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.

Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala

“…Each cage housed 2 rats. Diet restriction was done to ensure equal feeding between groups since previous studies had reported diminished food intake in rodents receiving a methyl-depleted diet [61, 62]. Animals were weighed each week starting on the first day of diet exposure.…”

The potential of epigenetics in stress-enhanced fear learning models of PTSD

“…Bidirectional changes in the methylation status of several memory-related genes, including Pp1cb, reelin, and Bdnf, have also been found in the hippocampus following fear learning (Miller and Sweatt 2007;Lubin et al 2008). Consistent with these findings, mice fed a diet deficient in the methyl donors folate, methionine, and choline from 3 to 6 wk of age to drive a global reduction in DNA methylation levels, have impaired fear memory formation that persists into adulthood (Ishii et al 2014). Finally, cortical DNA methylation supports the storage of remote (30-d-old) fear memory (Miller et al 2010), suggesting that targeting this epigenetic mechanism may be useful in treating the pathological persistence of fear memories in PTSD.…”

Methyl Donors Supplementation Attenuates the Adverse Effects of Maternal High Fructose Diet of Offspring Emotional and Cognitive Behaviors

“…We observed in literature significant effects of HFD on rats cognition [32], and the adverse effects of methyl donor-deficient diet during brain development on memory and anxiety in adulthood in mice [33]. In addition, previous studies demonstrated significant relationship between maternal fructose diet and metabolic disorders in their offspring [34].…”

“…Methyl donors is a factor of regulation of epigenetic mechanisms well-known as DNA methylation and histone acetylation involved actively in control of gene expres- [56]. Otherwise, a previous paper reported that methyl donors' supplementation diet induces an increasing of NMDA receptor subunit, NR2B gene expression in hippocampal cells [33].…”