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.

项目概要 再生疗法有可能扭转神经退行性疾病引起的缺陷， 但此类治疗的发展需要全面的治疗。 了解如何引导神经元采用适当的功能特性和电路特性。 该提案旨在通过确定允许的和 进化用来驱动求偶行为变化的预先形成的分子机制 使用我与合作者开发的比较神经生物学新模型，我 将比较四种密切相关的果蝇的信息素途径处理中的同源神经元 首先，我将利用高度刻板的、物种特异性的信息素偏好和体内信息素。 通过量化求爱来识别信息素处理回路中的适应位点。 每个物种的高分辨率，我将能够关联信息素偏好行为的差异 物种之间观察到的信息素线索处理方式的变化（目标 1）。 阐明控制 P1 重要群体差异激活的电路基序和动力学 接下来，我们将揭示控制雄性跨物种求爱的分子基础。 P1 连接性和兴奋性的适应，我将对每个 P1 神经元进行 RNA 测序 该分析将识别差异表达的基因，我将对其进行测试以确定它们如何表达。 调节 P1 的功能特性和择偶行为（目标 2）。 转录因子 Fruitless（负责指定雄性求偶回路）如何发挥作用来组织性行为 雄性黑腹果蝇 P1 神经元的二态性解剖结构和功能 此外，利用遗传优势。 在我构建的管道中，我将使用 Targeted DamID 来确定 Fruitless 目标基因的变化如何指定 在 Vanessa Ruta 博士的持续指导下，跨物种的新颖求爱行为（目标 3）。 在洛克菲勒大学大量资源的支持下，我已做好准备完成拟议的工作 研究并为进化用于编码新奇的分子和细胞机制提供了新的线索 此外，在我的咨询委员会的支持下，将制定全面的职业发展计划。 确保我接受成功过渡所需的概念、技术和职业培训 顶尖研究机构的独立性。