In neurobiologist Daria Peleg-Raibstein’s lab at the Swiss Federal Institute of Technology Zurich, a mouse navigates a complex eight-armed maze. As the animal scurries about, it answers some important research questions.
Peleg-Raibstein, who was intrigued by how people decide when presented with choices, wanted to “basically understand how our brain processes different options.” Specifically, she and her team investigated eating or exercising. Despite knowing better, people often do not exercise enough; some also indulge in overeating.1 Such choices can result in conditions like diabetes or obesity, among other risks.
When Peleg-Raibstein and her team investigated the neurons that mediate these decisions in mice, they found those producing a neuropeptide called orexin regulated the choice between exercise and snacking.2 Their findings, published in Nature Neuroscience, could help pinpoint potential therapeutic targets to promote physical activity and improve health.
“It is a stellar study,” said Catherine Kotz, a neurobiologist at the University of Minnesota who was not involved in the study. “They’ve described a model that I don't think I've seen described before in order to test what motivates animals to eat or be physically active.”
First, Peleg-Raibstein and her team designed a behavioral test where mice could freely choose between eight different options: water, light, another mouse, a dark area, a running wheel, food, a new object, and an empty space. Among all these options, the mice split most of their time between the running wheel and food.
When the researchers added a ‘milkshake bar’ where the mice could enjoy strawberry milkshake, the animals spent considerably less time eating their usual food. However, they continued visiting the running wheel, and ran almost as much as they did even in the absence of a milkshake-dispensing option.
“The animals love [the milkshake] because usually they get like the very normal laboratory chow, which is very boring,” said Peleg-Raibstein. “So, this was really surprising where the animals really continuously chose the running wheel in spite of having something to eat and drink.”
Previous studies indicated that among other neurons, those in the hypothalamus that secrete the neuropeptide orexin simultaneously control both food intake and energy expenditure.3 This prompted Peleg-Raibstein and her team to investigate whether orexin plays a role in the animals’ decisions.
Drug-treatment to block orexin neuropeptide signaling caused mice to spend much less time running and much more time drinking the milkshake, suggesting orexin’s role in prioritizing exercise. However, blocking orexin signaling did not change the behavior of mice when they were offered only the running wheel and not the milkshake: Both control and drug-treated mice ran similar distances. Similarly, mice with and without an intact orexin system drank similar quantities of the milkshake in the absence of the running wheel. This indicated that orexin neurons influence the decision between eating and exercising, rather than influencing how much the mice move or eat.
The researchers measured the changes in the activity of orexin-secreting neurons by imaging calcium signaling in these cells. They observed increased neuronal activity as the mouse decidedly scuttled from the running wheel to the milkshake or vice versa.
“[The study] gives us more information about orexin, knowledge of which has been complicated,” said Kotz. Unlike a lot of other neuropeptides that reduce physical activity if they increase eating behavior, orexin increases both. “This work kind of helps us understand why that could be.”
Kotz noted that the eventual goal of the work would be to know whether these results translate to humans to improve their health. If they do, orexin agonists are already in the market, she said, noting that these could facilitate easier drug development.
Orexin-targeting drugs are licensed, Peleg-Raibstein agreed. “But this is just the beginning. If we could understand and maybe manipulate the neurons that we know underlie this kind of choice [exercising versus eating] we can maybe increase our health suit.”
- Bleich SN, et al. Why is the developed world obese? Annu Rev Public Health. 2008;29(1):273-295.
- Tesmer AL, et al. Orexin neurons mediate temptation-resistant voluntary exercise. Nat Neurosci. 2024;27(9):1774-1782.
- Sakurai T. The role of orexin in motivated behaviors. Nat Rev Neurosci. 2014;15(11):719-731.
