Wednesday, April 2, 2025
4/2/2025
Mechanisms of amplification and nonlinearity in the mouse cochlea - PROJECT SUMMARY/ABSTRACT Mammalian hearing sensitivity depends on the amplification of sound-evoked cochlear vibrations by outer hair cells (OHCs). How these cells provide amplification across the frequency range of mammalian hearing remains unresolved. This limits our ability to rehabilitate and eventually restore what is missing in ears with OHC damage, which is a common cause of hearing loss. While amplification has been proposed to result from the OHCs’ ability to change length and generate force, multiple sources of low-pass filtering are thought to attenuate this motile response at high frequencies. It is therefore uncertain if OHC motility can work fast enough to provide high-frequency force generation on a cycle-by-cycle basis. Additionally, recent observations of large, sustained OHC length changes during sound stimulation suggest that these tonic responses may serve as an alternative mechanism for modulating high-frequency vibrations, possibly by altering OHC stiffness. However, the functional relevance of such tonic responses has yet to be tested. To study cycle-by- cycle and tonic OHC motility in vivo, we will use optical coherence tomography to measure vibrations of the OHC region in the mouse cochlea. Preliminary data from the cochlear apex supports the central hypothesis that OHC motility can indeed provide high-frequency, cycle-by-cycle amplification in spite of low-pass filtering, and that slow or tonic OHC length changes do not play a significant mechanical role. Here, we will test this hypothesis more definitively by examining vibrations from the base of the mouse cochlea, which responds to very high frequencies. In Aim 1, we will determine whether sound elicits fast OHC length changes in the cochlear base and assess how these responses are shaped by low-pass filtering. Our hypothesis predicts that sound will cause large OHC length changes at the requisite high frequencies, even if the responses are low- pass filtered. In Aim 2, we will test whether tonic OHC responses play a role in regulating high-frequency cochlear vibrations. Since direct observation of tonic OHC length changes may be constrained by the stiffness of the basal cochlear partition, the strength of tonic responses will be inferred from the presence of vibratory distortions that are thought to be generated by the same underlying nonlinear processes. OHC length will then be slowly, acoustically modulated in order to test whether slow and/or tonic length changes influence vibrations at higher frequencies. Regardless of the strength of any observed or inferred tonic responses, our hypothesis predicts that slowly modulating OHC length will have little effect on high-frequency vibrations. Pursuing these aims will reveal how OHCs operate in their natural mechano-electrical environment and identify the mechanisms underlying high-frequency hearing sensitivity. The knowledge gained may inform future efforts to develop novel rehabilitative strategies and regenerate functional, amplifying OHCs.
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