Epigenetics and persistent memory: implications for reconsolidation and silent extinction beyond the zero

Abstract

Targeting epigenetic mechanisms during initial learning or memory retrieval can lead to persistent memory. Retrieval induces plasticity that may result in reconsolidation of the original memory, in which critical molecular events are needed to stabilize the memory, or extinction, in which new learning during the retrieval trial creates an additional memory that reflects the changed environmental contingencies. A canonical feature of extinction is that the original response is temporarily suppressed, but returns under various conditions. These characteristics have defined whether a given manipulation alters extinction (when persistence does not occur) or reconsolidation (when persistence does occur). A problem arises with these behavioral definitions when considering the potential for persistent memory of extinction. Recent studies have found that epigenetic modulation of memory processes leads to surprisingly robust and persistent extinction. We discuss evidence from behavioral epigenetic approaches that forces a re-evaluation of widely used behavioral definitions of extinction and reconsolidation.

Figure 1

Enhancing histone acetylation promotes initial memory consolidation. In normal situations, an initial learning event triggers a signaling cascade that includes activation of HATs and inactivation and/or removal of HDACs. These HATs attach acetyl groups (Ac) to histone tails, which relaxes the nucleosome, allowing transcription factors to bind to the DNA. Depending on the task and type of memory, the conditioned response may not persist under normal conditions. When an HDACi is administered, however, these tails become hyperacetylated, which promotes memory consolidation, strengthening the response. Although the schematic is simplified to focus on the main concept, there are of course other epigenetic mechanisms involved that work in concert with HATs and HDACs.

Figure 2

Enhancing histone acetylation generates a persistent form of extinction. When memories are retrieved, similar signaling cascades are triggered, ultimately resulting in a loosening of chromatin structure. With a relatively brief retrieval trial, there is little to no long-term change in behavior. As a result of hyperacetylation induced by an HDACi, the behavioral effects of this brief retrieval trial are augmented. The two theoretical possibilities for these effects are an impairment of reconsolidation (shown in red) or an enhancement of extinction (shown in green). Both of these theoretical approaches predict weakened behavior and decreased persistence, as revealed through attenuated spontaneous recovery, contextual renewal and reinstatement.