Understanding the neural basis of hearing function and dysfunction in vivo.

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The auditory system is key to our daily life, as it allows us to perceive sound in all of its different forms, from noises to speech and music. The sensitivity and dynamic range of this sense are remarkable, allowing us to detect sounds from as quiet as a pin drop to as loud as an explosion or an airplane taking off. It is also key for survival in many animal species, since sounds can be detected from anywhere around the body and the speed of processing sound information is unparalleled among sensory systems (this is the reason why time-critical sports such as sprint races start with a gunshot and not, for example, with a flash of light).Sound is detected by extremely sensitive sensory cells named hair cells that are located in the inner ear. The function of these cells is critical for our ability to extract information from acoustic stimuli. How does the brain develop this ability? How does the brain adapt when hair cells become dysfunctional, for example after damage? These are critical questions in our quest to understand how the brain works, as well as to understand the physiological basis of hearing disorders.The aim of this proposal is to elucidate how the complexity of the auditory system is refined during development and to determine how the activity of the peripheral sensory cells shapes the responses in the brain that underlie the processing of auditory information.Achieving this task is technically prohibitive in mammals, due to the large size and complexity of the brain and the inaccessibility of the sensory hair cells for in vivo investigation. Therefore, for this study, we propose to use a smaller vertebrate, the zebrafish. This fish is among the so called "hearing specialists", having developed a sense of hearing that works in a broadly similar way to that of mammals. This includes the use of sensory hair cells, located within the inner ear, that convert acoustic stimuli into neural signals by a process known as mechanoelectrical transduction, which also occurs in mammals. In recent years, the zebrafish has provided invaluable information towards our understanding of the genetic basis of hearing and deafness. Crucial to this proposal, the small brain size (~1 mm diameter) and transparency of the zebrafish, make it possible to observe the entire brain under a microscope, while resolving the sound-induced activity of individual cells thanks to genetically encoded fluorescent reporter dyes. These benefits, when combined with the accessibility for behavioural analysis, make the zebrafish an ideal model organism to identify the mechanisms underlying the formation of nerve circuits and sensory integration in vivo. We will use zebrafish lines which express the fluorescent reporter dyes in hair cells and neurons. These molecules increase their brightness when hair cells and auditory neurons are stimulated by sound, allowing us to monitor in real time how sound is processed from the ear to the brain. We will combine this with zebrafish lines in which will disrupt the activity of the peripheral hair cells, either by silencing them using a technique called optogenetics or by damaging them with loud noise. This will allow us to understand how hair cells influence the encoding of auditory responses in the brain and how this change when hair cells become damaged. In the long term, the information obtained with this work could be used to better understand the mechanisms underlying pathological changes in the auditory system, such as noise induced hearing loss.