In Silico Identification and in Vivo Validation of miR-495 as a Novel Regulator of Motivation for Cocaine That Targets Multiple Addiction-Related Networks in the Nucleus Accumbens MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression and are implicated in the etiology of several neuropsychiatric disorders, including substance use disorders (SUDs). Using in silico genome-wide sequence analyses, we identified miR-495 as a miRNA whose predicted targets are significantly enriched in the Knowledgebase for Addiction Related Genes (ARG) database (KARG; http://karg.cbi.pku.edu.cn). This small non-coding RNA is also highly expressed within the nucleus accumbens (NAc), a pivotal brain region underlying reward and motivation. Using luciferase reporter assays, we found that miR-495 directly targeted the 3′UTRs of Bdnf, Camk2a and Arc. Furthermore, we measured miR-495 expression in response to acute cocaine in mice and found that it is downregulated rapidly and selectively in the NAc, along with concomitant increases in ARG expression. Lentiviral-mediated miR-495 overexpression in the NAc shell (NAcsh) not only reversed these cocaine-induced effects but also downregulated multiple ARG mRNAs in specific SUD-related biological pathways, including those that regulate synaptic plasticity. miR-495 expression was also downregulated in the NAcsh of rats following cocaine self-administration. Most importantly, we found that NAcsh miR-495 overexpression suppressed the motivation to self-administer and seek cocaine across progressive ratio, extinction and reinstatement testing, but had no effect on food reinforcement, suggesting that miR-495 selectively affects addiction-related behaviors. Overall, our in silico search for post-transcriptional regulators identified miR-495 as a novel regulator of multiple ARGs that have a role in modulating motivation for cocaine.
]]>autBastle, RyanautOliver, R. J.autGardiner, A. S.autPentkowski, NathanautBolognani, F.autAllan, A. M.autChaudhury, TrishaautSt. Peter, MadeleineautGalles, N.autSmith, ColtonautNeisewander, JanetautPerrone-Bizzozero, N. I.ctbCollege of Liberal Arts and SciencesengThe final version of this article, as published in Molecular Psychiatry, can be viewed online at: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2016238a.htmlBastle, R. M., Oliver, R. J., Gardiner, A. S., Pentkowski, N. S., Bolognani, F., Allan, A. M., . . . Perrone-Bizzozero, N. I. (2017). In silico identification and in vivo validation of miR-495 as a novel regulator of motivation for cocaine that targets multiple addiction-related networks in the nucleus accumbens. Molecular Psychiatry. doi:10.1038/mp.2016.238
]]>10.1038/mp.2016.2381359-41841476-5578https://hdl.handle.net/2286/R.I.452950010 pages115036968941638559530128014mogborn1In CopyrightAttribution-NonCommercial-NoDerivs2017-01-13Text