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
| Autor: | Amy S. Gardiner, Ryan M. Bastle, Colton Smith, Nathan S. Pentkowski, N. Galles, Janet L. Neisewander, Robert J. Oliver, Nora I. Perrone-Bizzozero, M. St. Peter, T. Chaudhury, Andrea M. Allan, Federico Bolognani |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male In silico media_common.quotation_subject Gene Expression Self Administration Pharmacology Nucleus accumbens Nucleus Accumbens Extinction Psychological Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience Cocaine-Related Disorders Mice 0302 clinical medicine Cocaine Gene expression microRNA CAMK2A Animals Humans Computer Simulation Molecular Biology 3' Untranslated Regions media_common Motivation Arc (protein) Neuronal Plasticity Three prime untranslated region Addiction Rats Behavior Addictive Mice Inbred C57BL Psychiatry and Mental health MicroRNAs 030104 developmental biology Gene Expression Regulation Conditioning Operant Original Article Psychology Reinforcement Psychology 030217 neurology & neurosurgery |
| Zdroj: | Molecular Psychiatry |
| ISSN: | 1476-5578 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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