Outer Hair Cell Electromotility Research Articles

Genetic tools for studying cochlear inhibition.

Efferent feedback to the mammalian cochlea includes cholinergic medial olivocochlear neurons (MOCs) that release ACh to hyperpolarize and shunt the voltage change that drives electromotility of outer hair cells (OHCs). Via brainstem connectivity, MOCs are activated by sound in a frequency- and intensity-dependent manner, thereby reducing the amplification of cochlear vibration provided by OHC electromotility. Among other roles, this efferent feedback protects the cochlea from acoustic trauma. Lesion studies, as well as a variety of genetic mouse models, support the hypothesis of efferent protection from acoustic trauma. Genetic knockout and gain-of-function knockin of the unique α9α10-containing nicotinic acetylcholine receptor (nAChR) in hair cells show that acoustic protection correlates with the efficacy of cholinergic inhibition of OHCs. This protective effect was replicated by viral transduction of the gain-of-function α9L9'T nAChR into α9-knockout mice. Continued progress with "efferent gene therapy" will require a reliable method for visualizing nAChR expression in cochlear hair cells. To that end, mice expressing HA-tagged α9 or α10 nAChRs were generated using CRISPR technology. This progress will facilitate continued study of the hair cell nAChR as a therapeutic target to prevent hearing loss and potentially to ameliorate associated pathologies such as hyperacusis.

Exploring the Effects of Alternate Auditory Attention Tasks on Electromotility of Cochlear Outer Hair Cells in Healthy Normal Hearing Adults

Background and Aim: There is limited study on the role of rostral efferent auditory pathway on Outer Hair Cell (OHC) activity. We investigated the effect of integrating alternate auditory attention (ALAUDIN©) tasks with White Noise (WN) and its reliability using contralateral suppression of Transient Evoked Otoacoustic Emission (TEOAE).
 Methods: This study was conducted at the Audiology Clinic, Universiti Kebangsaan Malaysia, with fifty normal-hearing adults. All subjects underwent standard audiological testing to ensure normal hearing, middle ear, and cochlear function. Contralateral suppressors with and without attention tasks were delivered randomly to the non-test ear while simultaneously measuring TEOAE amplitude in the test ear to investigate the effect of auditory attention on OHC electromotility. Suppressors with and without attention refer to the combination of a 1000 Hz tone and speech stimulus embedded in WN and WN alone, respectively. Subsequently, the difference in TEOAE amplitude during the presence and absence of suppressors was calculated, and thus suppression magnitude was determined.
 Results: Intraclass correlation revealed that 4 suppressors produced high reliability. In paired sample t-tests, the tasks significantly reduced the amplitude of the TEOAE in the right ear compared to the left ear (p<0.05). However, the suppression magnitude did not differ significantly between ears (p>0.05). Descriptively, females showed greater TEOAE suppression.
 Conclusion: This study demonstrated that directing ALAUDIN© tasks to one ear can affect OHC electromotility, as evidenced by TEOAE amplitude changes, but it did not impact the overall suppression magnitude. Additionally, it hinted at potential gender differences in TEOAE suppression, warranting further investigation.
 
 Keywords: Suppression; otoacoustic emissions; efferent pathway; auditory attention

Folding of prestin's anion-binding site and the mechanism of outer hair cell electromotility.

Prestin responds to transmembrane voltage fluctuations by changing its cross-sectional area, a process underlying the electromotility of outer hair cells and cochlear amplification. Prestin belongs to the SLC26 family of anion transporters yet is the only member capable of displaying electromotility. Prestin's voltage-dependent conformational changes are driven by the putative displacement of residue R399 and a set of sparse charged residues within the transmembrane domain, following the binding of a Cl- anion at a conserved binding site formed by the amino termini of the TM3 and TM10 helices. However, a major conundrum arises as to how an anion that binds in proximity to a positive charge (R399), can promote the voltage sensitivity of prestin. Using hydrogen-deuterium exchange mass spectrometry, we find that prestin displays an unstable anion-binding site, where folding of the amino termini of TM3 and TM10 is coupled to Cl- binding. This event shortens the TM3-TM10 electrostatic gap, thereby connecting the two helices, resulting in reduced cross-sectional area. These folding events upon anion binding are absent in SLC26A9, a non-electromotile transporter closely related to prestin. Dynamics of prestin embedded in a lipid bilayer closely match that in detergent micelle, except for a destabilized lipid-facing helix TM6 that is critical to prestin's mechanical expansion. We observe helix fraying at prestin's anion-binding site but cooperative unfolding of multiple lipid-facing helices, features that may promote prestin's fast electromechanical rearrangements. These results highlight a novel role of the folding equilibrium of the anion-binding site, and help define prestin's unique voltage-sensing mechanism and electromotility.

Folding of prestin’s anion-binding site and the mechanism of outer hair cell electromotility

Prestin responds to transmembrane voltage fluctuations by changing its cross-sectional area, a process underlying the electromotility of outer hair cells and cochlear amplification. Prestin belongs to the SLC26 family of anion transporters yet is the only member capable of displaying electromotility. Prestin’s voltage-dependent conformational changes are driven by the putative displacement of residue R399 and a set of sparse charged residues within the transmembrane domain, following the binding of a Cl− anion at a conserved binding site formed by the amino termini of the TM3 and TM10 helices. However, a major conundrum arises as to how an anion that binds in proximity to a positive charge (R399), can promote the voltage sensitivity of prestin. Using hydrogen–deuterium exchange mass spectrometry, we find that prestin displays an unstable anion-binding site, where folding of the amino termini of TM3 and TM10 is coupled to Cl− binding. This event shortens the TM3–TM10 electrostatic gap, thereby connecting the two helices, resulting in reduced cross-sectional area. These folding events upon anion binding are absent in SLC26A9, a non-electromotile transporter closely related to prestin. Dynamics of prestin embedded in a lipid bilayer closely match that in detergent micelle, except for a destabilized lipid-facing helix TM6 that is critical to prestin’s mechanical expansion. We observe helix fraying at prestin’s anion-binding site but cooperative unfolding of multiple lipid-facing helices, features that may promote prestin’s fast electromechanical rearrangements. These results highlight a novel role of the folding equilibrium of the anion-binding site, and help define prestin’s unique voltage-sensing mechanism and electromotility.

Elevator-like movements of prestin mediate outer hair cell electromotility

The outstanding acuity of the mammalian ear relies on cochlear amplification, an active mechanism based on the electromotility (eM) of outer hair cells. eM is a piezoelectric mechanism generated by little-understood, voltage-induced conformational changes of the anion transporter homolog prestin (SLC26A5). We used a combination of molecular dynamics (MD) simulations and biophysical approaches to identify the structural dynamics of prestin that mediate eM. MD simulations showed that prestin samples a vast conformational landscape with expanded (ES) and compact (CS) states beyond previously reported prestin structures. Transition from CS to ES is dominated by the translational-rotational movement of prestin’s transport domain, akin to elevator-type substrate translocation by related solute carriers. Reversible transition between CS and ES states was supported experimentally by cysteine accessibility scanning, cysteine cross-linking between transport and scaffold domains, and voltage-clamp fluorometry (VCF). Our data demonstrate that prestin’s piezoelectric dynamics recapitulate essential steps of a structurally conserved ion transport cycle.

Serotonin excites medial olivocochlear neurons of the auditory efferent pathway

Medial olivocochlear (MOC) efferent neurons are located in the superior olive of the brainstem and form a sound evoked feedback loop that inhibits cochlear amplification via suppression of outer hair cell (OHC) electromotility. MOC neurons putatively receive a diverse range of synaptic input from various auditory and non-auditory brain regions. Given the proposed role of these neurons in context dependent tasks such as selective attention, we are interested in investigating the non-auditory modulation of MOC activity by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). We used the ChAT-IRES-Cre;tdTomato mouse model to identify cholinergic MOC neurons in the brainstem. Immunohistochemical data have validated serotonergic terminals in apposition to both retrogradely labeled and genetically identified MOC neurons in mouse. During patch-clamp recordings from MOC neurons, exogenous application of serotonin increased neuron excitability by increasing action potential (AP) firing rate and decreasing both rheobase and AP threshold. Additionally, serotonin reduced the stimulation required to evoke a given AP firing rate in MOC neurons. These data will aid in our understanding of central auditory processing and how factors such as mood and attention are involved in modulating MOC responses in complex listening situations such as in the presence of background noise.

Megahertz Sampling of Prestin (SLC26a5) Voltage-Sensor Charge Movements in Outer Hair Cell Membranes Reveals Ultrasonic Activity that May Support Electromotility and Cochlear Amplification.

Charged moieties in the outer hair cell (OHC) membrane motor protein, prestin, are driven by transmembrane voltage to power OHC electromotility (eM) and cochlear amplification (CA), an enhancement of mammalian hearing. Consequently, the speed of prestin's conformational switching constrains its dynamic influence on micromechanics of the cell and the organ of Corti. Corresponding voltage-sensor charge movements in prestin, classically assessed as a voltage-dependent, nonlinear membrane capacitance (NLC), have been used to gauge its frequency response, but have been validly measured only out to 30 kHz. Thus, controversy exists concerning the effectiveness of eM in supporting CA at ultrasonic frequencies where some mammals can hear. Using megahertz sampling of guinea pig (either sex) prestin charge movements, we extend interrogations of NLC into the ultrasonic range (up to 120 kHz) and find an order of magnitude larger response at 80 kHz than previously predicted, indicating that an influence of eM at ultrasonic frequencies is likely, in line with recent in vivo results (Levic et al., 2022). Given wider bandwidth interrogations, we also validate kinetic model predictions of prestin by directly observing its characteristic cut-off frequency under voltage-clamp as the intersection frequency (Fis), near 19 kHz, of the real and imaginary components of complex NLC (cNLC). The frequency response of prestin displacement current noise determined from either the Nyquist relation or stationary measures aligns with this cut-off. We conclude that voltage stimulation accurately assesses the spectral limits of prestin activity, and that voltage-dependent conformational switching is physiologically significant in the ultrasonic range.SIGNIFICANCE STATEMENT The motor protein prestin powers outer hair cell (OHC) electromotility (eM) and cochlear amplification (CA), an enhancement of high-frequency mammalian hearing. The ability of prestin to work at very high frequencies depends on its membrane voltage-driven conformation switching. Using megahertz sampling, we extend measures of prestin charge movement into the ultrasonic range and find response magnitude at 80 kHz an order of magnitude larger than previously estimated, despite confirmation of previous low pass characteristic frequency cut-offs. The frequency response of prestin noise garnered by the admittance-based Nyquist relation or stationary noise measures confirms this characteristic cut-off frequency. Our data indicate that voltage perturbation provides accurate assessment of prestin performance indicating that it can support cochlear amplification into a higher frequency range than previously thought.

The Remarkable Outer Hair Cell: Proceedings of a Symposium in Honour of W. E. Brownell.

In 1985, Bill Brownell and colleagues published the remarkable observation that cochlear outer hair cells (OHCs) express voltage-driven mechanical motion: electromotility. They proposed OHC electromotility as the mechanism for the elusive "cochlear amplifier" required to explain the sensitivity of mammalian hearing. The finding and hypothesis stimulated an explosion of experiments that have transformed our understanding of cochlear mechanics and physiology, the evolution of hair cell structure and function, and audiology. Here, we bring together examples of current research that illustrate the continuing impact of the discovery of OHC electromotility.

Cryo-EM structures of thermostabilized prestin provide mechanistic insights underlying outer hair cell electromotility

Outer hair cell elecromotility, driven by prestin, is essential for mammalian cochlear amplification. Here, we report the cryo-EM structures of thermostabilized prestin (PresTS), complexed with chloride, sulfate, or salicylate at 3.52-3.63 Å resolutions. The central positively-charged cavity allows flexible binding of various anion species, which likely accounts for the known distinct modulations of nonlinear capacitance (NLC) by different anions. Comparisons of these PresTS structures with recent prestin structures suggest rigid-body movement between the core and gate domains, and provide mechanistic insights into prestin inhibition by salicylate. Mutations at the dimeric interface severely diminished NLC, suggesting that stabilization of the gate domain facilitates core domain movement, thereby contributing to the expression of NLC. These findings advance our understanding of the molecular mechanism underlying mammalian cochlear amplification.

A Gap-Junction Mutation Reveals That Outer Hair Cell Extracellular Receptor Potentials Drive High-Frequency Cochlear Amplification.

Cochlear amplification enables the enormous dynamic range of hearing through amplifying cochlear responses to low- to moderate-level sounds and compressing them to loud sounds. Amplification is attributed to voltage-dependent electromotility of mechanosensory outer hair cells (OHCs) driven by changing voltages developed across their cell membranes. At low frequencies, these voltage changes are dominated by intracellular receptor potentials (RPs). However, OHC membranes have electrical low-pass filter properties that attenuate high-frequency RPs, which should potentially attenuate amplification of high-frequency cochlear responses and impede high-frequency hearing. We made in vivo intracellular and extracellular electrophysiological measurements from the organ of Corti of male and female mice of the CBA/J strain, with excellent high-frequency hearing, and from the CD-1 mouse strain, which has sensitive hearing below 12 kHz but loses high-frequency hearing within a few weeks postpartum. The CD-1 mouse strain was transfected with an A88V mutation of the connexin 30 gap-junction protein. By blocking the action of the GJ protein to reduce input resistance, the mutation increased the OHC extracellular RP (ERP) magnitude and rescued high-frequency hearing. However, by increasing the organ of Corti resistance, the mutation rescued high-frequency hearing through preserving the OHC extracellular RP (ERP) magnitude. We measured the voltage developed across the basolateral membranes of OHCs, which controls their electromotility, for low- to high-frequency sounds in male and female mice of the CD-1 strain that expressed the A88V mutation. We demonstrate that ERPs, not RPs, drive OHC motility and cochlear amplification at high frequencies because at high frequencies, ERPs are not frequency attenuated, exceed RPs in magnitude, and are appropriately timed to provide cochlear amplification.SIGNIFICANCE STATEMENT Cochlear amplification, which enables the enormous dynamic range of hearing, is attributed to voltage-dependent electromotility of the mechanosensory outer hair cells (OHCs) driven by sound-induced voltage changes across their membranes. OHC intracellular receptor potentials are electrically low-pass filtered, which should hinder high-frequency hearing. We measured the intracellular and extracellular voltages that control OHC electromotility in vivo in a mouse strain with impaired high-frequency hearing. A gap-junction mutation of the strain rescued high-frequency hearing, increased organ of Corti resistance, and preserved large OHC extracellular receptor potentials but reduced OHC intracellular receptor potentials and impaired low-frequency hearing. We concluded intracellular potentials drive OHC motility at low frequencies and extracellular receptor potentials drive OHC motility and cochlear amplification at high frequencies.

On the frequency response of prestin charge movement in membrane patches

Outer hair cell (OHC) nonlinear membrane capacitance derives from voltage-dependent sensor charge movements within the membrane protein prestin (SLC26a5) that drive OHC electromotility. The ability of the protein to influence hearing depends on its reaction to membrane receptor potentials across auditory frequency. Estimates of prestin’s frequency response have been evaluated by several groups out to tens of kHz in voltage-clamped macro-patches of OHC membrane. The response is a power function of frequency that is down 40 dB at 77 kHz. Despite these observations, concerns remain that the macro-patch approach is flawed due to mechanical constraints of pipette solution column load or patch size itself. In the absence of these influences, prestin’s frequency response is posited by some to be ultrasonic in nature. Here we evaluate the influence of these putative confounding factors on prestin’s frequency response. We show that neither pipette column height nor negative or positive pipette pressure substantially influence total sensor charge frequency response. Additionally, patch surface area has negligible influence. We conclude that the speed of voltage-driven conformational changes in prestin within the plasma membrane is accurately assessed with the macro-patch technique, permitting investigations of membrane characteristics that can substantially alter prestin’s performance bandwidth. We illustrate significant alterations in bandwidth by perturbation of membrane fluidity and chloride anion concentration. Finally, we speculate that OHC membrane characteristics may differ along the tonotopic axis of the cochlea to tune nonlinear membrane capacitance frequency cutoffs.

Unloading outer hair cell bundles in vivo does not yield evidence of spontaneous oscillations in the mouse cochlea

Along with outer hair cell (OHC) somatic electromotility as the actuator of cochlear amplification, active hair bundle motility may be a complementary mechanism in the mammalian auditory system. Here, we searched the mouse cochlea for the presence of spontaneous bundle oscillations that have been observed in non-mammalian ears. In those systems, removal of the overlying membrane is necessary for spontaneous bundle oscillations to manifest. Thus, we used a genetic mouse model with a C1509G (cysteine-to-glycine) point mutation in the Tecta gene where the tectorial (TM) is lifted away from the OHC bundles, allowing us to explore whether unloaded bundles spontaneously oscillate. We used VOCTV in vivo to detect OHC length changes due to electromotility as a proxy for the spontaneous opening and closing of the mechanoelectrical transduction (MET) channels associated with bundle oscillation. In wild type mice with the TM attached to OHC bundles, we did find peaks in vibratory magnitude spectra. Such peaks were not observed in the mutants where the TM is detached from the OHC bundles. Statistical analysis of the time signals indicates that these peaks do not signify active oscillations. Rather, they are filtered responses of the sensitive wild type cochlea to weak background noise. We therefore conclude that, to the limits of our system (∼30 pm), there is no spontaneous mechanical activity that manifests as oscillations in OHC electromotility within the mouse cochlea, arguing that unloaded OHC bundles do not oscillate in vivo.This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.

Prestin's structural cycle and the molecular basis of electromotility in outer hair cells

In mammals, auditory sound detection relies on a mechanical amplification process to achieve its remarkable sensitivity and frequency selectivity. This “cochlear amplifier” depends on one of two types of sensory receptor cell in the cochlea, the outer hair cells (OHC). OHCs undergo voltage-dependent longitudinal contractions or elongations at their basolateral membrane, triggered by the concerted action of millions of the fast “motor” protein Prestin (SLC26A5), the only piezoelectric member of the SLC26 family of anion transporter.

Single particle cryo-EM structure of the outer hair cell motor protein prestin

The mammalian outer hair cell (OHC) protein prestin (Slc26a5) differs from other Slc26 family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification. Here, we use cryo-electron microscopy to determine prestin’s structure at 3.6 Å resolution. Prestin is structurally similar to the anion transporter Slc26a9. It is captured in an inward-open state which may reflect prestin’s contracted state. Two well-separated transmembrane (TM) domains and two cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domains form a swapped dimer. The transmembrane domains consist of 14 transmembrane segments organized in two 7+7 inverted repeats, an architecture first observed in the bacterial symporter UraA. Mutation of prestin’s chloride binding site removes salicylate competition with anions while retaining the prestin characteristic displacement currents (Nonlinear Capacitance), undermining the extrinsic voltage sensor hypothesis for prestin function.

Efferent neurons control hearing sensitivity and protect hearing from noise through the regulation of gap junctions between cochlear supporting cells.

It is critical for hearing that the descending cochlear efferent system provides a negative feedback to hair cells to regulate hearing sensitivity and protect hearing from noise. The medial olivocochlear (MOC) efferent nerves project to outer hair cells (OHCs) to regulate OHC electromotility, which is an active cochlear amplifier and can increase hearing sensitivity. Here, we report that the MOC efferent nerves also could innervate supporting cells (SCs) in the vicinity of OHCs to regulate hearing sensitivity. MOC nerve fibers are cholinergic, and acetylcholine (ACh) is a primary neurotransmitter. Immunofluorescent staining showed that MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChTs), and postsynaptic ACh receptors were visible at SCs and in the SC area. Application of ACh in SCs could evoke a typical inward current and reduce gap junctions (GJs) between them, which consequently enhanced the direct effect of ACh on OHCs to shift but not eliminate OHC electromotility. This indirect, GJ-mediated inhibition had a long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway decreased the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion product otoacoustic emission (DPOAE) showed a delayed reduction after noise exposure. Our findings reveal a new pathway for the MOC efferent system via innervating SCs to control active cochlear amplification and hearing sensitivity. These data also suggest that this SC GJ-mediated efferent pathway may play a critical role in long-term efferent inhibition and is required for protection of hearing from noise trauma.NEW & NOTEWORTHY The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

How much prestin motor activity is required for normal hearing?

Prestin (SLC26A5) is a membrane-based voltage-dependent motor protein responsible for outer hair cell (OHC) somatic electromotility. Its importance for mammalian cochlear amplification has been demonstrated using mouse models lacking prestin (prestin-KO) and expressing dysfunctional prestin, prestinV499G/Y501H (499-prestin-KI). However, it is still not elucidated how prestin contributes to the mechanical amplification process in the cochlea. In this study, we characterized several prestin mouse models in which prestin activity in OHCs was variously manipulated. We found that near-normal cochlear function can be maintained even when prestin activity is significantly reduced, suggesting that the relationship between OHC electromotility and the peripheral sensitivity to sound may not be linear. This result is counterintuitive given the large threshold shifts in prestin-KO and 499-prestin-KI mice, as reported in previous studies. To reconcile these apparently opposing observations, we entertain a voltage- and turgor pressure-based cochlear amplification mechanism that requires prestin but is insensitive to significant reductions in prestin protein expression.This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam

Coupling between outer hair cell electromotility and prestin sensor charge depends on voltage operating point

The OHC drives cochlear amplification, and prestin activity is the basis. The frequency response of nonlinear capacitance (NLC), which is a ratiometric measure of prestin's voltage-sensor charge movement (dQp/dVm), depends on the location of AC voltage excitation along prestin's operating voltage range, being slowest at the voltage (Vh) where NLC peaks. Here we directly investigate the coupling between prestin charge movement (Qp) and electromotility (eM) at frequencies up to 6.25 kHz, and find tight correspondence between the two at operating voltages displaced from Vh. Near Vh, however, eM shows a slower frequency response than Qp. We reason that coupling is more susceptible to molecular/cellular loads at Vh, where prestin compliance is expected to be maximal. Recent cryo-EM studies have begun to shed light on structural features of prestin that impact its performance against loads.This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam

The conformational cycle of prestin underlies outer-hair cell electromotility.

The voltage-dependent motor protein prestin (also known as SLC26A5) is responsible for the electromotive behaviour of outer-hair cells and underlies the cochlear amplifier1. Knockout or impairment of prestin causes severe hearing loss2-5. Despite the key role of prestin in hearing, the mechanism by which mammalian prestin senses voltage and transduces it into cellular-scale movements (electromotility) is poorly understood. Here we determined the structure of dolphin prestin in six distinct states using single-particle cryo-electron microscopy. Our structural and functional data suggest that prestin adopts a unique and complex set of states, tunable by the identity of bound anions (Cl- or SO42-). Salicylate, a drug that can cause reversible hearing loss, competes for the anion-binding site of prestin, and inhibits its function by immobilizing prestin in a new conformation. Our data suggest that the bound anion together with its coordinating charged residues and helical dipole act as a dynamic voltage sensor. An analysis of all of the anion-dependent conformations reveals how structural rearrangements in the voltage sensor are coupled to conformational transitions at the protein-membrane interface, suggesting a previously undescribed mechanism of area expansion. Visualization of the electromotility cycle of prestin distinguishes the protein from the closely related SLC26 anion transporters, highlighting the basis for evolutionary specialization of the mammalian cochlear amplifier at a high resolution.

Cochlear outer hair cell electromotility enhances organ of Corti motion on a cycle-by-cycle basis at high frequencies in vivo

Mammalian hearing depends on an amplification process involving prestin, a voltage-sensitive motor protein that enables cochlear outer hair cells (OHCs) to change length and generate force. However, it has been questioned whether this prestin-based somatic electromotility can operate fast enough in vivo to amplify cochlear vibrations at the high frequencies that mammals hear. In this study, we measured sound-evoked vibrations from within the living mouse cochlea and found that the top and bottom of the OHCs move in opposite directions at frequencies exceeding 20 kHz, consistent with fast somatic length changes. These motions are physiologically vulnerable, depend on prestin, and dominate the cochlea's vibratory response to high-frequency sound. This dominance was observed despite mechanisms that clearly low-pass filter the in vivo electromotile response. Low-pass filtering therefore does not critically limit the OHC's ability to move the organ of Corti on a cycle-by-cycle basis. Our data argue that electromotility serves as the primary high-frequency amplifying mechanism within the mammalian cochlea.

Examining influence of primary frequency ratio on distortion product otoacoustic emissions generation using an alternating frequency/time domain cochlear model

Distortion product otoacoustic emissions (DPOAEs) are sounds measured in the ear canal in response to a two-tone stimulus. Because DPOAEs are measured non-invasively, they have been intensively studied and widely applied for the clinical assessment of hearing function. In this work, we combine a three-dimensional computational model with mechanical-electrical-acoustic coupling with in vivo measurements of the pressure in scala tympani and the extracellular electrical outer hair cells (OHCs) response to study distortion product (DP) generation by OHCs in the gerbil cochlea. An efficiency non-linear frequency domain algorithm is used to simulation the nonlinear response of the cochlea in response to a two-tone stimulus. The influence of primary frequency ratio (on IDP generation and propagation is examined. The results show the IDPs are broadly generated by OHCs but their contribution to OAEs are spatially restricted. This work not only improves our understanding of the role of the OHC electromotility in DP generation, but will also benefit clinical noninvasive hearing assessment based on otoacoustic emissions.