{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:19:38Z","timestamp":1790835578679,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Deficiencies in methyl donors, folate, and vitamin B12 are known to lead to brain function defects. Fetal development is the most studied but data are also available for such an impact in elderly rats. To compare the functional consequences of nutritional deficiency in young versus adult rats, we monitored behavioral outcomes of cerebellum and hippocampus circuits in the offspring of deficient mother rats and in adult rats fed a deficient diet from 2 to 8 months-of-age. We present data showing that the main deleterious consequences are found in young ages compared to adult ones, in terms of movement coordination and learning abilities. Moreover, we obtained sex and age differences in the deleterious effects on these functions and on neuronal layer integrity in growing young rats, while deficient adults presented only slight functional alterations without tissue damage. Actually, the cerebellum and the hippocampus develop and maturate according to different time lap windows and we demonstrate that a switch to a normal diet can only rescue circuits that present a long permissive window of time, such as the cerebellum, whereas the hippocampus does not. Thus, we argue, as others have, for supplements or fortifications given over a longer time than the developmental period.<\/jats:p>","DOI":"10.3390\/ijms20225692","type":"journal-article","created":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T10:56:34Z","timestamp":1573728994000},"page":"5692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Brain Susceptibility to Methyl Donor Deficiency: From Fetal Programming to Aging Outcome in Rats"],"prefix":"10.3390","volume":"20","author":[{"given":"Ziad","family":"Hassan","sequence":"first","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7010-5789","authenticated-orcid":false,"given":"David","family":"Coelho","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tunay","family":"Kokten","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5126-2890","authenticated-orcid":false,"given":"Jean-Marc","family":"Alberto","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9my","family":"Umoret","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Daval","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5067-042X","authenticated-orcid":false,"given":"Jean-Louis","family":"Gu\u00e9ant","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Bossenmeyer-Pouri\u00e9","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-5026","authenticated-orcid":false,"given":"Gr\u00e9gory","family":"Pouri\u00e9","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de m\u00e9decine, INSERM 1256\/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1056\/NEJMe068086","article-title":"Vitamin B12, folic acid, and the prevention of dementia","volume":"354","author":"Clarke","year":"2006","journal-title":"New Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1093\/ajcn\/84.6.1259","article-title":"Assessing the association between vitamin B-12 status and cognitive function in older adults","volume":"84","author":"Miller","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.pneurobio.2009.04.004","article-title":"The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency","volume":"88","author":"Scalabrino","year":"2009","journal-title":"Prog. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1056\/NEJMoa011613","article-title":"Plasma homocysteine as a risk factor for dementia and Alzheimer\u2032s disease","volume":"346","author":"Seshadri","year":"2002","journal-title":"N Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1146\/annurev.nutr.012809.104751","article-title":"Nutrition, epigenetics, and developmental plasticity: Implications for understanding human disease","volume":"30","author":"Burdge","year":"2010","journal-title":"Annu. Rev. Nutr."},{"key":"ref_6","first-page":"106","article-title":"Vitamin B deficiency causes neural cell loss and cognitive impairment in the developing rat","volume":"6","author":"Daval","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12474","DOI":"10.1073\/pnas.0805350105","article-title":"B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice","volume":"105","author":"Troen","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/nutrit\/nuv107","article-title":"Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults","volume":"74","author":"Sechi","year":"2016","journal-title":"Nutr. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21930","DOI":"10.1073\/pnas.0811794106","article-title":"Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE","volume":"106","author":"Akchiche","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S126","DOI":"10.1177\/15648265080292S117","article-title":"Effects of vitamin B12 and folate deficiency on brain development in children","volume":"29","author":"Black","year":"2008","journal-title":"Food Nutr. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s10545-014-9803-7","article-title":"Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data","volume":"38","author":"Huemer","year":"2014","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0140-6736(07)60109-3","article-title":"Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial","volume":"369","author":"Durga","year":"2007","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1586\/ern.09.75","article-title":"Homocysteine, folate and vitamin B12in neuropsychiatric diseases: Review and treatment recommendations","volume":"9","author":"Stanger","year":"2009","journal-title":"Expert Rev. Neurother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2353\/ajpath.2007.060339","article-title":"Gestational Vitamin B Deficiency Leads to Homocysteine-Associated Brain Apoptosis and Alters Neurobehavioral Development in Rats","volume":"170","author":"Blaise","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1159\/000112845","article-title":"Cellular and Molecular Events Underlying the Dysregulated Response of the Aged Brain to Stroke: A Mini-Review","volume":"54","author":"Petcu","year":"2008","journal-title":"Gerontology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1093\/nutrit\/nuy006","article-title":"A crucial role for maternal dietary methyl donor intake in epigenetic programming and fetal growth outcomes","volume":"76","author":"McGee","year":"2018","journal-title":"Nutr. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S1474-4422(06)70598-1","article-title":"Vitamin B12, folic acid, and the nervous system","volume":"5","author":"Reynolds","year":"2006","journal-title":"Lancet. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/nutrit\/nuy007","article-title":"Effect of supplementation with methyl-donor nutrients on neurodevelopment and cognition: Considerations for future research","volume":"76","author":"McKee","year":"2018","journal-title":"Nutr. Rev."},{"key":"ref_19","first-page":"1162","article-title":"Dietary Choline Reverses Some, but Not All, Effects of Folate Deficiency on Neurogenesis and Apoptosis in Fetal Mouse Brain","volume":"140","author":"Zeisel","year":"2010","journal-title":"SciVee"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1753-4887.2009.00266.x","article-title":"Folate-mediated one-carbon metabolism and its effect on female fertility and pregnancy viability","volume":"68","author":"Laanpere","year":"2010","journal-title":"Nutr. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1007\/s12035-016-0035-8","article-title":"Bossenmeyer-Pouri\u00e9. Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways","volume":"54","author":"Geoffroy","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Moretti, R., and Caruso, P. (2019). The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010231"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Blusztajn, J.K., Slack, B.E., and Mellott, T.J. (2017). Neuroprotective Actions of Dietary Choline. Nutrrients, 9.","DOI":"10.3390\/nu9080815"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e755","DOI":"10.1038\/cddis.2013.278","article-title":"Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124","volume":"4","author":"Kerek","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Geoffroy, A., Saber-Cherif, L., Pouri\u00e9, G., Helle, D., Umoret, R., Gu\u00e9ant, J.-L., Bossenmeyer-Pouri\u00e9, C., and Daval, J.-L. (2019). Developmental Impairments in a Rat Model of Methyl Donor Deficiency: Effects of a Late Maternal Supplementation with Folic Acid. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040973"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1017\/S0029665114001554","article-title":"Emerging roles for folate and related B-vitamins in brain health across the lifecycle","volume":"74","author":"McGarel","year":"2015","journal-title":"Proc. Nutr. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0969-9961(03)00082-2","article-title":"Histopathological alterations and functional brain deficits after transient hypoxia in the newborn rat pup: A long term follow-up","volume":"14","author":"Grojean","year":"2003","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.1096\/fj.14-264267","article-title":"Folate- and vitamin B12\u2013deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor \u03b1","volume":"29","author":"Martin","year":"2015","journal-title":"Faseb J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.neuropsychologia.2018.04.011","article-title":"A systematic literature review of sex differences in childhood language and brain development","volume":"114","author":"Etchell","year":"2018","journal-title":"Neuropsychology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.pnpbp.2017.08.015","article-title":"Sex differences in the effects of pre- and postnatal caffeine exposure on behavior and synaptic proteins in pubescent rats","volume":"81","author":"Sallaberry","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Boil. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1097\/WNR.0000000000000052","article-title":"Estradiol decreases rat depressive behavior by estrogen receptor beta but not alpha: No correlation with plasma corticosterone","volume":"25","author":"Yang","year":"2014","journal-title":"Neuroreport"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.pnpbp.2017.10.013","article-title":"Behavioral effects of early life maternal trauma witness in rats","volume":"81","author":"Liu","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Boil. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.pnpbp.2012.02.004","article-title":"Sex differences in baseline and drug-induced behavioural responses in classical behavioural tests","volume":"37","author":"Simpson","year":"2012","journal-title":"Prog. Neuro-Psychopharmacol. Boil. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Xiao, Y., Fu, H., Han, X., Hu, X., Gu, H., Chen, Y., Wei, Q., and Hu, Q. (2014). Role of Synaptic Structural Plasticity in Impairments of Spatial Learning and Memory Induced by Developmental Lead Exposure in Wistar Rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115556"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0047-6374(01)00365-7","article-title":"Folic acid and homocysteine in age-related disease","volume":"1","author":"Mattson","year":"2002","journal-title":"Ageing Res. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/BF02982630","article-title":"Dietary and genetic compromise in folate availability reduces acetylcholine, cognitive performance and increases aggression: Critical role of S-adenosyl methionine","volume":"12","author":"Chan","year":"2008","journal-title":"J. Nutr. Heal. Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neurobiolaging.2017.10.014","article-title":"DNA damage and neurodegenerative phenotypes in aged Ciz1 null mice","volume":"62","author":"Khan","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.brainresbull.2016.12.015","article-title":"Age-related alterations in human neocortical plasticity","volume":"130","author":"Spriggs","year":"2017","journal-title":"Brain Res. Bull."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1113\/jphysiol.2005.089383","article-title":"Physiological and morphological development of the rat cerebellar Purkinje cell","volume":"567","author":"McKay","year":"2005","journal-title":"J. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0079-6123(07)63010-6","article-title":"Morphological development and maturation of granule neuron dendrites in the rat dentate gyrus","volume":"163","author":"Rahimi","year":"2007","journal-title":"Prog. Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1097\/YCO.0000000000000046","article-title":"Lifetime requirement of the methionine cycle for neuronal development and maintenance","volume":"27","author":"Shea","year":"2014","journal-title":"Curr. Opin. Psychiatry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5692\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:34:15Z","timestamp":1760189655000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,14]]},"references-count":41,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20225692"],"URL":"https:\/\/doi.org\/10.3390\/ijms20225692","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,14]]}}}