Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug, the environment, and circumstances of its use. However, the patterns of gene regulation critical for this learning remain unknown. Consolidation of explicit memories occurs through synaptic plasticity in the hippocampus, and some of the molecular mechanisms of this process are well characterized, but epigenetic regulation underlying changes in hippocampal gene expression and the distribution of altered gene expression is poorly understood. The transcription factor ΔFosB is an important arbitrator of activity-dependent gene expression, and its expression in hippocampus is critical for learning. Previous studies demonstrate that drugs of abuse strongly upregulate ΔFosB in rodent hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. I demonstrate here that ΔFosB induction occurs exclusively within the CA1 subregion of the hippocampus and is facilitated by cocaine-mediated decreases in a repressive histone modification, H3K9me2. Subsequent locus-specific increase of this histone mark in hippocampus is sufficient to impair general learning and memory and cocaine-environment associations. Furthermore, human hippocampus post-mortem samples reveal a decrease in multiple ΔFosB isoforms and some ΔFosB target genes in cocaine-addicted individuals, as well as in depressed individuals, indicating a potential role for this gene in hippocampal pathologies associated with human addiction. These findings collectively suggest that salient stimuli, such as formation of drug-environment associations, induce epigenetic changes in the hippocampal FosB gene promoter that regulate ΔFosB induction, which in turn may control the transcription of genes that underlie hippocampal cell function and cocaine-related learning. Moreover, dysregulation of the FosB gene may contribute to the effects of chronic drug exposure and may underlie cognitive deficits that accompany drug addiction and depression.
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