Regulation of Brain DNA Methylation Factors and of the Orexinergic System by Cocaine and Food Self-Administration

  • Lamis Saad
  • Maxime Sartori
  • Sarah Pol Bodetto
  • Pascal Romieu
  • Andries Kalsbeek
  • Jean Zwiller
  • Patrick AnglardEmail author


Inhibitors of DNA methylation and orexin type-1 receptor antagonists modulate the neurobiological effects driving drugs of abuse and natural reinforcers by activating common brain structures of the mesolimbic reward system. In this study, we applied a self-administration paradigm to assess the involvement of factors regulating DNA methylation processes and satiety or appetite signals. These factors include Dnmts and Tets, miR-212/132, orexins, and orx-R1 genes. The study focused on dopamine projection areas such as the prefrontal cortex (PFCx) and caudate putamen (CPu) and in the hypothalamus (HP) that is interconnected with the reward system. Striking changes were observed in response to both reinforcers, but differed depending on contingent and non-contingent delivery. Expression also differed in the PFCx and the CPu. Cocaine and food induced opposite effects on Dnmt3a expression in both brain structures, whereas they repressed both miRs to a different extent, without affecting their primary transcript in the CPu. Unexpectedly, orexin mRNAs were found in the CPu, suggesting a transport from their transcription site in the HP. The orexin receptor1 gene was found to be induced by cocaine in the PFCx, consistent with a regulation by DNA methylation. Global levels of 5-methylcytosines in the PFCx were not significantly altered by cocaine, suggesting that it is rather their distribution that contributes to long-lasting behaviors. Together, our data demonstrate that DNA methylation regulating factors are differentially altered by cocaine and food. At the molecular level, they support the idea that neural circuits activated by both reinforcers do not completely overlap.


Cocaine and food self-administration Drugs of abuse DNA methylation Epigenetics Orexins/hypocretins Addiction 



This work was supported by the CNRS and the Université de Strasbourg, by the Neurotime Erasmus + Mundus program of the European Commission including a doctoral fellowship attributed to Lamis Saad. Sarah Pol Bodetto was a former recipient of a fellowship from the “Ministère de l’Enseignement Supérieur et de la Recherche.” We thank Dr. J. Mendoza for kindly providing orexin A specific antibody and Dr. Katia Befort for comments on the manuscript.

Compliance with Ethical Standards

All procedures involving animal care were conducted in compliance with national laws and policies (Council directive 87848, 1987, Service Vétérinaire de la Santé et de la Protection animale, permission 67-165 to J.Z. and 67-370 to P.R.), with the Ministère de l’Education Nationale de l’Enseignement Supérieur et de la Recherche (project permission number APAFIS#2133-20151 00221 087072 to P.A.) and international guidelines (NIH publication 5586-23, 1985).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1453_MOESM1_ESM.doc (432 kb)
Supplementary Figure S1 Dissected brain regions for mRNA analysis (DOC 432 kb)
12035_2018_1453_MOESM2_ESM.doc (287 kb)
Supplementary Figure S2 miR-212/132 gene cluster located on chromosome 10 (DOC 287 kb)
12035_2018_1453_MOESM3_ESM.doc (46 kb)
Supplementary Figure S3 Global 5mC in the PFCx of rats self-administering cocaine in genome wide DNA methylation analysis (DOC 46 kb)
12035_2018_1453_MOESM4_ESM.doc (1 mb)
Supplementary Figure S4 MeDIP analysis of global 5mC and of 5hmC DMRs in the Orx R1 and Dnmt3a genes in the PFCx (DOC 1036 kb)
12035_2018_1453_MOESM5_ESM.doc (88 kb)
ESM 1 Gene differentially methylated regions in the PFCx (DOC 88 kb)


  1. 1.
    Carelli RM, Ijames SG, Crumling AJ (2000) Evidence that separate neural circuits in the nucleus accumbens encode cocaine versus “natural” (water and food) reward. J Neurosci 20(11):4255–4266PubMedGoogle Scholar
  2. 2.
    Levy D, Shabat-Simon M, Shalev U, Barnea-Ygael N, Cooper A, Zangen A (2007) Repeated electrical stimulation of reward-related brain regions affects cocaine but not "natural" reinforcement. J Neurosci 27(51):14179–14189PubMedGoogle Scholar
  3. 3.
    Cameron CM, Carelli RM (2012) Cocaine abstinence alters nucleus accumbens firing dynamics during goal-directed behaviors for cocaine and sucrose. Eur J Neurosci 35(6):940–951PubMedPubMedCentralGoogle Scholar
  4. 4.
    Cameron CM, Wightman RM, Carelli RM (2014) Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards. Neuropharmacology 86:319–328. PubMedPubMedCentralGoogle Scholar
  5. 5.
    Lu H, Chefer S, Kurup PK, Guillem K, Vaupel DB, Ross TJ, Moore A, Yang Y et al (2012) fMRI response in the medial prefrontal cortex predicts cocaine but not sucrose self-administration history. Neuroimage 62(3):1857–1866PubMedGoogle Scholar
  6. 6.
    DiLeone RJ, Taylor JR, Picciotto MR (2012) The drive to eat: comparisons and distinctions between mechanisms of food reward and drug addiction. Nat Neurosci 15(10):1330–1335PubMedPubMedCentralGoogle Scholar
  7. 7.
    Romieu P, Host L, Gobaille S, Sandner G, Aunis D, Zwiller J (2008) Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats. J Neurosci 28(38):9342–9348PubMedGoogle Scholar
  8. 8.
    Tian W, Zhao M, Li M, Song T, Zhang M, Quan L, Li S, Sun ZS (2012) Reversal of cocaine-conditioned place preference through methyl supplementation in mice: altering global DNA methylation in the prefrontal cortex. PLoS One 7(3):e33435PubMedPubMedCentralGoogle Scholar
  9. 9.
    Wright KN, Hollis F, Duclot F, Dossat AM, Strong CE, Francis TC, Mercer R, Feng J et al (2015) Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner. J Neurosci 35(23):8948–8958PubMedPubMedCentralGoogle Scholar
  10. 10.
    Cadet JL, Bisagno V, Milroy CM (2014) Neuropathology of substance use disorders. Acta Neuropathol 127(1):91–107PubMedGoogle Scholar
  11. 11.
    Anglard P, Zwiller J (2017) Cocaine and epigenetics: an overview. Book chapter in the neuroscience of cocaine: mechanisms and treatment Elsevier Inc. Academic Press, pp 79–88Google Scholar
  12. 12.
    de Sa Nogueira D, Merienne K, Befort K (2018) Neuroepigenetics and addictive behaviors: where do we stand? Neurosci Biobehav RevGoogle Scholar
  13. 13.
    Cassel S, Carouge D, Gensburger C, Anglard P, Burgun C, Dietrich JB, Aunis D, Zwiller J (2006) Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain. Mol Pharmacol 70(2):487–492PubMedGoogle Scholar
  14. 14.
    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(9):1120–1127PubMedPubMedCentralGoogle Scholar
  15. 15.
    Anier K, Malinovskaja K, Aonurm-Helm A, Zharkovsky A, Kalda A (2010) DNA methylation regulates cocaine-induced behavioral sensitization in mice. Neuropsychopharmacology 35(12):2450–2461PubMedPubMedCentralGoogle Scholar
  16. 16.
    LaPlant Q, Vialou V, Covington HE 3rd, Dumitriu D, Feng J, Warren BL, Maze I, Dietz DM et al (2010) Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci 13(9):1137–1143PubMedPubMedCentralGoogle Scholar
  17. 17.
    Pol Bodetto S, Carouge D, Fonteneau M, Dietrich JB, Zwiller J, Anglard P (2013) Cocaine represses protein phosphatase-1Cbeta through DNA methylation and methyl-CpG binding protein-2 recruitment in adult rat brain. Neuropharmacology 73:31–40PubMedGoogle Scholar
  18. 18.
    Carouge D, Host L, Aunis D, Zwiller J, Anglard P (2010) CDKL5 is a brain MeCP2 target gene regulated by DNA methylation. Neurobiol Dis 38(3):414–424PubMedGoogle Scholar
  19. 19.
    Fragou D, Zanos P, Kouidou S, Njau S, Kitchen I, Bailey A, Kovatsi L (2013) Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver. Toxicol Lett 218(3):260–265PubMedGoogle Scholar
  20. 20.
    Fonteneau M, Filliol D, Anglard P, Befort K, Romieu P, Zwiller J (2017) Inhibition of DNA methyltransferases regulates cocaine self-administration by rats: a genome-wide DNA methylation study. Genes Brain Behav 16(3):313–327PubMedGoogle Scholar
  21. 21.
    Baker-Andresen D, Zhao Q, Li X, Jupp B, Chesworth R, Lawrence AJ, Bredy T (2015) Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice. Neuroepigenetics 4:1–11PubMedPubMedCentralGoogle Scholar
  22. 22.
    Ausio J (2016) MeCP2 and the enigmatic organization of brain chromatin. Implications for depression and cocaine addiction. Clin Epigenetics 8(58):58PubMedPubMedCentralGoogle Scholar
  23. 23.
    Vaillancourt K, Ernst C, Mash D, Turecki G (2017) DNA methylation dynamics and cocaine in the brain: progress and prospects. Genes (Basel) 8(5):1–19Google Scholar
  24. 24.
    Panlilio LV, Goldberg SR (2007) Self-administration of drugs in animals and humans as a model and an investigative tool. Addiction 102(12):1863–1870PubMedPubMedCentralGoogle Scholar
  25. 25.
    Remenyi J, Hunter CJ, Cole C, Ando H, Impey S, Monk CE, Martin KJ, Barton GJ et al (2010) Regulation of the miR-212/132 locus by MSK1 and CREB in response to neurotrophins. Biochem J 428(2):281–291PubMedGoogle Scholar
  26. 26.
    Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92(4):573–585PubMedGoogle Scholar
  27. 27.
    Zhang GC, Mao LM, Liu XY, Wang JQ (2007) Long-lasting up-regulation of orexin receptor type 2 protein levels in the rat nucleus accumbens after chronic cocaine administration. J Neurochem 103(1):400–407PubMedGoogle Scholar
  28. 28.
    Calipari ES, Espana RA (2012) Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms. Front Behav Neurosci 6:54PubMedPubMedCentralGoogle Scholar
  29. 29.
    Espana RA, Oleson EB, Locke JL, Brookshire BR, Roberts DC, Jones SR (2010) The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. Eur J Neurosci 31(2):336–348PubMedGoogle Scholar
  30. 30.
    Hollander JA, Pham D, Fowler CD, Kenny PJ (2012) Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence. Front Behav Neurosci 6:47PubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhou L, Ghee SM, Chan C, Lin L, Cameron MD, Kenny PJ, See RE (2012) Orexin-1 receptor mediation of cocaine seeking in male and female rats. J Pharmacol Exp Ther 340(3):801–809PubMedPubMedCentralGoogle Scholar
  32. 32.
    Boutrel B, Steiner N, Halfon O (2013) The hypocretins and the reward function: what have we learned so far? Front Behav Neurosci 7:59PubMedPubMedCentralGoogle Scholar
  33. 33.
    Levy KA, Brodnik ZD, Shaw JK, Perrey DA, Zhang Y, Espana RA (2017) Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling. Psychopharmacology 234(18):2761–2776PubMedPubMedCentralGoogle Scholar
  34. 34.
    Gentile TA, Simmons SJ, Barker DJ, Shaw JK, Espana RA, Muschamp JW (2017) Suvorexant, an orexin/hypocretin receptor antagonist, attenuates motivational and hedonic properties of cocaine. Addict Biol 23:247–255. PubMedPubMedCentralGoogle Scholar
  35. 35.
    James MH, Mahler SV, Moorman DE, Aston-Jones G (2017) A decade of orexin/hypocretin and addiction: where are we now? Curr Top Behav Neurosci 33:247–281PubMedPubMedCentralGoogle Scholar
  36. 36.
    Scammell TE, Winrow CJ (2012) Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51:243–266Google Scholar
  37. 37.
    Pol Bodetto S, Romieu P, Sartori M, Tesone-Coelho C, Majchrzak M, Barbelivien A, Zwiller J, Anglard P (2014) Differential regulation of MeCP2 and PP1 in passive or voluntary administration of cocaine or food. Int J Neuropsychopharmacol 17:1–14. Google Scholar
  38. 38.
    Luo D, Mari B, Stoll I, Anglard P (2002) Alternative splicing and promoter usage generates an intracellular stromelysin 3 isoform directly translated as an active matrix metalloproteinase. J Biol Chem 277(28):25527–25536PubMedGoogle Scholar
  39. 39.
    Stalnaker TA, Takahashi Y, Roesch MR, Schoenbaum G (2009) Neural substrates of cognitive inflexibility after chronic cocaine exposure. Neuropharmacology 56(Suppl 1):63–72PubMedGoogle Scholar
  40. 40.
    van Holst RJ, Schilt T (2011) Drug-related decrease in neuropsychological functions of abstinent drug users. Curr Drug Abuse Rev 4(1):42–56PubMedGoogle Scholar
  41. 41.
    Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047):1300–1303PubMedPubMedCentralGoogle Scholar
  42. 42.
    Rasmussen KD, Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30(7):733–750PubMedPubMedCentralGoogle Scholar
  43. 43.
    Jin C, Qin T, Barton MC, Jelinek J, Issa JP (2015) Minimal role of base excision repair in TET-induced global DNA demethylation in HEK293T cells. Epigenetics 10(11):1006–1013PubMedPubMedCentralGoogle Scholar
  44. 44.
    Wanet A, Tacheny A, Arnould T, Renard P (2012) miR-212/132 expression and functions: within and beyond the neuronal compartment. Nucleic Acids Res 40(11):4742–4753PubMedPubMedCentralGoogle Scholar
  45. 45.
    Bali P, Kenny PJ (2013) MicroRNAs and drug addiction. Front Genet 4(43). eCollection 2013
  46. 46.
    Feng J, Nestler EJ (2013) Epigenetic mechanisms of drug addiction. Curr Opin Neurobiol 23(4):521–528PubMedPubMedCentralGoogle Scholar
  47. 47.
    Hollander JA, Im HI, Amelio AL, Kocerha J, Bali P, Lu Q, Willoughby D, Wahlestedt C et al (2010) Striatal microRNA controls cocaine intake through CREB signalling. Nature 466(7303):197–202PubMedPubMedCentralGoogle Scholar
  48. 48.
    Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, Jayne M, Ma Y et al (2006) Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci 26(24):6583–6588PubMedGoogle Scholar
  49. 49.
    Haruno M, Kawato M (2006) Different neural correlates of reward expectation and reward expectation error in the putamen and caudate nucleus during stimulus-action-reward association learning. J Neurophysiol 95(2):948–959PubMedGoogle Scholar
  50. 50.
    Sadri-Vakili G (2015) Cocaine triggers epigenetic alterations in the corticostriatal circuit. Brain Res 1628(Pt A):50–59. PubMedGoogle Scholar
  51. 51.
    Espana RA (2012) Hypocretin/orexin involvement in reward and reinforcement. Vitam Horm 89:185–208PubMedPubMedCentralGoogle Scholar
  52. 52.
    Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17(10):1298–1303PubMedPubMedCentralGoogle Scholar
  53. 53.
    Alexandre C, Andermann ML, Scammell TE (2013) Control of arousal by the orexin neurons. Curr Opin Neurobiol 23(5):752–759PubMedPubMedCentralGoogle Scholar
  54. 54.
    Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18(23):9996–10015PubMedGoogle Scholar
  55. 55.
    Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514PubMedGoogle Scholar
  56. 56.
    Challen GA, Sun D, Mayle A, Jeong M, Luo M, Rodriguez B, Mallaney C, Celik H et al (2014) Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells. Cell Stem Cell 15(3):350–364PubMedPubMedCentralGoogle Scholar
  57. 57.
    Liao J, Karnik R, Gu H, Ziller MJ, Clement K, Tsankov AM, Akopian V, Gifford CA et al (2015) Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat Genet 47(5):469–478PubMedPubMedCentralGoogle Scholar
  58. 58.
    Han J, Li Y, Wang D, Wei C, Yang X, Sui N (2010) Effect of 5-aza-2-deoxycytidine microinjecting into hippocampus and prelimbic cortex on acquisition and retrieval of cocaine-induced place preference in C57BL/6 mice. Eur J Pharmacol 642(1–3):93–98PubMedGoogle Scholar
  59. 59.
    Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, McGill BE, Goulding EH et al (2008) Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59(6):947–958PubMedPubMedCentralGoogle Scholar
  60. 60.
    Kleefstra T, Yntema HG, Oudakker AR, Romein T, Sistermans E, Nillessen W, van Bokhoven H, de Vries BB et al (2002) De novo MECP2 frameshift mutation in a boy with moderate mental retardation, obesity and gynaecomastia. Clin Genet 61(5):359–362PubMedGoogle Scholar
  61. 61.
    Torres-Andrade R, Moldenhauer R, Gutierrez-Bertin N, Soto-Covasich J, Mancilla-Medina C, Ehrenfeld C, Kerr B (2014) The increase in body weight induced by lack of methyl CpG binding protein-2 is associated with altered leptin signalling in the hypothalamus. Exp Physiol 99(9):1229–1240PubMedGoogle Scholar
  62. 62.
    Plucinska K, Barger SW (2018) Maternal obesity reprograms offspring's executive brain centers in a sex-specific manner?: An editorial for “Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain” on page 362. J Neurochem 145(5):358–361PubMedGoogle Scholar
  63. 63.
    Kerek R, Geoffroy A, Bison A, Martin N, Akchiche N, Pourie G, Helle D, Gueant JL et al (2013) Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124. Cell Death Dis 4:e755PubMedPubMedCentralGoogle Scholar
  64. 64.
    Geoffroy A, Kerek R, Pourie G, Helle D, Gueant JL, Daval JL, Bossenmeyer-Pourie C (2016) Late maternal folate supplementation rescues from methyl donor deficiency-associated brain defects by restoring Let-7 and miR-34 pathways. Mol Neurobiol 54(7):5017–5033PubMedPubMedCentralGoogle Scholar
  65. 65.
    Cadet JL (2016) Epigenetics of stress, addiction, and resilience: therapeutic implications. Mol Neurobiol 53(1):545–560PubMedGoogle Scholar
  66. 66.
    Tan L, Shi YG (2012) Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139(11):1895–1902PubMedPubMedCentralGoogle Scholar
  67. 67.
    Feng J, Shao N, Szulwach KE, Vialou V, Huynh J, Zhong C, Le T, Ferguson D et al (2015) Role of Tet1 and 5-hydroxymethylcytosine in cocaine action. Nat Neurosci 18(4):536–544PubMedPubMedCentralGoogle Scholar
  68. 68.
    Massart R, Barnea R, Dikshtein Y, Suderman M, Meir O, Hallett M, Kennedy P, Nestler EJ et al (2015) Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving. J Neurosci 35(21):8042–8058. PubMedGoogle Scholar
  69. 69.
    Chen ZX, Riggs AD (2011) DNA methylation and demethylation in mammals. J Biol Chem 286(21):18347–18353PubMedPubMedCentralGoogle Scholar
  70. 70.
    Barrot M, Olivier JD, Perrotti LI, DiLeone RJ, Berton O, Eisch AJ, Impey S, Storm DR et al (2002) CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc Natl Acad Sci U S A 99(17):11435–11440PubMedPubMedCentralGoogle Scholar
  71. 71.
    Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH (2007) Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci 10(12):1513–1514PubMedGoogle Scholar
  72. 72.
    Hansen KF, Sakamoto K, Wayman GA, Impey S, Obrietan K (2010) Transgenic miR132 alters neuronal spine density and impairs novel object recognition memory. PLoS One 5(11):e15497PubMedPubMedCentralGoogle Scholar
  73. 73.
    Bijkerk R, Trimpert C, van Solingen C, de Bruin RG, Florijn BW, Kooijman S, van den Berg R, van der Veer EP et al (2018) MicroRNA-132 controls water homeostasis through regulating MECP2-mediated vasopressin synthesis. Am J Physiol Renal Physiol 315:F1129–F1138PubMedGoogle Scholar
  74. 74.
    Im HI, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35(5):325–334PubMedPubMedCentralGoogle Scholar
  75. 75.
    Gan L, Denecke B (2013) Profiling pre-microRNA and mature microRNA expressions using a single microarray and avoiding separate sample preparation. Microarrays (Basel) 2(1):24–33Google Scholar
  76. 76.
    Chandrasekar V, Dreyer JL (2009) microRNAs miR-124, let-7d and miR-181a regulate cocaine-induced plasticity. Mol Cell Neurosci 42(4):350–362PubMedGoogle Scholar
  77. 77.
    Slezak-Prochazka I, Durmus S, Kroesen BJ, van den Berg A (2010) MicroRNAs, macrocontrol: regulation of miRNA processing. RNA 16(6):1087–1095PubMedPubMedCentralGoogle Scholar
  78. 78.
    Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R et al (2005) Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci U S A 102(49):17551–17558PubMedPubMedCentralGoogle Scholar
  79. 79.
    Cheng TL, Wang Z, Liao Q, Zhu Y, Zhou WH, Xu W, Qiu Z (2014) MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev Cell 28(5):547–560PubMedGoogle Scholar
  80. 80.
    Bayerlein K, Kraus T, Leinonen I, Pilniok D, Rotter A, Hofner B, Schwitulla J, Sperling W et al (2011) Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal. Alcohol 45(6):541–547PubMedGoogle Scholar
  81. 81.
    Hayakawa K, Hirosawa M, Tabei Y, Arai D, Tanaka S, Murakami N, Yagi S, Shiota K (2013) Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. J Biol Chem 288(24):17099–17110PubMedPubMedCentralGoogle Scholar
  82. 82.
    Dehan P, Canon C, Trooskens G, Rehli M, Munaut C, Van Criekinge W, Delvenne P (2013) Expression of type 2 orexin receptor in human endometrium and its epigenetic silencing in endometrial cancer. J Clin Endocrinol Metab 98(4):1549–1557PubMedGoogle Scholar
  83. 83.
    Maday S, Twelvetrees AE, Moughamian AJ, Holzbaur EL (2014) Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron 84(2):292–309PubMedPubMedCentralGoogle Scholar
  84. 84.
    Sahoo PK, Smith DS, Perrone-Bizzozero N, Twiss JL (2018) Axonal mRNA transport and translation at a glance. J Cell Sci 131(8):jcs196808PubMedGoogle Scholar
  85. 85.
    Bramham CR, Wells DG (2007) Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 8(10):776–789. PubMedGoogle Scholar
  86. 86.
    Baldo BA, Daniel RA, Berridge CW, Kelley AE (2003) Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464(2):220–237PubMedGoogle Scholar
  87. 87.
    Marcus JN, Elmquist JK (2006) Orexin projections and localization of orexin receptor. In: Nishino S, Sakurai T (eds) The orexin/hypocretin system contemporary clinical neuroscience. Humana Press, Chapter 3, pp 21–44Google Scholar
  88. 88.
    Paxinos GWC (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, ElsevierGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR 7364 CNRS, Neuropôle de StrasbourgUniversité de StrasbourgStrasbourgFrance
  2. 2.The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW)AmsterdamThe Netherlands
  3. 3.IGBMC, Inserm U 964, CNRS UMR 7104University of StrasbourgIllkirchFrance
  4. 4.Department of Endocrinology and Metabolism, Amsterdam UMCUniversity of AmsterdamAmsterdamNetherlands
  5. 5.INSERM, Institut National de la Santé et de la Recherche MédicaleParisFrance

Personalised recommendations