{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:18:23Z","timestamp":1785421103551,"version":"3.56.0"},"posted":{"date-parts":[[2025,6,8]]},"group-title":"Neuroscience","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["T32DA053558"],"award-info":[{"award-number":["T32DA053558"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K01DA062014"],"award-info":[{"award-number":["K01DA062014"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K01DA054306"],"award-info":[{"award-number":["K01DA054306"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P01DA047233"],"award-info":[{"award-number":["P01DA047233"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DA040620"],"award-info":[{"award-number":["R01DA040620"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DA007359"],"award-info":[{"award-number":["R01DA007359"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000874","name":"Brain & Behavior Research Foundation","doi-asserted-by":"crossref","award":["30609"],"award-info":[{"award-number":["30609"]}],"id":[{"id":"10.13039\/100000874","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Drug addiction is characterized by neuronal adaptations that support a shift from goal-directed behaviors to habitual, compulsive drug-seeking with persistent effects on cognition and decision-making. Emerging evidence increasingly indicates that astrocytes are also involved in nervous system disorders, including addiction, but the cocaine-induced astrocyte-specific transcriptome has not yet been investigated. We utilized whole cell sorting of astrocytes, RNA-sequencing, and bioinformatic approaches to characterize the astrocyte transcriptome in the nucleus accumbens (NAc), a key brain region involved in reward-processing, following cocaine self-administration, prolonged abstinence, and \u201crelapse\u201d in male mice. We found that astrocytes exhibit robust and contextually-specific transcriptional signatures that converge strongly with human cocaine use disorder. Bioinformatic analysis revealed CREB as a highly ranked predicted upstream regulator of cocaine-induced transcriptional regulation in NAc astrocytes, and CUT&amp;RUN-sequencing mapped increased CREB binding across the astrocyte genome in response to cocaine. Viral-mediated manipulation of CREB activity selectively in NAc astrocytes, in combination with several measures of addiction-related behaviors including conditioned place preference and self-administration, revealed that astrocytic CREB increases the rewarding and reinforcing properties of cocaine. This effect is sex-specific, with no change in astrocytic CREB activity or CPP found in females. Subsequent experiments identify potential molecular mechanisms of astrocytic CREB\u2019s influence through modulating astrocytic Ca\n                  <jats:sup>2+<\/jats:sup>\n                  signaling in response to cocaine. Finally, we show that astrocytic CREB selectively modulates D1-type medium spiny neurons in NAc to control cocaine-related behaviors. Together, these data demonstrate that the astrocyte transcriptome responds robustly to cocaine and that CREB mediates cocaine\u2019s effects on gene expression in astrocytes, with consequent effects on neuronal activity and rewarding responses to the drug.\n                <\/jats:p>","DOI":"10.1101\/2025.06.04.657899","type":"posted-content","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T02:50:29Z","timestamp":1749437429000},"source":"Crossref","is-referenced-by-count":1,"title":["Astrocytic CREB regulates transcriptional, neuronal, and behavioral responses to cocaine"],"prefix":"10.64898","author":[{"given":"Leanne M.","family":"Holt","sequence":"first","affiliation":[{"name":"Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Minier-Toribio","sequence":"additional","affiliation":[{"name":"Nash Family Department of 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