Brain Susceptibility to Methyl Donor Deficiency: From Fetal Programming to Aging Outcome in Rats

Abstract

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.

Early Appearance of Epicardial Adipose Tissue through Human Development

“…Of interest, the thickness of the EAT is a predictor of fatal and nonfatal coronary events in the general population, regardless of the traditional cardiovascular risk factors [18][19][20][21]. Increased EAT volume is associated with a lengthened electrocardiogram PR interval [22], suggesting that EAT can interfere with electrical conduction through the heart, modifying the heartbeat.…”

The Stimulation of Neurogenesis Improves the Cognitive Status of Aging Rats Subjected to Gestational and Perinatal Deficiency of B9–12 Vitamins

“…Globally, the level of expression of the N-methyl D-aspartate receptor 1 (NMDAR1) and the post-synaptic density-95 (PSD-95) were negatively correlated to the deficient diet alone, and positively correlated to hypoxia. This indicates that the deficiency in B-vitamins affected the hippocampus status in terms of circuit plasticity and that this aspect was maintained during the lifespan, as the Barker theory described for developmental or neonatal events leading to long term positive or negative effects [45,46]. At the same time, the hypoxia-stimulated-mechanism occurring in the same neonatal period could give advantages to receptive circuits such as the hippocampus leading to maintain a long term efficient plasticity even under transient deficiency in B-vitamins.…”

Folate and Vitamin B12 Gestational Deficiency Disturb Glucocorticoid Response in Hypothalamus Through N-Homocysteinilation of the Glucocorticoid Receptor

“…For several decades, this led to a supplementation program for pregnant women in some countries or food fortification in others [44][45][46]. Considering the brain specificity, which still develops and maturates its circuits after birth, several animal studies have also suggested a prolongation of vitamin status correction to favor a better birth status [47] or brain plasticity and maturation after birth [9,11]. Thus, some brain sub-regions still complete their circuits formation and connectivity based on a so-called hebbian mechanism, even long after birth while young individuals are subjected to internal and environmental factors [11,48].…”

“…Various mechanisms have been proposed to explain observed deleterious effects such as imbalanced proliferation and differentiation of neurons and also brain atrophy leading to cognitive decline and a durable behavioral change in offspring [5][6][7][8][9]. In the context of maternal deficiency in methyl donors, fetal programming is a mechanism described in specific brain functions defects such as locomotion coordination, learning and memory [10,11] . Nevertheless, numerous pathways have been shown to be involved after the deregulation of folate and/or methionine cycles [12][13][14][15][16].…”