Many individuals with PWS have sleepiness, abnormal rapid eye movement (REM) sleep, and falling episodes resembling cataplexy - episodes of muscle paralysis that are usually triggered by strong, positive emotions. Caregivers, physicians and patients with PWS report significant disruption of daily life as a result of these sleep-related symptoms. Although these symptoms are common in PWS, their underlying cause is unknown. Research in people with PWS and mouse models of PWS suggests that these symptoms may result from altered function in neurons of the hypothalamus that make oxytocin and orexins, neuronal signaling molecules that regulate social behavior, wakefulness and sleep. We hypothesize that the oxytocin and orexin neurons excite each other, and this positive feedback loop normally plays an essential role in promoting wakefulness. In patients with PWS, a reduction in oxytocin neurons reduces orexin signaling, resulting in daytime sleepiness, altered REM sleep, and cataplexy-like behavior.
We will use our expertise in mouse sleep physiology to characterize the sleep phenotype of MAGEL2 null mice, a mouse model of PWS. We will determine if MAGEL2 null mice have cataplexy, and we will use optogenetics to test whether selective activation of the oxytocin neurons promotes arousal via the orexin neurons. Collectively, these experiments will provide novel insights into how hypothalamic dysfunction results in the sleep/wake symptoms of PWS. Armed with a better understanding of these brain circuits, researchers will be better able to develop new and more effective therapies for PWS.
Research Outcomes: Publications
Cataplexy and Its Mimics: Clinical Recognition and Management. Pillen S, Pizza F, Dhondt K, Scammell TE, Overeem S. Current Treatment Options in Neurology. 2017 Jun;19(6):23.
Thomas Scammell, MD
Harvard Medical School