MicroRNA-132 in the Adult Dentate Gyrus is Involved in Opioid Addiction Via Modifying the Differentiation of Neural Stem Cells

  • Meng Jia
  • Xuewei Wang
  • Haolin Zhang
  • Can Ye
  • Hui Ma
  • Mingda Yang
  • Yijing Li
  • Cailian CuiEmail author
Original Article


MicroRNA-132 (miR-132), a small RNA that regulates gene expression, is known to promote neurogenesis in the embryonic nervous system and adult brain. Although exposure to psychoactive substances can increase miR-132 expression in cultured neural stem cells (NSCs) and the adult brain of rodents, little is known about its role in opioid addiction. So, we set out to determine the effect of miR-132 on differentiation of the NSCs and whether this effect is involved in opioid addiction using the rat morphine self-administration (MSA) model. We found that miR-132 overexpression enhanced the differentiation of NSCs in vivo and in vitro. Similarly, specific overexpression of miR-132 in NSCs of the adult hippocampal dentate gyrus (DG) during the acquisition stage of MSA potentiated morphine-seeking behavior. These findings indicate that miR-132 is involved in opioid addiction, probably by promoting the differentiation of NSCs in the adult DG.


miR-132 Opioid addiction Neural stem cell Dentate gyrus 



This work was supported by grants from the National Natural Science Foundation (81471353 and 81771433), the National Basic Research Development Program of China (2015CB553500), and the Science Fund for Creative Research Groups from the National Natural Science Foundation of China (81521063).

Conflict of interest

The authors declare no competing interests.


  1. 1.
    Pandey A, Singh P, Jauhari A, Singh T, Khan F, Pant AB, et al. Critical role of the miR-200 family in regulating differentiation and proliferation of neurons. J Neurochem 2015, 133: 640–652.CrossRefGoogle Scholar
  2. 2.
    Sim SE, Bakes J, Kaang BK. Neuronal activity-dependent regulation of microRNAs. Mol Cell 2014, 37: 511–517.CrossRefGoogle Scholar
  3. 3.
    Ashraf SI, Mcloon AL, Sclarsic SM, Kunes S. Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 2006, 124: 191–205.CrossRefGoogle Scholar
  4. 4.
    Wei CW, Luo T, Zou SS, Wu AS. Research progress on the roles of microRNAs in governing synaptic plasticity, learning and memory. Life Sci 2017, 188: 118–122.CrossRefGoogle Scholar
  5. 5.
    Nadim WD, Simion V, Benedetti H, Pichon C, Baril P, Morissetlopez S. MicroRNAs in neurocognitive dysfunctions: new molecular targets for pharmacological treatments? Curr Neuropharmacol 2017, 15: 260–275.CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Zhang T, Zhao X, Steer CJ, Yan G, Song G. A negative feedback loop between microRNA-378 and Nrf1 promotes the development of hepatosteatosis in mice treated with a high fat diet. Metabolism 2018, 85: 183–191.CrossRefGoogle Scholar
  7. 7.
    Mathew RS, Tatarakis A, Rudenko A, Johnsonvenkatesh EM, Yang YJ, Murphy EA, et al. A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory. eLife 2016, 5. pii: e22467.Google Scholar
  8. 8.
    Scott HL, Tamagnini F, Narduzzo KE, Howarth JL, Lee YB, Wong LF, et al. MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex. Eur J Neurosci 2012, 36: 2941–2948.CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Aten S, Hansen KF, Hoyt KR, Obrietan K. The miR-132/212 locus: a complex regulator of neuronal plasticity, gene expression and cognition. RNA Dis 2016, 3. pii: e1375.Google Scholar
  10. 10.
    Hansen KF, Sakamoto K, Wayman GA, Impey S, Obrietan K. Transgenic miR132 alters neuronal spine density and impairs novel object recognition memory. PLoS One 2010, 5: e15497.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Nudelman AS, Dirocco DP, Lambert TJ, Garelick MG, Le J, Nathanson NM, et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus 2010, 20: 492–498.PubMedCentralGoogle Scholar
  12. 12.
    Yoshimura A, Numakawa T, Odaka H, Adachi N, Tamai Y, Kunugi H. Negative regulation of microRNA-132 in expression of synaptic proteins in neuronal differentiation of embryonic neural stem cells. Neurochem Int 2016, 97: 26–33.CrossRefGoogle Scholar
  13. 13.
    Hancock ML, Preitner N, Quan J, Flanagan JG. MicroRNA-132 is enriched in developing axons, locally regulates Rasa1 mRNA, and promotes axon extension. J Neurosci 2014, 34: 66–78.CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Pathania M, Torres-Reveron J, Yan L, Kimura T, Lin TV, Gordon V, et al. miR-132 enhances dendritic morphogenesis, spine density, synaptic integration, and survival of newborn olfactory bulb neurons. PLoS One 2012, 7: e38174.CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Magill ST, Cambronne XA, Luikart BW, Lioy DT, Leighton BH, Westbrook GL, et al. microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc Natl Acad Sci U S A 2010, 107: 20382–20387.CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 2011, 70: 687–702.CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Gould E. How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 2007, 8: 481–488.CrossRefGoogle Scholar
  18. 18.
    Luikart BW, Perederiy JV, Westbrook GL. Dentate gyrus neurogenesis, integration and microRNAs. Behav Brain Res 2012, 227: 348–355.CrossRefGoogle Scholar
  19. 19.
    Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 2006, 442: 929–933.CrossRefGoogle Scholar
  20. 20.
    Nestler EJ, Hope BT, Widnell KL. Drug addiction: a model for the molecular basis of neural plasticity. Neuron 1993, 11: 995–1006.CrossRefGoogle Scholar
  21. 21.
    Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001, 2: 119–128.CrossRefGoogle Scholar
  22. 22.
    Yan B, Hu Z, Yao W, Le Q, Bo X, Xing L, et al. MiR-218 targets MeCP2 and inhibits heroin seeking behavior. Sci Rep 2017, 7: 40413.CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Jimenezgonzalez A, Garcíaconcejo A, Lópezbenito S, Gonzaleznunez V, Arévalo JC, Rodriguez RE. Role of morphine, miR-212/132 and mu opioid receptor in the regulation of bdnf in zebrafish embryos. Biochim Biophys Acta 2016, 1860: 1308–1316.CrossRefGoogle Scholar
  24. 24.
    Walker TL, Kempermann G. One mouse, two cultures: isolation and culture of adult neural stem cells from the two neurogenic zones of individual mice. J Vis Exp 2014, 84: e51225.Google Scholar
  25. 25.
    Miller EC, Zhang L, Dummer BW, Cariveau DR, Loh H, Law PY, et al. Differential modulation of drug-induced structural and functional plasticity of dendritic spines. Mol Pharmacol 2012, 82: 333.CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Sholl DA. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 1953, 87: 387–406.PubMedCentralGoogle Scholar
  27. 27.
    Sidiropoulou E, Sachana M, Flaskos J, Harris W, Hargreaves AJ, Woldehiwet Z. Fipronil interferes with the differentiation of mouse N2a neuroblastoma cells. Toxicol Lett 2011, 201: 86–91.CrossRefGoogle Scholar
  28. 28.
    Tremblay RG, Sikorska M, Sandhu JK, Lanthier P, Ribecco-Lutkiewicz M, Bani-Yaghoub M. Differentiation of mouse Neuro 2A cells into dopamine neurons. J Neurosci Methods 2010, 186: 60–67.CrossRefGoogle Scholar
  29. 29.
    Wu G, Fang Y, Lu ZH, Ledeen RW. Induction of axon-like and dendrite-like processes in neuroblastoma cells. J Neurocytol 1998, 27: 1–14.CrossRefGoogle Scholar
  30. 30.
    Dickey CA, De Mesquita DD, Morgan D, Pennypacker KR. Induction of memory-associated immediate early genes by nerve growth factor in rat primary cortical neurons and differentiated mouse Neuro2A cells. Neurosci Lett 2004, 366: 10–14.CrossRefGoogle Scholar
  31. 31.
    Saragoni L, Hernández P, Maccioni RB. Differential association of tau with subsets of microtubules containing posttranslationally-modified tubulin variants in neuroblastoma cells. Neurochem Res 2000, 25: 59–70.CrossRefGoogle Scholar
  32. 32.
    Pastrana E, Cheng LC, Doetsch F. Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proc Natl Acad Sci U S A 2009, 106: 6387–6392.CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Yue Z, Loh HH, Ping-Yee L. Effect of opioid on adult hippocampal neurogenesis. ScientificWorldJournal 2016, 2016: 2601264.Google Scholar
  34. 34.
    Kang E, Wen Z, Song H, Christian KM, Ming GL. Adult neurogenesis and psychiatric disorders. Cold Spring Harb Perspect Biol 2016, 8: a019026.CrossRefPubMedCentralGoogle Scholar
  35. 35.
    Impey S, Davare M, Lesiak A, Lasiek A, Fortin D, Ando H, et al. An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAK signaling. Mol Cell Neurosci 2010, 43: 146–156.CrossRefGoogle Scholar
  36. 36.
    Luikart BW, Bensen ASL, Washburn EK, Perederiy JV, Su KG, Li Y, et al. miR-132 mediates the integration of newborn neurons into the adult dentate gyrus. PLoS One 2011, 6: e19077.CrossRefPubMedCentralGoogle Scholar
  37. 37.
    Lambert TJ, Storm DR, Sullivan JM. MicroRNA132 modulates short-term synaptic plasticity but not basal release probability in hippocampal neurons. PLoS One 2016, 5: e15182.CrossRefGoogle Scholar
  38. 38.
    Gonçalves JT, Schafer ST, Gage FH. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 2016, 167: 897–914.CrossRefGoogle Scholar
  39. 39.
    Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci U S A 2006, 103: 17501–17506.CrossRefPubMedCentralGoogle Scholar
  40. 40.
    Hansen KF, Karelina K, Sakamoto K, Wayman GA, Impey S, Obrietan K. miRNA-132: a dynamic regulator of cognitive capacity. Brain Struct Funct 2013, 218: 817–831.CrossRefGoogle Scholar
  41. 41.
    Bossert JM, Gray SM, Lu L, Shaham Y. Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Neuropsychopharmacology 2006, 31: 2197–2209.Google Scholar
  42. 42.
    Yokel RA. Intravenous self-administration: response rates, the effects of pharmacological challenges, and drug preference. In: Bozarth MA (Ed.). Methods of Assessing the Reinforcing Properties of Abused Drugs. New York: Springer, 1987.Google Scholar
  43. 43.
    Shaham Y, Erb S, Stewart J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Rese Rev 2000, 33: 13–33.CrossRefGoogle Scholar
  44. 44.
    Bossert JM, Liu SY, Lu L, Shaham Y. A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. J Neurosci 2004, 24: 10726.CrossRefGoogle Scholar
  45. 45.
    Ge F, Wang N, Cui C, Li Y, Liu Y, Ma Y, et al. Glutamatergic projections from the entorhinal cortex to dorsal dentate gyrus mediate context-induced reinstatement of heroin seeking. Neuropsychopharmacology 2017, 42: 1860.Google Scholar
  46. 46.
    Wang N, Ge F, Cui C, Li Y, Sun X, Sun L, et al. Role of glutamatergic projections from the ventral CA1 to infralimbic cortex in context-induced reinstatement of heroin seeking. Neuropsychopharmacology 2018, 43: 1373–1384.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  • Meng Jia
    • 1
  • Xuewei Wang
    • 1
  • Haolin Zhang
    • 1
  • Can Ye
    • 1
  • Hui Ma
    • 1
  • Mingda Yang
    • 1
  • Yijing Li
    • 1
  • Cailian Cui
    • 1
    Email author
  1. 1.Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health and Family Planning Commission, Neuroscience Research InstitutePeking UniversityBeijingChina

Personalised recommendations