Researchers have identified specific neurons in mice that appear to play a crucial role in building endurance after periods of running. This discovery leads to speculation that similar neural pathways may exist in humans, potentially offering avenues for therapeutic interventions, such as medications or other treatments, to augment the health benefits derived from physical activity.
For many years, it has been established that the brain undergoes changes in response to physical exertion. However, a prevailing scientific view held that these brain adaptations were separate from the systemic bodily responses, like the strengthening of muscles. New findings, however, suggest a more integrated process. Nicholas Betley from the University of Pennsylvania posits that these brain alterations are, in fact, the coordinating mechanisms for all other physiological responses to exercise.
Investigating Neural Activity During Exercise
To gain a deeper understanding of how exercise impacts the brain, Betley and his research team meticulously observed neuronal activity in mice. They focused their attention on the ventromedial hypothalamus, a brain region where previous studies indicated that developmental impairments could hinder fitness improvements in rodents. Betley suggests this region likely holds similar significance for humans, given the consistent structure and function of this area across mammalian species.
The study revealed that following exercise, a particular group of neurons, identified by the presence of a receptor known as SF1, showed increased activity. These SF1-expressing neurons are known to influence brain development and metabolism. Notably, the researchers observed that the proportion of these activated neurons increased with each successive day of running. By the eighth day of the experiment, approximately 53 percent of these neurons were activated by exercise, a significant rise from the less than 32 percent activation observed on the first day. Betley likens this phenomenon to muscle growth, stating, “So, just like your muscles build when you’re exercising them, your brain activity builds.”
Experimental Manipulation of Neuronal Activity
In the next phase of their research, the scientists employed optogenetics, a sophisticated technique that uses light to control neuronal activity. A separate group of mice had these SF1 neurons temporarily deactivated for about an hour. This intervention was performed immediately after the mice completed their treadmill training, which consisted of five sessions per week over a period of three weeks. Each week concluded with an endurance test, where the mice ran until they reached exhaustion.
During the course of this trial, the mice whose neurons were deactivated showed an average increase of approximately 400 meters in the distance they could run during the endurance tests. While this represents an improvement, it was roughly half the progress observed in a control group of mice where the neurons were left intentionally active and unimpeded.
The Role of Neurons in Fuel Utilization
The precise function of these SF1 neurons remains a subject of ongoing investigation, but team member Morgan Kindel, also affiliated with the University of Pennsylvania, speculates it may be linked to fuel utilization during prolonged physical activity. Endurance activities typically rely on fat as a primary energy source, as carbohydrate stores are depleted more rapidly. However, Kindel noted that inhibiting these neurons appeared to cause the mice to “start using carbs a lot earlier on in the run,” leading to premature depletion of energy reserves. Further experiments indicated that deactivating these neurons prevented the release of a protein called PGC-1 in the muscles, a protein vital for efficient fuel use by cells. Additionally, these neurons were found to release a substance that helps elevate blood sugar levels and replenish energy stores, thereby supporting muscle recovery.
Potential Therapeutic Applications and Challenges
While optogenetics, due to its invasive nature requiring brain surgery, is not a viable direct application for humans, Betley suggests that alternative methods for targeting these neurons could be developed. He expresses optimism, stating, “I really do think that if we could find a way – a salt, a supplement – to activate these neurons, you can increase endurance.”
When the researchers reversed their approach, artificially enhancing rather than inhibiting activity in these specific neurons, the results were striking. The mice demonstrated a significant increase in endurance, running more than double the distance of the control subjects.
Betley suggests that such an intervention could offer particular advantages for individuals who find exercise challenging, including older adults or those recovering from a stroke. However, he acknowledges several significant obstacles. Foremost among these is the uncertainty regarding whether these findings in mice will directly translate to humans. Thomas Burris at the University of Florida highlights another concern: potential side effects. Given that these neurons appear to regulate energy uptake in muscles, overstimulation could potentially lead to a dangerously low blood sugar level.
Even if safe methods to stimulate these neurons in humans are developed, Burris cautions that it will not represent a singular solution for overall health. Physical activity offers a wide array of benefits beyond endurance, including improvements in mood, cognitive function, cardiovascular health, and muscle strength. Betley concludes by noting, “I don’t think that activating [these] neurons is necessarily going to be the bottleneck through which all of those good things happen.”