Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories

Abstract

Summary Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata.

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

“…It is currently not clear whether this within-session extinction also persists between sessions, but this would be worthy of future investigation. Consistent with this suggestion, previous research has shown that inhibition of Class I HDACs can enhance fear extinction memory (Bahari-Javan et al, 2012;Bredy and Barad, 2008;Graff et al, 2014;Lattal et al, 2007;Stafford et al, 2012;Whittle et al, 2013). Although systemic pharmacological HDAC3 inhibition fails to enhance cued fear extinction (Bowers et al, 2015), site-specific HDAC3 inhibition restricted to the hippocampus or amygdala might reveal an important role of HDAC3 in fear extinction memory.…”

Opening a New Time Window for Treatment of Stroke by Targeting HDAC2

“…All these data suggest that HDAC1 and HDAC2 contribute to the secondary functional loss after stroke. HDAC2 is an isoform negatively regulating cell survival (Nott et al, 2008) and neuronal plasticity (Gräff et al, 2014). In contrast, HDAC1 gain of function has a potent protection effect against neurotoxicity in vivo model for ischemia (Kim et al, 2008).…”

“…Histone deacetylases (HDACs) target histones, regulate chromosome dynamics, control cellular gene expression (Robert et al, 2011), and contribute to multiple signaling pathways linked to neuronal plasticity (Gräff et al, 2014), cell survival (Nott et al, 2008), neuroinflammation (Bie et al, 2014), and oxidative stress (Shimazu et al, 2013;Peng et al, 2015). Thus, HDACs may play a critical role in mediating pathophysiological events in the periinfarct area after stroke.…”

Spermidine-induced improvement of reconsolidation of memory involves calcium-dependent protein kinase in rats

“…In the same year, Misanin et al (1968) suggested that consolidated memories become labile and susceptible to modulation when they are reactivated; that is, when they are evoked, they must undergo a new stabilization process to persist (Nader et al 2000;Sara 2000;de la Fuente et al 2011;Gräff et al 2014). This new stabilization process has been termed "reconsolidation" (Przybyslawski et al 1999).…”