MCH neuron dysregulation in the pathophysiology of Prader-Willi Syndrome

Funding Summary

People with PWS have abnormally high amounts of REM sleep and inappropriate occurrence of REM sleep in the middle of active wake periods. A specific population of neurons in the lateral hypothalamus secretes a neuroactive substance called melanin-concentrating hormone (MCH), which control REM sleep. To determine if MCH neurons are overactive in PWS, Dr. Ramalingam and team will express ‘neural activity indicators’ in MCH neurons and measure the changes in their activity across several sleep-wake cycles in PWS mice. We hope, based on our past research, to observe higher activity of MCH neurons specifically during REM sleep in PWS mice compared to healthy mice. These experiments are vital to determine and establish the dysfunction of MCH system in PWS. 

Dr. Theresa Strong, Director of Research Programs, explains the details of this project in this short video clip.

Lay Abstract

Prader-Willi Syndrome (PWS), a rare neurodevelopmental disorder, affects 1 in 15000 to 30000 live births. In addition to slow development, overeating, and weight gain, PWS patients also experience several sleep disturbances, especially related to rapid eye movement sleep (REM sleep; stage of sleep when most dreams occur). PWS patients display abnormally high amounts of REM sleep and inappropriate occurrence of REM sleep in the middle of active wake periods. Because REM sleep is accompanied by ‘temporary paralysis’ of several skeletal muscles, their abnormal intrusions in wakefulness (referred to as ‘cataplexy’) can be severely debilitating and even life-threatening. For example, REM paralysis while driving can lead to vehicle crashes. In addition, higher amounts of REM sleep can cause depression and other mental health issues. Therefore, it is crucial to understand the specific alterations in the brain causing REM sleep abnormalities in PWS. We investigate this specific problem in the current application.  My research laboratory has been investigating the specific brain regions involved in REM sleep control for the past 15 years. A specific population of neurons in the hypothalamus (a region called the lateral hypothalamus) secretes a chemical messenger known as melanin-concentrating hormone (MCH). These MCH neurons are one of the key controllers of REM sleep. We found that activating these neurons increased REM sleep amounts and cataplexy in animal models. Based on these findings, we theorized that the MCH neurons are overactive in PWS, and this increased MCH activity is the cause of REM sleep abnormalities and cataplexy. We will test this idea using modern genetic tools and an animal model of PWS.  First, to determine if MCH neurons are overactive in PWS, we will express ‘neural activity indicators’ in MCH neurons and measure the changes in their activity across several sleep-wake cycles in PWS mice. Based on our past research, we expect to see a higher activity of MCH neurons during REM sleep in PWS mice compared to normal mice. But, this information is not sufficient to conclude that the hyperactivity of MCH neurons is indeed the underlying cause of REM sleep abnormalities in PWS. Hence, we will experimentally reduce the activity of MCH neurons or block their action at target sites and examine if these manipulations normalize the REM sleep amounts and abolish cataplexy. These are crucial experiments necessary to determine the importance of the MCH system in REM sleep abnormalities in PWS. The project outcomes will identify novel brain targets for developing better therapies for managing and treating sleep disorders in PWS. Given the consequences of abnormal REM sleep and cataplexy, improving sleep health will certainly improve overall health and quality of life in PWS patients. Moreover, the drugs that block MCH activity are currently tried for treating obesity. In this regard, our work will identify a newer purpose (treating sleep problems) for this class of medication; thus, a single drug may treat multiple issues of PWS. Thus, this work will have both an immediate and long-term impact on PWS therapy and management.

Research Outcomes: Public Summary

Sleep-wake profiling of Snord116del mice indicated that these mice exhibit high REM pressure, higher REM sleep amounts, and abnormal EEG features described in individuals with PWS. However, these mice do not exhibit hyperphagia and weigh less than wild-type littermates. Our data suggest that Snord116del mice are valuable tools for understanding the neural dysfunction responsible for sleep abnormalities in PWS.