It is well established in science as well as culture that the smell of food is linked to appetite, but despite the extensive research being conducted to understand the biology underlying the most notable symptom of Prader-Willi Syndrome, hyperphagia, little research has explored the impact of olfaction, the sense of smell, in PWS.
An article published this spring by laboratories in Toulouse, France, marks the first time PWS patients’ brain activity was monitored
In the initial published study, participants, which included PWS adults and neurotypical adults, were exposed to the smells of tulips or caramel while their brain activity was monitored by MRI. Both odors are considered pleasant, but only caramel is normally associated with food. PWS patients were equally successful at identifying odors, but they had notable differences in brain activity in response to the odors. Neurotypical individuals responded to both odors with the same increases in brain activity, whereas PWS patients show five times more activity in response to caramel than to tulip. Furthermore, increases in brain activity were correlated with the patient’s hyperphagia severity. What differences at a cellular level could cause this altered activity measured by MRI? FPWR has awarded a grant beginning in September 2023 to advance these studies using both human and mouse models concurrently.
Fortunately, olfaction systems develop and function similarly in mice as in humans, giving researchers more options to dissect and test aspects of the underlying biology more precisely. To that end, the group who completed the studies described above has partnered with experts in mouse neurodevelopment in Cologne, Germany to further these in tandem. The group has already demonstrated that Magel2-null PWS model mice have reduced expression of several olfactory genes. The proceeding work will thoroughly characterize the development and functionality of the olfactory system in Magel2-null PWS model mice from embryo to adulthood, measuring at each stage the size, shape, position, and gene expression of various kinds of brain cells involved in olfaction. This developmental description will be complemented by expanding the human studies described to children aged 3–18 years, pinpointing when the altered central responses to olfactory food cues occur in individuals with PWS.
Finally, the effects of oxytocin (OXT) therapy on olfaction system development will be assessed. PWS patients are deficient in the production of many hormones, including OXT, and OXT therapy has been shown to improve feeding and social skills in PWS infants. OXT has also been linked to the development of the olfactory system. Brain activity responses will be measured as above in children with PWS that received OXT intranasally as neonates as part of OXT clinical trials. The Magel2-null mice will also be treated postnatally with OXT to determine whether it affects the development of the olfactory system in any of the parameters described above.
This exciting new direction for PWS research has the potential to benefit patients in a number of ways. The most important takeaway is that food odors clearly have a much bigger impact on the PWS brain than expected. Your loved one with PWS may have a stronger reaction to an odor than you would expect. Could specific odors (or a lack thereof) be used to decrease hyperphagia or promote satiety? Could drugs that affect the sense of smell have unexpectedly beneficial effects for PWS patients? In the longer term, could interventions like the OXT therapy mentioned above restore the proper development of olfactory systems? These are all research topics that FPWR is now eager to promote, thanks to this remarkable discovery.
