Our knowledge of cochlear mechanics is currently undergoing a revolution. While the basilar membrane (BM) has long been considered the principal structure in cochlear motion, new techniques such as optical coherence tomography (OCT) have instead revealed not only that the reticular lamina (RL) moves in a different pattern from the BM, but that it moves 3?10 times more at low input sound levels. Additionally, RL motion is closer to the inner-hair-cell (IHC) stereocilia, making it more relevant than BM motion for triggering the output of the cochlea. The greater motion of the RL compared to the BM also suggests that RL motion may be the main source of otoacoustic emissions (OAEs). Another long-held idea ? now realized to be inadequate ? is that the IHC stereocilia are driven only by shearing action between the RL and tectorial membrane (TM). Current evidence suggests that rotation of the RL and oscillatory fluid flow in the sub-tectorial space between the RL and TM also drive IHC stereocilia, and may even be more important than RL?TM shearing. We hypothesize that the stereocilia bundles of the IHCs are stimulated by multiple mechanisms, including classic RL-TM shearing, oscillatory fluid flow in the sub-tectorial space, and tilting of the RL near the IHC bundles; that the relative influence of these mechanisms changes with frequency, sound level, and species; and that OAE generation is dominated by RL motion. To test these hypotheses, a high-resolution OCT system (approx. 3 m axial resolution) will be used to image and measure motions in the organ of Corti (OoC) in normal-hearing gerbils and mice, and in three mouse varieties with genetic mutations that affect the structure and mechanical properties of the TM. We will measure the transverse and radial motions of the BM, RL, and TM in response to acoustic stimulation at multiple sound levels and multiple cochlear locations. For comparisons to human hearing, responses will be measured from 0.5 to 12 kHz locations in gerbil and from 9 to 20 kHz locations in mouse. To translate the measured OoC motions into a detailed understanding of the mechanisms responsible for IHC and OHC stimulation and stimulus-frequency OAE production, we will use the OCT images to construct 3D cochlea finite-element models for gerbil and each mouse variety, and will test the models against the OCT vibrometry measurements. The models will contain, in a viscous-fluid environment, the key elements of OoC cytoarchitecture sandwiched between the BM and RL, including the pillar cells, three rows of outer hair cells, and IHCs, along with the TM, which together will allow clear relationships to be established between cochlear function and the structure and material composition of the OoC. This will improve our understanding of the various mechanical stages of hearing, will allow the health and structure of the OoC to be correlated with OAEs for diagnostic purposes, and will provide a powerful and efficient modeling framework appropriate for the future development of human cochlear models that can be validated using non-invasive hearing-threshold and OAE measurements.
The proposed research will help to address the needs of the millions of people with sensorineural hearing loss, by providing a better understanding of how the microscopic structures of the inner ear work together to produce both the sensation of hearing and clinically useful otoacoustic emissions (OAEs), which can be measured non-invasively in the ear canal. By measuring the motions of cochlear structures in animals using state-of-the-art optical coherence tomography (OCT) techniques, we will be able to create anatomically realistic 3D computational models of the inner ear, and these models will in turn allow us to predict how a patient's hearing and OAEs would be affected by specific types of structural damage or genetic mutations, thus providing a powerful way of diagnosing hearing problems in terms of their structural basis. Such models may also accelerate the development of future biological interventions centered around the regeneration of cochlear structures, by providing ways of predicting and comparing the hearing outcomes of various therapeutic strategies.
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