Neural and molecular mechanisms underlying sound-evoked behavior in C. elegans

线虫声音诱发行为的神经和分子机制

• 批准号: 9405096
• 负责人: Adam James Iliff
• 金额: $ 0.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9405096
• 关键词: Ablation; Address; Afferent Neurons; Animal Model; Auditory; Auditory system; Behavior; Behavioral; Biological Assay; Biological Models; Caenorhabditis elegans; Complex; Data; Detection; Drosophila genus; Electrophysiology (science); Etiology; Exhibits; Frequencies; Functional Imaging; Genes; Genetic; Genetic Models; Genetic Screening; Genome; Goals; Head; Health; Hearing; Human; Impairment; Individual; Interneurons; Invertebrates; Investigation; Ion Channel; Lasers; Lead; Locomotion; Mammals; Maps; Mechanoreceptors; Mediating; Mediator of activation protein; Membrane Proteins; Methods; Modeling; Molecular; Nature; Nervous system structure; Neurobiology; Neurons; Organism; Potassium Channel; Process; Proteins; RNA Interference; Research; Sense Organs; Sensory; Stimulus; Study models; System; TRP channel; Techniques; Testing; Touch sensation; Training; auditory pathway; avoidance behavior; base; behavioral response; calcium indicator; deafness; epithelial Na+ channel; experimental study; genome sequencing; hearing impairment; high throughput screening; insight; mechanotransduction; mutant; neural circuit; neuromechanism; novel; optogenetics; public health relevance; receptor; relating to nervous system; response; reverse genetics; sensory input; sound; therapy development; tool; vibration; whole genome

 DESCRIPTION (provided by applicant): Hearing loss is one of the most common sensory impairments impacting human health, with both genetic and environmental etiologies. The central mediators of hearing are mechanosensitive channels capable of transducing a sound stimulus into electrical activity of sensory neurons. Despite decades of intense investigation using vertebrate models, the identity of the mechanotransduction channel for mammalian hearing remains unknown. The use of genetically tractable invertebrate systems, such as the popular genetic model Caenorhabditis elegans, has proven to be an indispensable platform for identifying the mechanisms and machinery underlying mechanotransduction. C. elegans has a compact nervous system amenable to neural circuit analyses and a completely sequenced genome with sophisticated genetic tools available, but the ability to perceive sound in this organism hasn't been observed until now. Despite the lack of an overt specialized sound-sensing organ, I find that C. elegans is strongly responsive to sound, suggesting this organism possesses a simple auditory system. Multiple lines of evidence indicate that C. elegans can directly transduce airborne sounds over a range of frequencies. Pilot experiments indicate that sound detection in C. elegans involves transduction channels distinct from classical touch receptors, suggesting that studies of sound transduction in C. elegans have great potential to reveal a novel sound-sensitive channel, which may be conserved as the elusive channel underlying hearing in mammals. This proposal will test the hypothesis that sound is transduced by mechanosensitive channels expressed in sensory neurons that functionally couple the detection of sound with escape locomotion circuits. The objective of Aim 1 is to identify the neural circuit underlying the auditory response and characterize neuronal activity to further our understanding of how sensory input is transformed into behavioral responses. The goal of Aim 2 is to identify and characterize the molecular mechanisms responsible for transducing sound. By pursuing this project, I will gain training in both classic C. elegans methods and cutting-edge functional circuit analysis, as well as in the topic of sensory neurobiology. The proposed research is significant because it provides the first experimental approach to study hearing in C. elegans and is expected to yield novel insights into the molecular nature of the mechanosensitive channels mediating hearing in humans.

 描述（由申请人提供）：听力损失是影响人类健康的最常见的感觉障碍之一，有遗传和环境病因。听觉的中枢介质是能够将声音刺激转换成感觉神经元的电活动的机械敏感通道。尽管几十年来使用脊椎动物模型进行了深入的研究，但哺乳动物听力的机械传导通道的身份仍然未知。使用遗传上易处理的无脊椎动物系统，如流行的遗传模型秀丽隐杆线虫，已被证明是一个不可或缺的平台，用于确定机械转导的机制和机制。C.秀丽线虫有一个紧凑的神经系统，可以进行神经回路分析，还有一个完全测序的基因组，有复杂的遗传工具可用，但这种生物体感知声音的能力直到现在还没有被观察到。尽管缺乏一个明显的专门的声音感觉器官，我发现C。秀丽隐杆线虫对声音有强烈的反应，这表明这种生物体拥有简单的听觉系统。多种证据表明C.秀丽线虫可以直接传播一定频率范围内的空气传播的声音。初步实验表明，C. elegans涉及不同于经典触觉感受器的转导通道，这表明在C.秀丽线虫具有揭示一种新的声音敏感通道的巨大潜力，该通道可能是哺乳动物听觉中难以理解的通道。该提案将测试的假设，声音是由机械敏感通道在感觉神经元中表达，功能耦合的声音与逃逸运动电路的检测。目标1的目的是识别听觉反应的神经回路，并表征神经元活动，以进一步了解感觉输入如何转化为行为反应。目标2的目标是识别和表征负责转导声音的分子机制。通过这个项目，我将获得经典C语言的培训。elegans方法和尖端的功能电路分析，以及在感觉神经生物学的主题。本研究为C语言听觉研究提供了第一个实验方法，具有重要意义。elegans，并有望产生新的见解的机械敏感通道介导的人类听力的分子性质。