Research from our laboratories has demonstrated that choline supplementation during perinatal development produces long-term facilitation of spatial memory, attention, and temporal processing, and inoculates against age-related memory decline, while deficiency of choline produces some deleterious effects. These long-lasting behavioral changes are accompanied by a complex pattern of changes in the neuroanatomy, neurochemistry, and neurophysiology of the septohippocampal system. The findings from several of the laboratories during the past funding period provide the foundation of the Aims of this Project. We have discovered that supplementation with folate, like choline , during the second half of pregnancy improve memory performance of the offspring. This finding is particularly important because the metabolism of choline and methyl-folate are closely interrelated. We propose to carefully characterize the nature of folate effects on memory and compare these effects to choline in order to determine if there might be a common mechanism underlying the effects of both these nutrients on memory function. As well, despite recommendations to supplement folate to women periconceptually to prevent neural tube defects, little is known about the long-term effects of folate during the latter half of pregnancy on brain or behavior.
We aim to characterize the behavioral, neuroanatomical, and neurochemical effects of prenatal folate supplementation and deficiency. We have also determined that during choline supplementation to the dam's diet, the majority of choline ingested by the dam is converted to phospatidylcholine (PtdCho) and then delivered to the fetus. In addition, we have observed that a lipoprotein containing apolipoprotein E (apoE) can effectively deliver PtdCho to cells in vitro. We suggest that an apoE lipoprotein is responsible for delivery of PtdCho to brain cells in vivo. In addition, we have determined that apoE deficient mice have a selective deficit in working memory that can be detected in mice as young at 4-5 months of age. We hypothesize that apoE deficient mice may actually be suffering from choline insufficiency through life because they cannot effectively deliver PtdCho to brain cells. Thus, the second aim of our Project is to examine the behavioral neuroanatomical and biochemical consequences of prenatal or lifelong choline supplementation to apoE deficient mice in order to determine whether we can rescue them from these lifelong behavioral deficits.

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Blusztajn, Jan Krzysztof; Slack, Barbara E; Mellott, Tiffany J (2017) Neuroprotective Actions of Dietary Choline. Nutrients 9:
Mellott, Tiffany J; Huleatt, Olivia M; Shade, Bethany N et al. (2017) Perinatal Choline Supplementation Reduces Amyloidosis and Increases Choline Acetyltransferase Expression in the Hippocampus of the APPswePS1dE9 Alzheimer's Disease Model Mice. PLoS One 12:e0170450
Tosto, Giuseppe; Monsell, Sarah E; Hawes, Stephen E et al. (2016) Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates. J Alzheimers Dis 49:1085-93
Blusztajn, Jan Krzysztof; Mellott, Tiffany J (2013) Neuroprotective actions of perinatal choline nutrition. Clin Chem Lab Med 51:591-9
Blusztajn, Jan Krzysztof; Mellott, Tiffany J (2012) Choline nutrition programs brain development via DNA and histone methylation. Cent Nerv Syst Agents Med Chem 12:82-94
Cheatham, Carol L; Goldman, Barbara Davis; Fischer, Leslie M et al. (2012) Phosphatidylcholine supplementation in pregnant women consuming moderate-choline diets does not enhance infant cognitive function: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 96:1465-72
Wong-Goodrich, Sarah J E; Glenn, Melissa J; Mellott, Tiffany J et al. (2011) Water maze experience and prenatal choline supplementation differentially promote long-term hippocampal recovery from seizures in adulthood. Hippocampus 21:584-608
Pleil, Kristen E; Glenn, Melissa J; Williams, Christina L (2011) Estradiol alters Fos-immunoreactivity in the hippocampus and dorsal striatum during place and response learning in middle-aged but not young adult female rats. Endocrinology 152:946-56
McGowan, Patrick O; Hope, Thomas A; Meck, Warren H et al. (2011) Impaired social recognition memory in recombination activating gene 1-deficient mice. Brain Res 1383:187-95
Wong-Goodrich, Sarah J E; Tognoni, Christina M; Mellott, Tiffany J et al. (2011) Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood. Brain Res 1413:84-97

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