Genetic Analysis of Olfactory Coding in Drosophilia

描述(申请人提供)：嗅觉系统允许动物感知大量关键的环境刺激，发出食物、捕食者或配偶存在的信号。在不同物种中嗅觉分子生物学的最新进展揭示了这些统一的原理：给定的嗅觉神经元表达一个或几个特定的气味受体基因；所有表达一种气味受体的神经元聚集在大脑中有限数量的称为肾小球的靶点上；气味刺激引发大脑中肾小球激活的刻板模式。然而，气味的有意识感知是如何在大脑中编码的还不清楚。 这项提议的长期目标是了解气味编码的分子和细胞基础。实验将在果蝇的幼虫阶段进行，果蝇有一个解剖上简单的嗅觉系统，可以进行行为遗传分析。 初步研究表明，幼虫顶端背部器官中的21个神经元介导了对挥发性刺激的所有嗅觉反应；至少18个果蝇气味受体基因的一个以前未描述的子集编码了幼虫的气味受体；给定的嗅觉神经元表达这些气味受体基因中的一个或几个，并针对幼虫大脑中的一个专门的肾小球；单个嗅觉神经元的基因消融导致嗅觉行为的选择性改变。这些结果确立了果蝇幼虫是已知的最简单的可遗传操作的模式生物，它包含了脊椎动物嗅觉系统中发现的所有关键细胞元件，并为在基因、神经元、电路和行为水平上分析气味编码奠定了基础。 这些研究导致了一种假设，即表达不同气味受体的嗅觉神经元需要组合激活，以编码给定气味的显著特征，并激活适当的行为输出。为了验证这一假设，提出了以下具体目标：(1)分离完整的幼虫气味受体基因。(2)确定幼虫嗅觉神经元的外周和中枢组织。(3)阐明已鉴定的幼虫嗅觉神经元的行为输出。这些研究的健康相关之处在于，了解感官知觉背后的回路与具有神经学或精神病学基础的大脑障碍有关。

DESCRIPTION (provided by applicant): The olfactory system permits animals to perceive a vast number of critical environmental stimuli signaling the presence of food, predators, or mates. Recent advances in the molecular biology of olfaction in diverse species have uncovered these unifying principles: a given olfactory neuron expresses one or a few specific odorant receptor genes; all neurons expressing one odorant receptor converge upon a limited number of targets called glomeruli in the brain; odor stimuli elicit stereotyped patterns of glomerular activation in the brain. However, how the conscious perception of an odor is encoded in the brain is unclear. The long-term goals of this proposal are to understand the molecular and cellular basis for odor coding. Experiments will be carried out in the larval stage of the fruit fly, Drosophila melanogaster, which has an anatomically simple olfactory system amenable to behavior genetic analysis. Preliminary studies have demonstrated that 21 neurons in the dorsal organ at the tip of the larva mediate all olfactory responses to volatile stimuli; that a previously uncharacterized subset of at least 18 Drosophila odorant receptor genes encodes the larval odorant receptors; that a given olfactory neuron expresses one or a few of these odorant receptor genes and targets a dedicated glomerulus in the larval brain; that genetic ablation of a single olfactory neuron leads to selective alterations in olfactory behavior. These results establish the Drosophila larva as the simplest known genetically manipulable model organism that contains all the critical cellular elements found in vertebrate olfactory systems, and set the stage for analyzing odor coding at the level of genes, neurons, circuits, and behavior. These studies have led to the hypothesis that combinatorial activation of olfactory neurons expressing different odorant receptors is required to encode the salient features of a given odorant and activate the appropriate behavioral output. To test this hypothesis, the following specific aims are proposed: (1) Isolating the complete repertoire of larval odorant receptor genes. (2) Determining the peripheral and central organization of larval olfactory neurons. (3) Elucidating the behavioral output of identified larval olfactory neurons. The health relatedness of these studies is that an understanding of circuits underlying sensory perception is relevant for brain disorders with a neurological or psychiatric basis.