Abstract
Molecular adaptations underlying drug seeking and relapse remain largely unknown. Studies highlight post-transcriptional modifications mediated by microRNAs (miRNAs) in addiction and other neurological disorders. We have previously shown that chronic cocaine suppresses miR-124 and let-7d and induces the expression of miR-181a in mesolimbic pathway. To further address the role and target gene regulation network of these miRNAs in vivo in cocaine addiction, we developed lentiviral vector (LV)-expressing miRNAs and their corresponding silencers for stable and regulatable miRNA expression. We tested in vivo miRNA gain and loss of function on cocaine-induced conditioned place preference (CPP) by localized LV-miRNA regulation in the nucleus accumbens (NAc). LV-miR-124 and let-7d expression in the NAc attenuates cocaine CPP, whereas LV-miR-181a enhances it. Silencing miRNAs by corresponding LV-miRNA silencers expressing perfect miRNA target sequences inversed this effect on cocaine CPP. Doxycycline treatment for switching off silencer expression abolished the observed behavioral changes. Behavioral changes mediated by LV-miRNA regulation resulted in dynamic alterations in transcription factors, receptors, and other effector genes involved in cocaine-induced plasticity. Our results describe a complex regulatory pathway mediated by miRNAs in cocaine-mediated neuronal adaptations.
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References
Ambros V (2004). The functions of animal microRNAs. Nature 431: 350–355.
Ameres SL, Horwich MD, Hung JH, Xu J, Ghildiyal M, Weng Z et al (2010). Target RNA-directed trimming and tailing of small silencing RNAs. Science 328: 1534–1539.
Artinian J, De Jaeger X, Fellini L, de Saint Blanquat P, Roullet P (2007). Reactivation with a simple exposure to the experimental environment is sufficient to induce reconsolidation requiring protein synthesis in the hippocampal CA3 region in mice. Hippocampus 17: 181–191.
Arvanitis DN, Jungas T, Behar A, Davy A (2010). Ephrin-B1 reverse signaling controls a posttranscriptional feedback mechanism via miR-124. Mol Cell Biol 30: 2508–2517.
Ashraf SI, McLoon AL, Sclarsic SM, Kunes S (2006). Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 124: 191–205.
Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP (2008). The impact of microRNAs on protein output. Nature 455: 64–71.
Bahi A, Boyer F, Chandrasekar V, Dreyer JL (2008a). Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats. Psychopharmacology 199: 169–182.
Bahi A, Kusnecov AW, Dreyer JL (2008b). Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference. Behav Brain Res 191: 17–25.
Barco A, Alarcon JM, Kandel ER (2002). Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108: 689–703.
Bartel DP (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.
Bartel DP (2009). MicroRNAs: target recognition and regulatory functions. Cell 136: 215–233.
Bernardi RE, Lattal KM, Berger SP (2007). Anisomycin disrupts a contextual memory following reactivation in a cocaine-induced locomotor activity paradigm. Behav Neurosci 121: 156–163.
Betel D, Wilson M, Gabow A, Marks DS, Sander C (2008). The microRNA.org resource: targets and expression. Nucleic Acids Res 36: D149–D153.
Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W (2006). Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125: 1111–1124.
Blencowe BJ (2006). Alternative splicing: new insights from global analyses. Cell 126: 37–47.
Boyer F, Dreyer JL (2007). Alpha-synuclein in the nucleus accumbens induces changes in cocaine behaviour in rats. Eur J Neurosci 26: 2764–2776.
Care A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P et al (2007). MicroRNA-133 controls cardiac hypertrophy. Nat Med 13: 613–618.
Carlezon Jr WA, Duman RS, Nestler EJ (2005). The many faces of CREB. Trends Neurosci 28: 436–445.
Caygill EE, Johnston LA (2008). Temporal regulation of metamorphic processes in Drosophila by the let-7 and miR-125 heterochronic microRNAs. Curr Biol 18: 943–950.
Cazalla D, Yario T, Steitz J (2010). Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science; 328: 1563–1566.
Chandrasekar V, Dreyer JL (2009). microRNAs miR-124, let-7d and miR-181a regulate cocaine-induced plasticity. Mol Cell Neurosci 42: 350–362.
Chandrasekar V, Dreyer JL (2010a). The brain-specific neural zinc finger transcription factor 2b (NZF-2b/7ZFMyt1) causes suppression of cocaine-induced locomotor activity. Neurobiol Dis 37: 86–98.
Chandrasekar V, Dreyer JL (2010b). The brain-specific neural zinc finger transcription factor 2b (NZF-2b/7ZFMyt1) suppresses cocaine self-administration in rats. Front Behav Neurosci 4: 14–22.
Chang S, Wen S, Chen D, Jin P (2009). Small regulatory RNAs in neurodevelopmental disorders. Hum Mol Genet 18 (Suppl R1): R18–R26.
Conaco C, Otto S, Han JJ, Mandel G (2006). Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci USA 103: 2422–2427.
De Wit H, Stewart J (1981). Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl) 75: 134–143.
Ebert MS, Neilson JR, Sharp PA (2007). MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4: 721–726.
Esslinger S, Förstemann K (2009). MicroRNAs repress mainly through mRNA decay. Angew Chem Int Ed Engl 48: 853–855.
Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP et al (2005). The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310: 1817–1821.
Filipowicz W, Bhattacharyya SN, Sonenberg N (2008). Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9: 102–114.
Gentner B, Schira G, Giustacchini A, Amendola M, Brown BD, Ponzoni M et al (2009). Stable knockdown of microRNA in vivo by lentiviral vectors. Nat Methods 6: 63–66.
Grabowski PJ, Black DL (2001). Alternative RNA splicing in the nervous system. Prog Neurobiol 65: 289–308.
Haley B, Zamore PD (2004). Kinetic analysis of the RNAi enzyme complex. Nat Struct Mol Biol 11: 599–606.
Hellemans KG, Everitt BJ, Lee JL (2006). Disrupting reconsolidation of conditioned withdrawal memories in the basolateral amygdala reduces suppression of heroin seeking in rats. J Neurosci 26: 12694–12699.
Hollander JA, Im H, Amelio AL, Kocerha J, Bali P, Lu Q et al (2010). Striatal microRNA controls cocaine intake through CREB signaling. Nature 466: 197–202.
Huang W, Li MD (2008). Nicotine modulates expression of miR-140*, which targets the 3′-untranslated region of dynamin 1 gene (Dnm1). Int J Neuropsychopharmacol 10: 1–10.
Hutvagner G, Zamore PD (2002). A microRNA in a multiple-turnover RNAi enzyme complex. Science 297: 2056–2060.
Hyman SE (2005). Addiction: a disease of learning and memory. Am J Psychiatry 162: 1414–1422.
Hyman SE, Malenka RC (2001). Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2: 695–703.
Im HI, Hollander JA, Bali P, Kenny PJ (2010). MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat Neurosci 13: 1120–1127.
Itzhak Y, Martin JL (2002). Cocaine-induced conditioned place preference in mice: induction, extinction and reinstatement by related psychostimulants. Neuropsychopharmacology 26: 130–134.
Johnston RJ, Hobert O (2003). A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426: 845–849.
Kalivas PW, O’Brien C (2008). Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33: 166–180.
Kosik KS (2006). The neuronal microRNA system. Nat Rev Neurosci 7: 911–920.
Lee JL, Di Ciano P, Thomas KL, Everitt BJ (2005). Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior. Neuron 47: 795–801.
Lee JL, Milton AL, Everitt BJ (2006). Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation. J Neurosci 26: 5881–5887.
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al (2005). Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769–773.
Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ et al (2004). Argonaute2 is the catalytic engine of mammalian RNAi. Science 305: 1437–1441.
Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007). The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27: 435–448.
McClung CA, Nestler EJ (2008). Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33: 3–17.
Mueller D, Stewart J (2000). Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction. Behav Brain Res 115: 39–47.
Mumberg D, Lucibello FC, Schuermann M, Müller R (1991). Alternative splicing of fosB transcripts results in differentially expressed mRNAs encoding functionally antagonistic proteins. Genes Dev 5: 1212–1223.
Nestler EJ (2008). Review. Transcriptional mechanisms of addiction: role of DeltaFosB. Philos Trans R Soc Lond Ser B 363: 3245–3255.
Paxinos, Watson (1998). The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press: San Diego, CA.
Pietrzykowski AZ, Friesen RM, Martin GE, Puig SI, Nowak CL, Wynne PM et al (2008). Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 59: 274–287.
Rajasethupathy P, Fiumara F, Sheridan R, Betel D, Puthanveettil SV, Russo JJ et al (2009). Characterization of small RNAs in aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 63: 803–817.
Rogers JL, See RE (2007). Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats. Neurobiol Learn Mem 87: 688–692.
Rybak A, Fuchs H, Smirnova L, Brandt C, Pohl EE, Nitsch R et al (2008). A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol 10: 987–993.
Schaefer A, Im HI, Venø MT, Fowler CD, Min A, Intrator A et al (2010). Argonaute 2 in dopamine 2 receptor-expressing neurons regulates cocaine addiction. J Exp Med 207: 1843–1851.
Scherr M, Venturini L, Battmer K, Schaller-Schoenitz M, Schaefer D, Dallmann I et al (2007). Lentivirus-mediated antagomir expression for specific inhibition of miRNA function. Nucleic Acids Res 35: e149.
Schratt G (2009). Fine-tuning neural gene expression with microRNAs. Curr Opin Neurobiol 19: 213–219.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M et al (2006). A brain-specific microRNA regulates dendritic spine development. Nature 439: 283–289.
Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N (2008). Widespread changes in protein synthesis induced by microRNAs. Nature 455: 58–63.
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003). The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168: 3–20.
Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M et al (2009). A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 11: 705–716.
Vasudevan S, Tong Y, Steitz JA (2007). Switching from repression to activation: microRNAs can up-regulate translation. Science 318: 1931–1934.
Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007). The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev 21: 744–749.
Wu J, Xie X (2006). Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol 7: R85.
Yu JY, Chung KH, Deo M, Thompson RC, Turner DL (2008). MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation. Exp Cell Res 314: 2618–2633.
Acknowledgements
We are grateful to Mrs C Deforel-Poncet for skilful assistance. This study was supported by Swiss National Foundation Grants 3100-059350, 3100AO-100686, and 31003A-116492 (JLD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Chandrasekar, V., Dreyer, JL. Regulation of MiR-124, Let-7d, and MiR-181a in the Accumbens Affects the Expression, Extinction, and Reinstatement of Cocaine-Induced Conditioned Place Preference. Neuropsychopharmacol 36, 1149–1164 (2011). https://doi.org/10.1038/npp.2010.250
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DOI: https://doi.org/10.1038/npp.2010.250
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