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The dorsal hippocampus, particularly the dorsal dentate gyrus, plays a critical role in the precise encoding of spatial and contextual information. We hypothesized that the dentate gyrus is uniquely positioned to undergo epigenomic and transcriptomic changes because of the convergence of the contextual features of reward and cocaine-enhanced dopamine and norepinephrine signals during volitional drug-taking. We report that cocaine self-administration produces significant DNA methylation changes at an unusually large number of \u223c30,000 genomic regions (&gt;10%, q&lt;0.01) in dentate granule cells (DGCs) of male mice. Cocaine preferentially hypomethylated regions with heterogenous methylation, switching the methylation state in \u223c16% of DGCs on average. The cocaine-sensitive\/responsive epigenomic regions were overrepresented in enhancers and were associated with 9,833 genes, many of which were involved in diverse functions relevant to neuronal functioning. However, among the differentially methylated genes only two regulatory genes,\n                  <jats:italic>c-fos<\/jats:italic>\n                  and\n                  <jats:italic>cartpt<\/jats:italic>\n                  (known to be activated by cocaine), and a cluster of genes encoding components of the extracellular matrix (implicated in neuroplasticity) were differentially expressed (mostly upregulated) following cocaine self-administration, suggesting a gene regulatory network that is transcriptionally robust to perturbations but still specific for context-driven and reward associated neuroplasticity in DGCs. Overall, our data demonstrates that cocaine self-administration induces epigenomic and transcriptomic changes in the dorsal dentate gyrus that may contribute to dorsal hippocampal plasticity and contextual memory associated with cocaine self-administration.\n                <\/jats:p>","DOI":"10.64898\/2026.03.02.708518","type":"posted-content","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T11:15:24Z","timestamp":1772709324000},"source":"Crossref","is-referenced-by-count":0,"title":["Large-scale reorganization of DNA methylation and upregulation of extracellular matrix genes in the dorsal dentate gyrus following cocaine taking"],"prefix":"10.64898","author":[{"given":"Madelyn R.","family":"Baker","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065"},{"name":"Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9284-2595","authenticated-orcid":false,"given":"Elizabeth","family":"Brindley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7713-4512","authenticated-orcid":false,"given":"Kyle A.","family":"Windisch","sequence":"additional","affiliation":[{"name":"The Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065"},{"name":"Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Medical School, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4689-4401","authenticated-orcid":false,"given":"Rose","family":"Sciortino","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065"},{"name":"Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065"},{"name":"Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-5466","authenticated-orcid":false,"given":"Anjali","family":"Rajadhyaksha","sequence":"additional","affiliation":[{"name":"Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065"},{"name":"Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065"},{"name":"Feil Family Brain and Mind and Research Institute, Weill Cornell Medicine, New York, NY 10065"},{"name":"Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8545-6362","authenticated-orcid":false,"given":"Miklos","family":"Toth","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065"},{"name":"Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026030907250627000_2026.03.02.708518v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2013.04.004"},{"key":"2026030907250627000_2026.03.02.708518v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2010.05.015"},{"key":"2026030907250627000_2026.03.02.708518v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2010.128"},{"key":"2026030907250627000_2026.03.02.708518v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.nepig.2015.10.001"},{"issue":"3","key":"2026030907250627000_2026.03.02.708518v1.5","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/gbb.12354","article-title":"Inhibition of DNA methyltransferases regulates cocaine self-administration by rats: a genome-wide DNA methylation study","volume":"16","year":"2017","journal-title":"Genes Brain Behav"},{"key":"2026030907250627000_2026.03.02.708518v1.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5227-14.2015"},{"key":"2026030907250627000_2026.03.02.708518v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/syn.890050104"},{"key":"2026030907250627000_2026.03.02.708518v1.8","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3053-14.2015"},{"key":"2026030907250627000_2026.03.02.708518v1.9","doi-asserted-by":"crossref","unstructured":"Vaillancourt K , Ernst C , Mash D , Turecki G . 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