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.
Deafness and other hearing deficits are leading sensory impairments and greatly impact human health, yet we know very little about how sound is transduced by nervous systems. To aid in the development of treatments for hearing impairments, the proposed studies will address how sensory input is transformed by neural circuits into behavioral responses and identify the mechanoreceptors and related proteins transducing sound in a powerful genetic model, which may lead to discovery of the channel responsible for human hearing.
|Li, Zhaoyu; Iliff, Adam J; Xu, X Z Shawn (2016) An Elegant Circuit for Balancing Risk and Reward. Neuron 92:933-935|