March 2004 Archives

Since the research showing choline enhances memory in the offspring mammals that received choline supplements during pregnancy first became public in the mid to late 1990s, researchers have wonder about the exact process by which this could be taking place.  Why did the memories of these offspring of mothers that received higher choline levels have better memories, and what was the exact chemical or molecular process by which it took place.

A research paper published in March, 2004 has identified what looks to be the exact process by which the memory enhancement occurs.  Of specific interest is that this new resarch paper has been done by the original researchers who did the early research that revealed the Choline/memory link. Following is a write up of the paper:

Paper: Prenatal Choline supplementation advances hippocampal development and enhances MAPK and CREB activation (by J. Blusztajn, C Williams, W. Meck, T Mellott).

Principal Findings of this research paper:

1. Prenatal choline supplementation enhances the ability of juvenile rats to use relational cues in a water maze task (demonstrating an advancement in the supplemented group of approximately a 20% improvement in their spacial navigational abilities.

A new study by Scott Swartzwelder and other researchers at Duke University Medical Center suggests that choline taken during pregnancy can result in "supercharged" brains for the infant.  The new study shows this is due to having bigger brain cells in key segments of the brain.

Choline, is found in egg yolks, liver and other meats - "exactly the kind of things people were told not to eat" due to their high cholesterol content, says Swartzwelder.

Dr. Shartzwelder believes their results in the rats could translate to humans, and indeed the US Institute of Medicine added choline to the list of essential nutrients, particularly for pregnant women, in its 2003 recommendations.

The implications of the study's findings are "potentially huge" Swartzwelder believes: "If it turns out that it's true in humans and can make people smarter their whole lives and forestall age-related memory decline - that's potentially a very exciting prospect."

Hannah Theobald, a nutrition scientist at the British Nutrition Foundation, calls the study "really interesting" but cautions that more research needs to be done before any recommendations can be made in humans.

Anatomy and physiology - Behavioural studies have shown giving choline to pregnant rats improves learning and memory in their offspring. The pups also suffer significantly less from failing memories as they get old.

However, it was not known whether choline's effects were on the general brain environment or whether it fundamentally changed the brain's cells.

"Our study is the first time anyone has shown that prenatal choline supplementation actually changes the anatomy and physiology of single brain cells," Swartzwelder told New Scientist. No adverse effects could be seen in the rats, he adds.

The team gave pregnant rats three to four times their normal intake of choline for six days. Gestation lasts about 21 days in rats, and the period during which the rats were fed extra choline roughly corresponds to the start of the third trimester in women.

Electrical signals  - The pups born were raised to adulthood and then their brains were examined, in particular the hippocampus - the area of the brain critical for learning.

This part of the brain was sliced in a way that preserved its internal circuitry and kept it alive. A tiny electrode was then used to recording the behaviour of each cell. The neurons of rats born to mothers given extra choline fired electrical signals more rapidly and for longer periods, indicating a capacity to communicate more easily.

The team then injected a biological dye into the neurons to look at their shape and structure. The cells from rats receiving prenatal choline supplements were substantially bigger than those from rats that did not.

"We are looking at consistent changes in the range of 20 to 25 per cent," says Swartzwelder. "These are bigger cells with more dendrites, the areas of the cell specific to receiving incoming signals." He says the combined changes induced by choline in the physiology and anatomy of the brain cells would "hotwire" the system.

Better membranes  The team does not know exactly how choline boosts brains, but it is known to contribute to the building of cell membranes during the embryo stage of development. "My bet is it has something to do this," Swartzwelder says.

Previous work by Steven Zeiser at the University of North Carolina has shown choline alters a crucial gene by adding a methyl group on to it. This switches off the gene, CDKN-3, which usually inhibits cell division in the memory regions of the brain.

There is little information on how much choline women currently take. "But don't be afraid of eggs," Swartzwelder suggests. "I used to eat a low fat diet - I've started eating eggs and I'm not even pregnant!"

However, Theobald warns that some foods rich in choline should be avoided during pregnancy. For example, liver is also high in retinol which can cause birth defects. And certain choline-rich fish like swordfish and tuna can also have a high mercury content, which is harmful to fetuses.

Original Source of Research Study Information:  Journal of Neurophysiology (vol 91 April issue)

The important nutrient choline "super-charged" the brains of animals that received supplements in utero, making their cells larger and faster at firing electrical "signals" that release memory-forming chemicals, according to a new study.

These marked brain changes could explain earlier behavioral studies in which choline improved learning and memory in animals, say the researchers from the departments of pharmacology and psychiatry at Duke University Medical Center and from the Durham VA Medical Center.

The implications for humans are profound, said the researchers, because the collective data on choline suggests that simply augmenting the diets of pregnant women with this one nutrient could affect their children's lifelong learning and memory. In theory, choline could boost cognitive function, diminish age-related memory decline, and reduce the brain's vulnerability toxic insults.

The Duke group is part of a national team of scientists who are exploring the benefits of prenatal choline supplementation on learning and memory. This ongoing research has been instrumental in the Institute of Medicine's decision to elevate choline to the status of an essential nutrient for humans -- particularly pregnant and nursing women, the scientists said.

Results of their study, led by Qiang Li, M.D., of Duke and the Durham VAMC, will be published in the April issue of Journal of Neurophysiology.

"Previous studies at Duke have shown that choline-supplemented animals are smarter and have a greater learning capacity, but we hadn't known until now whether the cells that make up memory-relevant brain circuits are changed by choline" said Li. "Choline didn't just change the general environment of the brain, it changed the fundamental building blocks of brain circuits -- the cells themselves."

Choline is a naturally occurring nutrient found in egg yolks, milk, nuts, fish, liver and other meats as well as in human breast milk. It is the essential building block for a memory-forming brain chemical called acetylcholine, and it plays a vital role in the formation of cell membranes throughout the body.

In the current study, the researchers explored the effects of choline on neurons in the hippocampus, a brain region that is critical for learning and memory. They fed pregnant rats extra amounts of choline during a brief but critical window of pregnancy, then studied how their hippocampal neurons differed from those of control rats.

The researchers found that hippocampal neurons were larger, and they possessed more tentacle-like "dendrites" that reach out and receive signals from neighboring neurons.

"Having more dendrites means that a neuron has more surface area to receive incoming signals," said Scott Swartzwelder, Ph.D., senior author of the study and a neuropsychologist at Duke and the Durham VA Medical Center. "This could make it easier to push the neuron to the threshold for firing its signal to another neuron." When a neuron fires a signal, it releases brain chemicals called "neurotransmitters" that trigger neighboring neurons to react. As neurons successively fire, one to the next, they create a neural circuit that can process new information, he said.

Not only were neurons structured with more dendrites, they also "fired" electrical signals more rapidly and sustained their firing for longer periods of time, the study showed. The neurons also rebounded more easily from their resting phase in between firing signals. These findings complement a previous study by this group showing that neurons from supplemented animals were less susceptible to insults from toxic drugs that are known to kill neurons.

Collectively, these behaviors should heighten the neurons' capacity to accept, transmit and integrate incoming information, said Swartzwelder.

"We've seen before that the brains of choline-supplemented rats have a greater plasticity -- or an ability to change and react to stimuli more readily than normal rats -- and now we are beginning to understand why," he said.

The researchers demonstrated these neuronal behaviors by placing tiny electrodes within the neurons. Then, they prompted neurons to fire signals by changing the electrical voltage across the cells, (called depolarization). As neurons began to fire, they measured their firing rates and the recovery interval between each firing.

"Overall, we found that neurons in choline-exposed rats were more excitable, more robust in their physiologic response," said Wilkie Wilson, Ph.D., a Duke pharmacologist and member of the team at the Durham VAMC. "We've demonstrated a measurable change in brain cells prompted by moderate amounts of choline given during a narrow window of prenatal development."

Biochemical studies on the brain effects of choline at the University of North Carolina at Chapel Hill and Boston University have complemented the Duke findings, Wilson said.

Steven Zeisel, M.D.,at the University of North Carolina at Chapel Hill, has demonstrated that choline alters a gene called CDKN-3 by adding a "methyl group" of atoms to the gene. The methyl group switches off the gene and, in doing so, uninhibits the cell division process in the memory centers of the brain.

Tiffany Mellott and Jan Krzysztof Blusztajn, Ph.D., at Boston University -- in collaboration with Christina Williams, Ph.D., and Warren Meck, Ph.D., at Duke, -- recently found that two hippocampal proteins known to participate in learning and memory, called MAPK and CREB, are activated to a greater extent in the animals prenatally supplemented with choline. These studies provide biochemical correlates to the new data reported by the Swartzwelder group.

Source: Duke University