Behavioral roles of serotonin

描述(申请人提供)：人类5-羟色胺转运蛋白SERT是相当一部分人使用的抗抑郁药物的主要目标，也是几种药物滥用的直接目标，但其作用模式仍不清楚。这项建议利用遗传上易驯化的模式生物--黑腹果蝇，主要通过对5-羟色胺转运体dSERT的遗传操作，来研究5-羟色胺在果蝇中的行为作用。我们利用了这个简单但相关的模型中提供的独特的遗传、行为和解剖学工具。这一建议是基于dSERT非常轻微的等位基因在昼夜行为中显示出显著的异常这一发现。第一个目标是产生更多更严重的dSERT等位基因，并对dSERT过表达和定向低表达进行研究。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，将产生在5-羟色胺能神经元亚群中表达的新的驱动因素，以阐明5-羟色胺的各种行为效应所特有的大脑区域。第四个目标将利用在前面的目标中学到的信息，为5-羟色胺和多巴胺能途径中的新基因设计正向基因筛查。公共卫生相关性：5-羟色胺转运体是广泛处方的抗抑郁药物的主要靶点，但关于神经递质5-羟色胺的功能及其在人类福祉中的作用，仍有许多有待发现。果蝇含有高度保守的5-羟色胺系统，是一种与高等脊椎动物相关的重要行为模型。这项建议使用果蝇来更好地了解5-羟色胺的行为生物学。

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.