The hypothesis that underlies this Program Project is that brain development and adult cognition are modified during specific periods of pre- and postnatal development by changes in availability of two essential nutrients, choline and folate. The goals of this project are to: 1) further our understanding of the mechanisms by which choline supplemented to the diet of pregnant rats and mice leads to improved memory capacity and precision of the offspring compared to offspring of control-fed mothers and 2) begin a series of translational studies using mouse models of human genetic conditions characterized by abnormal choline metabolism. Recent findings have suggested that alterations in neurogenesis in the hippocampal formation may be associated with the ease of new memory formation. Because prenatal choline supplementation leads to improved memory in young animals, less age-related memory decline in old animals, and is accompanied by modifications in hippocampal physiology, alterations in levels of growth factors and changes in the morphology of cholinergic projections, one aim of this project is to investigate the effects of choline availability prenatally on neuron proliferation and survival in young and aging rats. The results of these studies will provide important new information about whether maternal diet can influence brain plasticity of the offspring throughout their lifespan. Recently, we extended our behavioral findings to mice, determined that supplementation with another methyl donor, relate, during prenatal development also aids cognition, and completed an initial translational study which shows that choline supplementation during prenatal development can rescue behavioral deficits seen in mutant mice (i.e, Apoe deficient) that normally suffer from choline insufficiency. These new data suggest that environmental scaffolding with choline can rescue a genetically imposed memory deficit. To investigate further this possibility we propose a series of translational studies using mice alterations in choline and methyl metabolism. Because several of the genes involved in choline and methyl metabolism are known to display considerable polymorphism and some of these mutations result in abnormal proteins and disease phenotypes in humans, studies of how genotype (both maternal and offspring) affects individual requirements for choline intake is critical for the design of human studies on the effects of perinatal exposure to choline on cognition.
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