Identification of mosquito brain neurons that drive blood-feeding behavior

识别驱动吸血行为的蚊子大脑神经元

• 批准号: 10726059
• 负责人: Trevor Sorrells
• 金额: $ 50.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726059
• 关键词: ATAC-seq; Area; Atlases; Automobile Driving; Behavior; Behavior Control; Biological Assay; Bite; Blood; Brain; Carbon Dioxide; Cells; Cessation of life; Communicable Diseases; Creativeness; Cues; Culicidae; Data; Data Set; Dengue; Disease; Enhancers; Face; Feeding behaviors; Foundations; Gene Expression; Genetic; Genetic Enhancer Element; Genomics; Goals; Hand; Human; Human Bites; Individual; Intervention; Knowledge; Malaria; Maps; Methods; Mosquito-borne infectious disease; Neurobiology; Neurons; Neurosciences; Parasites; Peripheral; Postdoctoral Fellow; Prevention; Role; Sensory; Signal Transduction; Stimulus; Techniques; Testing; Time; Transgenic Organisms; Vertebrates; Virus; Work; Yellow Fever; Zika Virus; behavioral study; cell type; design; feeding; genetic effector; genetic manipulation; improved; innovation; insight; interest; mosquito-borne; multiple omics; neural; neural circuit; neurogenetics; neuronal circuitry; novel strategies; optogenetics; pathogen; prevent; response; sensory integration; sensory stimulus; sensory system; single-cell RNA sequencing; success; tool; transcriptome; transmission process; vector control

PROJECT SUMMARY Mosquitoes transmit numerous pathogens to humans by virtue of their ability to locate and bite vertebrates. Current strategies to prevent these diseases face various limitations and new approaches are needed. One possibility would be to inhibit the neurons in the mosquito brain that direct the behavior of attraction to humans and feeding on blood, but such neurons have not been identified because the tools and knowledge to do so do not exist. This proposal describes my plan to use genetic and sequencing-based approaches to identify the neurons that are required for blood-feeding behavior. I will take advantage of the fact that mosquitoes require multiple human-derived cues, particularly heat and CO2, to engorge on blood. Using gene expression changes in single cells, I will identify neurons that show altered responses specifically in the presence of both stimuli. To enable the genetic targeting of specific cell types of interest, we will create an atlas of enhancer elements that are specific to each cell type in the mosquito brain, using paired single cell RNA and ATAC-seq data. Finally, we will target key neurons for blood feeding using an enhancer driver constructs and combine them with genetic effectors to test whether the neurons are necessary and sufficient for blood feeding behavior. This proposal combines my expertise in computational genomics, transgenic mosquitoes, and behavior to achieve the goal of identifying neurons at a key node in the neural circuits for blood feeding. The identification of these neurons that drive blood feeding would be useful for understanding how they are activated and thus allow the design of more attractive mosquito traps. These neurons, if inactivated, would prevent mosquitoes from biting humans so they also could serve as a potential target to disrupt the spread of mosquito borne illness.

项目摘要 蚊子通过其定位和叮咬脊椎动物的能力将许多病原体传播给人类。 目前预防这些疾病的战略面临各种限制，需要新的方法。一 一种可能性是抑制蚊子大脑中指导人类吸引行为的神经元 以血液为食，但这种神经元还没有被识别出来，因为这样做的工具和知识 不存在.这份提案描述了我的计划，即使用基于遗传和测序的方法来识别 供血行为所需的神经元。我会利用蚊子需要 多种人类来源的线索，特别是热量和二氧化碳，使血液充血。利用基因表达变化 在单个细胞中，我将识别出在两种刺激存在下表现出特异性反应改变的神经元。到 使基因靶向特定的细胞类型的兴趣，我们将创建一个图谱的增强子元件， 使用配对的单细胞RNA和ATAC-seq数据，对蚊子大脑中的每种细胞类型都是特异性的。最后， 我们将使用增强子驱动器结构来靶向关键神经元供血，并将它们与联合收割机结合， 遗传效应器，以测试神经元是否是必要的和足够的血液喂养行为。这 我的建议结合了我在计算基因组学、转基因蚊子和行为方面的专业知识， 目标是识别神经回路中关键节点的神经元，以供供血。鉴定这些 驱动血液供给的神经元将有助于理解它们是如何被激活的，从而使 设计更具吸引力的捕蚊器。这些神经元如果失活， 因此，它们也可以作为一个潜在的目标，以破坏蚊子传播的疾病的传播。