Behavioral changes and brain epigenetic alterations induced by maternal deficiencies of B vitamins in a mouse model

Psychopharmacology (2021)Cite this article

Abstract

Rationale

B vitamins play essential roles in brain development and functionality; however, the effects of their deficiency during early life on mental health are not thoroughly understood.

Objectives

The objective of this study is to investigate the effects of a maternal deficiency of vitamin B6, B9 (folate), and B12 on behavioral changes in adult offspring.

Methods

Female C57BL/6 J mice were put on a diet lacking vitamin B6, B9, B12, or the above three vitamins from pregnancy to weaning. The growth and developmental characteristics of both the pregnant mothers and offspring were collected. In the adult offspring, the serum levels of neuroactive substances were measured using an enzyme-linked immunosorbent assay. The level of BDNF and dimethylated lysine 9 on histone H3 (H3K9me2) was detected by immunohistochemical staining. In addition, their depressive-like behaviors, anxiety-like behaviors, and sociability were recorded using sucrose preference, a forced swim, social interaction, tail suspension, and open field tests.

Results

The maternal deficiency of the three B vitamins delayed offspring development. Compared to the controls, all of the groups showed decreased serum levels of 5-HT and neuropeptide Y. In the groups with deficiency of B9 or the three B vitamins, there were significant changes in sociability and social novelty preference. In groups with deficiencies in B9, B12, or all three B vitamins, the expression levels of BDNF and H3K9me2 in the hippocampus were significantly decreased.

Conclusions

Maternal deficiencies of the major B vitamins caused changes in social behaviors in adult mice accompanied with epigenetic alterations in the brain and changes in the serum levels of neuroactive substances.

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References

  1. Alexopoulos GS, Murphy CF, Gunning-Dixon FM, Glatt CE, Latoussakis V, Kelly RE Jr, Kanellopoulos D, Klimstra S, Lim KO, Young RC, Hoptman MJ (2009) Serotonin transporter polymorphisms, microstructural white matter abnormalities and remission of geriatric depression. J Affect Disord 119:132–141

    CAS  Article  Google Scholar 

  2. Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ (2010) B-vitamins reduce the long-term risk of depression after stroke: the VITATOPS-DEP trial. Ann Neurol 68:503–510

    CAS  Article  Google Scholar 

  3. Bottiglieri T (1996) Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev 54:382–390

    CAS  Article  Google Scholar 

  4. Brondino N, Fusar-Poli L, Rocchetti M, Bertoglio F, Bloise N, Visai L, Politi P (2018) BDNF levels are associated with autistic traits in the general population. Psychoneuroendocrinology 89:131–133

    CAS  Article  Google Scholar 

  5. Das UN (2013) Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids. Nutrition 29:1175–1185

    CAS  Article  Google Scholar 

  6. Devakumar D, Fall CH, Sachdev HS, Margetts BM, Osmond C, Wells JC, Costello A, Osrin D (2016) Maternal antenatal multiple micronutrient supplementation for long-term health benefits in children: a systematic review and meta-analysis. BMC Med 14:90

    Article  Google Scholar 

  7. Dhobale M (2014) Neurotrophins: role in adverse pregnancy outcome. Int J Dev Neurosci 37:8–14

    CAS  Article  Google Scholar 

  8. Gillman MW (2005) Developmental origins of health and disease. N Engl J Med 353:1848–1850

    CAS  Article  Google Scholar 

  9. Guilarte TR, Miceli RC, Moran TH (1991) Developmental effects of vitamin B-6 restriction on the locomotor behavior of rats. Brain Res Bull 26:857–861

    CAS  Article  Google Scholar 

  10. Hainmueller T, Bartos M (2018) Parallel emergence of stable and dynamic memory engrams in the hippocampus. Nature 558:292–296

    CAS  Article  Google Scholar 

  11. Haskell CF, Scholey AB, Jackson PA, Elliott JM, Defeyter MA, Greer J, Robertson BC, Buchanan T, Tiplady B, Kennedy DO (2008) Cognitive and mood effects in healthy children during 12 weeks’ supplementation with multi-vitamin/minerals. Br J Nutr 100:1086–1096

    CAS  Article  Google Scholar 

  12. Henzel KS, Ryan DP, Schroder S, Weiergraber M, Ehninger D (2017) High-dose maternal folic acid supplementation before conception impairs reversal learning in offspring mice. Sci Rep 7:3098

    Article  Google Scholar 

  13. Hing B, Sathyaputri L, Potash JB (2018) A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 177:143–167

    CAS  Article  Google Scholar 

  14. Jeyaraj SE, Sivasangari K, Garcia-Colunga J, Rajan KE (2020) Environmental enrichment enhances sociability by regulating glutamate signaling pathway through GR by epigenetic mechanisms in amygdala of Indian field mice Mus booduga. Gen Comp Endocrinol 300:113641

    Article  Google Scholar 

  15. Kemse N, Kale A, Chavan-Gautam P, Joshi S (2018) Increased intake of vitamin B12, folate, and omega-3 fatty acids to improve cognitive performance in offspring born to rats with induced hypertension during pregnancy. Food Funct 9:3872–3883

    CAS  Article  Google Scholar 

  16. Kennedy DO (2016) B vitamins and the brain: mechanisms, dose and efficacy--a review. Nutrients 8:68

    Article  Google Scholar 

  17. Kraus C, Castren E, Kasper S, Lanzenberger R (2017) Serotonin and neuroplasticity - links between molecular, functional and structural pathophysiology in depression. Neurosci Biobehav Rev 77:317–326

    CAS  Article  Google Scholar 

  18. Kupfer DJ, Frank E, Phillips ML (2011) Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet 379:1045–1055

    Article  Google Scholar 

  19. Le Duigou C, Simonnet J, Telenczuk MT, Fricker D, Miles R (2014) Recurrent synapses and circuits in the CA3 region of the hippocampus: an associative network. Front Cell Neurosci 7:262

    Article  Google Scholar 

  20. Li YF (2020) A hypothesis of monoamine (5-HT) - glutamate/GABA long neural circuit: aiming for fast-onset antidepressant discovery. Pharmacol Ther 107494

  21. Li C, Wu X, Liu S, Zhao Y, Zhu J, Liu K (2019) Roles of neuropeptide Y in neurodegenerative and neuroimmune diseases. Front Neurosci 13:869

    Article  Google Scholar 

  22. Liu Y, Zhao J, Fan X, Guo W (2019) Dysfunction in serotonergic and noradrenergic systems and somatic symptoms in psychiatric disorders. Frontiers in psychiatry 10:286

    Article  Google Scholar 

  23. Liu HY, Liu SM, Zhang YZ (2020) Maternal folic acid supplementation mediates offspring health via DNA methylation. Reproductive sciences. Thousand Oaks, Calif

    Google Scholar 

  24. Martinez-Moreno A, Rivera-Olvera A, Escobar ML (2020) BDNF induces in vivo long-lasting enhancement of synaptic transmission and structural reorganization at the hippocampal mossy fibers in a transcription and translation-independent manner. Neurobiol Learn Mem 167:107125

    CAS  Article  Google Scholar 

  25. Maze I, Covington HE 3rd, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, Ren Y, Sampath SC, Hurd YL, Greengard P, Tarakhovsky A, Schaefer A, Nestler EJ (2010) Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327:213–216

    CAS  Article  Google Scholar 

  26. Mellios N, Huang HS, Baker SP, Galdzicka M, Ginns E, Akbarian S (2009) Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 65:1006–1014

    CAS  Article  Google Scholar 

  27. Miller AL (2003) The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev 8:7–19

    PubMed  Google Scholar 

  28. Reynolds E (2006) Vitamin B12, folic acid, and the nervous system. Lancet Neurol 5:949–960

    CAS  Article  Google Scholar 

  29. Sable P, Kale A, Joshi A, Joshi S (2014) Maternal micronutrient imbalance alters gene expression of BDNF, NGF, TrkB and CREB in the offspring brain at an adult age. Int J Dev Neurosci 34:24–32

    CAS  Article  Google Scholar 

  30. Sakharkar AJ, Vetreno RP, Zhang H, Kokare DM, Crews FT, Pandey SC (2016) A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood. Brain Struct Funct 221:4691–4703

    CAS  Article  Google Scholar 

  31. Shende P, Desai D (2020) Physiological and therapeutic roles of neuropeptide Y on biological functions. Adv Exp Med Biol 1237:37–47

    Article  Google Scholar 

  32. Smithells RW, Sheppard S, Schorah CJ (1976) Vitamin deficiencies and neural tube defects. Arch Dis Child 51:944–950

    CAS  Article  Google Scholar 

  33. Steenweg-de Graaff J, Roza SJ, Steegers EA, Hofman A, Verhulst FC, Jaddoe VW, Tiemeier H (2012) Maternal folate status in early pregnancy and child emotional and behavioral problems: the generation R study. Am J Clin Nutr 95:1413–1421

    CAS  Article  Google Scholar 

  34. Stough C, Scholey A, Lloyd J, Spong J, Myers S, Downey LA (2011) The effect of 90 day administration of a high dose vitamin B-complex on work stress. Human psychopharmacol 26:470–476

    CAS  Article  Google Scholar 

  35. Toth M (2014) Mechanisms of non-genetic inheritance and psychiatric disorders. Neuropsychopharmacology 40:129–140

    Article  Google Scholar 

  36. van Gool JD, Hirche H, Lax H, De Schaepdrijver L (2018) Folic acid and primary prevention of neural tube defects: a review. Reproductive toxicology (Elmsford, NY) 80: 73-84

  37. Wang X, Li W, Li S, Yan J, Wilson JX, Huang G (2017) Maternal folic acid supplementation during pregnancy improves neurobehavioral development in rat offspring. Mol Neurobiol 55:2676–2684

    Article  Google Scholar 

  38. White DJ, Cox KH, Peters R, Pipingas A, Scholey AB (2015) Effects of four-week supplementation with a multi-vitamin/mineral preparation on mood and blood biomarkers in young adults: a randomised, double-blind, placebo-controlled trial. Nutrients 7:9005–9017

    CAS  Article  Google Scholar 

  39. Wolkowitz OM, Wolf J, Shelly W, Rosser R, Burke HM, Lerner GK, Reus VI, Nelson JC, Epel ES, Mellon SH (2011) Serum BDNF levels before treatment predict SSRI response in depression. Prog Neuro-Psychopharmacol Biol Psychiatry 35:1623–1630

    CAS  Article  Google Scholar 

  40. Yan Z, Jiao F, Yan X, Ou H (2017) Maternal chronic folate supplementation ameliorates behavior disorders induced by prenatal high-fat diet through methylation alteration of BDNF and Grin2b in offspring hippocampus. Molecular nutrition & food research 61

  41. Yang Y, Yang S, Liu J, Feng Y, Qi F, Zhao R (2019) DNA hypomethylation of GR promoters is associated with GR activation and BDNF/AKT/ERK1/2-induced hippocampal neurogenesis in mice derived from folic-acid-supplemented dams. Mol Nutr Food Res 63:e1801334

    Article  Google Scholar 

  42. Zhao M, Wang W, Jiang Z, Zhu Z, Liu D, Pan F (2020) Long-term effect of post-traumatic stress in adolescence on dendrite development and H3K9me2/BDNF expression in male rat hippocampus and prefrontal cortex. Front Cell Dev Biol 8:682

    Article  Google Scholar 

  43. Zhou HR, Zhang FF, Ma ZY, Huang HW, Jiang L, Cai T, Zhu JK, Zhang C, He XJ (2013) Folate polyglutamylation is involved in chromatin silencing by maintaining global DNA methylation and histone H3K9 dimethylation in Arabidopsis. Plant Cell 25:2545–2559

    CAS  Article  Google Scholar 

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Acknowledgments

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

Funding was provided by National Key R&D Program of China (grant no. 2018YFC1004104), the Guangdong Science and Technology Department Project (grant no. 2019B030316023), and the Key Project of Guangzhou Science and Technology Innovation Committee (grant no. 201804020057).

Author information

Author notes

  1. Pei Xu, Dejian Pang and Jiayi Zhou contributed equally to this work.

Affiliations

  1. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Pei Xu, Dejian Pang, Jiayi Zhou, Sihui Li, Dunjin Chen & Bolan Yu

  2. BioResource Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Pei Xu, Dejian Pang, Jiayi Zhou & Bolan Yu

  3. Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, No.63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong, China

    Pei Xu, Dejian Pang, Jiayi Zhou, Sihui Li, Dunjin Chen & Bolan Yu

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  1. Pei Xu
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Correspondence to Bolan Yu.

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Supplementary information

Figure S1

The immunohistochemical staining analysis of BDNF in five areas of the brain in adult offspring mice. (A) In CA3 area from five groups; (B) in mPFC area from five groups; (C) in NAc area from five groups; (D) in CPu area from five groups; (E) in VTA area from five groups. NOR, group with control diet; DB6, group with vitamin B6–deficient diet; DB9, group with B9-deficient diet; DB12, group with vitamin B12–deficient diet; DB6912, group with vitamin B6–, B9–, and B12–deficient diet. N = 16 mice per group. (PDF 311 kb)

Figure S2

The immunohistochemical staining analysis of H3K9me2 positive cells in five areas of the brain in adult offspring mice. (A) In CA3 area from five groups; (B) in mPFC area from five groups; (C) in NAc area from five groups; (D) in CPu area from five groups; (E) in VTA area from five groups. NOR, group with control diet; DB6, group with vitamin B6–deficient diet; DB9, group with B9–deficient diet; DB12, group with vitamin B12–deficient diet; DB6912, group with vitamin B6–, B9–, and B12–deficient diet. N = 16 mice per group. (PDF 225 kb)

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Xu, P., Pang, D., Zhou, J. et al. Behavioral changes and brain epigenetic alterations induced by maternal deficiencies of B vitamins in a mouse model. Psychopharmacology (2021). https://doi.org/10.1007/s00213-021-05766-2

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Keywords

  • Maternal nutrition
  • B vitamins
  • BDNF
  • H3K9me2