Identification of Sleep Substances in the Brain Using Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry

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Abstract Sleep is a basic biological need and sufficient sleep is required for physical and mental health. Reduced or disordered sleep contributes to an array of metabolic, inflammatory, cardiovascular, and neurological disorders, reduces productivity and performance, and is a threat to public safety. Understanding the control of sleep is therefore critical for human health and society. Sleep pressure (or sleepiness) has long been thought to be driven by substances that accumulate in the brain, where they promote sleep by acting on neural centers of sleep control. The identification of molecular mediators of sleep pressure in the brain would be highly significant, in that it would provide obvious targets for the improvement of daily sleep. Here we propose a large and unbiased screen for molecules that the fit the criteria for sleep promoting substances that drive daily changes in sleep pressure and promote homeostatic increases in sleep following sleep deprivation. To this end we have developed methods to differentiate molecules that rise with increasing sleep pressure from those that rise in direct response to the mechanical perturbation necessary to keep animal subjects awake. In doing so we have addressed a fundamental challenge to the identification of molecular correlates of sleep pressure. Using Matrix Assisted Laser Desorption/Ionization – Time of Flight Mass Spectrometry, we will identify molecules whose abundance tracks sleep pressure within the central brain, where sleep is controlled. The identification of candidate sleep substances will set the stage for new mechanistic investigations of sleep in Drosophila whose aim is to identify conserved molecular mechanisms of its homeostatic control. Given the existence of sleep-like states across the animal kingdom and the presence of homeostatic sleep control even in animals with extremely simple nervous systems, discoveries made in Drosophila are likely to reveal conserved features physiological systems regulating sleep.