STUDY OF ODOR PERCEPTION AND APPETITIVE MOTIVATION IN DROSOPHILA - Resubmission -

描述(由申请者提供)：理解气味是如何转化为行为的仍然是极具挑战性的。在昆虫和哺乳动物中，高级嗅觉中心是远离外围的两个突触，对于解释环境气味线索的动机意义至关重要。目前，高级嗅觉中枢功能的分子和回路机制在任何生物体中都很少被探索。遗传上易驯化的果蝇幼虫有一个高度进化的神经系统，但在数字上却很简单。在这个应用中，我们将使用苍蝇幼虫模型来阐明：1)一个 突触后到二级投射神经元的一小部分多巴胺能神经元(类似于哺乳动物的二尖瓣细胞)接收和处理气味表示；2)这种DA神经元如何介导嗅觉输入到激励值的转换，以刺激对美味食物的胃口。我们最近的发现表明，自由摄食的果蝇幼虫表现出对美味食物的嗅觉奖励驱动的胃口，这种非稳态控制机制需要神经纤维(称为侧角)来进行更高级别的嗅觉处理。我们已经发现，一小部分DA神经元以及四个神经肽Y样NPF产生神经元投射到幼虫的侧角，它们介导了气味表征向食欲动机的转化。这项应用有三个目标：1)多巴胺(DA)在接收食欲嗅觉信息中的功能分析；2)DA神经元中神经肽F和其他分子通路的遗传分析；3)DA受体神经元将气味输入转化为食欲动机的功能分析。我们期望这些拟议研究的成功结果将为阐明气味表征转化为食欲动机的分子和神经基础提供苍蝇幼虫模型的验证。这些知识还应有助于更好地了解食欲相关疾病的病理生理学，并有助于此类疾病的遗传风险评估。

DESCRIPTION (provided by applicant): Understanding how smell is transformed to behavior remains highly challenging. The higher-order olfactory centers, which are two synapses away from the periphery in insects and mammals, are crucial for interpreting the motivational significance of environmental odor cues. At present, molecular and circuit mechanisms underlying the functioning of higher-order olfactory centers have been rarely explored in any organisms. Genetically tractable Drosophila larvae have a highly evolved nervous system that is yet numerically simple. In this application, we will use the fly larva model to elucidate: 1) how a small subset of dopaminergic neurons postsynaptic to second-order projection neurons (analogous to mitral cells in mammals) receives and processes odor representations; 2) how such DA neurons mediate the transformation of olfactory inputs into motivational values to drive appetite for palatable food. Our recent findings demonstrate that Drosophila larvae fed ad libitum display olfactory reward-driven appetite for palatable food, and this non-homeostatic control mechanism requires the neuropil (named the lateral horn) for higher-order olfactory processing. We have found that a small subset of DA neurons as well as four neuropeptide Y-like NPF-producing neurons project to larval lateral horns, and they mediate the transformation of odor representations to appetitive motivation. This application has three objectives: 1) Functional analyses of dopamine (DA) in reception of appetitive olfactory information; 2) Genetic analysis of a neuropeptide F and other molecular pathways in DA neurons; 3) Functional analyses of DA receptor neurons in transforming odor inputs to appetitive motivation. We expect that the successful outcomes from the proposed studies will provide validations of the fly larva model for elucidating the molecular and neural basis of transformation of odor representations to appetitive motivation. Such knowledge should also provide better understanding of the pathophysiology of appetite-related disorders, and aid the genetic risk assessment for such disorders.