Furthermore, our experiments testing the combination of VPA with partial extinction training indicate that cue exposure is crucial for any VPA effect on H4 acetylation. The findings that fear conditioning with and without extinction result in unique patterns of histone acetylation support, and extend to specific promoters of a single gene, the findings of Levenson et al. poor 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 Dihydroberberine a useful pharmacological ILKAP antibody adjunct to psychotherapy for human stress disorders. Substantial evidence indicates that extinction of conditioned fear, the reduction in responding to a feared cue when the cue is usually repeatedly presented without any adverse consequence, is usually 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 usually 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 (Berman and Dudai 2001; Dihydroberberine Cammarota et al. 2003; Lin et al. 2003; Sangha et al. 2003; Vianna et al. 2003; Herry and Mons 2004; Suzuki et al. 2004; Yang and Lu 2005; Chhatwal et al. 2006; Herry et al. 2006; Lattal et al. 2006). Dynamic changes in chromatin structure make an important contribution to the regulation of Dihydroberberine 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. 2006). Histone acetylation contributes an early step to the process of Dihydroberberine chromatin modification by disassembling nucleosomes to make DNA promoter regions accessible for transcription factor binding and for methylation. Histone acetylation says are regulated by specific enzymes, including histone deacetylases (HDACs), which can be both tissue- and cell-type-specific. Thus, the omnipresence and specificities of these enzymes may make them potential therapeutic targets for the treatment of neuropsychiatric disorders and disorders of learning and memory. In addition to its trophic function during development, brain-derived neurotrophic factor (BDNF) is critical for learning-related synaptic plasticity and the maintenance of long-term memory. The role of BDNF in fear conditioning is usually well defined, and, within the amygdala of the rat, both fear conditioning and its extinction lead to an increase in BDNF protein and gene transcripts (Rattiner et al. 2004; Chhatwal et al. 2006; Ou and Gean 2006). Recent data indicate that this medial prefrontal cortex also plays an important role in fear extinction learning (Milad and Quirk 2002; Milad et al. 2004; Santini et al. 2004), but the function of BDNF in the prefrontal cortex during extinction remains undefined. Thus, regulation of BDNF in the prefrontal cortex is usually a reasonable candidate mechanism to make a contribution to extinction learning. BDNF has four unique transcripts each regulated by a specific promoter that is sensitive to epigenetic modification (Martinowich et al. 2003; Tsankova et al. 2004). We chose Dihydroberberine to examine histone acetylation around two of those promoters in the prefrontal.