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

描述（由申请人提供）：了解气味如何转化为行为仍然具有高度挑战性。在昆虫和哺乳动物中，高级嗅觉中心距离外围两个突触，对于解释环境气味线索的动机意义至关重要。目前，在任何生物体中，高级嗅觉中心功能的分子和电路机制很少被探索。遗传学上易于驯服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。在本申请中，我们将使用蝇幼虫模型来阐明：1） 多巴胺能神经元的一个小的子集突触后二级投射神经元（类似于哺乳动物中的二尖瓣细胞）接收和处理气味表征; 2）这样的DA神经元如何介导嗅觉输入转化为动机值，以驱动对可口食物的食欲。我们最近的研究结果表明，随意进食的果蝇幼虫表现出嗅觉奖励驱动的对可口食物的食欲，这种非稳态控制机制需要神经毡（称为侧角）进行高级嗅觉处理。我们已经发现，DA神经元的一个小的子集，以及四个神经肽Y-样NPF-生产神经元项目幼虫侧角，他们调解的气味表征食欲动机的转变。本申请有三个目的：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受体神经元在将气味输入转化为食欲动机中的功能分析。我们期望，从拟议的研究的成功结果将提供验证的蝇幼虫模型，阐明气味表征的食欲动机的转化的分子和神经基础。这些知识也应该提供更好地了解食欲相关疾病的病理生理学，并帮助这些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.