A recent study published in the journal Neuron suggests that the brain plays a direct role in building endurance after physical activity. Scientists have discovered that certain groups of brain cells become active immediately after a workout, sending signals that tell your muscles to adapt and grow stronger. This study provides evidence that the benefits of exercise depend as much on the brain as they do on the muscles themselves.
The study was led by J. Nicholas Betley, professor of biology and neuroscience at the University of Pennsylvania, Eric Bross, assistant professor at the Jackson Laboratory, and Kevin W. Williams, associate professor of internal medicine at the University of Texas Southwestern Medical Center. Co-first authors on the project were Morgan Kindel, a neuroscience doctoral candidate at the University of Pennsylvania, and Ryan J. Post, an assistant professor at Providence College.
Scientists conducted a study to investigate how physical training provides long-term health benefits. People naturally believe that increasing endurance is a process that occurs entirely within the body. When a person runs or lifts weights, their heart beats faster and their muscles lift heavier objects. As a result, changes in the cardiovascular system and muscle tissue appear to be the obvious cause of increased stamina.
But scientists suspected that the central nervous system might do more than just respond to physical stress. They designed this project to see if the brain actively regulates the body’s metabolic response to physical activity. “Our lab has long been interested in how the brain regulates metabolism, and exercise is one of the most powerful interventions in metabolism and health,” Williams told PsyPost.
At UT Southwestern, he runs a lab that examines how neural networks control eating behavior, energy expenditure, and glucose metabolism. “We have previously shown that hypothalamic neurons undergo structural and functional changes in response to exercise,” Williams said. “In this study, we focused on how hypothalamic neurons facilitate peripheral adaptations to exercise.”
Specifically, the researchers wanted to understand the function of cell clusters in the ventromedial hypothalamus. The hypothalamus is a small region deep in the brain that helps regulate metabolism, energy levels, and hunger. The authors focused on cells known as steroidogenic factor 1 neurons within this brain region.
“Steroidogenic factor 1 neurons in the ventromedial hypothalamus are well positioned to integrate signals about energy status and physical activity, so we decided to test whether they were causally involved in exercise-induced endurance gains,” Williams said.
The researchers designed a series of experiments using adult male and female mice to track and change the activity of these neurons. To test the role of these specific brain cells, the scientists genetically modified a group of mice so that steroidogenic factor 1 neurons were unable to communicate. They accomplished this by introducing tetanus toxin into these specific neurons, preventing them from emitting chemical signals.
The researchers then placed these mice on an electric treadmill for an exercise stress test. The speed was gradually increased until the animal was exhausted. Although the modified mice consumed oxygen at a normal rate, they depleted it much faster than normal mice. They also used their energy stores differently, with an altered balance of carbohydrate and fat utilization.
The researchers harvested skeletal muscle tissue from the mice three hours after the last treadmill session. They analyzed the tissue using an experimental technique that allows scientists to see which genes are turned on or turned off. In normal mice, exercise induced a series of genetic changes in the muscles that improved energy expenditure.
In mice whose brain cells were silenced, these normal genetic changes in muscle were almost completely abolished. The lack of brain signaling left muscles unable to rebuild themselves. This finding suggests that muscles need permission signals from the brain to become stronger.
The researchers then put the mice through a three-week training program. The mice ran on a treadmill five days a week at gradually increasing speeds. The normal mice rapidly improved their running time and distance over three weeks. Mice whose brain cells were silenced were unable to improve their stamina at all.
“We were struck by how pronounced the effects were when these neurons were silenced,” Williams said. “Inhibiting the activity of SF1 neurons significantly slowed the improvement in endurance, even while the animals were still running, suggesting that the neurons were not only responding to exercise, but were actively mediating adaptation. This degree of specificity was convincing.”
Even when they were given free access to a running wheel inside their cages, the modified mice showed little interest in running. To make sure this wasn’t just a side effect of an initial lack of fitness, the scientists ran another test. They knocked down different activity-related genes in the mice, which initially caused them to gain weight and run poorly. Despite having poor initial fitness, these mice rapidly gained stamina even after just one week of training, demonstrating that the modification of tetanus toxin uniquely blocked increased endurance.
To understand what these brain cells were doing in real time, scientists used a miniature microscope attached to the mouse’s head. These microscopes recorded calcium activity within neurons. This is a reliable marker of when brain cells are firing. The researchers noticed that certain subsets of these neurons were highly active during a single running session. Interestingly, the activity of these cells did not peak during running, but rather shortly after exercise ended.
The researchers tracked these same individual cells while the mice continued a three-week training regimen. They found that repeated exercise increased the total number of brain cells that were activated after a run. As the mice became healthier, the magnitude of the electrical activity in these cells also became stronger. This provides evidence that the brain learns to respond more reliably to physical training over time.
Using a technique that measures electrical currents in individual brain cells from slices of brain tissue, the scientists observed that the resting charge of these cells changed in mice that exercised. In the mice that exercised, the spontaneous firing rate of neurons more than doubled compared to the sedentary mice. There were also no neurons that were completely silent in the exercised group, unlike in the sedentary group.
Scientists also took a closer look at the physical structure of these neurons. Brain cells connect and communicate at junctions called synapses. Synapses are often located on small branch-like structures known as dendritic spines. By counting these microstructures, the authors found that exercised mice had twice as many dendritic spines as sedentary mice. This physical change provides evidence that repeated exercise physically rewires the brain to receive more signals.
Finally, the researchers used a technique to manipulate these brain cells with light. By shining specific wavelengths of light into the brain through tiny fiber optic cables, they could turn neurons on or off like a switch. During a three-week training program, researchers turned off brain cells for 15 minutes immediately after each day’s run. Because of this short maneuver, these mice were unable to improve their stamina.
In a separate group of mice, the researchers used light to stimulate neurons for a full hour after each training session. Mice that received brain activation after this training had significantly greater stamina than mice that received the exact same physical training. By the end of the test, they were able to run longer and faster. This suggests that the activity of these brain cells after training is an important trigger for building physical endurance.
Although these findings provide new ways of thinking about movement, readers may misunderstand the exact role of the brain. This study doesn’t suggest that muscle tissue isn’t important or that you should just think about how to improve your fitness. Physical movement is still required to initiate biological processes.
“The brain is not just a passenger in motion,” Williams says. “It is actively involved in the adaptation to become healthier over time. We found that improved endurance through regular aerobic training requires a specific population of hypothalamic neurons.”
This study has several limitations that should be considered when interpreting the data. “This study was done in preclinical models, specifically mice,” Williams said. “Although the hypothalamic circuits we study are conserved across mammals, we must be careful in extrapolating these findings to humans.”
“We also focused on endurance performance as a key outcome,” Williams added. “Future studies will be important to examine how broadly these neurons influence other aspects of exercise adaptation, such as metabolic flexibility and cardiovascular responses.”
Future research will attempt to identify the exact biological pathway that connects tired muscles to this specific brain region. “We want to better understand the circuitry involved in this reaction,” Williams told PsyPost. “What signals do SF1 neurons receive/send and where do they send them to facilitate these adaptations?”
Understanding these pathways tends to open the door to new treatments. “This raises the possibility that by targeting these brain circuits, people who are unable to exercise can fully benefit from some of the metabolic effects,” Williams said. “In the long term, understanding these pathways at a mechanistic level may open new therapeutic strategies for metabolic diseases.”
“Exercise remains one of the best medicines we have, and our understanding of the biology of exercise in the brain is still in its infancy,” Williams said. “Studies like this remind us that the brain’s role in physical fitness is much more active and specific than we once realized.”
The study, “Exercise-induced activation of ventromedial hypothalamic steroidogenic factor 1 neurons mediates improved endurance performance,” was authored by Morgan Kindel, Ryan J. Post, Kyle Grose, Louise Lantier, Eunsang Hwang, Jamie RE Carty, Lenka Dohnalová, Lauren Lepeak, Hallie C. Kern, Rachael Villari, Nitsan Goldstein, and Emily. Law, Albert Yang, Lucas Ritchie, Bridget Skelly, Jenna Golub, Manmeet Rai, Teppei Fujikawa, Julio E. Ayala, Joel K. Elmquist, Christoph A. Theis, David H. Wasserman, Kevin W. Williams, Eric B. Bross, and J. Nicholas Betley.
