Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens
Abstract Cocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven in part by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-06-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08327-x |
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| _version_ | 1849691189222047744 |
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| author | Philipp Mews Autumn VA Mason Emily G. Kirchner Molly Estill Eric J. Nestler |
| author_facet | Philipp Mews Autumn VA Mason Emily G. Kirchner Molly Estill Eric J. Nestler |
| author_sort | Philipp Mews |
| collection | DOAJ |
| description | Abstract Cocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven in part by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated nucleus sorting coupled with single-nucleus RNA sequencing to analyze D1 and D2 medium spiny neurons in this brain region of male mice subjected to acute cocaine exposure or to prolonged withdrawal from repeated cocaine exposure without or with an acute cocaine rechallenge. This approach allowed us to precisely delineate and contrast transcriptionally distinct neuronal subpopulations─or ensembles─across various treatment conditions. We identified significant heterogeneity within both D1 and D2 MSNs, revealing distinct clusters with unique transcriptional profiles. Notably, we identified a discrete D1 MSN population characterized by the upregulation of immediate early genes, as well as another group of D1 MSNs linked to prolonged withdrawal, uncovering novel regulators of withdrawal-related transcriptome dynamics. Our findings provide a high-resolution transcriptomic map of D1 and D2 MSNs, illustrating the dynamic changes induced by cocaine exposure and withdrawal. These insights into the molecular mechanisms underlying cocaine use disorder highlight potential targets for therapeutic intervention aimed at preventing relapse. |
| format | Article |
| id | doaj-art-c6cbb96bb7c242ca97b680555ddecdc1 |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-c6cbb96bb7c242ca97b680555ddecdc12025-08-20T03:21:06ZengNature PortfolioCommunications Biology2399-36422025-06-018111410.1038/s42003-025-08327-xCocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbensPhilipp Mews0Autumn VA Mason1Emily G. Kirchner2Molly Estill3Eric J. Nestler4Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Pharmacology, Physiology, and Biophysics, Boston University Chobanian & Avedisian School of MedicineNash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiAbstract Cocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven in part by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated nucleus sorting coupled with single-nucleus RNA sequencing to analyze D1 and D2 medium spiny neurons in this brain region of male mice subjected to acute cocaine exposure or to prolonged withdrawal from repeated cocaine exposure without or with an acute cocaine rechallenge. This approach allowed us to precisely delineate and contrast transcriptionally distinct neuronal subpopulations─or ensembles─across various treatment conditions. We identified significant heterogeneity within both D1 and D2 MSNs, revealing distinct clusters with unique transcriptional profiles. Notably, we identified a discrete D1 MSN population characterized by the upregulation of immediate early genes, as well as another group of D1 MSNs linked to prolonged withdrawal, uncovering novel regulators of withdrawal-related transcriptome dynamics. Our findings provide a high-resolution transcriptomic map of D1 and D2 MSNs, illustrating the dynamic changes induced by cocaine exposure and withdrawal. These insights into the molecular mechanisms underlying cocaine use disorder highlight potential targets for therapeutic intervention aimed at preventing relapse.https://doi.org/10.1038/s42003-025-08327-x |
| spellingShingle | Philipp Mews Autumn VA Mason Emily G. Kirchner Molly Estill Eric J. Nestler Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens Communications Biology |
| title | Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens |
| title_full | Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens |
| title_fullStr | Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens |
| title_full_unstemmed | Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens |
| title_short | Cocaine-induced gene regulation in D1 and D2 neuronal ensembles of the nucleus accumbens |
| title_sort | cocaine induced gene regulation in d1 and d2 neuronal ensembles of the nucleus accumbens |
| url | https://doi.org/10.1038/s42003-025-08327-x |
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