The precisely organized circuits of the auditory system allow animals to detect, recognize, and locate sounds in the environment. The frequency, intensity, and timing of each sound stimulus is encoded in the activity of spiral ganglion neurons, which receive input from mechanosensitive hair cells in the cochlea and transmit this acoustic information to a variety of target neurons in the auditory brainstem. Frequency information is captured in the spatial pattern of activation, with hair cells and spiral ganglion neurons organized from low frequencies in the apex to high frequencies in the base of the cochlea. In addition, spiral ganglion neurons make specialized synaptic contacts that enable unusually accurate preservation of the timing of the original sound stimulus as electrical signals pass from hair cells to the spiral ganglion neurons and from the spiral ganglion neurons to the cochlear nuclei. The goal of our work is to understand how developing spiral ganglion neurons establish the correct pattern and types of connections necessary for the perception of sound.Despite the fundamental importance of the sense of hearing for animal survival and reproduction, the development and function of this key sensory system have been challenging to unravel. One obstacle has been the small size of the cochlea, which houses too few hair cells and spiral ganglion neurons for standard molecular approaches. In addition, the cochlea is difficult to access experimentally, as it is surrounded by bone and embedded in the skull. Unfortunately, few in vitro assays are available, making it difficult to perform high throughput unbiased screens to identify new molecular players or to define mechanisms. My laboratory has been applying newly developed approaches to circumvent the difficulties of manipulating and labeling spiral ganglion neurons in mice. Using genetic labeling techniques, we mapped the behavior of individual developing spiral ganglion neurons from the initial extension of peripheral and central processes towards their targets to the formation of specialized synapses and the onset of hearing. We are now able to visualize these same events in real time and in situ by time lapse confocal imaging of fluorescently labeled neurons in embryonic cochlear explants. In parallel, we performed a large scale analysis of gene expression to identify new markers and candidate genes, focusing on those genes that are uniquely enriched in auditory neurons vs. the closely related neurons of the vestibular system. These studies indicated a particularly prominent role for the transcription factor Gata3 during spiral ganglion neuron development and differentiation. Based on these findings, we have begun to develop new high throughput methods for generating and analyzing spiral ganglion neurons in vitro. With the introduction of progressively more sophisticated tools and technologies, the future holds the exciting opportunity to make important new discoveries into the development and function of the auditory system.
Physiology 2014 (London, UK) (2014) Proc Physiol Soc 31, SA003
Research Symposium: A tool-kit for dissecting mechanisms of auditory circuit assembly
L. Goodrich1
1. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, United States.
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Where applicable, experiments conform with Society ethical requirements.