In 1998, Gage of the Salk Institute and Peter Eriksson at the Sahlgrenska University Hospital in Göteborg, Sweden, studied hippocampal tissue in deceased cancer victims ranging in age from 57 to 72 years old at death. Each patient while living had received an injection of bromodeoxyuridine, or BrdU, for diagnostic purposes.
BrdU is absorbed only by cells that are dividing, meaning they are creating new cells. In cancer patients it is used to see if cancer cells are multiplying. When BrdU-labeled neurons were found in the hippocampus, it was a the equivalent of a smoking gun for Gage and Eriksson. They could only conclude that neurogenesis was taking place.
"The way you detect (new neurons) is in part by determining whether or not they're undergoing cell division," Gage says. More important, these new cells weren't just floating around aimlessly.
"We found these new neurons were known and recognized by the other cells. And they looked as though they're wired up to the appropriate area" to potentially play a role in cognition.
Meanwhile, Gage and other Salk scientists were engaged in different research, this time on the effects of learning on the brains of mice. What they found could have big meaning for us humans. The mice were exposed to a rich environment of toys, treats and other incentives to think.
Almost as an afterthought, running wheels — mouse treadmills — were introduced as another variable. The mice ran at their own pace, as often and for as long as they liked. And the mice that did the running grew twice the new brain cells as mice in a control group.
The Salk researchers do not know why running should have such an enhancing effect on neural development. There are some informed guesses: Running might increase the flow of oxygen and nutrients to brain tissues or release special growth factors that promote new neurons, Gage said. Or it could be that running prompts the nervous system to prepare for an onslaught of new information as an animal navigates unfamiliar terrain in the pursuit of prey or in flight from an enemy.
Meanwhile, at Princeton, neuroscientists Elizabeth Gould and Charles Gross of the university's psychology department brought neurogenesis a step further, finding new neurons not just in the hippocampus of adult rhesus monkeys but also in the more advanced cerebral cortex.
In order to test for the presence of new neurons in the adult brain, Gould and Gross injected the monkeys with BrdU. At different times after the injection, ranging from two hours to seven days, the researchers examined the cerebral cortex and found evidence of BrdU in cells in three different regions, all of which play a role in higher thought.
The researchers were able to detect several different proteins in the cells that are found specifically in neurons. Also, they showed that the cells containing BrdU had the long axon extensions characteristic of neurons.
To get those results, Gould and Gross used a technique called fluorescent retrograde tracing. In this technique a chemical dye is applied to a small region of the brain, and the dye travels from the end of an axon back to the cell body, making the axon visible under a microscope.
And when the monkeys engaged in various stimulating exercises, the number of new cells jumped.
Taken together these recent findings suggest that neurogenesis is found across the range of mammalian species, including human beings.
Gould and Gross reiterate that it's not yet known what purpose the new cells serve in the cortex, but if the newly formed neurons are found to have a functional role, scientists may have to reexamine current theories about how the brain works.
In the not-too-distant future, Gage says, advanced brain imaging techniques will probably show how exercise, both physical and mental, causes new neural development in humans. What we already know, he says, is that the brain is not a one-way street where it simply controls our behavior.
"We are finding that the behaviors that people engage in in return have an effect on the underlying structure of the brain and on the number of cells and how they're wired in the brain, which then will subsequently have an affect on what your next behavior is going to be."
Even clearer proof that the human brain benefits from aerobic exercise was found in a study at the University of Illinois' Beckman Institute for Advanced Science and Technology. Its study, funded by the National Institute on Aging, examined the cognitive impact of walking or doing toning exercises on 124 adults ranging in age from 60 to 75.
Participants in both exercise groups showed improvement doing a repetitive task, such as pushing a button, when given a visual cue. However, the walkers were better able to process and ignore irrelevant cues and successfully complete tasks than were those who had done only toning exercises.
Processing relevant information and discarding distractions are essential to "executive control," a term that covers such things as planning, inhibition and temporarily maintaining information in memory.
"Executive control processes are largely controlled by the frontal and prefrontal regions of the brain, areas which show negative metabolic and morphological changes during the normal aging process," says Arthur F. Kramer, a psychologist and researcher at the Beckman Institute. "Cells shrink and blood flow decreases. The benefits you get from walking are in the varieties of cognition that show the largest age-related decline."