Role of drosophila Neuropeptide F in Ethanol Response

描述（由申请人提供）：神经肽Y （NPY）信号系统在果蝇和哺乳动物之间在结构和功能上都是保守的。本实验室最近的研究表明，果蝇神经肽F （NPF）是果蝇基因组中唯一的NPY同源物，在调节动机摄食、运动和酒精反应中起重要作用。在npf缺陷果蝇和npy敲除小鼠之间观察到相似的表型：两种动物均表现出正常的基线摄食，但动机摄食不足；缺乏npf的蝇幼虫表现出食物引起的过度活跃运动，而敲除NPY的蝇幼虫表现出对癫痫发作的敏感性增加；npf缺陷果蝇和NPY敲除小鼠均表现出乙醇敏感性下降。此外，过表达NPF的果蝇对乙醇镇静的敏感性增加，与过表达npy的小鼠的表型相似。这些观察结果有力地表明，果蝇是研究NPF/NPY信号系统作用的神经、细胞和分子机制的合适遗传模型。

DESCRIPTION (provided by applicant): The neuropeptide Y (NPY) signaling system is both structurally and functionally conserved between Drosophila and mammals. Recent studies from this laboratory have shown that Drosophila neuropeptide F (NPF), the single NPY homologue in the fly genome, plays important roles in modulating motivational feeding, locomotion and alcohol response. Parallel phenotypes have been observed between NPF-deficient flies and NPY-knockout mice: both animals displayed normal baseline feeding but deficits in motivational feeding; NPF-deficient fly larvae showed food-elicited hyperactive locomotion whereas NPY knockouts exhibited increased susceptibility to seizure; both NPF-deficient flies and NPY knockout mice displayed decreased ethanol sensitivity. Moreover, flies overexpressing NPF showed increased sensitivity to ethanol sedation, similar to the phenotypes of NPY-overexpressing mice. These observations strongly suggest that Drosophila is a suitable genetic model for the study of the neural, cellular and molecular mechanisms underlying the action the NPF/NPY signaling system. This proposed research aims to further elucidate the neurobiological basis of. NPY-mediated regulation of ethanol related behaviors. The specific aims of this application include: 1) Identification and functional analysis of the neuroanatomical sites of the NPF system involved in modulation of ethanol response; 2) EMS-mutagenesis screen of genes involved in NPF/NPFR1-mediated ethanol response; 3) gain-of-function screen for genes involved in NPF/NPFR1 -mediated ethanol response.. The results from these studies should provide novel insights into understanding why a common neural signaling system underlies the controls of feeding and alcohol related behaviors, what components of the signaling pathway are conserved, and how genetic factors contribute to ethanol sensitivity in diverse organisms