Caregivers, physicians and patients with PWS report that daytime sleepiness in PWS significantly disrupts daily life. However, the underlying cause of excessive daytime sleepiness in PWS is unknown. Dr. Scammell’s group is exploring the contribution of reduced neuronal function in the hypothalamus region of the brain, specifically, oxytocin/orexin signaling. Using a photoactivation technique that specifically targets and activates certain subsets of neurons, this project will improve our understanding of how hypothalamic dysfunction impairs sleep and wakefulness in PWS, and provide potential targets for intervention.
ABSTRACT: Caregivers, physicians and patients with PWS report significant disruption of daily life as a result of daytime sleepiness. Although excessive daytime sleepiness is common in PWS, the underlying cause is unknown. Research in people with PWS and mouse models of PWS suggests that sleepiness may result from reduced function in neurons of the hypothalamus that make oxytocin and orexins, neuronal signaling molecules that regulate social behavior, wakefulness and sleep. In the first year of FPWR funding, we found that oxytocin neurons project to the lateral hypothalamic area (LHA), and photoactivation of oxytocin terminals in the LHA promotes wake even in the absence of the orexin neuropeptides. This finding may help explain the sleepiness of PWS, but we do not know whether this oxytocin pathway is necessary for normal wakefulness or which target neurons in the LHA mediate this response. We hypothesize that the sleepiness of PWS is caused by reduced oxytocin neuron signaling in the LHA. We propose experiments to test this hypothesis that will improve our understanding of how hypothalamic dysfunction impairs sleep and wakefulness in PWS. Armed with a better understanding of these brain circuits, researchers will be better able to develop new and more effective therapies for PWS.
Thomas Scammell, MD
Harvard Medical School