Project Summary/Abstract Sleep benefits the nervous system but the mechanisms underlying its restorative and neuroprotective properties are unknown. This understanding is important: without a circuit, cellular and molecular understanding we limit our ability to address disorders, such as Alzheimer's disease, that are exacerbated by lack of sleep or to devise treatments based on sleep's benefits. By examining and manipulating the most compact circuit that requires sleep to consolidate memory, we hope to decipher the molecular and cellular rules by which sleep enhances the performance of a neural network. Rules employed by a simple circuit are likely to be followed by cells within circuit modules that are linked together to form the much more complicated neural network of a human brain. We will utilize the anatomic simplicity and optical malleability of the C. elegans olfactory circuit to test hypotheses designed to elucidate the rules by which sleep acts to promote memory. Specifically, we will: Aim 1. Test the hypothesis that sleep is required for olfactory memory consolidation in a C. elegans classical conditioning model. We will examine sleep in animals that have been conditioned to avoid butanone. We will test the hypothesis that sleep is correlated with the strength of the memory and that it is both necessary and sufficient to promote memory consolidation. We will identify the cells that are required for sleep post training. These studies will lay the groundwork for understanding if sleep occurs post training and whether it is indeed necessary and sufficient to promote memory consolidation. Aim 2. Identify the synaptic basis of memory consolidation during sleep. First, we will observe the synapses via GRASP Then, using light-driven tools to activate or inactivate the animals during the consolidation period, we will test memory consolidation. We will then ask if visible markers for connections between cells are altered. These would provide the first study with synaptic resolution in a live animal of a memory trace being consolidated by sleep. Upon completion of these aims, we will have a conceptual, molecular, cellular, and circuit framework to understand how sleep alters the cell's function to benefit memory storage and thus behavioral fitness. The impact of this study is that it will ultimately inform study and treatment of disorders of sleep and memory and harness sleep's benefits to tackle aging and neurodegeneration.