The Program Project's major premise is that the development of brain during critical periods of embryogenesis is vulnerable to changes in diet, specifically changes in choline or folate intake. The Project teams finds that variations in maternal choline intake during days 12-17 of pregnancy causes biochemical, structural, electrophysiological and behavioral changes consistent with this hypothesis. For variation in dietary folate, the team describes similar behavioral changes. Project #5 of the Program Project focuses on the events that are occurring in fetal brain right at the time that maternal diet is manipulated. Some of our proposed studies build on the metabolic approached used in the previous funding period. We described changes in fetal and metal choline metabolism when mother's choline intake was varied. We characterized the choline content of human milk and infant formulas. We found that pregnancy depletes stores of choline in rats, and makes them vulnerable to choline deficiency. For variation in dietary folate, the team describes similar behavioral changes. Project #5 of the Program Project focuses on the events that are occurring in fetal brain right the time that maternal diet is manipulated. Some of our proposed studies build on the metabolic approach used in the previous funding period. Some of our proposed studies build on the metabolic approach used in the previous funding period. Some of our proposed studies build on the metabolic approach used in the previous funding period. We described changes in fetal and maternal choline metabolism when mother choline intake was varied. We characterized the choline content of human milk an infant formulas. We found that pregnancy depletes of choline in rats, and makes them vulnerable to choline deficiency. We described changes in fetal and maternal choline metabolism when mother's pregnancy depletes stores of choline in rats, and makes them vulnerable to choline deficiency. We hypothesize that intermittent periods when choline supply to developing fetal brain is not optimal; dietary choline supplements prevent this. Choline and folate metabolism are highly inter-related and we hypothesize that there may be a common mechanism explain both the choline and folate effects. We will vary dietary choline and folate to pregnant rats during E12-18 an determine whether choline perturbs folate or homocysteine metabolism and visa versa in the rat dam's liver and in fetal hippocampus, septum and amygdala on days E15, E16, E17, E18, E20 and P6. We will also measure concentration of putative apoptosis-inducers in the fetal brains. In an interactive project to be conducted with the Williams project, we will determine whether transfer of choline from dam to fetal brain is inhibited in APoE knockout mice. During the previous funding period we made the discovery that choline deficiency increases apoptosis, and diminishes mitosis in septum and hippocampus. The major premise for this section of the Program Project is that diet-induced changes in mitosis and apoptosis within critical areas of brain are the earliest events which eventually result in the changes in structure, electrophysiology and function of brain that the Program Project team observes in adult and aged rats. We proposed studies which will more completely characterize the relationships between maternal diet (choline and folate) and the timing and anatomic distribution of cell replication and apoptosis in fetal rat brain. We will vary dietary choline and folate to pregnant rats during E12-18 and assess in fetal hippocampus, septum and amygdala the three dimensional distribution pattern and extent of mitosis and apoptosis on days E15, E16, E17, E18, E20 and P6. We will determine the birth date of cells in areas identified as hot spots for apoptosis, and the type of cell (marker proteins) in areas identified as hot spots for apoptosis and mitosis. In ApoE control mice we will determine if the ApoE knockout mouse appears as if it were choline deficient in terms of apoptosis and mitosis in fetal brain on day E18. In cultured hippocampal and septal cells, we will conduct studies on molecular mechanisms for choline (folate) deficiency apoptosis. We focus on elements of the pathways that are likely to be unique to choline metabolism and on elements that are likely to be amenable to manipulation by pharmacologic interventions which could be used by investigators studying dietary manipulation of memory and long term potentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG009525-08
Application #
6098293
Study Section
Project Start
1999-04-15
Project End
2000-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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
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
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
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
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
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
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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