The mammalian cochlea achieves its remarkable sensitivity, exquisite frequency selectivity, and enormous dynamic range through an active amplification mechanism called the "cochlear amplifier", which uses metabolic energy to boost basilar membrane (BM) vibration. Although it is well established that outer hair cells (OHCs) can generate forces through somatic and hair-bundle motility, the mechanical mechanism of cochlear amplification remains unclear. This application is to study the role of somatic and hair-bundle motility in cochlear amplification by conducting a set of novel experiments in normal and genetically modified cochleae using our recently developed scanning low-coherence heterodyne interferometer.
Specific aim one will measure the BM, reticular lamina (RL), and tectorial membrane (TM) vibration in sensitive mouse and gerbil cochleae. The hypothesis is that, in sensitive mouse cochleae, the OHC-based cochlear amplifier produces a larger and more nonlinear vibration at the RL than that at the BM. BM and RL vibrations in mice are highly sensitive, and show sharp tuning and nonlinearity as in other commonly used animals for cochlear mechanics study, such as gerbils. The data from this experiment will be essential for studying cochlear micromechanics in mice and gerbils.
Specific aim two will determine the role of the OHC somatic motility by measuring the BM, RL, and TM vibration in mouse cochleae without somatic motility. The hypothesis is that, in prestin 499 knockin mice, the lack of somatic motility results in decreased sensitivity and loss of sharp tuning and nonlinearity of the BM, RL, and TM vibration. Because the mechanoelectrical transduction, stiffness, and morphology of OHCs in prestin 499 knockin mice are normal, the expected changes will be attributed to the absence of somatic motility.
Specific aim three will determine the role of the OHC hair-bundle motility by measuring the BM, RL, and TM vibration in mouse cochleae with ineffective hair-bundle motility. The hypothesis is that shortened and detached TM with free-standing hair bundles compromises hair-bundle motility, mechanoelectrical transduction, and cochlear amplification in TectaC1509G/C1509G mice, decreasing sensitivity, sharp tuning, and nonlinearity of acoustically evoked BM, RL, and TM vibration. However, electrical stimulation activates both somatic and hair-bundle motility and results in BM, RL, and TM vibration and electrically evoked otoacoustic emissions. After somatic motility is suppressed by salicylate, hair-bundle motility-mediated responses can be measured in wild-type but not in TectaC1509G /C1509G mice. The contribution of hair-bundle motility to cochlear amplification will be determined by measuring and comparing electrically evoked responses in TectaC1509G /C1509G and wild-type mice after salicylate application. The new data from this study will provide critical information on the essential role of OHC somatic and hair-bundle motility in cochlear amplification and for understanding mechanisms of auditory disorders in humans.

Public Health Relevance

Using an innovative technique, this project will make the first measurement of the micro structural vibrations inside the cochlear partition in the normal and genetically modified mouse cochleae. The proposed experiments will be conducted in prestin 499 knockin mice without functional somatic motility and in TectaC1509G/C1509G mice with a shortened and detached tectorial membrane. Because it has been found that prestin is defective in human non-syndromic hearing loss, and that a Tecta-gene mutation is associated with a progressive hearing loss in humans, knowledge gained from this project will be critical for understanding mechanisms of these human diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DC004554-13
Application #
8703067
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97239
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He, W; Ren, T (2013) Basilar membrane vibration is not involved in the reverse propagation of otoacoustic emissions. Sci Rep 3:1874
Wang, Lingyan; Bresee, Chris S; Jiang, Han et al. (2011) Scleraxis is required for differentiation of the stapedius and tensor tympani tendons of the middle ear. J Assoc Res Otolaryngol 12:407-21
Ren, Tianying; He, Wenxuan; Gillespie, Peter G (2011) Measurement of cochlear power gain in the sensitive gerbil ear. Nat Commun 2:216
Ren, Tianying; He, Wenxuan; Gillespie, Peter G (2011) Reply to "on cochlear impedances and the miscomputation of power gain" by Shera et Al. J. Assoc. Re. Otolaryngol. J Assoc Res Otolaryngol 12:677-80
Zheng, Jiefu; Ramamoorthy, Sripriya; Ren, Tianying et al. (2011) Persistence of past stimulations: storing sounds within the inner ear. Biophys J 100:1627-34
Ren, Tianying; He, Wenxuan; Porsov, Edward (2011) Localization of the cochlear amplifier in living sensitive ears. PLoS One 6:e20149
He, Wenxuan; Fridberger, Anders; Porsov, Edward et al. (2010) Fast reverse propagation of sound in the living cochlea. Biophys J 98:2497-505
Wu, Xudong; Steigelman, Katherine A; Bonten, Erik et al. (2010) Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice. Biochim Biophys Acta 1802:259-68
Ng, Lily; Hernandez, Arturo; He, Wenxuan et al. (2009) A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function. Endocrinology 150:1952-60

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