Such changes were absent in dorsal striatum (Figures S2A and S2B). Next, to examine potential similarities between

cocaine- and stress-induced regulation of histone methylation in this brain region, the standard 10 day chronic social defeat stress protocol was used (Berton et al., 2006). As previously reported (Krishnan et al., 2007 and Vialou et al., 2010), two distinguishable groups of defeated mice, susceptible and unsusceptible, were observed based on a measure of social avoidance, in which susceptible mice displayed decreased social interaction compared to both control and unsusceptible mice (Figure 2C). Ten days after the final defeat, susceptible and unsusceptible mice, as well as nondefeated controls, were analyzed for G9a protein levels in NAc. G9a expression was significantly decreased in NAc of susceptible

mice compared to unsusceptible animals (Figure 2D), which were no different from nonstressed controls. These effects were VX-770 in vivo not observed in dorsal striatum (Figure S2C). Consistent with a reduction in G9a expression in susceptible animals, global levels of H3K9me2 were decreased in NAc of these mice compared to both control and unsusceptible mice (Figure 2E). Additionally, Glp mRNA, similar to G9a mRNA, was significantly reduced in NAc of susceptible mice, a molecular response that was absent in unsusceptible mice ( Figure 2H). Numerous other repressive chromatin modifiers, such as Suv39h1, many of which form multimeric-binding complexes with G9a and GLP ( Fritsch et al., 2010), were also significantly induced in NAc of unsusceptible mice ( Figure 2H), indicating that increased repressive chromatin regulation ABT-263 concentration may contribute to proadaptive responses to stressful stimuli. In dorsal striatum, in contrast, H3K9me2 of was significantly increased after social stress in both susceptible and unsusceptible mice ( Figure S2D). Regulation of H3K9me2 in NAc after chronic social stress is specific for this mark, which is euchromatic, as global levels of the associated heterochromatic mark H3K9me3 were unaltered in NAc of both susceptible and unsusceptible mice ( Figure S3A). To extend these findings in mice to clinical

depression, we evaluated G9a and Glp levels, as well as other repressive chromatin modifiers, in NAc of postmortem human depressed patients (all symptomatic at their time of death; see Supplemental Experimental Procedures for detailed methods on tissue collection). Similar to results observed in mice susceptible to social stress, G9a ( Figure 2F) and Glp ( Figure 2H) mRNA levels were significantly reduced in these patients. Numerous other enzymes involved in transcriptional repression—shown to be significantly induced in NAc of unsusceptible mice—were also downregulated in NAc of human depressed subjects ( Figure 2H). Consistent with decreased G9a and Glp expression in NAc of depressed humans, global levels of H3K9me2 were also significantly reduced ( Figure 2G).