Ethanol-Induced Locomotor Behaviors in Drosophila

乙醇诱导的果蝇运动行为

• 批准号: 6929308
• 负责人: ULRIKE A HEBERLEIN
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929308
• 关键词: Drosophilidae; brain mapping; ethanol; genetically modified animals; invertebrate locomotion; neuroanatomy; neurochemistry; neurogenetics; neuropsychology; neurotransmitter receptor; receptor expression; site directed mutagenesis; tetanus toxin; transfection

DESCRIPTION (provided by applicant): In most model organisms in which it has been studied, low doses of ethanol have central nervous system- activating effects, whereas high doses are sedative. These acute effects of ethanol are commonly measured as changes in locomotor activity. Interestingly, a growing body of evidence suggests that the molecular, neurochemical, and neuroanatomical mechanisms that regulate ethanol's effect on locomotion are at least in part shared with those that underlie the drug's rewarding effects. For example, pharmacological and genetic manipulations have shown that midbrain dopaminergic pathways are involved in both the activating and rewarding effects of ethanol in rodent models. It is therefore likely that insights into ethanol's addicting effects can be obtained by studying the relatively simple effects of the drug on locomotor activity. The goal of this proposal is to study the genetic, molecular, and neural mechanisms that regulate ethanol- induced locomotor behaviors in Drosophila. Preliminary experiments have revealed that fruitflies show a biphasic locomotor response to ethanol similar to that observed in mammals, and that, as in rodents, dopaminergic systems play a role in ethanol's acute activating effects in flies. We propose to generate and characterize mutants with altered ethanol-induced locomotor activity. The genes disrupted by these mutations will be studied molecularly and their function will be analyzed in vivo upon establishment of transgenic flies. The brain regions that mediate ethanol's effect on locomotion will be mapped by selectively inactivating specific brain regions by means of targeted expression of a tetanus toxin-encoding transgene. The neurochemical profiles of these brain regions will be ascertained by determining the expression of neurotransmitters, the enzymes involved in their synthesis, and/or the receptor systems upon which they act. Together, these approaches will help us understand the basic molecular pathways and neural circuits that regulate ethanol-induced locomotor behaviors in Drosophila. Because the mechanisms of ethanol's action share common features in organisms as different as flies and mice, we predict that knowledge gained from Drosophila will provide novel and general insights into the processes by which ethanol acts in the nervous system to regulate behavior.

描述（由申请人提供）：在大多数已研究的模型生物中，低剂量的乙醇具有中枢神经系统激活作用，而高剂量是镇静的。这些乙醇的急性作用通常被测量为运动活性的变化。有趣的是，越来越多的证据表明，调节乙醇对运动作用的分子，神经化学和神经化学机制至少部分与构成药物奖励作用的基础的分子和神经化学机制。例如，药理学和遗传操作表明，中脑多巴胺能途径参与啮齿动物模型中乙醇的激活和奖励作用。因此，可以通过研究药物对运动活性的相对简单影响来获得对乙醇上瘾作用的见解。该建议的目的是研究调节果蝇中乙醇诱导的运动行为的遗传，分子和神经机制。初步实验表明，果蝇显示出对乙醇的双相运动反应，类似于哺乳动物中观察到的乙醇，并且与啮齿动物一样，多巴胺能系统在乙醇的急性激活蝇中起着作用。我们建议以改变乙醇诱导的运动活性改变并表征突变体。这些突变破坏的基因将进行分子研究，并在建立转基因苍蝇后在体内分析其功能。介导乙醇对运动作用的大脑区域将通过选择性地通过针对破伤风毒素编码的转基因的靶向表达选择性地灭活特定的大脑区域来映射。这些大脑区域的神经化学特征将通过确定神经递质的表达，涉及其合成的酶和/或它们作用的受体系统的表达来确定。这些方法一起，将有助于我们理解调节果蝇乙醇诱导的运动行为的基本分子途径和神经回路。由于乙醇作用的机制在有机体中具有与苍蝇和小鼠不同的生物具有共同的特征，因此我们预测从果蝇中获得的知识将为乙醇在神经系统中起作用以调节行为的过程提供新颖和一般的见解。