People with PWS experience abnormally high amounts of REM sleep and an inappropriate occurrence of REM sleep in the middle of active wake periods. Previous research has shown that neurons secreting a certain hormone (MCH) control REM sleep. To determine if MCH neurons are overactive in PWS, this research team will express ‘neural activity indicators’ in MCH neurons and measure the changes in their activity across several sleep-wake cycles in PWS mice, with the ultimate goal of identifying new drug targets for normalizing sleep in PWS.
Lay Abstract
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects 1 in 15,000 to 30,000 live births. Besides slow development, overeating, and weight gain, individuals with PWS often experience significant sleep disturbances, primarily related to rapid eye movement (REM) sleep, the stage of sleep when most dreams occur. PWS individuals exhibit unusually high amounts of REM sleep and inappropriate intrusions of REM sleep during active wake periods. High REM pressure and the associated sleepiness lead to decreased energy levels and reduced ability to perform everyday tasks, including school or work activities, due to impaired concentration and motivation. Also, elevated REM sleep levels are strongly linked to anxiety, depression, obsessive-compulsive disorder, and psychotic illnesses, which affect a significant portion of the PWS population. Thus, it is vital to understand the specific brain alterations causing REM abnormalities in PWS, which is the focus of this proposal.
My research laboratory has investigated the brain mechanisms controlling REM sleep for >15 years. A specific population of neurons in a region called the lateral hypothalamus secretes a chemical messenger known as melanin-concentrating hormone (MCH). When activated, these MCH neurons specifically increase REM sleep. Based on these data, we theorized that the MCH neurons are overactive in PWS, and this higher activity is the cause of REM sleep abnormalities and cataplexy. We propose to test this idea using modern genetic tools and an animal model of PWS.
These experiments are expected to establish the MCH neuron hyperactivity as a primary cause of REM sleep abnormalities in PWS. This work will also identify MCH signaling as a novel brain target for developing better therapies for managing and treating sleep disorders in PWS. Given the negative consequences of abnormally higher REM sleep on physical and mental health, treating sleep issues will undoubtedly improve the overall health and quality of life in PWS individuals. Moreover, the drugs that block MCH activity are currently tried for treating obesity in PWS. In this regard, our work will identify a newer purpose (treating sleep problems) for this class of medication. Thus, this work will have both an immediate and long-term impact on PWS therapy and management.