Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.29.069229v1?rss=1 Authors: Driscoll, M., Coleman, V., McLaughlin, M., Nguyen, A., Sitaraman, D. Abstract: Diseases associated with impaired sleep regulation negatively impact motor skills, emotional states, and cognitive performance. Neural circuits involved in sleep homeostasis play a critical role in sleep-wake transition but the precise circuit mechanisms underlying persistence of sleep, arousal and wakefulness remain unclear. The fruit fly, Drosophila melanogaster, provides a powerful model system for the study of sleep and circuit mechanisms underlying state transitions and persistence of states to meet the organisms motivational and cognitive needs. Here we investigate the role of specific subsets of dopamine neurons innervating the mushroom body (MB), a region implicated in sleep and associative learning in Drosophila. We find that inhibition of specific subsets of PAM and PPL1 dopamine neurons projecting to the MB increase sleep in the presence of strong wake-inducing stimuli. The wakefulness induced by activity of the PAM neurons is mediated by both Dop1 R1 and Dop1R2 receptors located in downstream Kenyon cells and mushroom body output neurons (MBONs). Further, we find that unlike the activity of the MBONs, whose activity is modulated by sleep-need and sleep-debt, the dopamine neuronal activity is independent of sleep-need. The sleep-regulating dopamine neurons characterized in these studies are also involved in mediating short-term courtship memories, appetitive memories and memory extinction processes. Taken together, we have identified and characterized the dopamine circuit and cellular mechanisms that link motivation-dependent behavioral output and suppression of sleep to coordinate motivated processes with wakefulness. Copy rights belong to original authors. Visit the link for more info