Behavioral roles of serotonin

描述（由申请人提供）：人血清素转运蛋白SERT是相当一部分人群使用的抗抑郁药的主要靶点，也是几种滥用药物的直接靶点，但作用方式仍不清楚。该建议利用遗传学上易处理的模式生物，果蝇，研究5-羟色胺在果蝇中的行为作用，主要是通过遗传操纵的5-羟色胺转运蛋白，dSERT。我们利用独特的遗传，行为和解剖工具，在这个简单而相关的模型。该提议是基于这样的发现，即dSERT的非常温和的等位基因显示出昼夜节律行为的显著异常。有四个目标：在第一个目标中，将产生和表征另外的和更严重的dSERT等位基因，并且将研究dSERT过表达和定向表达不足。在第二个目标中，将研究dSERT与昼夜节律基因通路的相互作用。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驱动因子，这将阐明对5-羟色胺的各种行为效应具有特异性的大脑区域。第四个目标将利用以前的目标中学到的信息，为多巴胺能和多巴胺能通路中的新基因设计正向遗传筛选。 公共卫生相关性：5-羟色胺转运蛋白是广泛使用的抗抑郁药的主要靶点，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许多有待发现。果蝇（Drosophila melanogaster）含有高度保守的5-羟色胺系统，是一种重要的行为模型，与高等脊椎动物具有相关性。这项提案使用果蝇来更好地了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.