al, 1986;Miller et al, 1986).…”

“…In particular, medial prefrontal cortices (mPFCs) have been reported to undergo a major reorganization over time and gradually take a more important integrative role for remote emotional memories such as contextual fear memory (CFC; Einarsson et al, 2014;Frankland et al, 2004;Goshen et al, 2011;Restivo et al, 2009;Vetere et al, 2011) or food aversion memory (Ding et al, 2008;Frankland and Bontempi, 2005). The mPFC and specifically its ventral subregion, the infralimbic part (IL), was also reported to be critical for extinction of emotional memories as transient pharmacological manipulation of the IL altered extinction of recent memory of CFC (Kritman and Maroun, 2012;Laurent and Westbrook, 2009;Sierra-Mercado et al, 2010) and conditioned food aversion (Akirav et al, 2006a).…”

The prefrontal cortical endocannabinoid system modulates fear–pain interactions in a subregion‐specific manner

“…Roles for the PrL in fear‐induced antinociception (Freitas et al ., ) and formalin‐induced conditioned place avoidance (Jiang et al ., ) have also been demonstrated. The anterior cingulate cortex (ACC) is a subregion of the mPFC involved in the modulation of fear behaviour (Einarsson et al ., ), cognitive‐affective component of pain (Johansen et al ., ) and in top‐down descending modulation of pain (Fuchs et al ., ). The ACC is connected reciprocally with both the PrL and the IfL and may play a role in modulating their output (Vertes, ).…”