Molecular and cellular mechanisms of circuit evolution

电路进化的分子和细胞机制

• 批准号: 10189897
• 负责人: Rory Tristan Coleman
• 金额: $ 10万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189897
• 关键词: Adaptive Behaviors; Address; Adopted; Advisory Committees; Affect; Afferent Neurons; Alzheimer' s Disease; Anatomy; Automobile Driving; Behavior; Behavioral; Binding Sites; Brain; Clustered Regularly Interspaced Short Palindromic Repeats; Computer software; Courtship; Cues; Decision Making; Development; Development Plans; Discrimination; Disease; Drosophila genus; Ectopic Expression; Electrophysiology (science); Elements; Engineering; Ensure; Equilibrium; Evolution; Female; Gene Expression; Genes; Genetic; Genomics; Goals; Institution; Interneurons; Knock-out; Knowledge; Lead; Light; Masculine; Mentorship; Modeling; Molecular; Neurobiology; Neurodegenerative Disorders; Neurons; Output; Partner in relationship; Pathway interactions; Pheromone; Population; Process; Production; Property; Protocols documentation; RNA interference screen; Reagent; Regenerative Medicine; Research; Resolution; Resources; Ritual compulsion; Ruta; Shapes; Signal Transduction; Site; Specific qualifier value; Stereotyping; Stroke; Synapses; Testing; To specify; Training; Traumatic Brain Injury; Universities; Work; autism spectrum disorder; career; career development; comparative; court; design; differential expression; experimental study; fly; functional restoration; in vivo; in vivo calcium imaging; innovation; interest; male; mating behavior; nerve stem cell; nervous system disorder; neurogenetics; neuroimaging; neuromechanism; neurophysiology; novel; optogenetics; preference; programs; receptor; regenerative therapy; relating to nervous system; sensory signal detection; sexual dimorphism; transcription factor; transcriptome sequencing

Project Summary Regenerative therapies offer the potential to reverse deficits arising from neurodegenerative disease, stroke, and traumatic brain injury. But the development of such treatments requires a comprehensive understanding of how to direct neurons to adopt appropriate functional properties and circuit identities. This proposal seeks to reveal fundamental principles of circuit design by identifying the permissible and predisposed molecular mechanisms evolution uses to drive changes in the courtship behaviors of drosophilids. Using a new model for comparative neurobiology that I have developed with my collaborators, I will compare homologous neurons in the pheromone processing pathways of four closely related Drosophila species. First, I will take advantage of highly stereotyped, species-specific pheromone preferences and in vivo neuroimaging to identify the sites of adaptation in pheromone processing circuits. By quantifying the courtship of each species in high resolution, I will be able to correlate differences in the pheromone preference behaviors observed between species to the changes observed in how pheromone cues are processed (Aim 1). This will elucidate the circuit motifs and dynamics that control the differential activation of an essential population of P1 interneurons that gate male entry into courtship across species. Next, to reveal the molecular underpinnings of adaptations in P1 connectivity and excitability, I will perform RNA sequencing on the P1 neurons of each species. This analysis will identify differentially expressed genes which I will test to determine how they regulate the functional properties of P1 and mate preference behaviors (Aim 2). Finally, I will assess when and how the transcription factor Fruitless–which specifies the male courtship circuitry–acts to organize the sexually dimorphic anatomy and function of P1 neurons in melanogaster males. Further, taking advantage of genetic pipelines I have built, I will use Targeted DamID to determine how changes in Fruitless target genes specify novel courtship behaviors across species (Aim 3). Under the continued mentorship of Dr. Vanessa Ruta, and supported by the substantial resources of Rockefeller University, I am well poised to complete the proposed research and shed new light on the molecular and cellular mechanisms that evolution uses to encode novel behaviors. In addition, a comprehensive career development plan, supported by my advisory committee, will ensure that I receive the conceptual, technical, and career training I require to successfully transition to independence at a top research institution.

项目摘要 再生疗法提供了反向定义神经退行性疾病引起的潜力， 中风和创伤性脑损伤。但是这种治疗的发展需要全面 了解如何指导神经元采用适当的功能特性和电路身份。这 提案试图通过确定许可和 进化用于推动求爱行为变化的倾向分子机制 果蝇。使用我与合作者一起开发的比较神经生物学的新模型，我 将比较四个密切相关的果蝇的信息素处理途径中的同源神经元 物种。首先，我将利用高度定型的，特定物种的信息素偏好和体内 神经成像以识别信息素处理电路中适应位点。通过量化求爱 在高分辨率的每个物种中，我将能够将信息素偏好行为的差异相关联 观察到在如何处理信息素提示中观察到的变化之间（AIM 1）。这会 阐明控制P1基本种群的差异激活的电路基序和动力学 男性跨物种进入求爱的中间神经元。接下来，揭示了分子的基础 P1连接性和令人兴奋的适应，我将在每个P1神经元上进行RNA测序 物种。该分析将确定不同表达的基因，我将测试以确定它们如何 调节P1和MATE偏好行为的功能特性（AIM 2）。最后，我将评估何时和 转录因子如何毫无结果（指定男性求爱巡回赛）来组织性行为 Melanogaster雄性中P1神经元的二态解剖学和功能。此外，利用通用 我建造的管道，我将使用目标DAMID来确定无效目标基因的变化如何指定 跨物种的新型求爱行为（目标3）。在凡妮莎·鲁塔（Vanessa Ruta）博士的持续心态下， 在洛克菲勒大学的大量资源的支持下，我很毒，可以完成拟议的 研究并为进化用来编码新颖的分子和细胞机制开发了新的灯光 行为。此外，由我的咨询委员会支持的全面职业发展计划将 确保我收到成功过渡到的概念，技术和职业培训 顶级研究机构的独立性。