Brain Development

During the fetal and neonatal period, the availability of choline to tissues fluctuates because of the varied dietary intake of choline among neo-nates and the slower oxidation of choline during the first weeks of life. However, ensured availability of this amine appears to be vital to infants because organ growth, which is extremely rapid in the neonate, requires large amounts of choline for membrane biosynthesis. Choline is also particularly important during the neonatal period because it appears to change brain function. There are two sensitive periods in rat brain development during which treatment with choline produces long-lasting enhancement of spatial memory that is lifelong and has been detected in elderly rats. The first occurs during embryonic days 12-17 and the second, during postnatal days 16-30. Choline supplementation during these critical periods elicits a major improvement in memory performance at all stages of training on a 12-arm radial maze.

The choline-induced spatial memory facilitation correlates with altered distribution and morphology of neurons involved in memory storage within the brain, with biochemical changes in the adult hippocampus and with electrophysiological changes in the adult hippocampus. It also correlates with changes in proliferation, apoptosis, and migration of neuronal precursor cells in the hippocampus during fetal brain development. When pregnant rats were treated with varying levels of dietary choline between day 12 and 18 of gestation, it was found that choline deficiency significantly decreased the rate of mitosis in the neuroepithelium of fetal brain adjacent to the hippocampus. An increased number of apoptotic cells were found in the region of the dentate gyrus of choline-deficient hippocampus compared to controls. Modulation of dietary choline availability changed the distribution and migration of precursor cells produced on embryonic day 16 in the fimbria, primordial dentate gyrus, and Ammon's horn of the fetal hippocampus. Choline deficiency also decreased the migration of newly proliferating cells from the neuroepithelium into the lateral septum, thus indicating that the sensitivity of fetal brain to choline availability is not restricted to the hippocampus. The expression of TOAD-64 protein, an early neuronal differentiation marker, increased in the hippocampus of cho-line-deficient day E18 fetal brains compared to controls. These findings show that dietary choline availability during pregnancy alters the timing of mitosis, apoptosis, migration, and the early commitment to neuronal differentiation by progenitor cells in fetal brain hippocampus and septum, two regions known to be associated with learning and memory.

A disruption in choline uptake and metabolism during neurulation produces neural tube defects in mouse embryos grown in vitro. Exposing early somite staged mouse embryos in vitro with an inhibitor of choline uptake and metabolism, 2-dimethy-laminoethanol (DMAE) causes craniofacial hypoplasia and open neural tube defects in the fore-brain, midbrain, and hindbrain regions. Embryos exposed to an inhibitor of phosphatidylcholine synthesis, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) exhibit similar defects or expansion of the brain vesicles and a distended neural tube at the posterior neuropore as well as increased areas of cell death. Thus, choline like folic acid is important during neural tube closure.

Are these findings in rats likely to apply to humans? We do not know. Human and rat brains mature at different rates; rat brain is comparatively more mature at birth than is the human brain, but in humans synaptogenesis may continue for months after birth. Are we varying the availability of cho-line when we substitute infant formulas for human milk? Does choline intake in infancy contribute to variations in memory observed between humans? These are good questions that warrant additional research.

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