Scientists have found that a lessened supply of new nerve cells in the adult brain apparently triggers short-term memory loss typically associated with aging, setting the stage for one day developing therapies designed to maintain a steady supply of fresh neurons to keep the mind sharp.

"Neurogenesis (nerve-cell production) goes down with age … it's known that with old age there's a decrease in short- term memory," says Ronald Evans, a genetics professor at the Salk Institute for Biological Studies in La Jolla, Calif. "We know that if we can increase the process, we know what the consequence could be in the brain, which would be to increase short-term learning and memory."

"New experiences, new memories [and] new learning [are] greatly facilitated by neurogenesis," he adds. "Neurogenesis is in fact a fundamental feature of learning and memory. … Neurogenesis goes down with age; and, it's known that with old age there's a decrease in short-term memory."

Evans is co-author of a study published in Nature that shows impaired short-term memory and learning in adult mice, in which scientists blocked the process of neurogenesis. They did this by engineering mice that lacked one copy of the gene responsible for the production of Tlx, a protein that the team had previously determined was crucial to maintaining and renewing the arsenal of neural stem cells.

"The other allele (gene copy) is normal, but it is susceptible to knockout upon ingestion of [the] orally active estrogen antagonist" tamoxifen, Evans says. "It's a very effective knockdown." After being given tamoxifen (perhaps best known as a breast cancer drug) for eight days, an otherwise normally developing mouse had more than 80 percent fewer new neural stem cells in its hippocampus (a structure in the brain's frontal region linked to short-term memory).

The genetically altered mice performed as well as normal peers did in experiments based on learning out of fear, such as associating a sound or light flash with a shock to a paw. They failed, however, to perform up to speed on a spatial memory task: It took days for the mice lacking new nerve cells to lessen the time it took for them to find a platform floating in a pool of opaque liquid on which they could stand.

Normal mice took about three days to make the connection, but Evans says the knockout mice were still on "a learning curve" six days into the experiment." They eventually learn," he says, "but it takes them much longer."

Martin Wojtowicz, a physiologist at the University of Toronto, downplayed the finding, noting that it contradicts his own research on rats, which found a link between neurogenesis and fear, but not memory. "They see a very subtle effect in the water maze," he says, "but other than that, nothing."

Evans, however, sticks by the team's conclusions, pointing out that Nature required several additional tests be conducted to verify the data. He also notes that in previous studies, researchers irradiated parts of the animals' brains or injected them with cancer drugs that destroyed more than targeted nerve cells, making it difficult to determine whether it was the suspect cells or other damaged areas that were to blame for certain behaviors. In contrast, he says, his team explicitly links neurogenesis to short-term memory, which in the future could lead to a drug designed to stimulate nerve cell production and potentially counter memory loss in older adults.