Neuropeptide Modulation of Courtship Behaviors

求爱行为的神经肽调节

• 批准号: 8101339
• 负责人: DAVID Allan SCHOOLEY
• 金额: $ 35.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101339
• 关键词: Address; Afferent Neurons; Aggressive behavior; Animals; Antibodies; Area; Attention; Base of the Brain; Behavior; Behavior Disorders; Behavioral; Biochemical Genetics; Biological Assay; Biological Models; Brain; Brain region; Calcitonin; Calcitonin Gene-Related Peptide; Calcitonin Receptor; Cells; Circadian Rhythms; Clinical; Complement; Complex; Courtship; Cyclic AMP; Defect; Desire for food; Development; Drosophila garnet protein; Drosophila genus; Enzyme-Linked Immunosorbent Assay; Evolution; Exhibits; Family; Family member; Fluorescence Resonance Energy Transfer; G-Protein-Coupled Receptors; Gender; Gene Expression; Genes; Genetic; Genetic Models; Goals; Hand; Head; Health; High Pressure Liquid Chromatography; Laboratories; Lead; Learning; Libido; Ligands; Link; Measurement; Memory; Mental disorders; Molecular; Molecular Genetics; Monitor; Moods; Mushroom Bodies; Neuropeptide Receptor; Neuropeptides; Olfactory Receptor Neurons; Orphan; Pathway interactions; Peptide Receptor; Peptides; Pheromone; Process; Reagent; Receptor Signaling; Reporter; Reproductive Behavior; Research; Role; Sensory; Sensory Process; Shapes; Signal Pathway; Signal Transduction; Social Behavior; Staging; System; Technical Expertise; Therapeutic Intervention; Time; Transgenes; base; circadian pacemaker; experience; fly; gain of function; in vivo; male; monoamine; mutant; neural circuit; neuroregulation; novel; peptide G; programs; promoter; receptor; receptor expression; receptor function; research study; response; secretin receptor; skills; tool

DESCRIPTION (provided by applicant): This research program addresses how a neuropeptide modulates olfactory processing of volatile pheromone information and shapes downstream courtship behavior. We are approaching this issue as a Multi-PI team using the model genetic system, Drosophila. The CG4395 gene encodes a Class B peptide G protein-coupled receptor (GPCR) highly related to mammalian receptors for Calcitonin and Calcitonin Gene Related Peptide. CG4395 specific antibodies and CG4395-promoter constructs reveal that CG4395 is prominently expressed in olfactory receptor neurons that respond to pheromone as well as in higher regions of the brain that have been implicated in courtship behavior and plasticity. Significantly, mutant male flies that lack CG4395 gene expression exhibit aberrant courtship behavior. Furthermore, this behavioral defect can be restored to mutant animals by expressing a CG4395 transgene in olfactory sensory neurons. These findings lead us to hypothesize that peptide neuromodulation via CG4395 regulates courtship-relevant pheromone processing. The CG4395 GPCR is an orphan, but it responds potently to a peptide factor in Drosophila head extracts which we have greatly enriched by three HPLC steps and now propose to purify to homogeneity. We also propose to use the power afforded by Drosophila genetics to study the CG4395 receptor and peptide ligand, separately and together, in vivo to learn where and when receptor signaling occurs. We will combine a battery of molecular genetic tools with detailed behavioral analyses to understand the roles of the receptor and ligand in courtship. In addition we will employ a novel genetically-encoded real-time reporter of cAMP levels that uses in vivo FRET measurement regulated by CG4395 as revealed by a novel genetic reporter. To achieve these goals demands skills greater than can be assembled in any current Drosophila laboratory. Therefore, this research program represents the collaborative efforts of three independent groups, each of which contributes specific expertise and technical experience. Neuromodulatory transmitter systems regulate numerous higher brain functions including attention, memory, mood, appetite, social behavior and aggression. When transmitter systems go awry, clinical problems often arise. Identifying modulatory peptides and cognate receptors is therefore a key endeavor in studying the mechanisms underlying behavior. GPCRs and their signaling pathways are highly conserved in evolution, thus the molecular mechanisms of neuromodulation we aim to describe will offer potential avenues for therapeutic intervention. PUBLIC HEALTH RELEVANCE Neuromodulation is fundamentally important for higher brain functions and regulates diverse brain-based phenomena including attention, memory, mood, appetite and aggressive behaviors. The normal actions of monoamine and peptide transmitters systems are keys to such modulation and when these transmitter systems go awry, these processes are compromised and clinical problems arise. This research program uses biochemical and genetic approaches to explore fundamental mechanisms underlying modulation of the neural circuits that regulate reproductive behaviors (courtship) in the model system Drosophila.

描述(由申请者提供)：这项研究计划研究神经肽如何调节挥发性信息素信息的嗅觉处理，并塑造下游的求偶行为。我们是一个多PI团队，使用模型遗传系统--果蝇--来解决这个问题。CG4395基因编码一种与哺乳动物降钙素和降钙素基因相关肽受体高度相关的B类肽G蛋白偶联受体(GPCR)。CG4395特异性抗体和CG4395启动子结构表明，CG4395在对信息素做出反应的嗅觉感受器神经元以及与求爱行为和可塑性有关的大脑高级区域中显著表达。值得注意的是，缺乏CG4395基因表达的突变雄性果蝇表现出异常的求偶行为。此外，通过在嗅觉神经元中表达CG4395转基因，这种行为缺陷可以恢复到突变动物身上。这些发现使我们假设，通过CG4395进行的多肽神经调节调节了与求偶相关的信息素的处理。CG4395 GPCR是一个孤儿，但它对果蝇头部提取物中的一种多肽因子有很强的反应，我们通过三个高效液相步骤极大地丰富了这种多肽因子，现在建议将其纯化到均一。我们还建议利用果蝇遗传学提供的力量，在体内单独和共同研究CG4395受体和多肽配体，以了解受体信号发生的地点和时间。我们将结合一系列分子遗传学工具和详细的行为分析来了解受体和配体在求爱中的作用。此外，我们将采用一种新的遗传编码的cAMP水平的实时报告，它使用由CG4395调节的体内FRET测量，这是由一种新的遗传报告揭示的。要实现这些目标，需要比目前任何果蝇实验室都具备的技能更高的技能。因此，该研究计划代表了三个独立小组的合作努力，每个小组都贡献了特定的专业知识和技术经验。神经调节递质系统调节许多高级大脑功能，包括注意力、记忆、情绪、食欲、社交行为和攻击性。当发射器系统出现故障时，往往会出现临床问题。因此，识别调节肽和同源受体是研究行为潜在机制的关键。GPCRs及其信号通路在进化过程中高度保守，因此我们旨在描述的神经调节的分子机制将为治疗干预提供潜在的途径。 与公共健康相关神经调节对于更高的大脑功能至关重要，并调节各种基于大脑的现象，包括注意力、记忆、情绪、食欲和攻击行为。单胺和多肽递质系统的正常作用是这种调节的关键，当这些递质系统出错时，这些过程就会受到影响，临床问题就会出现。这项研究计划使用生化和遗传方法来探索在模式系统果蝇中调节生殖行为(求爱)的神经回路潜在的基本机制。