No brain, no gain: Neuronal activity enhances benefits of exercise

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With the Winter Olympics in full swing, coaches are closely scrutinizing their athletes, hoping that the carefully honed, intensive physical training programs they crafted for them will give them the strength and endurance to carry them to Olympic glory. But new research from the University of Pennsylvania’s J. Nicholas Betley suggests the true engine of successful fitness may sit far from flexors and extensors or skis and skates.

In a paper published in Neuron, Betley, his team and collaborators have discovered that the lasting gains from repeated exercise—specifically the ability to run farther, faster, longer—depend on activity in the ventromedial hypothalamus (VMH), a small brain region traditionally known for regulating energy, weight, and blood sugar.

Researchers have long known that the brain benefits significantly from exercise. Studies have shown that exercise reduces inflammation and causes increases in neurogenesis rates and synaptic connectivity, explains co-first author Morgan Kindel, a graduate researcher in the Betley Lab.

But the results of this new study suggest that physical training alone is not enough to build endurance, reframing exercise as a collaboration between neurons and muscle fibers rather than a simple matter of physical exertion.

“The old Latin phrase mens sana in corpore sano—a healthy mind in a healthy body—has guided countless athletes in recent centuries,” says Betley, associate professor in the School of Arts & Sciences. “This research sharpens that slogan into something more literal: that without the brain, the body cannot effectively get stronger with exercise.”

Previously, the team had observed an increase in neuronal activity following exercise that was comparable to the neural activity seen while “having a good meal, sipping coffee, and having a stimulating conversation all at once,” says Betley.

The team was interested in the cascade of events triggered by this massive neural activation, narrowing their focus to the VMH and specifically to steroidogenic factor-1 (SF1) neurons. These neurons, which play vital roles in energy and glucose homeostasis, also stayed active for at least an hour in preclinical models of exercise.

To test the importance of their neurons, the team performed two experiments. First, they blocked these neurons from firing and found the training effect vanished—despite continued training, improvements in endurance over the three-week training period hit a permanent plateau.

Conversely, boosting the activity of these neurons following exercise training acted as an exercise mimetic, enhancing endurance capacity beyond the level achieved with training alone.

“Through our collaborations with the Bloss Lab at Jackson labs and the Williams Lab at University of Texas Southwestern, we were able to show that exercise not only builds muscle, but it also builds the strength of the VMH circuit that drives adaptation after exercise,” says co-first author Ryan J. Post, a former postdoctoral researcher in the Betley Lab. “Together, we found that training leads to ever increasing activity in VMH neurons and that this occurs by an exercise-induced increase in excitatory inputs to these neurons.”

By identifying this specific brain circuit as a key relay point between physical effort and physical improvement, the study sharpens where scientists might look to mimic exercise’s benefits when movement itself is limited. Rather than acting directly on muscles or the heart, future therapies could target the neural wiring that interprets exertion and tells the body how to rebuild—effectively working on the brain’s exercise-control system instead of the muscles alone.

Betley hopes that one day these insights could help people recovering from stroke or injury or patients with limited mobility maintain the health benefits of activity.

For future work, the researchers are determining the mechanism of transmission. While the team knows the brain receives a signal that exercise has occurred, they do not yet know how that message travels from the body to hypothalamus. Additionally, the lab is investigating if SF1 neurons are the sole integration site for exercise signals, or if they work in parallel with other circuits. This is particularly relevant for understanding the mental health benefits of activity.

“We know that exercise regulates mood and anxiety—many people feel ‘off’ if they miss a workout,” Betley says. “A major open question is whether SF1 neurons regulate those cognitive changes alongside the metabolic ones, or if there is a separate pathway for the neuropsychological benefits. Distinguishing these circuits could allow us to target specific health outcomes more effectively.”

J. Nicholas Betley is an associate professor in the Department of Biology in the School of Arts & Sciences at the University of Pennsylvania.

Morgan Kindel is a Ph.D. candidate in the Betley Lab at Penn Arts & Sciences.

Ryan J. Post was a postdoctoral researcher in the Betley Lab during this study. He is currently an assistant professor of psychology and neuroscience at Providence College.

Other authors include Jamie R. E. Carty, Lenka Dohnalová, Nitsan Goldstein, Jenna Golub, Hallie C. Kern, Emily Lo, Manmeet Rai, Lukas Richie, Bridget Skelly, Rachael Villari, and Albert Yeung of the University of Pennsylvania; Erik B. Bloss and Lauren Lepeak of The Jackson Laboratory; Christoph A. Thaiss of Stanford University; Joel K. Elmquist, Teppei Fujikawa, Kyle Grose, Eunsang Hwang, and Kevin W. Williams of the University of Texas Southwestern; and Julio E. Ayala, Louise Lantier, and David H. Wasserman of Vanderbilt University.

This research was supported by the Klingenstein Foundation, the University of Pennsylvania School of Arts and Sciences, the National Institutes of Health (F31DK131870, 1P01DK119130, 1R01DK133399, 1R01DK124801, 1R01NS134976, F32NS128392, K00NS124190, F32DK135401, T32DK731442, R61NS126026, R01NS120663, R01NS134976-02, R00MH117264, and 1DP1DK140021-01), the National Science Foundation Graduate Research Fellowship Program, the Blavatnik Family Foundation Fellowship, the American Neuromuscular Foundation Development Grant, the American Heart Association (25POST1362884), the Swiss National Science Foundation (206668), the Canadian Institutes of Health Research Project Grant (PJT-175156), the Simons Foundation, a McKnight Foundation Scholar Award, and a Pew Biomedical Scholar Award.