Behavioral roles of serotonin

描述（由申请人提供）：人血清素转运蛋白SERT是抗抑郁药的主要靶点，被很大一部分人群使用，也是几种滥用药物的直接靶点，但其作用模式尚不清楚。本研究利用遗传易感的模式生物——黑腹果蝇，主要通过对血清素转运体（dSERT）的遗传操纵，来研究血清素在果蝇中的行为作用。我们利用独特的遗传、行为和解剖学工具，在这个简单但相关的模型中可用。这一建议是基于一项发现，即非常轻微的dSERT等位基因在昼夜节律行为中表现出惊人的异常。有四个目标：第一个目标是产生更多更严重的dSERT等位基因并对其进行表征，研究dSERT过表达和定向低表达。在第二个目标中，将研究dSERT与昼夜节律基因途径的相互作用。在第三个目标中，在血清素能神经元亚群中表达的新驱动因子将产生，这将阐明血清素的各种行为效应的特定大脑区域。第四个目标将利用在之前的目标中学习到的信息来设计在血清素能和多巴胺能途径中的新基因的遗传筛选。公共卫生相关性：5 -羟色胺转运体是广泛处方抗抑郁药的主要目标，但关于神经递质5 -羟色胺的功能及其在人类健康中的作用仍有待发现。果蝇（Drosophila melanogaster）含有高度保守的血清素系统，是一种重要的行为模式，已被证明与高等脊椎动物相关。这个建议利用果蝇来更好地理解血清素的行为生物学。

DESCRIPTION (provided by applicant): The human serotonin transporter protein SERT is the primary target for antidepressants used by a significant fraction of the population and also is a direct target for several drugs of abuse, yet modes of action are still unclear. This proposal utilizes the genetically tractable model organism, Drosophila melanogaster, to study the behavioral roles of serotonin in Drosophila, primarily via genetic manipulation of the serotonin transporter, dSERT. We take advantage of the unique genetic, behavioral and anatomical tools available in this simple yet relevant model. The proposal is based on the finding that very mild alleles of dSERT show striking abnormalities in circadian behaviors. There are four aims: In the first aim, additional and more severe dSERT alleles will be generated and characterized, and dSERT overexpression and directed under-expression will be studied. In the second aim, the interactions of the dSERT with the circadian gene pathways will be studied. In the third aim, new drivers expressing in subsets of serotonergic neurons will be generated that will elucidate brain regions specific for the various behavioral effects of serotonin. The fourth aim will take advantage of information learned in the previous aims to design forward genetic screens for new genes in the serotonergic and dopaminergic pathways. PUBLIC HEALTH RELEVANCE: The serotonin transporter is the primary target of widely prescribed antidepressants, yet much remains to be discovered regarding the function of the neurotransmitter serotonin and its role in human well-being. The fruit fly, Drosophila melanogaster, contains a highly conserved serotonin system and is an important behavioral model with demonstrated relevance for higher vertebrates. This proposal uses the fruit fly to better understand the behavioral biology of serotonin.