A new study from The Jackson Laboratory and the University of Pennsylvania finds that key neurons in the brain must activate after a workout for endurance to improve. The discovery could one day help people who cannot exercise intensely still gain some of its protective benefits.
When your legs are burning at the end of a run, it is easy to think your muscles are doing all the work. But new research suggests your brain may be the real driver of long-term endurance gains.
Scientists at The Jackson Laboratory and the University of Pennsylvania have discovered that a specific set of brain cells must switch on after exercise for the body to build stamina over time. In mice, when those neurons were silenced, the animals stopped improving their endurance, even though they kept up the same intense training.
The work, published in the journal Neuron, challenges the long-held idea that endurance is mainly about muscles adapting to repeated workouts.
“The idea that muscle remodeling requires the output of these brain neurons is a pretty big surprise,” co-senior author Erik Bloss, an associate professor at The Jackson Laboratory, said in a news release. “It really challenges conventional thinking about how exercise works.”
Tracking the brain after a run
Scientists have known for years that regular physical activity benefits the brain, improving cognition and strengthening connections between neurons. But most of that research has focused on long-term changes. Bloss and co-senior author J. Nicholas Betley, an associate professor of biology at UPenn, wanted to know what happens in the brain in the minutes and hours right after a workout.
They focused on the hypothalamus, a deep brain region that helps regulate hunger, body temperature, hormones and metabolism. Using mice running on treadmills, the team recorded the activity of hypothalamus cells during and after exercise.
They zeroed in on a cluster of neurons that produce a protein known as steroidogenic factor-1, or SF1. These SF1 neurons did something surprising: they lit up not during the run, but for about an hour afterward.
That timing caught the researchers’ attention.
“The fact that these neurons are most active post-run was quite intriguing,” Bloss added. “It suggested that they play a role in signaling the body to start the recovery process.”
As the mice trained over several weeks, more and more SF1 neurons became active after each session. Experiments at JAX showed that the connections between these neurons also grew stronger and more numerous in trained animals. Mice that exercised had roughly twice as many connections between SF1 neurons as sedentary mice, a sign that this brain circuit was being remodeled by repeated workouts.
Shutting down the circuit stops endurance gains
To test whether this post-run brain activity actually mattered for performance, the researchers turned to optogenetics, a technique that uses light to control specific neurons.
In one set of experiments, they switched off SF1 neurons for just 15 minutes after each treadmill session. The mice still ran hard every day for three weeks, following the same rigorous training schedule as control animals. But unlike the controls, they stopped getting better. Their endurance plateaued, even though their workouts did not.
When the team used other methods to silence the SF1 neurons, the effects went beyond the brain. The usual changes in gene activity that occur in muscle after exercise — changes needed to remodel muscle fibers and support endurance — failed to appear. In other words, without the brain’s signal, the muscles did not fully enter training mode.
The mice also behaved differently when given the chance to run on their own.
“If you give a normal mouse access to a running wheel, they will run kilometers at a time,” added Bloss. “When we silence these neurons, they effectively don’t run at all. They hop on briefly but can’t sustain it.”
Boosting the neurons supercharges training
The opposite experiment produced an equally striking result. When the researchers artificially stimulated SF1 neurons for an hour after each treadmill session, the mice gained more endurance than usual.
Compared with control animals, these mice ran longer distances and reached higher top speeds by the end of the training period. Simply put, turning up the post-exercise brain signal appeared to amplify the benefits of the same workout.
Together, the findings suggest that the brain is not just a passenger during training. It acts more like a master coordinator, sensing a workout and then sending instructions that drive metabolic changes and muscle remodeling across the body.
Why it matters
The study was done in mice, and it will take more research to understand whether similar circuits operate in people and how they might be safely targeted. Still, the work opens intriguing possibilities.
If scientists can learn to tap into or mimic these brain signals, they might one day help people who cannot exercise intensely — such as many older adults or individuals with mobility challenges — gain more from moderate activity. It might also inform new strategies for rehabilitation after injury or illness, or for protecting the brain and body against age-related decline.
Bloss sees potential far beyond the lab.
“There’s the very real possibility that we can eventually take advantage of this circuit to boost the effects of moderate exercise,” he said. “If we can mimic or enhance exercise-like patterns in the brain, that could be particularly valuable for older adults or people with mobility limitations who can’t engage in intensive physical activity but could still benefit from exercise’s protective effects on the brain and body.”
What comes next
Future studies will likely explore how SF1 neurons communicate with muscles and other organs, what chemical signals they use, and whether similar neurons in the human brain respond to exercise in the same way.
For now, the research offers a new way to think about training: the workout is not over when you step off the treadmill. In the crucial hour after you stop, your brain may be hard at work, setting the stage for your next personal best.
Source: The Jackson Laboratory