An important goal of biomedical science is the design of treatments which prevent memory loss associated with aging. We have observed that administration of choline to rats during two specific perinatal periods results in enhanced performance on memory tests which persists throughout animals' lifetime. These behavioral changes are accompanied by neuroanatomical and neurochemical modifications of the brain. We have also described several mechanisms which lead to maintenance of high plasma choline concentrations early in the development of animals and humans. We hypothesize that, during critical perinatal periods, availability of choline influences the anatomical and biochemical organization of developing brain. These organizational changes influence memory performance in adult and aged animals. Choline administration may alter either cholinergic neurotransmission or membrane events or both. Choline is a precursor of a neurotransmitter, acetylcholine, in cholinergic neurons and cholinergic mechanisms are important in memory processes. Choline is also a precursor of phosphatidylcholine, sphingomyelin and plasmenylcholine; phospholipids which collectively are the most abundant components of all biological membranes. In addition, after oxidation to betaine, choline is a methyl donor, and thus its availability influencess the metabolism of methionine and folic acid. Our studies to date indicate that perinatal choline supplementation alters the biosynthesis of brain phosphatidylcholine and affects the development of brain cholinergic system. The overall goal of this study is to characterize the physiological processes which underlie the long- term memory enhancement associated with perinatal choline status and to characterize further the factors which influence choline availability to brain during the perinatal period. We propose to vary the supply of choline (using choline-deficient; choline-sufficient; and choline- supplemented treatment protocols) to male and female rats during defined periods of brain development [embryonic (E) days E12-17, postnatal (P) days P1-P15, days P16-P30, and days E12-P30] and to correlate behavioral measurements with: changes in the metabolism of choline; function of cholinergic neurons and membrane turnover; and changes in the anatomy of the brain. Since males and females respond differently to choline supplementation, we propose to investigate the effects of genetic sex and of gonadal steroids on these parameters. In order to characterize fully these processes throughout animals' life, these measurements will be made in animals between the embryonic day 17 and 30 months of age. The studies will provide new information on brain development and aging. The biochemical physiological and anatomical correlates of memory enhancement in aged rats associated with perinatal choline will be established. The ultimate goal of our studies is to relate our results to the age- associated changes in memory in humans, and to develop perinatal nutritional strategies which could benefit people.
NIH ExPorter
NIH ExPorter