Epigenetic Regulation of Hippocampal Fosb Expression Controls Behavioral Responses to Cocaine

Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug and the circumstances of consumption. However, drug-induced changes in gene expression underlying the saliency of these associations remain understudied. Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor Delta FosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate Delta FosB in hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. We investigated differences in mouse dorsal and ventral hippocampal Delta FosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of Delta FosB was subregion-specific, and that Delta FosB transcriptional activity in both the dorsal and ventral hippocampus is necessary for cocaine conditioned place preference. Further, we characterize changes in histone modifications at the FosB promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for FosB induction and multiple hippocampus-dependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal FosB gene promoter to cause Delta FosB induction critical for cocaine-related learning.