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Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor \u0394FosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate \u0394FosB 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 \u0394FosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of \u0394FosB was subregion-specific, and that \u0394FosB 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<jats:italic>FosB<\/jats:italic>promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for<jats:italic>FosB<\/jats:italic>induction and multiple hippocampus-dependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal<jats:italic>FosB<\/jats:italic>gene promoter to cause \u0394FosB induction critical for cocaine-related learning.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Although cocaine addiction is driven in part by the formation of indelible associations between the drug and the environment, paraphernalia, and circumstances of use, and although this type of associative learning is dependent upon changes in gene expression in a brain region called the hippocampus, the mechanisms by which cocaine alters hippocampal gene expression to drive formation of these associations is poorly understood. Here, we demonstrate that chronic cocaine engages locus-specific changes in the epigenetic profile of the<jats:italic>FosB<\/jats:italic>gene in the hippocampus, and that these alterations are required for cocaine-dependent gene expression and cocaine\u2013environment associations. This work provides novel insight into addiction etiology and potential inroads for therapeutic intervention in cocaine addiction.<\/jats:p>","DOI":"10.1523\/jneurosci.0800-19.2019","type":"journal-article","created":{"date-parts":[[2019,9,2]],"date-time":"2019-09-02T21:45:11Z","timestamp":1567460711000},"page":"8305-8314","source":"Crossref","is-referenced-by-count":41,"title":["Epigenetic Regulation of Hippocampal<i>Fosb<\/i>Expression Controls Behavioral Responses to Cocaine"],"prefix":"10.1523","volume":"39","author":[{"given":"Paula A.","family":"Gajewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7879-5996","authenticated-orcid":false,"given":"Andrew L.","family":"Eagle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth 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