Understanding the neural basis of hearing function and dysfunction in vivo.
Lead Research Organisation:
University of Sheffield
Department Name: School of Biosciences
Abstract
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.
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.
Technical Summary
The processing of auditory stimuli by the nervous system, which occurs with unparalleled temporal precision, is key across animal species for performing vital tasks such as navigation, predation and communication. These tasks require the brain to extract the relevant spectral and spatiotemporal features of auditory stimuli (e.g. frequency, loudness, location), and to perform the necessary computations to instruct appropriate behavioural responses. How immature auditory circuits are assembled into functional networks during development and how their functional refinement is affected by hair cell dysfunction, such as that caused by noise exposure, is still poorly understood.
Currently, most of our knowledge on auditory circuit function comes from ex vivo studies, or from investigating activity in specific brain nuclei. As such we lack a comprehensive view of how the entire pathway functions as one. The complexity and size of the mammalian brain makes reconstructing the fine temporal and spatial details of neural activity a technically impractical task. Therefore, we propose to address the above research questions using the zebrafish, a small vertebrate whose auditory pathway grossly resembles that of mammals. The small brain size, transparency and availability of zebrafish lines expressing fluorescent reporters of neuronal and synaptic activity, make it accessible for whole-brain functional imaging in vivo.
Using the zebrafish, we will investigate sound-induced processing at different scales in vivo, from individual synapses to entire auditory circuits. By combining single-cell whole brain confocal imaging with targeted disruption of peripheral activity, we will provide an understanding of how acoustic stimuli are encoded at the auditory ribbon synapses in vivo, how hair cell activity shapes the functional refinement of the central neural responses during development, and how hair cell dysfunction affects auditory processing in the brain of live zebrafish.
Currently, most of our knowledge on auditory circuit function comes from ex vivo studies, or from investigating activity in specific brain nuclei. As such we lack a comprehensive view of how the entire pathway functions as one. The complexity and size of the mammalian brain makes reconstructing the fine temporal and spatial details of neural activity a technically impractical task. Therefore, we propose to address the above research questions using the zebrafish, a small vertebrate whose auditory pathway grossly resembles that of mammals. The small brain size, transparency and availability of zebrafish lines expressing fluorescent reporters of neuronal and synaptic activity, make it accessible for whole-brain functional imaging in vivo.
Using the zebrafish, we will investigate sound-induced processing at different scales in vivo, from individual synapses to entire auditory circuits. By combining single-cell whole brain confocal imaging with targeted disruption of peripheral activity, we will provide an understanding of how acoustic stimuli are encoded at the auditory ribbon synapses in vivo, how hair cell activity shapes the functional refinement of the central neural responses during development, and how hair cell dysfunction affects auditory processing in the brain of live zebrafish.
