Taste Receptor Genes and Sensory Coding

描述（由申请人提供）：化学感觉感知为从细菌到人类的所有生物体提供有关外部世界化学成分的基本信息。在昆虫和脊椎动物中，这种“化学世界”通常通过两种不同的感觉方式来感知，味觉和嗅觉。我们的长期目标是了解动物如何识别环境中存在的化学线索，并研究这些线索如何调节摄食行为。行为学和电生理学研究表明，果蝇具有发达的味觉，可以检测大量化学上不同的底物（配体）。遗传学对几乎所有生物学学科的广泛影响使果蝇成为分子和行为神经生物学中极有价值的模型系统。它的作用在揭示化学感觉感知的逻辑方面具有特别重要的意义，因为它的化学感觉系统与脊椎动物/哺乳动物的化学感觉系统有许多相似之处，并且因为它也是昆虫的模型系统，其中许多对人类的繁荣和健康有直接影响。果蝇味觉受体神经元（GRN）表达7种跨膜受体（Gustatory Receptors或GR），检测可溶性配体。GRNs的激活传播到CNS中的味觉中心，其将感觉输入转化为各种行为输出。这些行为味觉反应可以大致分为接受行为或回避行为。最近几个实验室的研究表明，接受和回避行为是由两个不同的GRNs（“甜”和“苦”神经元）亚群介导的，每个亚群表达不同的GR。有趣的是，个别神经元亚群表达部分重叠，但不相同的成员推定的苦味传感GRs，这表明苍蝇可以区分不同的品质的“苦”的味道。分子遗传学方法，结合行为和电生理学研究，也导致糖味觉受体的鉴定，这也表达在复杂和重叠的“甜”神经元。最后，这些研究还建立了证据，味觉受体是由不同GR组成的多聚体复合物。然而，尽管取得了这些进展，关于味觉受体本身的许多基本问题，以及味觉器官中的化学物质检测如何转化为大脑中味觉质量的感知，仍然没有答案。本应用程序将研究其中的一些问题。我们建议确定GR的膜拓扑结构和信号传导模式。此外，我们将研究糖受体的异聚体组成，使用分子遗传和行为分析，最后，我们将测试苍蝇是否有能力区分不同的口味内的苦味模态。公共卫生相关性：喂养是所有行为中最基本和最重要的。它对人类的健康和健身有直接的影响。这项资助将研究味觉受体的分子功能和结构，以及由这些受体介导的摄食行为。在这些研究中，我们将使用果蝇的遗传模型系统，其味觉系统与哺乳动物（包括人类）的味觉系统有许多基本原理。

DESCRIPTION (provided by applicant): 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.