Forget, BenoitMartín García, Elena, 1975-Godino, ArthurDomingo Rodriguez, Laura, 1992-Kappes, VincentPoirier, PierreAndrianarivelo, AndrySenabre, EricAllichon, Marie-CharlotteMarias, MélanieVanhoutte, PeterGirault, Jean-AntoineMaldonado, Rafael, 1961-Caboche, Jocelyne2021-12-152021-12-152022Forget B, Garcia EM, Godino A, Rodriguez LD, Kappes V, Poirier P, Andrianarivelo A, Marchan ES, Allichon MC, Marias M, Vanhoutte P, Girault JA, Maldonado R, Caboche J. Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons. Mol Psychiatry. 2022 Feb;27(2):918-28. DOI: 10.1038/s41380-021-01328-21359-4184http://hdl.handle.net/10230/49213The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations.application/pdfeng© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41380-021-01328-2Molecular biologyNeurosciencePhysiologyinfo:eu-repo/semantics/openAccess