Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear

Abstract

Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders.Substantial evidence indicates that 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). Efforts to understand the mechanisms of this form of learning have increased recently, particularly since it is an important model of anxiety disorder treatment.Many forms of learning, including extinction, are dependent on changes in gene expression ( . Dynamic changes in chromatin structure make an important contribution to the regulation of tissue-specific gene expression. In particular, histone acetylation/deacetylation and dimethylation of specific lysine residues on nucleosomal histone proteins (i.e., H3-K9) and DNA methylation of CpG dinucleotides within promoter regions are ways that chromatin remodeling can influence ongoing transcription and synaptic plasticity (Martinowich et al. 2003;Levenson et al. 2...

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.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Fear extinction involves the gradual reduction in the fear response through the repeated presentation of a nonreinforced conditioned stimulus, which generates a new memory that competes with the original fear memory trace. As hippocampal acetylation or HATs such as CBP/P300 are essential to form contextual fear, fear extinction also involves epigenetic mechanisms [185,[220][221][222]. Notably, as discussed above, HDAC1 regulates extinction learning via a mechanism involving H3K9 deacetylation and the subsequent trimethylation of target genes [185].…”

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

“…It has become clear that histone acetylation contributes to memory formation (Wood et al 2006b; Barrett and Wood 2008;Sweatt 2009;Morris et al 2010). Histone acetylation increases after learning (Levenson et al 2004;Chwang et al 2006;Bredy et al 2007;Peleg et al 2010), and the histone acetyltransferase CREB-binding protein (CBP) is critical for memory storage (Oike et al 1999;Alarcon et al 2004;Korzus et al 2004;Wood et al 2005Wood et al , 2006a. 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.…”