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.
