Secret Life of the Grown-Up Brain (18 page)

Small and his colleagues found what they expected. The mice that had run on their wheels had increased blood flow in their dentate gyruses, those tiny sections of the memory-crucial hippocampus. The increase was there long after the mice stopped exercising, too, which meant it did not come from the transient boost in metabolism that regularly occurs while exercising. And right in the middle of those mouse brain dentate gyruses, Small and his team also saw those green dots of new brain cells. There were nearly
twice
as many green-dotted new brain cells in the exercising mice as in the nonexercisers.

For Small and his colleagues, it was a powerful finding, a clear sign that exercise was not only a potent producer of new neurons, as some earlier results had suggested, but also seemed to “selectively target” the brain’s dentate gyrus—right in the middle of the brain’s memory machinery—an area that appears to decline with the normal aging processes. This means that exercise may, in fact, help boost our memories as we age.

“The hippocampus is really a circuit of different regions,” Small says, “and exercise targets this specific area of that hippocampus, the dentate gyrus.”

While it’s true that Small’s green-dot study was tiny, it makes sense in part because it builds on solid research by other top neuroscientists. In fact, some of the first clear evidence that exercise boosts our brains came from the coauthor on the Small exercise study, Fred Gage.

One of the most well-known neuroscientists working today, Gage was the first to find that running—and running alone—could give birth to new brain cells. In the late 1990s, Gage and his colleagues, including Henriette van Praag, at the Salk Institute in La Jolla, California, decided to see what would happen if mice were allowed to run as much as they wanted, which usually meant four or five hours a night, or up to five kilometers.

Gage then put the mice to a classic test. He placed them in a tank of murky water and let them find a tiny platform hidden below the surface that they could land on. This is called the Morris water maze and is one of best ways to determine how smart a mouse is—a kind of mouse IQ test, if you will. Mice don’t really like to swim, so when they’re dunked they try as hard as possible to find the little platform. Those that locate it faster on subsequent dunkings are considered cognitively ahead of their peers.

What Gage and his colleagues found was that the mice that exercised the most were not only much better at finding the platform on the second and third tries but also had twice as many new neurons in their brains.

And where were the new neurons? Just where he and Small later found them in the Columbia University mice—in the middle of the dentate gyrus. “Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity and learning,” Gage concluded in his 1999 paper. In later studies, he found that exercise woke up the newborn neuron machinery in elderly mice, too.

Of course, these experiments were conducted only on mice. But Gage, once called the “impresario of neuroscience,” was determined. He was on the trail to find the roots and promise of neurogenesis.

Like most new concepts, the idea that an adult brain—animal or human—could actually grow new brain cells got off to a bad start, a prime example of how science moves ahead in fits and starts at best. Until recently, most neuroscientists had not budged from conclusions drawn in 1913 by Spanish researcher and Nobel Prize winner Santiago Ramón y Cajal, who confidently wrote: “In the adult brain nervous pathways are fixed and immutable. Everything may die; nothing may be regenerated.”

It was an idea that seemed to make sense. But it was wrong. Gage himself has written about why it was so hard to believe that this idea could be incorrect in a 2003 article in
Scientifi c American
:

As far as anyone recalls, the first hint that this might not be so came from a young scientist at the Massachusetts Institute of Technology, Joseph Altman. As Sharon Begley writes in
Train Your Mind, Change Your Brain,
which traces the history of neurogenesis (and, interestingly, relates the latest neuroscience to the teachings of Buddhism), Altman was itching to test out a new technique that allowed researchers to tag newly formed DNA in cells with a radioactive substance.

In the early 1960s, he decided to use it to see if he could find any new neurons in the brains of adult rats. And he did. He then went on to find newly formed brain cells in the brains of cats and even guinea pigs. He published his findings in a scientific journal, but it attracted little attention and he soon transferred to Purdue University and dropped the still-too-controversial concept of neurogenesis.

The idea, however, did not go away. Studies in the early 1980s in songbirds, in particular canaries, found that they, too, created new neurons, even as adult canaries. Each spring, as the canaries learn a new mating song, new sets of neurons are created and migrate into their song-making brain area, which becomes correspondingly huge.

Then, in the late 1990s, Fred Gage found that the same thing happened in rats. Adult rats that lived in stimulating environments—with other rats, toys, and wheels—as well as rats that exercised, created many more new brain cells. He also found that exercise alone produced new neurons. Later, other researchers found new neurons in adult monkeys as well.

Next came humans, and for this study Gage teamed up with Swedish neuroscientist Peter Eriksson, who had obtained brain slices from older Swedish cancer patients who had been injected with a substance that would tag dividing cells. They were able to show that even adult humans were producing new neurons. And where were those baby neurons showing up? “We demonstrate that new neurons . . . are generated from dividing progenitor cells in the dentate gyrus of adult humans,” Gage wrote when his research was published in the journal
Nature Medicine
in 1998. “Our results further indicated that the human hippocampus retains its ability to generate neurons throughout life.” It was a study that changed brain-research forever.

And it did not stop there. Gage, along with Small, went on to extend the green-dot mouse study at Columbia to include humans as well. That was where Kevin Bukowski came in. Piggybacking on an exercise study that was being conducted by his colleague Richard Sloan, a behavior psychologist at Columbia University, Small decided to take a peek at the dentate gyruses of eleven people who were in Sloan’s experiment. (The Sloan study asked whether high-intensity exercise could cut down on markers of inflammation, which can harm cells. It did.)

After Small scanned the brains of the humans, he found pretty much what he’d found in mice. The humans, like Bukowski, who had exercised the most had twice the blood flow as the nonexercisers, and the increase occurred in that crucial memory area, the dentate gyrus.

What’s more, the dentate gyrus blood flow jumped the most in those who became the most fit, as measured by their level of VO2 max, or the maximum amount of oxygen they took in as they exercised, the gold standard for measuring fitness. And that same most-fit group also improved the most in cognitive tests.

“We were not sure what we would see, but it was one of those days when the muses of science were smiling on us,” says Small.

Because the researchers could not cut open Kevin Bukowski’s head, and radioactive substances that tag new cells are now off limits for use with humans, the study did not technically prove that new neurons were born in Bukowski’s brain. They can point to no green dots. Still, because of the striking increase in the level of blood flow—a measure that correlated directly with the growth of brain cells in mice—Small and others feel safe in saying that exercising appears to promote the birth of new brain cells.

“We can’t validate the finding in humans, but by inference we can say that exercise drives neurogenesis,” Small says.

That leaves, of course, the question of what difference any of this means to us. What’s so special about a few more neurons? Can a few brain cells here and there hold off the assault of aging? Put another way, are a handful of baby neurons in something so small and obscure as the dentate gyrus really a good enough reason to turn off the TV and get out on the track?

In fact, when I went to see Gage at his California lab, this was the main question on my mind.

Gage’s office is on the bottom floor of a row of concrete buildings that make up the Salk Institute for Biological Studies in La Jolla. The buildings, with their unadorned style, famously designed by Louis Kahn, make the most of their astonishing setting—on a high isolated bluff overlooking the Pacific Ocean. Inside are dozens of working labs that produce some of the most important biological research in the world.

Despite its prominence, the institute is a surprisingly informal place, with bikes leaning against walls and open-air hallways. After I finally found his office in the maze of concrete, Gage was relaxed and informal. Dressed in a short-sleeved yellow shirt, he was, at age fifty-seven, still trim and athletic and bounded up to greet me with a big handshake and a genial grin.

After we settled into his small office, I asked him, “Why
should
we care about these baby neurons?”

The question made Gage laugh.

After all, he has spent the last ten years working to prove that new neurons exist at all, an idea, he says, that has only recently reached a point of “growing acceptance.” It takes a strong and energetic mind to take on the next challenging questions of what these new little neurons do, how they do it, and, why, in fact, we should care.

Gage, of course, has just that kind of strong and energetic mind and these are precisely the questions he is now addressing.

“The new brain cells are integrated into the existing circuit, no question,” Gage told me. “But the question now is, how do they do it and why?”

At this point, he still shakes his head over how long it took to convince the scientific community that neurons are, in fact, continually born in grown-up brains. Doubts persisted, he said, because “for the longest time we thought that the brain was like a computer and if you threw a new wire into that existing circuit you would just screw it all up. Now we know that is not the case,” he told me as we sat in his tiny office. “The brain is an organ. It is tissue that is changing all the time and it is regulated by our environment. Our brains are affected by what we do.”

We now know, too, that the new brain cells—which are stem cells, the very earliest and most versatile version of cells—are primarily produced in that tiny area of the hippocampus, the dentate gyrus. We know that about half of the new cells die off and half survive. And we know that they are produced in a variety of ways. We get new neurons when we focus on a task that’s highly complex or even when we’re focused on a specific goal (such concentrated brain activity produces theta waves, the same kind of waves that are produced with meditation—so the claim that theta waves help our brains may not, in fact, be just hype).

And we know that exercise—regular exercise, which includes just about anything that increases heart rate and blood flow—leads to a boomlet of such babies.

“Just look at this,” said Gage, wheeling his chair around to click on his office computer, where a slide appeared. One squiggle of magenta on the screen was the enlarged picture of a mouse hippocampus. On top of that was a sliver of dark blue, the dentate gyrus. Extending out of that sliver were dozens of branches—mature neurons. And scattered among those branches were tiny bright-green dots. The same dots—the same baby neurons—that made believers—and joggers—out of the workers in Scott Small’s lab.

These new brain cells that I was looking at on the computer screen, Gage explained, had been produced in only an hour and a half in the brain of a mouse that had exercised. And seeing those green dots for the first time, I must admit, was impressive, inspirational, even. And this was just one small brain slice from one short moment in the life of one small mouse.

“The thing we have to remember is that neurogenesis is not an event, it’s a process,” Gage said. “And there’s no question, physical activity makes new brain cells proliferate.”

Details, of course, are still being worked out, but Gage is convinced—by his own work and that of others—that exercise produces new brain cells in a fairly straightforward way. When muscles contract, they produce growth factors, with names like VEGF and IGF. Normally, those growth-factor molecules are too large to make it through the blood-brain barrier, but for reasons that are still unknown, exercise makes that barrier more porous, allowing those growth factors, once referred to as Miracle-Gro for the brain, to get through and help stimulate the neurons. (The same thing has been shown to happen with serotonin, which is increased in the brain with exercise and also makes new brain cells grow.)

After that, things get fuzzier. The number of new neurons we produce, as Gage says, “has tremendous genetic variability.” No one knows exactly how many we churn out overall. In all likelihood, it’s a relatively small number, perhaps, Gage says, in the “single digit percentages,” compared with the total number of brain cells.