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

R. M. Bastle, R. J. Oliver, A. S. Gardiner, N. S. Pentkowski, F. Bolognani, A. M. Allan, T. Chaudhury, M. St. Peter, N. Galles, C. Smith, Janet Neisewander, N. I. Perrone-Bizzozero

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.Molecular Psychiatry advance online publication, 3 January 2017; doi:10.1038/mp.2016.238.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 3 2017

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Nucleus Accumbens
Cocaine
Computer Simulation
Motivation
Down-Regulation
MicroRNAs
Substance-Related Disorders
Gene Expression
Small Untranslated RNA
Neuronal Plasticity
Self Administration
Knowledge Bases
Regulator Genes
Luciferases
Reward
Genes
Sequence Analysis
Psychiatry
Publications
Identification (Psychology)

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

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, R. M.; Oliver, R. J.; Gardiner, A. S.; Pentkowski, N. S.; Bolognani, F.; Allan, A. M.; Chaudhury, T.; St. Peter, M.; Galles, N.; Smith, C.; Neisewander, Janet; Perrone-Bizzozero, N. I.

In: Molecular Psychiatry, 03.01.2017.

Research output: Contribution to journalArticle

Bastle, R. M. ; Oliver, R. J. ; Gardiner, A. S. ; Pentkowski, N. S. ; Bolognani, F. ; Allan, A. M. ; Chaudhury, T. ; St. Peter, M. ; Galles, N. ; Smith, C. ; Neisewander, Janet ; Perrone-Bizzozero, N. I. / 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. In: Molecular Psychiatry. 2017.
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abstract = "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.Molecular Psychiatry advance online publication, 3 January 2017; doi:10.1038/mp.2016.238.",
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