"Sleep disruption leads to cognitive impairments, mood disorders and metabolic dysregulations demonstrating the critical importance of sleep in human health. In addition, sleep disorders such as insomnia are highly prevalent in the general population with major medical and societal consequences. Despite decades of research, the cellular and molecular processes by which sleep maintains normal brain function remain elusive. Maintenance of neurotransmission systems, regulation of energy metabolism, and learning and memory processing have been identified as potential sleep functions. Importantly, all these processes are modulated by glial cells in response to neuron signals. This means that neuron-glia interactions may potentially play a key role in sleep function. However, this role is largely under-explored worldwide. Using a Drosophila genetic model of insomnia, gene expression studies and a novel learning assay, we have uncovered a sleep-dependent neuron-glia signaling pathway. Specifically, this signaling pathway constitutes a novel function for the trans-membrane receptor Notch and its ligand Delta. The nature of the Notch-controlled signaling in this context is unknown. In this proposal, we will thus identify the components of the Notch pathway involved in sleep-wake regulation and determine how they influence neuronal physiology and learning. In a second step we will use a gene profiling approach combined with neurogenetic tools to identify in the brain the Notch-dependent neuronal circuits/systems involved in sleep-wake control. The influence of Notch signaling in the context of sleep deficits associated with Parkinson’s disease, will finally be evaluated using a Drosophila model. Because Notch receptors are also present in the mammalian brain the findings generated from the present project would have relevance for understanding sleep in all organisms and, in particular, lead to new therapeutic concepts applicable to human sleep-wake disorders."