Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

Abstract

Adverse early life events are associated with altered stress responsiveness and metabolic disturbances in the adult life. Dietary methyl donor supplementation could be able to reverse the negative effects of maternal separation by affecting DNA methylation in the brain. In this study, maternal separation during lactation reduced body weight gain in the female adult offspring without affecting food intake, and altered total and HDLcholesterol levels. Also, maternal separation induced a cognitive deficit as measured by NORT and an increase in the immobility time in the Porsolt forced swimming test, consistent with increased depression-like behaviour. An 18-week dietary supplementation with methyl donors (choline, betaine, folate and vitamin B12) from postnatal day 60 also reduced body weight without affecting food intake. Some of the deleterious effects induced by maternal separation, such as the abnormal levels of total and HDL-cholesterol, but especially the depression-like behaviour as measured by the Porsolt test, were reversed by methyl donor supplementation. Also, the administration of methyl donors increased total DNA methylation (measured by immunohistochemistry) and affected the expression of insulin receptor in the hippocampus of the adult offspring. However, no changes were observed in the DNA methylation status of insulin receptor and corticotropin-releasing hormone (CRH) promoter regions in the hypothalamus. In summary, methyl donor supplementation reversed some of the deleterious effects of an early life-induced model of depression in rats and altered the DNA methylation profile in the brain.

Neonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress‐reactive Wistar Kyoto rats

“…Depleting dietary methyl donor content has been shown to decrease DNA methylation markers in the brain (Pogribny et al ., ), and impede fear memory (Ishii et al ., ; Tomizawa et al ., ). On the other hand, boosting levels of methyl donors (or SAM itself) increases DNA methylation levels in brain (Paternain et al ., ), and elicits antidepressant effects in rats and mice, such as decreased immobility in the FST and improved stress‐induced anhedonia (Czyrak et al ., ; Benelli et al ., ; Brocardo et al ., ; Molina‐Hernandez et al ., ; Paternain et al ., ). This study showed that increasing WKY male rats’ dietary methyl donor content elicited a series of positive behavioral effects including: increased exploratory behavior, increased social interaction and decreased behavioral despair (immobility) in the FST.…”

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

“…Depleting dietary methyl donor content has been shown to decrease DNA methylation markers in the brain [89], and impair fear memory [62, 90]. On the other hand, boosting levels of methyl donors (or SAM itself) increases DNA methylation levels in brain [91], and elicits antidepressant effects in rats and mice, such as decreased immobility in the FST and improved stress-induced anhedonia [92–95]. Since our methylome profiling data revealed a greater number of hypomethylated genomic regions in brain tissue from adult LR vs. HR rats, we hypothesized that manipulating DNA methylation in LR rats (by altering dietary methyl donor content) could influence aspects of their behavioral phenotype.…”

“…Since our methylome profiling data revealed a greater number of hypomethylated genomic regions in brain tissue from adult LR vs. HR rats, we hypothesized that manipulating DNA methylation in LR rats (by altering dietary methyl donor content) could influence aspects of their behavioral phenotype. Specifically we predicted: ( a) that supplementing methyl donors in LR rats’ diet (which has been shown to enhance methylation levels in brain [91]) would have antidepressant effects, whereas ( b) depleting dietary methyl donors (which would lower DNA methylation levels in the brain [89]) would exacerbate LRs’ anxiety/depression-like phenotype. We found that, indeed, depleting dietary methyl donor content worsened LRs’ depression-like behavior (immobility) in the FST.…”

Bromocriptine treatment at the end of lactation prevents hyperphagia, higher visceral fat and liver triglycerides in early‐weaned rats at adulthood

“…13 Conversely, maternal deprivation caused considerable stress to both dams and their pups. 21,22 The differences in these two models may be associated with differences in maternal care because in the present model, the dams continued to groom and lick their pups.…”