Molecular and cellular mechanisms of circuit evolution

项目摘要 再生疗法提供了扭转神经退行性疾病引起的缺陷的潜力， 中风和创伤性脑损伤。但这种治疗方法的发展需要一个全面的 了解如何引导神经元采用适当的功能特性和电路特性。这 提案旨在通过确定允许的和可选的 进化用来驱动求偶行为变化的易感分子机制 果蝇。使用我和我的合作者开发的比较神经生物学的新模型，我 将比较四种近缘果蝇信息素处理途径中的同源神经元 物种。首先，我将利用高度刻板的、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回路中的适应位置。通过量化求爱 在高分辨率的每个物种中，我将能够关联信息素偏好行为的差异 物种间观察到信息素线索如何处理的变化(目标1)。这将是 阐明控制P_1必需群体差异激活的电路基序和动力学 通向雄性进入交配通道的中间神经元跨越物种。接下来，为了揭示分子基础 为了适应P1连接性和兴奋性，我将对每个神经元的P1神经元进行RNA测序 物种。这项分析将确定差异表达的基因，我将测试这些基因以确定它们是如何 调节P1的功能特性和择偶行为(目标2)。最后，我将评估何时和 转录因子无果--它规定了雄性求爱回路--如何组织有性 男性黑素胃病患者P1神经元的二态解剖和功能。此外，利用基因 我已经建立了管道，我将使用靶向DamID来确定无果靶基因的变化如何指定 跨物种的新奇求偶行为(目标3)。在Vanessa Ruta博士的持续指导下，以及 在洛克菲勒大学的大量资源支持下，我已经做好准备完成拟议的 研究并阐明进化用来编码小说的分子和细胞机制 行为。此外，在我的咨询委员会的支持下，一项全面的职业发展计划将 确保我接受了成功过渡到所需的概念、技术和职业培训 在顶尖研究机构的独立性。

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.