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.
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- 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
- Bastle, Ryan (Author)
- Oliver, R. J. (Author)
- Gardiner, A. S. (Author)
- Pentkowski, Nathan (Author)
- Bolognani, F. (Author)
- Allan, A. M. (Author)
- Chaudhury, Trisha (Author)
- St. Peter, Madeleine (Author)
- Galles, N. (Author)
- Smith, Colton (Author)
- Neisewander, Janet (Author)
- Perrone-Bizzozero, N. I. (Author)
- College of Liberal Arts and Sciences (Contributor)
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Digital object identifier: 10.1038/mp.2016.238
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Identifier TypeInternational standard serial numberIdentifier Value1359-4184
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Identifier TypeInternational standard serial numberIdentifier Value1476-5578
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The 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.html
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Bastle, 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