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

Benoit Forget,Laura Domingo Rodriguez,Andry Andrianarivelo,Arthur Godino,Elena Martin Garcia,Jean-Antoine Girault,Peter Vanhoutte,Marie-Charlotte Allichon,Pierre Poirier,Vincent Kappes,Jocelyne Caboche,Rafael Maldonado,Mélanie Marias,Eric Senabre Marchan

doi:10.1038/s41380-021-01328-2

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.

Highlights

Drug addiction is a clinically devastating neuropsychiatric disorder thought to result from neural adaptations at the molecular, cellular, and circuit levels, following repeated drug exposure [1]
The Having established the inhibitory role of miR-1 on Fosb and Npas4 repeated exposure to cocaine did not significantly alter miRNA mRNA expression levels, we investigated the potential role of miR
We identified 9 potential interesting targets: Bdnf, Fosb, Npas4, Gria2, Grin2b, Gria3, Pi3k, Drd1 and Mef2c (Fig. 1d) and induced conditioned place preference We measured the effects of cell-type-specific overexpression studied expression levels of these mRNAs in the dorsal striatal (DS) and nucleus accumbens (NAc) after our of miR-1 on the rewarding properties of cocaine using the protocol of sustained cocaine administration

Summary

Introduction

Drug addiction is a clinically devastating neuropsychiatric disorder thought to result from neural adaptations at the molecular, cellular, and circuit levels, following repeated drug exposure [1]. While the NAc underlies the primary reinforcing effects of drugs of abuse such as cocaine, the emergence of compulsive cocaine-seeking habits, a hallmark of drug addiction, is associated with a shift to the dorsal striatal (DS) control over behavior [7, 8]. In the DS the D1-SPNs represent the “direct pathway”, which activation facilitates the initiation and execution of movement, while the activation of D2SPNs of the “indirect pathway” inhibit movement [9, 10]. Both pathways are necessary for action initiation [11].

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