Project Summary The public health and economic impact of chronic sleep deprivation (SD) have grown enormously with the increasingly global and 24-hour nature of our society. The human costs are also high; SD is an exacerbating factor in many mental illnesses. In spite of this, however, we know very little about the mechanisms by which SD alters memory circuits. Memory formation is bidirectionally sensitive to sleep levels. SD has negative effects on its formation, while learning has been shown to enhance sleep drive, suggesting that there are circuit interactions binding memory and sleep centers. In Drosophila, we have a very detailed understanding both of the computations that underlie memory formation and the structure of sleep circuits. This proposal leverages this knowledge to understand, for the first time at a circuit and molecular level, how SD dysregulates both short-term and long-term memory formation. In Aim 1 we investigate the effects of sleep deprivation on short-term memory formation. Based on preliminary data, we hypothesize that SD-dependent changes in dopamine dynamics degrade coincidence detection. We test specific circuit and molecular mechanisms and propose strategies to ameliorate SD pathology. In Aim 2 we probe the effect of SD on protein synthesis-dependent long-term memory. Preliminary data demonstrate that pre-training SD blocks activity-dependent local protein synthesis and that local synthesis is sensitive to inhibition of MAPK pathways. We will uncover the molecular mechanisms of how spaced training promotes this critical step in initiation of stable memory formation and we will determine how SD disrupts the process. Looking at SD through a lens of plasticity dysfunction will provide a strong molecular understanding of how memory formation is adversely affected by lack of sleep. Importantly, these studies also will deepen our knowledge of how memory is formed in well-rested brains and give us insight into what parts of the process are vulnerable to disruption, making this work relevant to understanding a wide range of other pathologies.