The longterm objective of this program is to determine how, and by what mechanisms, changes in the morphology and cholingeric phenotype of basal forebrain neurons and their targets in the hippocampus and neocortex correlate with choline-induced facilitation of spatial memory in young adult and aged rats. First, we will use computer-assisted morphometry to determine if the same treatment periods which elicit behavioral improvement also produce these morphological changes in young adults rats. Second, we will use similar morphometric test to determine if perinatal choline treatment prevents the naturally-occurring cell atrophy in aged rats. Third, to test the hypothesis that morphological changes may result from prevention of naturally-occurring shrinkage during development and aging, we will examine juvenile rates for the effects of perinatal choline treatment on morphology and size of NGFR-positive septal neurons. Fourth, to determine if this morphological plasticity is selective for cholinergic and/or septal neurons, we will evaluate septal and striatal neurons in young adults and aged rats morphometrically using immunocytochemistry of choline acetyltransferase (ChAT) and GABAergic markers glutamic acid decarboxylase (GAD), parvalbumin and calbindin. Fifth, we will test the hypothesis that changes in cell size and/or redistribution of cells within nuclear boundaries may be related either to selective withdrawal of axon collateral during development/aging or to altered cycles of mitosis within the septum, using retrograde and anterograde tracing techniques and (3)H-thymidine autoradiography in juvenile and young adults rats. Sixth, we will quantify choline-dependent changes in NGH and NGFR protein by ELISA and their respective mRNAs by in situ hybridization in septum and hippocampus to determine if choline may be regulating septal cell size via growth factor production in the target region. These studies will help elucidate the roles of septal neurons size, collateral connectivity and cortical growth factor activity in spatial memory function. Since cholingeric activity and memory function decline in Alzheimer's disease, evaluation of early treatments which may prevent these declines should assist in the design of interventions in young adults permitting similar enhancement of septo-hippocampal function.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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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
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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