Motion sickness is a very common condition that affects about 1 in 3 people, but the brain circuits involved are largely unknown. Newly reported work outlines a brain circuit involved in motion sickness that also contributes to regulating body temperature and metabolic balance. Findings from the team’s work, including studies in a mouse model of motion sickness, may also point to new strategies for treating obesity.
Co-corresponding author, Yong Xu, MD, PhD, professor of pediatrics–nutrition and associate director for basic sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, and colleagues, reported on their studies in Nature Metabolism. In their paper, titled “Vestibular neurons link motion sickness, behavioral thermoregulation, and metabolic balance in mice,” the team concluded that their collective findings “… could help to provide potential targets to treat motion sickness in humans, and highlight the underappreciated function of the vestibular system in obesity control.”
Symptoms of motion sickness in humans, including facial pallor, nausea, and vomiting, have been well-documented and investigated, the authors wrote. Interestingly the researchers stated, “… research suggests a potential link between obesity and impairments in balance and sensory processing, which contribute to motion sickness.” In addition, they commented, “… many genetic variants associated with motion sickness are implicated in the regulation of glucose tolerance, insulin sensitivity, and body-weight balance.” However, the exact relationship between motion sickness, metabolic regulations, and the underlying mechanisms isn’t known.
The Xu lab works with mouse models to investigate how the brain regulates metabolism and how this may be related to obesity and inform the development of more effective obesity drugs. Mouse models offer an abundance of molecular and genetic tools, as well as relevant behavioral assays to elucidate the neural mechanisms underlying physiological responses.
Motion sickness hadn’t been a key focus for the lab’s research. “When Longlong Tu, PhD, a postdoctoral fellow in my lab, proposed to investigate the brain circuits involved in motion sickness, a condition for which he is highly susceptible, I was not very excited about the idea because it’s not one of the main interests of my lab,” said Xu. “However, I became more interested and supported Tu’s idea when he explained the emerging evidence suggesting a link between motion sickness and metabolic balance, which is one of my research interests.”
But there was a challenge—mice are incapable of vomiting, one of the main manifestations of motion sickness in people. But mice and humans subjected to motion sickness stimuli, such as experiencing horizontal motion back and forth for some time, do both demonstrate hypothermia, a reduction in body temperature. “Notably, motion sickness leads to changes in thermoregulation, as evidenced by a reduction in body temperature observed in mouse, shrews, rats, and humans,” the authors wrote.” Xu added, “This allowed us to develop a mouse model of motion sickness in which we measured core body temperature, physical activity, and brain activity as the animals experienced motion stimuli.”
The authors further explained, that this mouse model of motion sickness “… exhibits prominent hypothermia during provocation, accompanied by associated perturbed thermoregulatory and other physiological adaptations typical of what is seen in people experiencing the condition.”
Through their reported studies the researchers found that motion activates glutamatergic neurons—neurons that produce glutamate, the primary excitatory neurotransmitter in the central nervous system—in the medial vestibular nucleus parvocellular part (MVePC) of the brain. Activation of these MVePCGlu neurons is required and sufficient to mediate motion-induced thermal adaptations, they found. “We show that motion-activated neurons in the MVePC are glutamatergic (MVePCGlu), and that optogenetic stimulation of MVePCGlu neurons mimics motion-induced hypothermia by signaling to the lateral parabrachial nucleus (LPBN),” they further explained in their paper. The researchers validated the model by showing that motion sickness-induced hypothermia does not occur when the mice are given the anti-nausea drug scopolamine.
“Given that the activation of the MVePC→LPBN circuit mimics motion-induced hypothermia, we next investigated whether inhibiting this circuit would attenuate it,” the investigators wrote. Xu added, “We further studied this motion sickness circuit by inhibiting the MVePCGlu neurons in the absence of motion stimuli. Inhibiting these neurons led to an increase in body temperature, along with increased physical activity. These physiological alterations suggest that chronic inhibition of MVePCGlu neurons may result in a higher energy expenditure in mice.”
The authors further noted, “Chemogenetic inhibition of MVePCGlu neurons can almost fully abolish motion-induced hypothermia, as well as cold-seeking behavior. Moreover, inhibition of the MVePC→LPBN circuit largely alleviates provocation-induced hypothermic responses and reverses cold-seeking behavior.”
When the researchers investigated the potential metabolic benefits of chronic inhibition of MVePCGlu neurons they found that while the mice ate more they gained less weight and exhibited better glucose tolerance and enhanced insulin sensitivity, physiological responses associated with better health. The collective results, they noted, “… highlight that chronic inhibition of MVePCGlu neurons prevents diet-induced obesity through increased energy expenditure in female mice.” Xu stated, “These results highlight the underappreciated function of the brain’s vestibular system in metabolic balance, and further raise the possibility that better understanding of the neural basis for thermoregulation during motion sickness may provide unconventional targets for the treatment of obesity.”
And for first author Tu, the findings offer hope that a better understanding of the brain circuit for motion sickness could also lead to improved medications for his condition. “Overall, these findings highlight MVePCGlu neurons as a potential target for motion-sickness treatment and obesity control,” the authors concluded.