What exactly happens in our brain when we make the decision about whether to exercise, or whether to reach for a particularly tempting snack, has to date been a mystery to science. Studies in mice by researchers at ETH Zurich now indicate that the brain chemical orexin, and the neurons that produce it, may mediate that decision. The team developed a task that allowed them to study how mice freely alternate between wheel running and other voluntary activities, such has opting for a tasty strawberry milkshake instead of exercise. They found that animals with a pharmacologically or genetically blocked orexin system would opt more frequently for the proffered milkshake, and less for voluntary exercise.
These neuroscientific fundamentals are relevant because many people don’t get enough exercise. And while further research will be needed to translate their preclinical studies toh umans, the investigators expect that orexin may also be responsible for similar decision making in people – the brain functions involved are known to be practically the same in both.
The findings could, the investigators suggest, help point to new strategies for promoting physical activity in people. “It will now be a matter of verifying our results in humans”, said research co-lead Daria Peleg-Raibstein, PhD, a group leader at ETH Zurich. “If we understand how the brain arbitrates between food consumption and physical activity, we can develop more effective strategies for addressing the global obesity epidemic and related metabolic disorders.” In particular, interventions could be developed to help overcome exercise barriers in healthy individuals and those whose physical activity is limited.
Peleg-Raibstein, together with research co-lead Denis Burdakov, Professor of Neuroscience at ETH Zurich, and colleagues, reported on their findings in Nature Neuroscience. Their paper is titled “Orexin neurons mediate temptation-resistant voluntary exercise.”
Most of us have probably already decided once or even several times to skip exercising in favor of one of the numerous alternative temptations of daily life. According to World Health Organization statistics noted by the authors, 80% of adolescents and 27% of adults don’t get enough exercise. Obesity is increasing at an alarming rate not only among adults but also among children and adolescents. “While some people choose to exercise over other social and recreational activities, many people underexercise and overeat highly palatable food (HPF) that is widely available in many societies,” the team stated. “This is considered a global health problem.”
But as Burdakov added, “Despite these statistics, many people manage to resist the constantly present temptations and get enough exercise. We wanted to know what it is in our brain that helps us make these decisions.”
Both classic and more recent studies implicate the lateral hypothalamus region of the brain as important for the motivation to move, the authors noted. Yet “… whether lateral hypothalamic neurons regulate attraction to, and engagement in, voluntary exercise, and whether this depends on the availability of alternative activities, is unclear,” they pointed out. Lateral hypothalamic hypocretin/orexin neurons (HONs) are thought to regulate both food consumption and energy balance over chronic timescales, they continued. These HONs produce and release the peptide neurotransmitters orexins/hypocretins. “However, the acute role of HONs in eating is unclear, and whether they are involved in rapid arbitration between HPF and exercise when multiple choices are available is not known.”
Orexin is one of over a hundred messenger substances that are active in the brain. Other chemical messengers, such as serotonin and dopamine, were discovered a long time ago and their roles have largely been decoded. The situation for orexin is different: researchers discovered it relatively late, around 25 years ago, and they are now clarifying its functions step by step. Burdakov is one of the scientists who have devoted their efforts to studying orexin.
“In neuroscience, dopamine is a popular explanation for why we choose to do some things but avoid others,” said Burdakov. This brain messenger is critical for our general motivation. “However, our current knowledge about dopamine does not easily explain why we decide to exercise instead of eating,” the scientist continued. “Our brain releases dopamine both when we eat and when we exercise, which does not explain why we choose one over the other.”
To find out what does the researchers devised a sophisticated behavioral experiment for mice, which were able to choose freely from among eight different options in ten-minute trials. These included a wheel they could run on and a “milkshake bar” where the animals could enjoy a standard strawberry-flavored milkshake, a highly palatable food. “Mice like a milkshake for the same reason people do: it contains lots of sugar and fat and tastes good,” Burdakov said. Voluntary wheel running is also “… a well-established model for human health-beneficial voluntary exercise,” the team further explained. The sessions were kept short to capture the animals’ initial decision-making process.
The scientists compared activities between different groups of mice: one made up of normal mice and one in which the animal’s orexin system was blocked, either using a drug called almorexant (ALMO) that blocks orexin receptors, or through genetic modification of their cells.
They found that mice with an intact orexin system spent twice as much time on the running wheel and half as much time at the milkshake bar as did mice whose orexin system had been blocked. Interestingly, the behaviors of the two groups didn’t differ in experiments in which the scientists only offered the mice either the running wheel or the milkshake.
“This means that the primary role of the orexin system is not to control how much the mice move or how much they eat,” Burdakov says. “Rather, it seems central to making the decision between one and the other, when both options are available.” Without orexin, the decision was strongly in favor of the milkshake, and the mice gave up exercising in favor of eating. These results indicated that HONs, and orexin receptor signaling is necessary for “temptation-resistant voluntary exercise” (TRVE) the scientists noted. “We identified endogenous HON activity as a regulator of the process that maintains exercise in the presence of an HPF alternative,” they stated. “In our maze paradigm, which examined acute decision-making in a multiple choice scenario, the effect of pharmacological or optogenetic disruption of HON activity on exercise or HPF consumption was greater when both options were available than when only one of these options was available.”
While the ETH Zurich researchers expect that their findings in mice may also be relevant to humans, they acknowledge that further study will be necessary. “Because HONs are present in humans, it is tempting to speculate that our findings may be relevant to humans, although direct tests of this remain to be performed,” they pointed out.
Some future studies might involve examining patients who have a restricted orexin system for genetic reasons—this is the case in around one in two thousand people. These people suffer from narcolepsy (a sleeping disorder). Another possibility would be to observe people who receive a drug that blocks orexin. Such drugs are authorized for patients with insomnia. “If we understand how the brain arbitrates between food consumption and physical activity we can develop more effective strategies for addressing the global obesity epidemic and related metabolic disorders,” said Peleg-Raibstein.
In particular, interventions could be developed to help overcome exercise barriers in healthy individuals and those whose physical activity is limited. “… further understanding of adaptive and maladaptive choices relating to exercise may shed light on individual decisions impacting global human health, such as diet-induced or under-exercising-induced obesity, or exercise during anorexia,” the authors suggested.
Burdakov and his group are themselves focused on the basic neuroscientific research. “Our findings describe a method and a genetically defined entry point for further study of the biological underpinnings of voluntary exercise in a multiple-alternative environment,” the scientists noted. Next, he wants to find out how the orexin neurons interact with the rest of the brain when making decisions like the one between exercise and snacking.
