Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons

Benoit Forget (1, 2, 3) , Elena Martin Garcia (4) , Arthur Godino (1, 2, 5) , Laura Domingo Rodriguez (4) , Vincent Kappes (1, 2) , Pierre Poirier (1, 2) , Andry Andrianarivelo (1, 2, 6, 7) , Eric Senabre Marchan (4) , Marie-Charlotte Allichon (1, 2) , Mélanie Marias (1, 2) , Peter Vanhoutte (1, 2) , Jean-Antoine Girault (8) , Rafael Maldonado (4) , Jocelyne Caboche (2, 1)

1 NPS - Neuroscience Paris Seine
2 IBPS - Institut de Biologie Paris Seine
3 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
4 UPF - Universitat Pompeu Fabra [Barcelona]
5 MSSM - Icahn School of Medicine at Mount Sinai [New York]
6 SPPIN - UMR 8003 - Saints-Pères Paris Institute for Neurosciences
7 LPC - UMR 8118 - Laboratoire de physiologie cérébrale
8 IFM - Inserm U1270 - SU - Institut du Fer à Moulin

Abstract The 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.

Domaines: Neurosciences [q-bio.NC]

Benoit Forget, Elena Martin Garcia, Arthur Godino, Laura Domingo Rodriguez, Vincent Kappes, et al.. Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons. Molecular Psychiatry, 2022, 27, pp.918-928. ⟨10.1038/s41380-021-01328-2⟩. ⟨hal-03432265v2⟩