The birth of new neurons appears to facilitate certain types of complex learning.

The birth of new neurons—which continues in the adult brain but slows with age—appears to facilitate certain types of complex learning, according to new research in mice. The new experiments suggest that drugs to encourage the proliferation of stem cells in the brain might one day enhance learning ability in older adults and in those with Alzheimer's disease or other neurodegenerative disorders.

Howard Hughes Medical Institute investigator Ronald M. Evans and his colleagues reported their findings January 30, 2008, in an advance online publication of the journal Nature. Evans collaborated on the studies with senior author Fred Gage of the Salk Institute and first author Chun-Li Zhang, who is a postdoctoral fellow in Evans's laboratory at Salk.

“This is very strong genetic evidence that adult neural stem cells are important in creating new memories, which was not known before.”

Ronald M. Evans

Stem cells are immature progenitor cells that differentiate to give rise to more specialized cells in the body. In earlier studies, Gage and former HHMI investigator Charles Stevens had grown neural stem cells in the lab and shown that they can form functioning neurons. They used stem cells that were isolated from the hippocampus, the brain's major learning center. In adults, factors such as exercise, stress, and learning can spur neural stem cells to differentiate into new neurons.

“However, there was no proof that these cells had any purpose other than just becoming part of the club of functioning neurons,” said Evans. “There was no evidence that they were doing anything especially useful.” In fact, he said, studies by other researchers had indicated that the stem cells do not play a significant role in hippocampal function.

To better understand the role of neural stem cells in the adult brain, the researchers engineered mutant mice in which they could selectively eliminate TLX, a gene that regulates neural stem cell proliferation. The technique allowed them to knock out the gene in adult animals, after the animals were fully developed.

Test tube studies of stem cells from the mutant mice confirmed that without TLX, neural stem cell proliferation slowed dramatically. They also found that eliminating TLX altered the activity of more than 400 other genes, many of which were known to be involved in the growth of new nerve cells.

“These findings gave us the basis for believing that when we knocked out this gene in the mice, we would terminate stem cell proliferation in their brains,” said Evans. “We could allow these animals to grow normally, stop neurogenesis at a time of our choosing, and then ask whether it had any measurable impact.”

When the scientists shut off stem cell growth in this way, the animals' health and behavior did not change noticeably. The mice without TLX were just as capable of simple learning tasks—such as learning to associate a tone with a mild electric shock—as their normal counterparts. This was surprising, because previous studies had shown that the creation of new nerve cells is required for this type of fear conditioning in mice.

Knocking out TLX did, however, cause deficiencies in the dentate gyrus, a region of the hippocampus believed to contribute to the formation of new memories. The researchers next tested the knockout animals' ability to form more complex memories. They measured how well the mice learned and remembered the location of a platform submerged in a tank of opaque water. In those tests, the knockout mice showed significant deficits in learning and memory.

“Their learning curve goes way off,” said Evans. “After they learned where the platform was, the mutant mice were more forgetful, swimming around a lot more than normal mice, missing the platform.

“We were very surprised to find that while these stem cells are not required for learning and memory, they greatly facilitate the process,” he said. “The presence of a normal stem cell population made learning and memory much more effective and efficient. While these mice can still do some kinds of learning, they can't do complex learning effectively. This is very strong genetic evidence that adult neural stem cells are important in creating new memories, which was not known before.”

Evans said that their targeted knockout strategy offers an important technical advance. While neural stem cells can be killed with toxins or radiation, those techniques also damage other cells in the brain and nervous system. “Our technique puts in the cross hairs just the key cells you want to eliminate and does not have a collateral impact on any other cells,” he said.

By demonstrating that neurogenesis can be reduced dramatically by eliminating TLX, Evans and his colleagues have opened an important new research pathway. “Now we can purify this stem cell population and dissect it molecularly to ask how TLX helps create the stem cell environment,” he said. And Evans noted that researchers can manipulate neurogenesis with drugs or genetic techniques that target TLX.

“We can ask whether drugs that enhance neurogenesis could improve learning and memory in diseases such as Alzheimer's, in which learning and memory are compromised,” he said. “Also, it is known that neurogenesis naturally decreases with age; and an important question is whether stimulating neurogenesis in older people could improve memory. Our belief is that it will probably be the case.”

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