Choline - The Key to a Better Memory? Fetal Origins of Adult Brain Function

Choline
Choline has been shown to play a critical role in brain development.

Steven H. Zeisel, MD, PhD| Department of Nutrition | School of Public Health and School of Medicine | University of North Carolina at Chapel Hill | Chapel Hill, NC 

Most pediatricians may have never learned about choline in medical school, yet new research indicates that this nutrient has a critical role in brain development. We know that women with inadequate intake of folate during the very early stages of pregnancy have a greater risk of having a baby with neural tube birth defects. Now we're beginning to understand how choline intake during pregnancy affects brain development and memory in the baby. In fact, early animal studies have linked prenatal exposure to higher-than-normal amounts of choline in the womb with improved learning and memory.

Though we are already witnessing new food products that are adding choline to their recipes, human studies are just beginning, so at this point there are no conclusive recommendations for pregnant mothers and their babies. However, we may soon find a benefit from boosting choline intake, either with food sources or supplements.

What is Choline?
Choline is a nutrient required by humans,1 but its importance was not officially recognized until 1998. Therefore, many pediatricians may have never learned much about it. 

Recent research indicates that choline availability modulates brain development in the fetus and infant, and in the adult is important for normal liver and muscle function. It's used to make nerve transmitters, cell membranes and other important chemicals that are essential to the body's functioning. It's also the major source of methyl-groups in the diet, and affects very low-density lipoprotein transport from the liver.2-3

Although our bodies are able to synthesize choline, we're just beginning to understand the need for choline intake in the diet. Common genetic variations that occur in approximately half of the population (single nucleotide polymorphisms) contribute to variation in human choline dietary requirements, and though the recommended intake is about half a gram a day, some individuals require significantly more. In particular, when women are pregnant or breastfeeding, they can become depleted of choline because there is a greater demand for it. 

Choline is critical during fetal development, when it influences brain stem cell proliferation and apoptosis (cell suicide), thereby altering brain and spinal cord structure and function. Choline availability to the fetus also permanently influences memory function. At least in part, this effect of choline on brain development is mediated by altering the on-off switches that control genes (epigenetic changes involving DNA methylation). In adults deprived of dietary choline, fatty liver, liver cell death and muscle cell death (rhabdomyolysis) ensues.

What Foods Contain Choline?
Choline is widely distributed in foods.4-5 One egg has approximately 200 milligrams of choline. Other sources include chicken liver (290 milligrams), beef liver (418 milligrams), chicken (roasted with no skin, 78 milligrams), wheat germ (152 milligrams), and soybeans (115 milligrams).* Human milk is rich in choline content. In addition, choline is found in milk, nuts, fish, and certain vegetables. These dietary sources are complemented by a capacity to form choline, mainly in the liver,6 but this internal source is meaningful only in women with estrogen. 

How Much Choline do Humans Require?
Most men and postmenopausal women (about 80%), but less than half of premenopausal women, develop signs of organ dysfunction (fatty liver, liver damage, or muscle damage) when fed a diet low in choline.7-8 This difference in dietary requirement occurs because estrogen induces the gene (Pemt) in the liver responsible for biosynthesis of choline and allows premenopausal women to make more of their needed choline endogenously. In addition, there is significant variation in the dietary requirement for choline that can be explained by common genetic variations.9-10

Dietary choline deficiency in humans results in fatty liver (hepatosteatosis)11-12 because phosphatidylcholine (made from choline) is required for secretion of very low-density lipoprotein (VLDL) from the liver, and this is the major route for the export of excess triglyceride.13-14 Also, choline deficiency in humans causes liver damage15-18 because liver cells die by apoptosis (cell suicide) when choline-deprived.10-21 In addition, we now recognize that choline deficiency in humans can cause muscle damage.22 This occurs because muscle membranes are more fragile and because of induction of apoptosis via mechanisms similar to those described in the liver.23-24

Understanding the dietary choline requirement is important for clinical practice because low plasma choline concentration occurs in up to 84% of patients that require total parenteral nutrition (TPN)25-30
as does liver damage (elevated transaminases)31-32 and fatty liver.33 In some patients, the hepatic steatosis associated with TPN resolved with choline-supplementation and returned when standard TPN was reinstituted.34

Evidence that choline was required by healthy humans—along with the effects of choline deficiency in TPN patients—built up in the early 1990s. In 1998 the U.S. Institute of Medicine's Food and Nutrition Board recognized that dietary choline was essential for humans and established an Adequate Intake (AI) and Tolerable Upper Limit (UL) for choline.35 (See chart, "Dietary Reference Intake Values for Choline.") For babies, the recommendation was based on the choline content of human milk. For children, the calculation was a direct extrapolation from adults based on body weight. The official recommendation for pregnant women is 450 mg/day; for women who are breastfeeding it is 550 mg/day. For adult men the current recommendation is 550 mg/day; but recent data from our laboratories suggest that 825 mg/day would be more appropriate (publication submitted). 

Moms Provide Choline to their Fetuses and Babies
During pregnancy and lactation mothers export large amounts of choline to the fetus or baby. This depletes maternal stores of choline36-37 as reflected by maternal plasma choline concentrations.38 Thus, it is fortunate that estrogen induces the capacity to form choline in liver (see earlier discussion), as even with this extra capacity maternal choline stores are depleted.

Genetic variations that increase susceptibility to choline deficiency (and that occur in half the population) might be important for identifying women who need more dietary choline during pregnancy and lactation. This is a real possibility, as the data of Shaw and colleagues show that women in the U.S. vary enough in dietary choline intake (from <300mg/d to >500 mg/d) to influence the risk that they will have a baby with a birth defect.39

Choline and the Neural Tube
The placenta delivers choline to the fetus, building up higher concentrations in the fetus than in the mother.40 Choline concentration in amniotic fluid is 10-fold greater than that present in maternal blood (Zeisel, unpublished observations). Plasma or serum choline concentrations are 6-7-fold higher in the newborn infant than they are in the adult.41-42High levels of choline circulating in the neonate presumably ensure enhanced availability of choline to tissues. Human milk provides large amounts of choline to the neonate; choline content of infant formulas vary.43

Pediatricians are already familiar with the role that folic acid plays in development of the brain and spinal cord. This vitamin is required during the critical period when the neural tube is formed, and when it is not available neural tube defects occur.44 Folate and choline are both important in methyl-group metabolism, and they participate in two parallel pathways. (See sidebar, "Choline and Folate, Working Together.") When one pathway is not working well, the other can substitute. For this reason, a mother who eats a diet low in folate and in choline would have maximal impairment of methylation reactions. Thus, it is not surprising that choline availability is also important during the stage of fetal development when the neural tube is closing (around gestational day 22 in humans). 

In rodents, choline is needed for normal neural tube closure,45-46 and in humans, women in the lowest quartile for dietary choline intake had 4x the risk (compared with women in the highest quartile) of having a baby with a neural tube defect.47

Choline and the Memory Center
In research with laboratory animals, supplemental choline given to mothers during critical periods of development results in offspring with better brain development and who perform better on memory tests later in life. Animals whose mothers are deprived of choline during that critical period of pregnancy do worse on memory tests. 

Choline is important in later periods of pregnancy when the memory center of the brain (hippocampus) is developing. Perturbed choline availability in the maternal rodent's diet mediated significant and irreversible changes in hippocampal function in the adult rodent offspring. More choline (about 4x dietary levels fed to mother) during days 11-18 of gestation in the rodent increased hippocampal neural progenitor cell proliferation,48-49decreased apoptosis in these cells,50-51 enhanced long term potentiation (LTP; an electrophysiological property of hippocampus associated with memory storage) in the offspring when they were adult animals 52-54 and enhanced visuospatial and auditory memory by as much as 30% in the adult animals throughout their lifetimes.55-61

Indeed, the memory of adult rodents deteriorates as they age, and offspring exposed to extra choline in utero do not show this "senility."62-65 Rodents fed choline-deficient diets during late pregnancy have offspring with diminished proliferation of the stem cells that form the memory center of the brain, and at the same time have increased rates of cell suicide in this developing brain region.66-67 When these offspring are adult animals, this results in changes in the electrical properties of the memory center (insensitivity to long-term potentiation (LTP)),68 and permanently decremented visuospatial and auditory memory.69 The effects of perinatal choline supplementation on memory were initially found using radial-arm maze tasks and the Sprague-Dawley rat strain, but other laboratories have found similar results using other spatial memory tasks, such as the Morris water maze70-71, using passive avoidance paradigms72 and measures of attention,73 using other strains of rats such as Long-Evans,74-76 and using mice.77

The effects of choline supplementation in utero were also detected in studies on effects of fetal alcohol exposure, where supplementation with choline attenuated behavioral alterations but not motor abnormalities.78-79 Thus, we have an excellent example of the fetal origins of adult brain function. Choline supplementation during a critical period in pregnancy causes lifelong changes in brain structure and function. However, studies also show that trying to make up for the deficiency later in life doesn't result in subsequent gains in development or memory. In other words, if you don't get the choline during the critical period of development, you are never able to make it up.

The Mechanism of Action
The mechanism whereby a choline supplement supplied to the dam results in a permanent change in memory of her offspring is not completely clear. Our hypothesis is that the effects we have seen in animals are due to choline-induced changes in the methyl switches that turn on and off gene expression.

The effects of choline on neural tube closure and on brain development are, at least in part, mediated by changes in the expression of genes. Dietary choline deficiency not only depletes choline and choline metabolites in rats, but also decreases availability of the important methyl-donor for biochemical reactions (S-adenosylmethionine). 80-81 Genes have on-off switches (promoters) that are regulated by the addition of a methyl-group to DNA; choline deficiency results in undermethylation of DNA.82-83 DNA methylation occurs at cytosine bases that are followed by a guanosine (CpG sites)84 and influences many cellular events, including gene transcription, genomic imprinting and genomic stability.85-87

In mammals, about 60 to 90% of CpG sites in the on-off switches of genes are methylated.88 When these sites are not methylated, gene expression is altered;89decreased methylation is usually associated with increased gene expression.90 In choline-deficient cells in culture, and in fetal rodent brains from mothers fed choline-deficient diets, methylation of the CDKN3 gene on-off switch is decreased, resulting in over expression of this gene which inhibits cell proliferation.91-92

There are other examples of maternal diet altering gene methylation with resultant lifelong changes in phenotype of the offspring. For example, feeding pregnant Pseudoagouti Avy/a mouse dams a choline methyl-supplemented diet permanently altered expression of a gene in their offspring that controls hair color.93-94

Applications for Pregnant Women
Whether these remarkable observations in rodents are applicable to humans is not known. The development of the rodent brain is in many ways similar to the development of the human brain. Of course, human and rat brains mature at different rates, with rat brain comparatively more mature at birth than is the human brain. In humans, the architecture of the hippocampus continues to develop after birth, and by 4 years of age it closely resembles adult structure.95 This area of brain is one of the few areas in which nerve cells continue to multiply slowly throughout life.96-97 However, the observation by Shaw and colleagues98 that women eating low choline diets have greatly increased risk for having a baby with a neural tube defect supports the suggestion that the basic research in rodents is applicable to the human condition. 

Are we varying the availability of choline when we feed infant formulas instead of breast milk? Does the form and amount of choline ingested by women during pregnancy and lactation contribute to variations in memory observed between humans? These questions are worthy of additional research. We are working on a pilot study assessing choline supplementation in pregnant women. The women will get the equivalent of twice as much choline as is in a normal diet by eating three eggs a day or taking a supplement from their 15th week of pregnancy until a month after giving birth. Infant-oriented memory tests will then be performed on their babies when they are 10 months old and 1 year old. This is a small study, but if the effect is large, it won't take long to see it.

To encourage optimal health of the fetus, pediatricians should make sure that lactating mothers eat a varied diet that contains sources of choline, as the diet directly effects breast milk choline content. There is probably no downside to eating as many as three eggs a day if a woman is pregnant, but it is probably more important to eat a healthy, balanced diet. We may identify a benefit from boosting choline, either with food sources or with supplements, but at this point I would be cautious.

If an infant formula is being used to substitute for breast-feeding, choose a formula with choline content similar to human milk (approximately 131 mg/L of choline equivalents), as formulas can vary significantly in choline content.00 (Note that several infant formulas are currently being reformulated so that they contain more choline). 

Because brain development continues for several years after birth, pediatricians need to be concerned that infant diets contain adequate sources of choline. Because choline is found in many foods, a varied diet is best; if an infant is on a diet that is restricted for any reason, a dietitian should review it for choline content. The United States Department of Agriculture makes food composition information available that contains this information (http://www.nal.usda.gov/fnic/foodcomp/Data/Choline/Choline.html).

Finally, the benefits of choline are not restricted to just pregnant women. Brain development continues in humans from 25 weeks gestation through years after birth. Stem cells are even dividing in middle-aged brains. Though there is a critical period in early development in which lack of choline cannot be made up, choline intake may have some (though smaller) effect on brain throughout a person's lifetime. In addition, adults need choline for normal liver and muscle function. Therefore, everyone should aim for a diet with great variety that includes foods rich in choline.

Steve H. Zeisel, M.D., Ph.D., is the Sarah Graham Keenan Distinguished University Professor in Nutrition, and Associate Dean for Research at the School of Public Health, University of North Carolina at Chapel Hill. He is the director of one of eight national centers of excellence in human clinical nutrition research funded by the National Institutes of Health. His research focuses on nutrition and brain development, environmental agents that modify brain development, and human requirements for the nutrient choline. Dr. Zeisel has written more than 200 publications in peer-reviewed journals, and is the author of more than 70 review articles and book chapters.

References

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  34. Ibid.
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Sidebar References

S1. Finkelstein, J. D. (2000) Pathways and regulation of homocysteine metabolism in mammals. Semin Thromb Hemost 26, 219-225. 
S2. Olthof, M. R., van Vliet, T., Boelsma, E., and Verhoef, P. (2003) Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J. Nutr. 133, 4135-4138. 
S3. Kim, Y.-I., Miller, J. W., da Costa, K.-A., Nadeau, M., Smith, D., Selhub, J., Zeisel, S. H., and Mason, J. B. (1995) Folate deficiency causes secondary depletion of choline and phosphocholine in liver. J. Nutr. 124, 2197-2203. 
S4. Selhub, J., Seyoum, E., Pomfret, E. A., and Zeisel, S. H. (1991) Effects of choline deficiency and methotrexate treatment upon liver folate content and distribution. Cancer Res. 51, 16-21. 
S5. Varela-Moreiras, G., Selhub, J., da Costa, K., and Zeisel, S. H. (1992) Effect of chronic choline deficiency in rats on liver folate content and distribution. J. Nutr. Biochem. 3, 519-522.

S1. Finkelstein, J. D. (2000) Pathways and regulation of homocysteine metabolism in mammals. Semin Thromb Hemost 26, 219-225. 
S2. Olthof, M. R., van Vliet, T., Boelsma, E., and Verhoef, P. (2003) Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J. Nutr. 133, 4135-4138. 
S3. Kim, Y.-I., Miller, J. W., da Costa, K.-A., Nadeau, M., Smith, D., Selhub, J., Zeisel, S. H., and Mason, J. B. (1995) Folate deficiency causes secondary depletion of choline and phosphocholine in liver. J. Nutr. 124, 2197-2203. 
S4. Selhub, J., Seyoum, E., Pomfret, E. A., and Zeisel, S. H. (1991) Effects of choline deficiency and methotrexate treatment upon liver folate content and distribution. Cancer Res. 51, 16-21. 
S5. Varela-Moreiras, G., Selhub, J., da Costa, K., and Zeisel, S. H. (1992) Effect of chronic choline deficiency in rats on liver folate content and distribution. J. Nutr. Biochem. 3, 519-522.
S1. Finkelstein, J. D. (2000) Pathways and regulation of homocysteine metabolism in mammals. Semin Thromb Hemost 26, 219-225. 
S2. Olthof, M. R., van Vliet, T., Boelsma, E., and Verhoef, P. (2003) Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J. Nutr. 133, 4135-4138. 
S3. Kim, Y.-I., Miller, J. W., da Costa, K.-A., Nadeau, M., Smith, D., Selhub, J., Zeisel, S. H., and Mason, J. B. (1995) Folate deficiency causes secondary depletion of choline and phosphocholine in liver. J. Nutr. 124, 2197-2203. 
S4. Selhub, J., Seyoum, E., Pomfret, E. A., and Zeisel, S. H. (1991) Effects of choline deficiency and methotrexate treatment upon liver folate content and distribution. Cancer Res. 51, 16-21. 
S5. Varela-Moreiras, G., Selhub, J., da Costa, K., and Zeisel, S. H. (1992) Effect of chronic choline deficiency in rats on liver folate content and distribution. J. Nutr. Biochem. 3, 519-522.

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