How Brain Changes Drive Physical Fitness Gains

When people think about getting stronger, they often picture muscles—lifting heavier weights or climbing stairs without losing their breath. But new research suggests those gains don’t happen unless the brain changes first.

In a study published February 12 in Neuron, mice that trained on treadmills showed increased activity in cells in the brain’s ventromedial hypothalamus. When those cells were blocked after exercise, the mice failed improve endurance after their workouts. The research suggests that the body relies on signals from the brain to get fit.

Exercise doesn’t just move muscles—it trains the body to adapt. Over time, strength builds, endurance improves, and systems that regulate energy become more efficient.

But the brain also changes with exercise, says J. Nicholas Betley, a neuroscientist at the University of Pennsylvania in Philadelphia. Mice who run on wheels or treadmills grow new brain cells in areas like the hippocampus, and the brain cells they have form new connections. “You exercise, your muscles get stronger, your lungs get stronger, your heart gets stronger and your brain gets stronger, and it's a consequence of exercise,” Betley says.

But what struck Betley and his colleagues was how active the brain was during the exercise itself. “Throughout the brain, and especially in the hypothalamus, there's a ton of engagement” during exercise, he says. “What the heck is all this neural activity doing?”

In particular, there was increased activity in the ventromedial part of the hypothalamus (VMH), a region deep in the center of the brain. This area is best known for its role in metabolism and energy use, controlling functions such as body temperature, hunger, and thirst.

Because endurance depends on how the body manages fuel and effort, Betley and his colleagues suspected the VMH might not just respond to exercise but also help drive the body’s ability to adapt to it.

Betley and his colleagues started with mice on treadmills. After a single exercise session, the mice showed increased expression of growth factors in VMH cells, particularly those expressing the protein SF-1. Cells that express SF-1 help to bring together signals from the body, from hormones like insulin and leptin, controlling how the body uses energy.

After eight days of exercise, the VMH recruited more SF-1-containing neurons, which became more active than before. SF-1-containing neurons also sprouted additional synaptic “spines,” tiny structures that allow brain cells to communicate. Three weeks of mouse distance training, Betley says, “doubles the activity.” Just as the mice could run further over time, the VMH was being “trained” by the exercise.

To test whether those neurons were merely responding to exercise—or driving its benefits—the researchers selectively silenced the SF-1 cells. Without SF-1-containing brain cell activity, the mice could train, but they made fewer gains. They couldn’t run as far or as fast as animals with normal SF-1 signaling.

Using a method called optogenetics to control the SF-1 neurons with a burst of light, the researchers showed that cutting off the SF-1 neurons right after each training session prevented them from developing better endurance. But enhancing SF-1 cell signaling had the opposite effect; animals with exercise and a burst of light showed better endurance.

Scientists have long known that the brain is important for activating muscles, stimulating heart and lung responses, and controlling energy intake and output, says Mark Hargreaves, an exercise physiologist at the University of Melbourne in Australia. “These results suggest that the VMH SF1 neurons within the [central nervous system] are also involved in the adaptation to regular exercise.”

It’s a loop that benefits both body and brain. “These results emphasize again the beauty of integrative physiology,” Hargreaves says. “All relevant organ systems work together to ensure there is an appropriate response” to the challenge of the exercise.

The results suggest a new role for this area of the brain, says Dayu Lin, a neuroscientist at New York University Grossman School of Medicine in New York City. But she notes that it’s important to consider the results from a non-human perspective. “Mice don’t exercise,” she says. “Do they voluntarily think, ‘I need to get fit to so I’m gonna get on the running wheel?’”

Instead, Lin notes that this area of the hypothalamus is also associated with how animals respond to predators. Lin wonders if the effects of the exercise on the brain could be because the animals are running like they would if they were under extreme stress—the stress of predation.

Betley and his colleagues repeated some of the studies with mice that were not on treadmills. Instead, the animals were given access to running wheels in their cages, but not forced to run. The mice ran with gusto, and the researchers showed that when they blocked SF-1-containing cells in these animals, they failed to benefit from the increased movement.

“The science is top notch, and the results—which are obtained using state of the art techniques—are important,” says Alan Watts, a neuroscientist at the University of Southern California in Los Angeles. But mice, he notes, are much smaller than humans. “As a species mice are very poor models for human energy control,” he says. Humans are going to have to get on treadmills to find out if our brains work the same way.

The next step, Betley says, is to find out what, exactly, the signals are between the hypothalamus and the body during exercise. What are the molecules underlying endurance? Finding out could help scientists develop treatments for people unable to exercise, such as those recovering from strokes, or to prevent muscle wasting.

But Betley is quick to add that no drug would replace movement itself and adds that research has changed his own habits. “After these experiments in the lab, I try to stick to 300 minutes [five hours] a week of exercise,” he says, “You’re a completely different human after 300 minutes a week.”