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Viral-mediated overexpression of the Myelin Transcription Factor 1 (MyT1) in the dentate gyrus attenuates anxiety- and ethanol-related behaviors in rats

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Abstract

Rationale

Myelin Transcription Factor 1 (MyT1), a member of the Zinc Finger gene family, plays a fundamental role in the nervous system. Recent research has suggested that this transcription factor is associated with the pathophysiology of psychiatric disorders including addiction, schizophrenia, and depression. However, the role of MyT1 in anxiety- and ethanol-related behaviors is still unknown.

Objectives

We evaluated the effects of lentiviral-mediated overexpression of MyT1 in the dentate gyrus (DG) on anxiety- and ethanol-related behaviors in rats.

Methods

We used the elevated plus maze (EPM) and the open field (OF) tests to assess anxiety-like behavior and a two-bottle choice procedure to measure the effects of MyT1 on ethanol intake and preference.

Results

MyT1 overexpression produced anxiolytic-like effects in the EPM test and decreased the number of fecal boli in the OF test, without affecting locomotor activity in both behavioral tests. Next, we demonstrated that ethanol intake and preference were decreased in the MyT1-overexpressing rats with no effect on saccharin and quinine, used to assess taste discrimination, and no effect on ethanol clearance suggesting specific alterations in the rewarding effects of ethanol. Most importantly, ectopic MyT1 overexpression increased both MyT1 and BDNF mRNA levels in the DG. Using Pearson’s correlation, results showed a strong negative relationship between MyT1 mRNA and anxiety parameters and ethanol consumption and a positive correlation between MyT1 and BDNF mRNAs.

Conclusion

Taken together, MyT1 along with being a key component in anxiety may be a suitable candidate in the search of the molecular underpinnings of alcoholism.

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Abbreviations

BDNF:

Brain-derived neutrophic factor

BEC:

Blood ethanol concentration

DG:

Dentate gyrus

EPM:

Elevated plus maze

LV:

Lentiviral vectors

MyT1:

Myelin Transcription Factor 1

NZF-2b:

Neural Zinc Finger 2b

OF:

Open field

References

  • Amorim D, David-Pereira A, Pertovaara A, Almeida A, Pinto-Ribeiro F (2014) Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis. Behav Brain Res 265:12–21

    Article  CAS  PubMed  Google Scholar 

  • Anderson ML, Nokia MS, Govindaraju KP, Shors TJ (2012) Moderate drinking? Alcohol consumption significantly decreases neurogenesis in the adult hippocampus. Neuroscience 224:202–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aubrecht TG, Weil ZM, Nelson RJ (2014) Melatonin treatment during early life interacts with restraint to alter neuronal morphology and provoke depressive-like responses. Behav Brain Res 263:90–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bahi A (2013) Viral-mediated knockdown of mGluR7 in the nucleus accumbens mediates excessive alcohol drinking and increased ethanol-elicited conditioned place preference in rats. Neuropsychopharmacology 38:2109–2119

    Article  CAS  PubMed  Google Scholar 

  • Bahi A (2016) Sustained lentiviral-mediated overexpression of microRNA124a in the dentate gyrus exacerbates anxiety- and autism-like behaviors associated with neonatal isolation in rats. Behav Brain Res 311:298–308

    Article  CAS  PubMed  Google Scholar 

  • Bahi A, Dreyer JL (2013) Striatal modulation of BDNF expression using microRNA124a-expressing lentiviral vectors impairs ethanol-induced conditioned-place preference and voluntary alcohol consumption. Eur J Neurosci 38:2328–2337

    Article  PubMed  Google Scholar 

  • Bahi A, Boyer F, Chandrasekar V, Dreyer JL (2008) Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats. Psychopharmacology 199:169–182

    Article  CAS  PubMed  Google Scholar 

  • Bahi A, Al Mansouri S, Al Maamari E (2016) Nucleus accumbens lentiviral-mediated gain of function of the oxytocin receptor regulates anxiety- and ethanol-related behaviors in adult mice. Physiol Behav 164:249–258

    Article  CAS  PubMed  Google Scholar 

  • Berman AK, Lott RB, Donaldson ST (2014) Periodic maternal deprivation may modulate offspring anxiety-like behavior through mechanisms involving neuroplasticity in the amygdala. Brain Res Bull 101:7–11

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, Hempstead BL, Lee FS (2006) Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314:140–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A 98:12796–12801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Darcq E, Warnault V, Phamluong K, Besserer GM, Liu F, Ron D (2015) MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption. Mol Psychiatry 20:1219–1231

    Article  CAS  PubMed  Google Scholar 

  • Deltheil T, Tanaka K, Reperant C, Hen R, David DJ, Gardier AM (2009) Synergistic neurochemical and behavioural effects of acute intrahippocampal injection of brain-derived neurotrophic factor and antidepressants in adult mice. Int J Neuropsychopharmacol 12:905–915

    Article  CAS  PubMed  Google Scholar 

  • Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, Mohler H, Luscher B (2007) GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci 27:3845–3854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eom KS, Cheong JS, Lee SJ (2016) Structural analyses of zinc finger domains for specific interactions with DNA. J Microbiol Biotechnol 26:2019–2029

  • Fajemiroye JO, Galdino PM, Florentino IF, Da Rocha FF, Ghedini PC, Polepally PR, Zjawiony JK, Costa EA (2014) Plurality of anxiety and depression alteration mechanism by oleanolic acid. J Psychopharmacol 28:923–934

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Enright F, Andrews JL, Newell KA, Pantelis C, Huang XF (2014) Novel implications of lingo-1 and its signaling partners in schizophrenia. Transl Psychiatry 4:e348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fulk LJ, Stock HS, Lynn A, Marshall J, Wilson MA, Hand GA (2004) Chronic physical exercise reduces anxiety-like behavior in rats. Int J Sports Med 25:78–82

    Article  CAS  PubMed  Google Scholar 

  • Gamsjaeger R, O’Connell MR, Cubeddu L, Shepherd NE, Lowry JA, Kwan AH, Vandevenne M, Swanton MK, Matthews JM, Mackay JP (2013) A structural analysis of DNA binding by myelin transcription factor 1 double zinc fingers. J Biol Chem 288:35180–35191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghisleni G, Kazlauckas V, Both FL, Pagnussat N, Mioranzza S, Rocha JB, Souza DO, Porciuncula LO (2008) Diphenyl diselenide exerts anxiolytic-like effect in Wistar rats: putative roles of GABAA and 5HT receptors. Prog Neuro-Psychopharmacol Biol Psychiatry 32:1508–1515

    Article  CAS  Google Scholar 

  • Gould E, Tanapat P, Rydel T, Hastings N (2000) Regulation of hippocampal neurogenesis in adulthood. Biol Psychiatry 48:715–720

    Article  CAS  PubMed  Google Scholar 

  • Govindarajan A, Rao BS, Nair D, Trinh M, Mawjee N, Tonegawa S, Chattarji S (2006) Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc Natl Acad Sci U S A 103:13208–13213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grant BF, Stinson FS, Dawson DA, Chou SP, Dufour MC, Compton W, Pickering RP, Kaplan K (2004) Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 61:807–816

    Article  PubMed  Google Scholar 

  • Hensler JG, Ladenheim EE, Lyons WE (2003) Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/−) mice. J Neurochem 85:1139–1147

    Article  CAS  PubMed  Google Scholar 

  • Hill MN, Gorzalka BB (2006) Increased sensitivity to restraint stress and novelty-induced emotionality following long-term, high dose cannabinoid exposure. Psychoneuroendocrinology 31:526–536

    Article  CAS  PubMed  Google Scholar 

  • Jeanblanc J, He DY, McGough NN, Logrip ML, Phamluong K, Janak PH, Ron D (2006) The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption. J Neurosci 26:1457–1464

    Article  CAS  PubMed  Google Scholar 

  • Jeanblanc J, He DY, Carnicella S, Kharazia V, Janak PH, Ron D (2009) Endogenous BDNF in the dorsolateral striatum gates alcohol drinking. J Neurosci 29:13494–13502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Y, Yu VC, Buchholz F, O’Connell S, Rhodes SJ, Candeloro C, Xia YR, Lusis AJ, Rosenfeld MG (1996) A novel family of Cys-Cys, His-Cys zinc finger transcription factors expressed in developing nervous system and pituitary gland. J Biol Chem 271:10723–10730

    Article  CAS  PubMed  Google Scholar 

  • Jindal A, Mahesh R, Bhatt S (2013) Etazolate rescues behavioral deficits in chronic unpredictable mild stress model: modulation of hypothalamic-pituitary-adrenal axis activity and brain-derived neurotrophic factor level. Neurochem Int 63:465–475

    Article  CAS  PubMed  Google Scholar 

  • Kampman KM, Pettinati H, Volpicelli J, Kaempf G, Turk E, Insua A, Lipkin C, Sparkman T, O’Brien CP (2002) Concurrent cocaine withdrawal alters alcohol withdrawal symptoms. J Addict Dis 21:13–26

    Article  PubMed  Google Scholar 

  • Karpyak VM, Biernacka JM, Geske JR, Abulseoud OA, Brunner MD, Chauhan M, Hall-Flavin DK, Lewis KA, Loukianova LL, Melnyk GJ, Onsrud DA, Proctor BD, Schneekloth TD, Skime MK, Wittkopp JE, Frye MA, Mrazek DA (2016) Gender-specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states. Addiction 111:1366–1375

    Article  PubMed  PubMed Central  Google Scholar 

  • Kendler KS, Davis CG, Kessler RC (1997) The familial aggregation of common psychiatric and substance use disorders in the National Comorbidity Survey: a family history study. Br J Psychiatry 170:541–548

    Article  CAS  PubMed  Google Scholar 

  • Kitahara Y, Ohta K, Hasuo H, Shuto T, Kuroiwa M, Sotogaku N, Togo A, Nakamura K, Nishi A (2016) Chronic fluoxetine induces the enlargement of perforant path-granule cell synapses in the mouse dentate gyrus. PLoS One 11:e0147307

    Article  PubMed  PubMed Central  Google Scholar 

  • Koponen E, Voikar V, Riekki R, Saarelainen T, Rauramaa T, Rauvala H, Taira T, Castren E (2004) Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of the trkB-PLCgamma pathway, reduced anxiety, and facilitated learning. Mol Cell Neurosci 26:166–181

    Article  CAS  PubMed  Google Scholar 

  • Lacaille H, Duterte-Boucher D, Liot D, Vaudry H, Naassila M, Vaudry D (2015) Comparison of the deleterious effects of binge drinking-like alcohol exposure in adolescent and adult mice. J Neurochem 132:629–641

    Article  CAS  PubMed  Google Scholar 

  • Laity JH, Lee BM, Wright PE (2001) Zinc finger proteins: new insights into structural and functional diversity. Curr Opin Struct Biol 11:39–46

    Article  CAS  PubMed  Google Scholar 

  • Leal-Galicia P, Saldivar-Gonzalez A, Morimoto S, Arias C (2007) Exposure to environmental enrichment elicits differential hippocampal cell proliferation: role of individual responsiveness to anxiety. Dev Neurobiol 67:395–405

    Article  CAS  PubMed  Google Scholar 

  • Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm DH (2016) Effects of systemic administration of ibuprofen on stress response in a rat model of post-traumatic stress disorder. Korean J Physiol Pharmacol 20:357–366

    Article  PubMed  PubMed Central  Google Scholar 

  • Li W, Wang X, Zhao J, Lin J, Song XQ, Yang Y, Jiang C, Xiao B, Yang G, Zhang HX, Lv LX (2012) Association study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population. Genes Brain Behav 11:87–93

    Article  PubMed  Google Scholar 

  • Lund TD, Rovis T, Chung WC, Handa RJ (2005) Novel actions of estrogen receptor-beta on anxiety-related behaviors. Endocrinology 146:797–807

    Article  CAS  PubMed  Google Scholar 

  • Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110

    CAS  PubMed  Google Scholar 

  • Matthews JM, Sunde M (2002) Zinc fingers—folds for many occasions. IUBMB Life 54:351–355

    Article  CAS  PubMed  Google Scholar 

  • McGough NN, He DY, Logrip ML, Jeanblanc J, Phamluong K, Luong K, Kharazia V, Janak PH, Ron D (2004) RACK1 and brain-derived neurotrophic factor: a homeostatic pathway that regulates alcohol addiction. J Neurosci 24:10542–10552

    Article  CAS  PubMed  Google Scholar 

  • Nielsen JA, Hudson LD, Armstrong RC (2002) Nuclear organization in differentiating oligodendrocytes. J Cell Sci 115:4071–4079

    Article  CAS  PubMed  Google Scholar 

  • Nielsen JA, Berndt JA, Hudson LD, Armstrong RC (2004) Myelin transcription factor 1 (Myt1) modulates the proliferation and differentiation of oligodendrocyte lineage cells. Mol Cell Neurosci 25:111–123

    Article  CAS  PubMed  Google Scholar 

  • Pandey SC, Zhang H, Roy A, Misra K (2006) Central and medial amygdaloid brain-derived neurotrophic factor signaling plays a critical role in alcohol-drinking and anxiety-like behaviors. J Neurosci 26:8320–8331

    Article  CAS  PubMed  Google Scholar 

  • Pandey SC, Zhang H, Ugale R, Prakash A, Xu T, Misra K (2008) Effector immediate-early gene arc in the amygdala plays a critical role in alcoholism. J Neurosci 28:2589–2600

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. San Diego Academic Press

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33

    Article  CAS  PubMed  Google Scholar 

  • Raivio N, Miettinen P, Kiianmaa K (2014) Innate BDNF expression is associated with ethanol intake in alcohol-preferring AA and alcohol-avoiding ANA rats. Brain Res 1579:74–83

    Article  CAS  PubMed  Google Scholar 

  • Schmidt HD, Duman RS (2010) Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 35:2378–2391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shang L, Xu TL, Li F, Su J, Li WG (2015) Temporal dynamics of anxiety phenotypes in a dental pulp injury model. Mol Pain 11:40

    PubMed  PubMed Central  Google Scholar 

  • Tapocik JD, Barbier E, Flanigan M, Solomon M, Pincus A, Pilling A, Sun H, Schank JR, King C, Heilig M (2014) microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking. J Neurosci 34:4581–4588

    Article  PubMed  PubMed Central  Google Scholar 

  • Trejo JL, Llorens-Martin MV, Torres-Aleman I (2008) The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci 37:402–411

    Article  CAS  PubMed  Google Scholar 

  • Wang T, Zeng Z, Li T, Liu J, Li J, Li Y, Zhao Q, Wei Z, Wang Y, Li B, Feng G, He L, Shi Y (2010) Common SNPs in myelin transcription factor 1-like (MYT1L): association with major depressive disorder in the Chinese Han population. PLoS One 5:e13662

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang B, Zheng Y, Shi H, Du X, Zhang Y, Wei B, Luo M, Wang H, Wu X, Hua X, Sun M, Xu X (2016) Zfp462 deficiency causes anxiety-like behaviors with excessive self-grooming in mice. Genes Brain Behav 16:296–307

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Acknowledgements

The authors would like to acknowledge Mrs. Christine Deforel-Poncet and Dr. Vijay Chandrasekar for their technical assistance with the lentiviral vector preparation. The authors are also grateful to Mr. Mohamed Shafiullah and Dr. Mahmoud Hag Ali from the Central Animal Facility for their advice on animal care and welfare.

Role of the funding source

AB was supported by grants from the United Arab Emirates University (No. NP/13/05) and the National Research foundation (No. 31M082). JLD received grants from the Swiss National Science Foundation 3100-059350 and 3100AO-100686 (JLD). The funders had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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Authors and Affiliations

  1. Department of Anatomy, Tawam Medical Campus, United Arab Emirates University, Al Ain, UAE

    Amine Bahi

  2. Division of Biochemistry, Department of Medicine, University of Fribourg, 1700, Fribourg, Switzerland

    Jean-Luc Dreyer

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  1. Amine Bahi
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Correspondence to Amine Bahi.

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The authors have no financial interests that might be perceived to influence the results or the discussion reported in this article.

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Bahi, A., Dreyer, JL. Viral-mediated overexpression of the Myelin Transcription Factor 1 (MyT1) in the dentate gyrus attenuates anxiety- and ethanol-related behaviors in rats. Psychopharmacology 234, 1829–1840 (2017). https://doi.org/10.1007/s00213-017-4588-7

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