Chemosensory perception provides all organisms, from bacteria to humans, with essential information about the chemical composition of the external world. In insects and vertebrates, this 'chemical world'is generally perceived by two distinct sensory modalities, gustation and olfaction. Our long-tem objective is to understand how animals recognize chemical cues present in their environment and to investigate how these cues regulate feeding behaviors. Behavioral and electrophysiological studies have indicted that Drosophila possesses a well-developed sense of taste that can detect a large number of chemically diverse substrates (ligands). The broad impact of genetics in virtually all disciplines of biology has made Drosophila an extremely valuable model system in molecular and behavioral neurobiology. Its role has been of particular significance in uncovering the logic of chemosensory perception, because its chemosensory systems exhibit many parallels with those of vertebrates/mammals, and because it also serves as a model system for insects, many of which have a direct impact on human prosperity and health. Drosophila gustatory receptor neurons (GRNs) express putative seven transmembrane receptors (Gustatory Receptors or GRs) that detect soluble ligands. Activation of GRNs is propagated to taste centers in the CNS, which translate sensory input into various behavioral outputs. These behavioral taste responses can be broadly divided into acceptance behavior or avoidance behavior. Recent work in several laboratories has shown that acceptance and avoidance behaviors are mediated by two molecularly distinct subpopulations of GRNs ("sweet" and "bitter" neurons), each expressing different sets of GRs. Interestingly, individual neuron subpopulations express partially overlapping but not identical members of putative bitter-sensing GRs, suggesting that flies can discriminate distinct qualities of "bitter" taste. Molecular-genetics approaches, combined with behavioral and electrophysiological studies have also led to the identification of sugar taste receptors, which are also expressed in complex and overlapping sets of "sweet" neurons. Finally, these studies also established evidence that taste receptors are multimeric complexes composed of different GRs. Yet, despite all this progress, many basic questions about the taste receptors themselves, and about how detection of chemicals in taste organs is translated in the percept of a taste quality in the brain, remain unanswered. This application will investigate some of these questions. We propose to determine membrane topology and mode of signaling of GRs. Furthermore, we will investigate the heteromeric composition of sugar receptors using molecular genetic and behavioral analyses, and lastly, we shall test whether flies have the ability to discriminate between different flavors within the bitter taste modality. PUBLIC HEALTH RELEVANCE: Feeding is the most basic and essential of all behaviors. It has an immediate impact on human health and fitness. This grant will investigate the molecular function and structure of taste receptors, and the feeding behaviors that are mediated by these receptors. For these studies, we will use the genetically amenable model system of Drosophila, whose taste sensory system shares many basic principles with that of mammals, including humans.