Exercise the mind

From Science News.

While exercise may be the path to looking great in a two-piece, everyone knows that it's also healthy for the body. It strengthens the heart and lungs, shores up thinning bones, and wards off a host of evils, including diabetes, heart disease, and stroke. …

New research suggests that physical exercise encourages healthy brains to function at their optimum levels. Fitness prompts nerve cells to multiply, strengthens their connections, and protects them from harm. Benefits seem to extend to brains and nerves that are diseased or damaged. These findings could suggest new treatments for people with Alzheimer's disease, Parkinson's disease, and spinal cord injuries. …

Out of the variety of neurotrophic factors released during exercise, however, scientists found that one in particular stood out: brain-derived neurotrophic factor, or BDNF. This protein seems to act as a ringleader, both prompting brain benefits on its own and triggering a cascade of other neural health–promoting chemicals to spring into action.

"I think of BDNF as brain fertilizer. It's thrilling to see what it does to cells in culture," says Carl Cotman, a neuroscientist at the University of California, Irvine. Sprinkling a dilute solution of BDNF onto neurons in a lab dish makes the cells "grow like crazy," he adds. The cells sprout branches prolifically and extend them rapidly.

Let's get physical
Knowing what BDNF can do to neurons in the lab, researchers wondered whether the BDNF that exercising animals produce has similar effects on neurons in their brains. If so, could these physical effects translate into behavioral ones, making the animals learn quicker and better?

In 1999, Fred H. Gage of the Salk Institute in La Jolla, Calif., and his colleagues, including Salk's Henriette Van Praag, began exploring these questions. They studied two groups of healthy mice housed individually in cages that were identical except for one detail: One group of mice had running wheels.

"The mice just love [the wheel]. They run on it as soon as you put it in their cages," says Van Praag. "If you let them run as much as they want, they run all night long."

Over the next several weeks, the researchers kept track as the runners voluntarily racked up an average of 4 to 5 kilometers on their wheels every night. The scientists then tested whether the groups differed in how quickly each mouse solved a popular learning test known as the Morris water maze.

Although both groups of mice swam at about the same speed, Gage and his colleagues noticed that the runners learned the location of a platform hidden under the maze's opaque water significantly sooner than their less-fit counterparts did.

Dissections showed that the runners had about twice as many new brain neurons as the sedentary mice did. When the researchers tested individual neurons isolated from both groups, they discovered that neurons taken from the runners showed greater signs of strengthened connections and cellular learning.

In a related study published in 2004, Gage's team teased out the molecular factors responsible for the behavioral effects that come with exercise. The researchers provided a group of rats with running wheels and compared them with rats without access to the wheels. On average, the runners voluntarily racked up an astounding 48 km per day over the next several weeks.

When they dissected the rats' brains, Gage's team found changes similar to those that they'd seen in the previous study's mice: The runners had more new neurons and stronger connectivity, which is evidence of learning, than did the rats that didn't have running wheels. After examining the messenger RNA of both groups, an indicator of gene expression, the researchers found that the running rats had consistently higher activity in the gene that codes for BDNF than the nonrunners did.

Gómez-Pinilla and his colleagues added more evidence that BDNF is a primary source for the behavioral benefits of exercise. Like Gage's group, Gómez-Pinilla's team worked with rats that were either sedentary or had access to a running wheel. After a week, some members of each group began receiving daily injections of a drug that blocked the action of BDNF. The rest of the animals were injected daily for several days with a chemical called cytochrome-C, which isn't known to cause any physical or behavioral effects.

The researchers then tested all the animals on the Morris water maze. While runners receiving cytochrome-C excelled at the test, runners that received the chemical that blocked BDNF performed only as well as the sedentary mice did. Performance by the nonrunners was about the same, regardless of which injection they received. "If we block the action of BDNF, we block learning and memory," concludes Gómez-Pinilla.

Keep on moving
With mounting evidence of what exercise and its associated BDNF can do for healthy animals, researchers speculated that a similar mechanism could benefit animals and people stricken with neurological disease or injury. For example, in the April 27, 2005 Journal of Neuroscience, Cotman and his colleagues suggested that exercise could slow the progression of Alzheimer's disease.

In the study, Cotman's team worked with mice that were genetically predisposed to develop an Alzheimer's-like disease. When they're a few weeks old—that's young adulthood in mice—the rodents' brains start accumulating a protein known as beta-amyloid. In the brains of people with Alzheimer's, this protein surges to form thick plaques that are one of the hallmarks of the disease.

As in other exercise-related studies, Cotman housed Alzheimer's-prone mice individually in cages, some of which were equipped with running wheels. At the start of the experiment, the animals were around 1 month old. Alzheimer's-like symptoms "had barely started by then," says Cotman.

After 5 months, the researchers tested the animals in the Morris water maze. As in the earlier studies, the exercisers fared significantly better on that memory test than the sedimentary mice did.

However, in the "really exciting" part of the study, says Cotman, he and his colleagues dissected the animals' brains at 6 months of age to measure the beta-amyloid. They were surprised to find about half as much accumulation of the substance in the runners as in the nonrunners.

Cotman says that his team hasn't figured out how exercise reduces the buildup of amyloid-beta. But regardless of the mechanism, he notes that his results suggest that physical activity could eventually fight early Alzheimer's disease.

Exercise also shows promise in preventing Parkinson's-like symptoms from developing in animal models of that disease.

Surveys of lifestyle and health have suggested that people who exercise moderately, such as walking an hour each day, are less likely than others to develop Parkinson's disease. For the past 5 years, Michael Zigmond of the University of Pittsburgh and his colleagues have been experimenting with rats to explain this preventive effect.

In one study, the researchers forced healthy rats to exercise on a treadmill daily for a week. They then injected the animals with a chemical called 6-hydroxydopamine, which selectively kills dopamine-producing neurons. These cells also die in Parkinson's disease patients.

After several days, Zigmond's team examined the animals' brains. Compared with rats that received 6-hydroxydopamine but hadn't worked out on the treadmill, the exercisers lost fewer dopamine-producing neurons. Earlier studies had suggested that a protein called glial cell–derived neurotrophic factor (GDNF) protects dopamine-producing neurons in patients with Parkinson's disease and that neurons produce GDNF, just as they do BDNF, in response to exercise. So, Zigmond proposes that GDNF protected brain cells in the rats that exercised. He described his team's findings at the Society for Neuroscience meeting in October 2005 in Washington, D.C.