Molecular and cellular mechanisms of circuit evolution

项目摘要 再生疗法提供了逆转神经退行性疾病引起的缺陷的潜力， 中风和脑外伤但这种治疗方法的发展需要一个全面的 理解如何指导神经元采用适当的功能特性和电路特性。这 该提案旨在通过识别允许的和 进化用来驱动求偶行为变化的易感分子机制， 果蝇使用我与合作者开发的比较神经生物学的新模型，我 将比较四种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，物种特异性信息素偏好和体内 神经成像来识别信息素处理回路中的适应位点。通过量化求爱 每一个物种的高分辨率，我将能够关联信息素偏好行为的差异， 观察物种之间的变化，观察信息素线索是如何处理（目的1）。这将 阐明电路图案和动力学控制的差异激活的一个必要的人口P1 中间神经元是雄性进入跨物种求偶的大门。接下来，为了揭示 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。 物种这项分析将确定差异表达的基因，我将测试，以确定他们是如何表达的。 调节P1的功能特性和择偶行为（目的2）。最后，我将评估何时和 转录因子Fruitless--它指定了雄性求爱回路--是如何组织性行为的？ 雄性黑腹鱼P1神经元的二态解剖和功能。此外，利用基因 我已经建立了一个管道，我将使用Targeted DamID来确定Fruitless靶基因的变化如何指定 新的求偶行为跨物种（目标3）。在Vanessa Ruta博士的持续指导下， 在洛克菲勒大学大量资源的支持下，我准备好完成拟议的 研究并揭示了进化用于编码新的基因的分子和细胞机制 行为。此外，在我的咨询委员会的支持下， 确保我接受成功过渡到 在顶级研究机构的独立性。

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.