Scientists discover why not enough choline results in fewer brain cells, poorer memory

03/16/04

CHAPEL HILL Five years ago, University of North Carolina at Chapel Hill researchers first reported finding that the nutrient choline played a critical role in memory and brain function by positively affecting the brain's physical development.

Differences in development influenced action, the scientists and their colleagues found. In animal experiments conducted at Duke University, both young and old rats performed significantly better on memory tasks if they received enough choline before birth compared with same-age rats whose mothers were fed choline-deficient diets. The latter showed deficits in the hippocampus and septums of their brains.

Because humans and rodents are so similar biologically, something comparable probably happens in humans, the investigators believe.

Now, working with nerve tissue derived from a human cancer known as a neuroblastoma, the UNC researchers have discovered why more choline causes stem cells -- the parents of brain cells -- to reproduce more than they would if insufficient choline were available.

A report on the findings will appear in the April issue of the Journal of Neurochemistry. Authors are doctoral student Mihai D. Niculescu and Dr. Steven H. Zeisel, professor and chair of nutrition at the UNC schools of public health and medicine. Dr. Yutaka Yamamuro, a former postdoctoral fellow in Zeisel's laboratory now with Nihon University in Japan, was a key contributor.

"We found that if we provided them with less choline, those nerve cells divided less and multiplied less," Zeisel said. "We then went on to try to explain why by looking at genes known to regulate cell division."

Scientists focused on cyclin-dependent kinase inhibitor 3 genes, which keep cells from dividing until a biochemical message turns the genes off, he said. They found exactly what they expected.

"We showed that choline donates a piece of its molecule called a methyl group and that gets put on the DNA for those genes," Zeisel said. "When the gene is methylated, its expression is shut down."

But when the gene is under-methylated -- such as when there's not enough choline in the diet -- then it's turned on -- halting or slowing nerve cell division, he said.

"Nature has built a remarkable switch into these genes something like the switches we have on the walls at home and at work," Zeisel said. "In this very complicated study, we've discovered that the diet during pregnancy turns on or turns off division of stem cells that form the memory areas of the brain. Once you have changed formation of the memory areas, we can see it later in how the babies perform on memory testing once they are born. And the deficits can last a lifetime."

The next step, Zeisel said, will be confirm that the same things happen in living mouse fetuses when the mothers receive either high or low doses of choline.

Developing babies get choline from their mothers during pregnancy and from breast milk after they are born, he said. Other foods rich in choline include eggs, meat, peanuts and dietary supplements. Breast milk contains much more of this nutrient than many infant formulas.

Pregnancy and nursing make female rats -- and presumably women -- especially susceptible to becoming choline deficient, the scientist said. The months before and immediately after childbirth appear to be special times when women need more in their diets.

Choline is a vitamin-like substance that is sometimes treated like B vitamins and folic acid in dietary recommendations. The body uses it in making the nerve messenger chemical known as acetylcholine and in building cell membrane -- the biological "wrapper" that keeps cells from leaking.

A paper Zeisel's laboratory published in January in the Journal of Nutrition also showed that the nutrient folic acid is not just critical for brain development in embryos during the earliest stages of pregnancy, but it's a key to healthy brain growth and function late in pregnancy too.

Humans and other mammals lacking sufficient folic acid shortly before they are born can suffer lifelong brain impairment, the earlier UNC animal studies indicated. Such research can never be done directly in growing human fetuses for obvious reasons.

"In the past few years, folic acid has been the single greatest success story in nutrition and in preventing birth defects," Zeisel said. "Spina bifida, the early birth defect in which the spinal cord doesn't close, and anencephaly, a condition in which the brain doesn't form normally, can be eliminated between 50 and 85 percent of the time if women get sufficient folic acid before they become pregnant."

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