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The Effect of Maternal Methyl-Enriched Diet on the Number of Dopaminergic Neurons in the Ventral Tegmental Area in Adult Offspring of WAG/Rij Rats

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Abstract

The WAG/Rij rats are a genetic model of absence epilepsy with comorbid depression. Pathological phenotype in WAG/Rij rats is associated with reduced dopamine (DA) tone in the mesolimbic DA system. Perinatal maternal methyl-enriched diet (MED) is known to increase DA levels in the mesolimbic DA system and reduce manifestations of absence seizures with comorbid depression in an adult offspring of WAG/Rij rats. The ventral tegmental area (VTA), which contains DAergic neurons and gives rise to the mesocortical and mesolimbic DAergic pathways, is the main source of mesolimbic DA synthesis. The aim of this study was to test the hypothesis that increases in mesolimbic DA tone, induced in offspring by a maternal MED, may be due to an increase in the number of thyrosine hydroxylase (TH)-synthesizing DAergic neurons in the VTA. Immunohistochemical staining for TH was used to assess the number of TH-immunopositive cells in the adult offspring of WAG/Rij rats born to mothers that were fed a control diet (CD) or MED and exposed or not exposed to behavioral testing for two consecutive days in the light–dark choice, open field, elevated plus maze, and forced swim tests. Animals were anesthetized 1 h after the forced swim test. Brains were fixed via transcardial perfusion. The number of DAergic neurons was determined by the number of TH-immunopositive cells in brain slices taken at the VTA level and counted in the left and right hemispheres separately. We found a significant effect of a maternal MED on the number of TH-expressing neurons in the VTA. Adult WAG/Rij offspring born to MED-fed mothers showed an increased number of TH-immunopositive cells compared to the offspring born to CD-fed mothers. Moreover, in the WAG/Rij offspring born to MED-fed mothers, the number of TH-immunopositive cells was greater in animals exposed vs. unexposed to behavioral testing. The effects of a maternal MED and behavioral testing on the number of TH-immunopositive cells in the VTA were equally pronounced in the left and right cerebral hemispheres. Our results suggest that maternal MED can affect the development of the mesolimbic DA system, contributing to the generation and/or preservation of DAergic neurons in the VTA and thus preventing the occurence of genetic absence epilepsy and comorbid depression in the offspring of WAG/Rij rats.

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REFERENCES

  1. Sarkisova KY, Kulikov MA (2000) A new experimental model of depression: WAG/Rij rats genetically predisposed to absence epilepsy. Dokl Biol Sci 374(5): 706–709 (In Russ).

    CAS  Google Scholar 

  2. Sarkisova KY, Midzyanovskaya IS, Kulikov MA (2003) Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy. Behav Brain Res 144: 211–226. https://doi.org/10.1016/s0166-4328(03)00090-1

    Article  CAS  PubMed  Google Scholar 

  3. Sarkisova K, van Luijtelaar G (2011) The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Prog Neuropsychopharmacol Biol Psychiatry 35(4): 854–876. https://doi.org/10.1016/j.pnpbp.2010.11.010

    Article  CAS  PubMed  Google Scholar 

  4. Deransart C, Riban V, Lê B, Marescaux C, Depaulis A (2000) Dopamine in the striatum modulates seizures in a genetic model of absence epilepsy in the rat. Neuroscience 100(2): 335–344. https://doi.org/10.1016/s0306-4522(00)00266-9

    Article  CAS  PubMed  Google Scholar 

  5. Tugba EK, Medine GIO, Ozlem A, Deniz K, Filiz OY (2022) Prolongation of absence seizures and changes in serotonergic and dopaminergic neurotransmission by nigrostriatal pathway degeneration in genetic absence epilepsy rats. Pharmacol Biochem Behav 213: 173317. https://doi.org/10.1016/j.pbb.2021.173317

    Article  CAS  PubMed  Google Scholar 

  6. Sarkisova KYu, Kulikov MA, Midzianovskaia IS, Folomkina AA (2007) Dopamine-dependent character of depressive-like behavior in WAG/Rij rats with genetic absence epilepsy. Zh Vyssh Nerv Deiat Im IP Pavlova 57(1): 91–102. https://doi.org/10.1007/s11055-008-0017-z

    Article  CAS  Google Scholar 

  7. Sarkisova KYu, Kulikov MA, Kudrin VS, Narkevich VB, Midzianovskaia IS, Biriukova LM, Folomkina AA, Basian AS (2014) Neurochemical mechanisms of depression-like behavior in WAG/Rij rats. Zh Vyssh Nerv Deiat Im I P Pavlova 63(3): 303–315. https://doi.org/10.7868/s0044467713030106

    Article  Google Scholar 

  8. Sarkisova KJu, Kulikov MA, Kudrin VS, Midzyanovskaya IS, Birioukova LM (2014) Age-related changes in behavior, in monoamines and their metabolites content, and in density of D1 and D2 dopamine receptors in the brain structures of WAG/Rij rats with depression-like pathology. Zh Vyssh Nerv Deiat Im I P Pavlova 64(6): 668–685. https://doi.org/10.7868/S0044467714060094

    Article  PubMed  Google Scholar 

  9. Sarkisova KY, Gabova AV, Kulikov MA, Fedosova EA, Shatskova AB, Morosov AA (2017) Rearing by foster Wistar mother with high level of maternal care counteracts the development of genetic absence epilepsy and comorbid depression in WAG/Rij rats. Dokl Biol Sci 473(1): 39–42. https://doi.org/10.1134/S0012496617020077

    Article  PubMed  Google Scholar 

  10. Sarkisova KY, Gabova AV (2018) Maternal care exerts disease-modifying effects on genetic absence epilepsy and comorbid depression. Genes Brain Behav 17(7): e12477. https://doi.org/10.1111/gbb.12477

    Article  CAS  PubMed  Google Scholar 

  11. Sarkisova K, van Luijtelaar G (2022) The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities. IBRO Neurosci Rep 13: 436–468. https://doi.org/10.1016/j.ibneur.2022.10.012

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sarkisova KY, Gabova AV, Fedosova EA, Shatskova AB (2020) Gender-Dependent Effect of Maternal Methyl-Enriched Diet on the Expression of Genetic Absence Epilepsy and Comorbid Depression in Adult Offspring of WAG/Rij Rats. Dokl Biol Sci 494(1): 244–247. https://doi.org/10.1134/S0012496620050075

    Article  CAS  PubMed  Google Scholar 

  13. Sarkisova KY, Fedosova EA, Shatskova AB, Rudenok MM, Stanishevskaya VA, Slominsky PA (2023) Maternal Methyl-Enriched Diet Increases DNMT1, HCN1, and TH Gene Expression and Suppresses Absence Seizures and Comorbid Depression in Offspring of WAG/Rij Rats. Diagnostics (Basel) 13(3): 398. https://doi.org/10.3390/diagnostics13030398

  14. Van den Veyver IB (2002) Genetic effects of methylation diets. Annu Rev Nutr 22: 255–282. https://doi.org/10.1146/annurev.nutr.22.010402.102932

    Article  CAS  PubMed  Google Scholar 

  15. Herbeck YE, Gulevich RG, Amelkina OA, Plyusnina IZ, Oskina IN (2010) Conserved methylation of the glucocorticoid receptor gene exon 1(7) promoter in rats subjected to a maternal methyl-supplemented diet. Int J Dev Neurosci 28(1): 9–12. https://doi.org/10.1016/j.ijdevneu.2009.10.004

    Article  CAS  PubMed  Google Scholar 

  16. Poletaeva II, Surina NM, Ashapkin VV, Fedotova IB, Merzalov IB, Perepelkina OV, Pavlova GV (2014) Maternal methyl-enriched diet in rat reduced the audiogenic seizure proneness in progeny. Pharmacol Biochem Behav 127: 21–26. https://doi.org/10.1016/j.pbb.2014.09.018

    Article  CAS  PubMed  Google Scholar 

  17. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 (Suppl 1): 245–254. https://doi.org/10.1038/ng1089

    Article  CAS  PubMed  Google Scholar 

  18. Vanyushin BF (2013) Epigenetics today and tomorrow. Vavilovsk zhurn genetiki i selektsii 17 (4): 805–832. (In Russ).

    Google Scholar 

  19. Morgan HD, Santos F, Green K, Dean W, Reik W (2005) Epigenetic reprogramming in mammals. Hum Mol Genet 14(1): 47–58. https://doi.org/10.1093/hmg/ddi114

    Article  CAS  Google Scholar 

  20. Nagatsu T, Levitt M, Udenfriend S (1964) Tyrosine Hydroxylase. The Initial Step In Norepinephrine Biosynthesis. J Biol Chem 239: 2910–2917.

    Article  CAS  PubMed  Google Scholar 

  21. Tekin I, Roskoski R Jr, Carkaci-Salli N, Vrana KE (2014) Complex molecular regulation of tyrosine hydroxylase. J Neur Transm 121(12): 1451–1481. https://doi.org/10.1007/s00702-014-1238-7

    Article  CAS  Google Scholar 

  22. Sarkisova KY, Fedosova EA, Shatskova AB, Narkevich VB, Kudrin VS (2022) Maternal Methyl-Enriched Diet Increases Dopaminergic Tone of the Mesolimbic Brain System in Adult Offspring of WAG/Rij Rats. Dokl Biol Sci 506(1): 145–149. https://doi.org/10.1134/S001249662205012X

    Article  CAS  PubMed  Google Scholar 

  23. Trutti AC, Mulder MJ, Hommel B, Forstmann BU (2019) Functional neuroanatomical review of the ventral tegmental area. Neuroimage 191: 258–268. https://doi.org/10.1016/j.neuroimage.2019.01.062

    Article  PubMed  Google Scholar 

  24. Margolis EB, Coker AR, Driscoll JR, Lemaître AI, Fields HL (2010) Reliability in the identification of midbrain dopamine neurons. PLoS One 5(12): e15222. https://doi.org/10.1371/journal.pone.0015222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lapshina KV, Abramova YuYu, Guzeev MA, Ekimova IV (2022) TGN-020, Inhibitor of the Water Channel Aquaporin-4, Accelerates Nigrostriatal Neurodegeneration in the Rat Model of Parkinson’s Disease. J Evol Biochem Physiol 58(6): 2035–2047. https://doi.org/10.31857/S0869813922120081

    Article  CAS  Google Scholar 

  26. Fedosova EA, Shatskova AB, Sarkisova KY (2021) Еthosuximide increases exploratory motivation and improves episodic memory in the novel object recognition test in WAG/Rij rats with genetic absence epilepsy. Neurosci Behav Physiol 51(4): 501–512. https://doi.org/10.1007/s11055-021-01097-z

    Article  CAS  Google Scholar 

  27. Kraeuter AK, Guest PC, Sarnyai Z (2019) The Elevated Plus Maze Test for Measuring Anxiety-Like Behavior in Rodents. Methods Mol Biol 1916: 69–74. https://doi.org/10.1007/978-1-4939-8994-2_4

    Article  CAS  PubMed  Google Scholar 

  28. Ahmadi M, Dufour JP, Seifritz E, Mirnajafi-Zadeh J, Saab BJ (2017) The PTZ kindling mouse model of epilepsy exhibits exploratory drive deficits and aberrant activity amongst VTA dopamine neurons in both familiar and novel space. Behav Brain Res 330: 1–7. https://doi.org/10.1016/j.bbr.2017.05.025

    Article  CAS  PubMed  Google Scholar 

  29. Peña CJ, Neugut YD, Calarco CA, Champagne FA (2014) Effects of maternal care on the development of midbrain dopamine pathways and reward-directed behavior in female offspring. Eur J Neurosci 39(6): 946–956. https://doi.org/10.1111/ejn.12479

    Article  PubMed  Google Scholar 

  30. Tomas D, Prijanto AH, Burrows EL, Hannan AJ, Horne MK, Aumann TD (2015) Environmental modulations of the number of midbrain dopamine neurons in adult mice. J Vis Exp 95: 52329. https://doi.org/10.3791/52329

    Article  CAS  Google Scholar 

  31. Sukhareva EV, Kalinina TS, Bulygina VV, Dygalo NN (2016) Tyrosine hydroxylase of the brain and its regulation by glucocorticoids. Vavilov J Genet Breed 20(2): 212–219. https://doi.org/10.18699/VJ16.156

    Article  Google Scholar 

  32. Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, Kim SY, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten IB, Deisseroth K (2013) Dopamine neurons modulate neural encoding and expression of depression-related behavior. Nature 493(7433): 537–541. https://doi.org/10.1038/nature11740

    Article  CAS  PubMed  Google Scholar 

  33. Barrot M, Sesack SR, Georges F, Pistis M, Hong S (2012) Braking Dopamine Systems: A New GABA Master Structure for Mesolimbic and Nigrostriatal Functions. J Neurosci 32(41): 14094–14101. https://doi.org/10.1523/JNEUROSCI.3370-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Root DH, Mejias-Aponte CA, Zhang S, Wang HL, Hoffman AF, Lupica CR, Morales M (2014) Single rodent mesohabenular axons release glutamate and GABA. Nat Neurosci 17(11): 1543–1551. https://doi.org/10.1038/nn.3823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rollo CD (2009) Dopamine and aging: intersecting facets. Neurochem Res 34(4): 601–629. https://doi.org/10.1007/s11064-008-9858-7

    Article  CAS  PubMed  Google Scholar 

  36. Gabova AV, Sarkisova KYu, Fedosova EA, Shatskova AB, Morozov AA (2020) Developmental Changes in Peak-Wave Discharges in WAG/Rij Rats with Genetic Absence Epilepsy. Neurosci Behav Physi 50: 245–252. https://doi.org/10.1007/s11055-019-00893-y

    Article  Google Scholar 

  37. Fedosova EA, Sarkisova KYu, Kudrin VS, Narkevich VB, Bazyan AS (2015) Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy. Int J Clini Exp Neurol 3(2): 32–44. https://doi.org/10.12691/ijcen-3-2-2

    Article  Google Scholar 

  38. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 138(2): 155–175. https://doi.org/10.1016/j.pharmthera.2013.01.004

    Article  CAS  PubMed  Google Scholar 

  39. Cortés D, Carballo-Molina OA, Castellanos-Montiel MJ, Velasco I (2017) The Non-Survival Effects of Glial Cell Line-Derived Neurotrophic Factor on Neural Cells. Front Mol Neurosci 10: 258. https://doi.org/10.3389/fnmol.2017.00258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Roussa E, Oehlke O, Rahhal B, Heermann S, Heidrich S, Wiehle M, Krieglstein K (2008) Transforming growth factor beta cooperates with persephin for dopaminergic phenotype induction. Stem Cells 26(7): 1683–1694. https://doi.org/10.1634/stemcells.2007-0805

    Article  CAS  PubMed  Google Scholar 

  41. Sariola H, Saarma M (2003) Novel functions and signaling pathways for GDNF. J Cell Sci 116(19): 3855–3862. https://doi.org/10.1242/jcs.00786

    Article  CAS  PubMed  Google Scholar 

  42. Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S, Sumi-Ichinose C, Nomura T, Metzger D, Chambon P, Lindqvist E, Larsson NG, Olson L, Björklund A, Ichinose H, Perlmann T (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29(50): 15923–15932. https://doi.org/10.1523/JNEUROSCI.3910-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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ACKNOWLEDGMENTS

The authors are grateful to the staff members of Institute of Higher Nervous Activity and Neurophysiology (Russian Academy of Sciences) N.V. Panov for performing transcardial perfusion and preparing the rat brain for further immunohistochemical studies, and A.B. Shatskova for her aid at the initial stage of experiments, concerned with obtaining an offspring of WAG/Rij rats.

Funding

This work was supported by the Russian Foundation for Basic Research (project no. 20-15-00327a).

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Authors and Affiliations

  1. Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia

    E. A. Fedosova, N. A. Loginova & K. Yu. Sarkisova

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  1. E. A. Fedosova
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  2. N. A. Loginova
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  3. K. Yu. Sarkisova
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Contributions

Conceptualization and experimental design (K.Yu.S., N.A.L.); data collection (E.A.F., N.А.L.); data processing (E.A.F., K.Yu.S.); writing and editing a manuscript (E.A.F., K.Yu.S.).

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Correspondence to E. A. Fedosova.

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COMPLIANCE WITH ETHICAL STANDARDS

This study was carried out in compliance with the international rules for keeping and handling animals (Directive 2010/63/EU) and the principles formulated in the guidelines of the Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences (IHNA & NPh RAS) on working with experimental animals. The experimental protocols were approved by the Ethics Committee at IHNA & NPh RAS (Meeting minutes No. 5 dated December 2, 2020).

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 7, pp. 902–920https://doi.org/10.31857/S086981392307004X.

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Fedosova, E.A., Loginova, N.A. & Sarkisova, K.Y. The Effect of Maternal Methyl-Enriched Diet on the Number of Dopaminergic Neurons in the Ventral Tegmental Area in Adult Offspring of WAG/Rij Rats. J Evol Biochem Phys 59, 1262–1276 (2023). https://doi.org/10.1134/S0022093023040191

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