The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear

Abstract

Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.Histone modification is a fundamental mechanism involved in epigenetic regulation of gene regulation, now recognized to contribute toward the consolidation of long-term memory. Histone modifications are mediated by direct enzymatic interactions with lysine residues on chromatin, and cause dynamic changes in chromatin structure that make an important contribution to the regulation of learning-induced gene expression (Levenson et al. 2004;Bredy et al. 2007). Among the superfamily of mammalian histone-modifying enzymes, prototypical compounds such as trichostatin (TSA), sodium valproate (VPA), and sodium butyrate (NaBt), which inhibit histone deacetylase (HDAC), have been shown to enhance long-term memory (Levenson et al. 2004;Yeh et al. 2004;Wood et al. 2006;Bredy et al. 2007;Lattal et al. 2007;Vecsey et al. 2007). The ability of HDAC inhibitors to modulate behavior makes them potential therapeutic targets for treating cognitive disorders, particularly disorders of fear-related learning including phobias and post-traumatic stress disorder (PTSD).The extinction of conditioned fear, the reduction in responding to a feared cue when the cue is repeatedly presented without any adverse consequence, is new learning that inhibits the expression of a conditioned association rather than erasing it. For example, conditioned fear shows "spontaneous recovery" after the passage of time (Baum 1988), "reinstatement" after presentations of the unconditioned stimulus (US) alone (Rescorla and Heth 1975), and "renewal" when the feared cue is presented in a context different from that of extinction training (Bouton and King 1983). Another important learning-related phenomenon is reconsolidation, in which memories become labile and sensitive to modification upon retrieval until restabilized over time ...

Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation

“…The data also show that these marks occur at the zif268 promoter and correlate with a shift of zif268 expression from the hippocampus to the PFC as the memory matures, suggesting an important functional role of these histone PTMs in memory consolidation. The results are in line with several recent findings showing that enhancing histone acetylation favours memory, including object 13,31 , fear 10,12,14,15,17,[32][33][34] , spatial 13,34 and taste 19,35 memory. They significantly extend these findings by showing that in addition to histone acetylation, histone phosphorylation and methylation (on H3K36) are activated in a temporally and spatially regulated manner during memory consolidation in both the hippocampus and the cortex.…”

Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory

“…Most previous studies examined the hippocampus-dependent contextual fear-conditioning task (Alarcon et al 2004;Levenson et al 2004;Vecsey et al 2007;Guan et al 2009;Peleg et al 2010) or extinction of fear memory Bredy and Barad 2008). Recently, memory enhancement by HDAC inhibitor treatment was observed for object-recognition memory (Stefanko et al 2009) and object-location memory (Haettig et al 2011).…”

“…Specific point mutations in CBP that block the recruitment of CBP to CREB (Wood et al 2006a) or that eliminate the histone acetyltransferase activity of CBP (Korzus et al 2004) selectively impair long-term memory. Also, the contextual fear memory deficit observed in mice lacking one copy of CBP is ameliorated by pharmacologically inhibiting the histone deacetylases (HDACs) that oppose CBP (Alarcon et al 2004), presumably through enhancing the efficacy of histone acetylation by the CBP that remains.Treatment of rodents with inhibitors of HDACs enhances long-term memory (Alarcon et al 2004;Korzus et al 2004;Levenson et al 2004;Yeh et al 2004;Lattal et al 2007;Vecsey et al 2007;Bredy and Barad 2008;Guan et al 2009;Stefanko et al 2009;Peleg et al 2010;Roozendaal et al 2010). Most previous studies examined the hippocampus-dependent contextual fear-conditioning task (Alarcon et al 2004;Levenson et al 2004;Vecsey et al 2007;Guan et al 2009;Peleg et al 2010) or extinction of fear memory Bredy and Barad 2008).…”

Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging

“…Guided by reports that non-selective compounds with HDACi activity can enhance longterm memory for contextual fear conditioning (CFC) (Bredy and Barad, 2008;Fischer et al, 2007;Kilgore et al, 2010;Vecsey et al, 2007;Levenson et al, 2004), here we tested the effects of systemic EVX, scheduling drug administration specifically to ensure that hippocampal histone acetylation was increased during CFC training, at 90 min postinjection. Despite the marked blunting of open field activity noted earlier (Fig.…”