Project Summary The functions of the brain emerge from communication between neurons. The language of neuronal communication is mediated by chemicals that are released from one neuron and sensed by another. These chemical signals consistent of both classical “fast acting” neurotransmitters such as glutamate and GABA that signal across synapses in milliseconds, as well as more than 100 diverse neuromodulators that act on longer timescales. Neuromodulators are the major targets of most neuropsychiatric drugs as well as drugs of abuse, and their dysregulation is implicated in medical conditions ranging from obesity to psychiatric disorders. Yet we still lack a clear understanding, at both the cellular and neural circuit level, of how these neuromodulators and their fast acting counterparts cooperate to generate the diverse behavioral outputs of the brain. Neuropeptides are the largest and most diverse class of neuromodulators that neurons use to communicate with each other and regulate behavior. Yet we know little about the general rules that govern and constrain neuromodulatory signaling in any organism. Here I propose to use the compact nervous system of C. elegans as a unique paradigm to link neuropeptide signaling and neural circuits in a whole animal model. Despite its anatomical simplicity, C. elegans makes rich use of neuropeptide signaling to regulate its behavior and physiology and in shares a similar number of neuropeptide genes with mammals and a conserved set of enzymatic pathways that regulate neuropeptide synthesis, processing, transport, and exocytosis. Our goal is to discover, for the first time, how the biochemical network of neuromodulators relates to the fixed anatomy of the brain in a whole animal model. Understanding this relationship is key to develop tools to monitor brain activity, and ultimately to discover treatments for cognitive and behavioral dysfunction.