Project Summary Learned avoidance of harmful food is a powerful survival strategy and therefore evolutionarily conserved from invertebrates to humans. The underlying signaling mechanisms enabling the nervous system to associate the internal state of sickness with the sensory cues of a food source to trigger the formation of an aversive memory have remained elusive. In order to trace a molecular signal from non-nervous tissues to the nervous system, the work proposed here will be conducted in the model organism C. elegans, which has the advantage of simple anatomy and a compact nervous system, as well as an abundance of tools for quantitative imaging and genetic manipulation. After prolonged exposure to pathogenic food, C. elegans can learn to avoid the pathogen upon subsequent encounter. This learned aversion requires serotonin signaling from a pair of sensory neurons called ADF. The following specific aims will address how information about the internal state of the animal changes the coupling between sensory activation and serotonin release in ADF neurons: 1) to identify molecular signals that activate ADF sensory neurons; 2) to characterize ADF function in pathogen learning circuits. Serotonin is involved in modulating food-related behaviors across the animal kingdom including in humans. ADF neural activity in response to bacterial odors will be examined using calcium imaging, and C. elegans behavioral response to pathogenic bacteria will be characterized using behavioral pathogen learning assays. The goal of this project is to elucidate circuit mechanisms through which modulation of ADF neurons leads to learned pathogen avoidance behavior in C. elegans. This project focuses on taste and smell, specifically on how chemosensation serves the defensive function of triggering avoidance behaviors. In particular, this project fits within the priority area of understanding normal function and fundamental biology of chemosensation. Understanding the signaling mechanisms by which information from non-nervous tissues to the brain has implications for health-related conditions where this communication is disrupted such as obesity and nausea induced by chemotherapy treatment.