title: Methyl donor-deficient diet during development can affect fear and anxiety in adulthood in C57BL/6J mice.
abstract: DNA methylation is one of the essential factors in the control of gene expression. Folic acid, methionine and choline (methyl donors)--all nutrients related to one-carbon metabolism--are known as important mediators of DNA methylation. A previous study has shown that long-term administration of a diet lacking in methyl donors caused global DNA hypermethylation in the brain (Pogribny et al., 2008). However, no study has investigated the effects of a diet lacking in methyl donors during the developmental period on emotional behaviors such as fear and anxiety-like behavior in association with gene expressions in the brain. In addition, it has not been elucidated whether a diet supplemented with methyl donors later in life can reverse these changes. Therefore, we examined the effects of methyl donor deficiency during the developmental period on fear memory acquisition/extinction and anxiety-like behavior, and the relevant gene expressions in the hippocampus in juvenile (6-wk) and adult (12-wk) mice. We found that juvenile mice fed a methyl-donor-deficient diet had impaired fear memory acquisition along with decreases in the gene expressions of Dnmt3a and Dnmt3b. In addition, reduced anxiety-like behavior with decreased gene expressions of Grin2b and Gabar2 was observed in both the methyl-donor-deficient group and the body-weight-matched food-restriction group. After being fed a diet supplemented with methyl donors ad libitum, adult mice reversed the alteration of gene expression of Dnmt3a, Dnmt3b, Grin2b and Gabar2, but anxiety-like behavior became elevated. In addition, impaired fear-memory formation was observed in the adult mice fed the methyl-donor-deficient diet during the developmental period. Our study suggested that developmental alterations in the one-carbon metabolic pathway in the brain could have effects on emotional behavior and memory formation that last into adulthood.
authors.affiliation: Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishii
authors.affiliation: Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, Chiba, Japan; Research Center for Child Mental Development, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsuzawa
authors.affiliation: Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Tomizawa
authors.affiliation: Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, Chiba, Japan; Research Center for Child Mental Development, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sutoh
authors.affiliation: Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, Chiba, Japan; Research Center for Child Mental Development, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism; D001522:Behavior, Animal; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004032:Diet / Q000009:adverse effects*; D005239:Fear; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D016194:Receptors, N-Methyl-D-Aspartate; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse; C121001:NR2B NMDA receptor