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Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea

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ABSTRACT

Sound pressure fluctuations striking the ear are conveyed to the cochlea, where they vibrate the basilar membrane on which sit hair cells, the mechanoreceptors of the inner ear. Recordings of hair cell electrical responses have shown that they transduce sound via submicrometer deflections of their hair bundles, which are arrays of interconnected stereocilia containing the mechanoelectrical transducer (MET) channels. MET channels are activated by tension in extracellular tip links bridging adjacent stereocilia, and they can respond within microseconds to nanometer displacements of the bundle, facilitated by multiple processes of Ca2+‐dependent adaptation. Studies of mouse mutants have produced much detail about the molecular organization of the stereocilia, the tip links and their attachment sites, and the MET channels localized to the lower end of each tip link. The mammalian cochlea contains two categories of hair cells. Inner hair cells relay acoustic information via multiple ribbon synapses that transmit rapidly without rundown. Outer hair cells are important for amplifying sound‐evoked vibrations. The amplification mechanism primarily involves contractions of the outer hair cells, which are driven by changes in membrane potential and mediated by prestin, a motor protein in the outer hair cell lateral membrane. Different sound frequencies are separated along the cochlea, with each hair cell being tuned to a narrow frequency range; amplification sharpens the frequency resolution and augments sensitivity 100‐fold around the cell's characteristic frequency. Genetic mutations and environmental factors such as acoustic overstimulation cause hearing loss through irreversible damage to the hair cells or degeneration of inner hair cell synapses. © 2017 American Physiological Society. Compr Physiol 7:1197‐1227, 2017.

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Figure 1. Figure 1. Schematic of the sound transmission pathway from the eardrum to the cochlea. Sound stimuli impinge on the tympanum (t), or eardrum, at the end of the ear canal and the vibrations (denoted by red arrows) are transmitted through the three bones of the middle ear: malleus (m), incus (i), and stapes (s). The footplate of the stapes behaves like a piston in the oval window and initiates pressure waves in the cochlear fluids so setting in vibration the basilar membrane. The pressure is relieved at the round window (rw). The cochlea, here depicted as straight, is in situ coiled like a snail's shell and embedded in the petrous temporal bone. It is subdivided into three compartments containing perilymph or endolymph fluid, the two outer compartment being connected by the helicotrema. The total length of the cochlea is 35 mm (humans), 26 mm (cat), 18 mm (guinea pig), and 6 mm (mice).
Figure 2. Figure 2. Cross section though the cochlear duct showing the cellular structure. The scala media is delimited by Reissner's membrane, the spiral ligament, and the basilar membrane, which is surmounted by the organ of Corti. The width of the basilar membrane ranges from approximately 100 to 500 μm in humans. The scala media is filled with a K+‐based endolymph, here colored pink. The organ of Corti contains the sensory hair cells embedded in assorted supporting cells of distinct shape. The hair‐cell stereociliary bundles are covered in an acellular tectorial sheet and the cells are innervated by the cochlear branch of the VIIIth cranial nerve. Inner hair cells are contacted by afferents (orange) whereas outer hair cells are innervated mainly by efferent fibers (yellow). The stria vascularis is an epithelial strip on the lateral wall that is specialized for secreting endolymph.
Figure 3. Figure 3. Schematic of the stria vascularis. The stria comprises two cellular layers separated by an intrastrial space. Marginal cells face the endolymph and intermediate/basal cells, interconnected by gap junctions (blue pairs of lines), are exposed to fibrocytes of the strial ligament and perilymph; adjacent cells in each layer are linked by tight junctions (purple). (Note that the orientation is reversed with regard to that shown in Fig. 2.) Flow of K+ ions is facilitated by the inwardly rectifying KCNJ10 K+ channel on intermediate cells and the KCNQ1/KCNE1 K+ channel on the endolymphatic aspect of the marginal cells. Ionic balance is maintained by Na/K ATPase, Na‐2Cl‐K and Cl transporters. The voltages given (+90, +100, and +10 mV) refer to the static potentials of the extracellular spaces with respect to the scala tympani. The endolymphatic potential of +90 mV is attributable to a Nernst K+ equilibrium potential of ∼100 mV across the highly K+ selective apical membrane of intermediate cells. The intrastrial space has low K+ due to uptake of the ion by the Na‐2Cl‐K cotransporter and the Na/K ATPase and K+ is then secreted into endolymph across the K+‐selective membrane of marginal cell.
Figure 4. Figure 4. Stereociliary bundles and the transduction apparatus. Scanning electron micrographs of stereociliary bundles of (A) an outer hair cell and (B) an inner hair cell, showing the staircase in heights of the rows. (C) Transmission electron micrograph of an outer hair cell showing a tip link connecting two stereocilia; the insertion sites of the tip link (TL) are heavily electron dense suggesting dense protein densities. (D) Schematic of the molecular structure of the tip link apparatus deduced from various mutations. USH‐1 and USH‐2 denote different Usher type 1 and type 2 mutations. The association between the N‐termini of protocadherin‐15 and cadherin‐23 is Ca2+ dependent. Two MET channels (red) are situated at the lower end of the tip link and are present as complexes with TMIE, LHFPL5, TMC1, and possibly other proteins. Modified, with permission, from ().
Figure 5. Figure 5. Mechanoelectrical transducer (MET) currents in outer hair cells. (A) Schematic of the stimulating and recording techniques. OHCs are patch clamped and the stereociliary bundle is deflected either by a glass probe attached to a piezoelectric device or by a fluid jet. Displacement of the bundle are calibrated by projection of image onto a photodiode array (). (B) MET currents for family of step displacements, X, of a hair bundle, displaying rapid rise to peak and then adaptive decline to a steady level. (C) Plot of peak MET current against bundle displacement with an operating range of ∼0.25 μm. (D) Expanded scale of MET current onset showing that it develops as quickly as the displacement step (shown above) but then adapts with a time constant, τA, of 100 μs. (E) MET currents in OHCs from the apex and base of the cochlea for sinusoidal modulation of hair bundle position (top). Bundle motion was calibrated by projecting its image on to a pair of photodiodes, the noisy grey trace denoting the photocurrent. (F) MET current increases from apex to base of cochlea; current amplitude was 50% larger in the reduced Ca2+ of the endolymph solution‐bathing bundle. All currents measured at a holding potential of −84 mV. Modified, with permission, from ().
Figure 6. Figure 6. Single MET channels in mouse hair cells. (A) Apical outer hair cell: four representative single channel records for 150 nm hair bundle displacement steps; middle, ensemble average of 10 responses; bottom amplitude histograms giving mean single‐channel current of 6.2 pA. (B) Basal outer hair cell: four representative single channel records for 150 nm hair bundle stimuli; middle, ensemble average of 10 responses; bottom, amplitude histograms giving mean single‐channel current of 12 pA. (C) Single‐channel current and conductance (mean ± 1 SD) as a function of position in the cochlea, expressed as relative distance from the apical end. Total length of cochlea is 6 mm. All measurements made at room temperature and −84 mV holding potential. Modified, with permission, from ().
Figure 7. Figure 7. Adaptation assayed with two‐pulse experiment. (A) MET currents for two series of brief bundle displacements, the first are control steps and the second are test steps, which are preceded by a long adapting step. Note the current decay during the adapting step. (B) Current‐displacement relationships for first (control) pulse and for second (test) pulse after adapting step. The current I is scaled to its maximum value, Imax. Note the positive shift, ΔX0.5, in the current‐displacement relationship. (C) Schematic of experiment where the amplitude of the adapting step was varied. (D) Plot of shift in current‐displacement relation, ΔX0.5, as a function of the size of the adapting step. The slope is typically 0.5–0.6. All currents measured in outer hair cells at a holding potential of −84 mV. Results, with permission, from reference ().
Figure 8. Figure 8. Tonotopic variations in membrane properties of rodent outer hair cells. (A) Principal membrane currents determining potential of outer hair cell. MET current, IMT, carried mainly by K+ ions, flows in through MET channels down a potential gradient determined by the positive endolymphatic potential (EP, 90 mV) and the resting potential (VR, ∼ −50 mV); the K+ current exits mainly via GK,n channels in lateral wall, down a K+ concentration gradient into the perilymph. (B) MET conductance, GMT, increases with the characteristic frequency at the location of the hair cell. (C) Voltage‐dependent K+ conductance, GK,n, increases with hair‐cell characteristic frequency. (D) Membrane capacitance decreases with hair‐cell characteristic frequency, signifying a progressive decrease in the size, mainly the length, of the outer hair cell. Combining results in B, C, and D, implies a significant reduction in the membrane time constant determined by C/(GMET + GKn). Results are combined measurements from gerbils (filled circles) and rats (filled squares) and were taken, with permission, from (). (E) OHC length (and hence membrane area and electrical capacitance) decreases with increase in characteristic frequency in different mammals: (a) chinchilla, human; (b) guinea pig; (c) chinchilla, gerbil; (d) guinea pig, chinchilla; (e) gerbil, rat; (f) chinchilla, mouse, rat; (g) guinea pig, rat, human; (h) rat, bat; (i) mouse; (j) bat. Data, with permission, from [(); rat, bat, guinea pig, and gerbil], [(); chinchilla], [(); human], and from author's laboratory (rat, mouse, and gerbil).
Figure 9. Figure 9. Filtering of receptor potentials by inner hair cell. (A) Changes in IHC membrane potential elicited by current pulses of magnitudes given next to each trace in isolated guinea pig inner hair cell. Note the voltage inactivation for larger responses. (B) Schematic of organ of Corti showing the IHC and innervation by multiple afferents. The medial and lateral sides of the IHC are often referred to as “modiolar” and “pillar,” the orientation of which is shown beneath the schematic. (C) Receptor potentials in an inner hair cell of an anesthetized guinea pig for tones of different frequencies, given in Hz alongside the traces. At low frequencies, the response is purely sinusoidal, reflecting the sound stimulus. At frequencies above 1000 Hz, the periodic (AC) component is filtered by the membrane time constant leaving a sustained depolarizing (DC) component. (D) Synchronization index, indicating phase‐locking in auditory nerve discharge, as a function of the frequency of the sound stimulus in auditory nerve fibers of cats (crosses) and guinea pigs (filled and open squares). An index of 1.0 denotes perfect synchronization of the spikes to a specific phase on every cycle of the tone, whereas an index of 0 denotes no relationship between the spike firing and the sound cycle. Records in (A) modified, with permission, from () and (C) and (D), with permission, from (). See also Figure 14 for examples of phase locking.
Figure 10. Figure 10. Tonotopic organization of the turtle auditory papilla. Left, medial view with the hair‐cell papilla on the right‐hand side of the basilar membrane; scale bar = 100 μm. Right, examples of electrical resonance in hair cells at different positions along the epithelium. Resonant frequency, given beside traces, increases from apex to base. Each record is the voltage response to a small depolarizing current step, the timing of which is shown at top; cells had resting potentials in the range −44 to −51 mV. Figure taken, with permission, from ().
Figure 11. Figure 11. Mechanical and electrical tuning curves in the mammalian cochlea. (A) Solid curves are frequency‐threshold tuning curves for two auditory nerve fibers in the chinchilla cochlea, with characteristic frequencies of 0.4 and 9.5 kHz. Superimposed on each nerve‐fiber tuning curve at similar locations are the basilar membrane vibrations: iso‐displacement response (dotted curves, 1‐nm left and 2.7 nm right) and isovelocity response (dashed curves, 2.5 μm/s left, and 164 μm/s right). The results indicate almost all of the frequency tuning is present in the basilar membrane vibrations, with isovelocity responses giving better fits to the nerve fiber frequency‐threshold curve; from (). (B) Schematic of auditory nerve fiber tuning curves for the cat cochlea based on results in references (). Similar sets of tuning curves are also available for other mammals including the Mongolian gerbil () and the mouse ().
Figure 12. Figure 12. Outer hair cell contractility mediated by prestin. (A) Schematic of outer hair cell with prestin molecules in lateral wall. Force applied to hair bundle open MET channels, causing depolarization and cell contraction due to change in conformation of prestin. (B) Transmission electron micrograph of rat outer hair cell immunolabeled for prestin shows gold particles in the lateral wall; abbreviations: st, stereociliary bundle; cp cuticular plate; cy, cytoplasm; jc junctional complex. (C) Contractions of outer hair cell evoked by voltage steps from −120 mV to +50 mV; length change measured with dual photodiode; (D) plots of length change in outer hair cell recorded with chloride‐based and sulfate‐based intracellular solutions. With chloride, the prestin was half‐activated at −50 mV, but sulfate shifted the activation relationship ∼150 mV positive. B taken, with permission, from (); C and D taken, with permission, from ().
Figure 13. Figure 13. Deformation of organ of Corti during stimulation. (A) Excitatory (rarefaction) sound stimulus causes upward deflection of basilar membrane and organ of Corti. On conventional view, the entire organ moves upward without changing shape and causes abneural displacement of hair bundles; brown background denotes resting position and black outline new stimulated position. (B) Electrical stimulation elicits contraction of outer hair cells and compression of the organ of Corti, with the reticular lamina being pulled down and basilar membrane pulled up. During normal stimulation it is envisage that both processes in A and B will occur sequentially but the exact timing is still uncertain.
Figure 14. Figure 14. Synaptic potentials and action potentials in an auditory afferent. (A) Microelectrode recordings from an auditory nerve terminal in the turtle cochlea showing the spontaneous synaptic potentials and action potentials in the absence of a sound stimulus (top) and the response evoked by a tone at 265 Hz, 54 dB SPL (bottom). (B) Peristimulus histograms showing phase locking of action potentials to a 265 Hz tone (top) and a 520 Hz tone (bottom) from cell in (A); modified, with permission, from reference ().
Figure 15. Figure 15. The synapse between the inner hair cell and cochlear afferent fiber. (A) Inner hair cell makes synaptic contacts with multiple (10‐20) afferent fibers on its basolateral aspect, each synapse having one presynaptic ribbon (blue) and release site onto one afferent. Fibers synapsing on the pillar side are thought to have low thresholds and high resting spontaneous firing; fibers synapsing on the modiolar side have high threshold and low spontaneous discharge. The ribbons are smaller and the postsynaptic glutamate receptor densities (blue strip) are larger for the low threshold fibers. (B) Enlargement of the (blue) ribbon surrounded by halo of (yellow) synaptic vesicles. The ribbon is composed of ribeye and piccolo proteins and anchored to the membrane of the release site by bassoon. Vesicles are exocytosed by Ca2+ influx through Cav1.3 Ca2+ channels on presynaptic membrane and glutamate neurotransmitter binds to GluA2/3 receptors on the postsynaptic membrane. (C) High power view of synaptic vesicle, glutamate transporter Vglut3, and Ca2+ sensor otoferlin with six #c2 domains. (D) Conventional view of the life cycle of the synaptic vesicle, from docking at the release site, interaction of vesicular and target SNARE proteins and priming for release, fusion and reuptake. Several of these processes are thought to be Ca2+‐sensitive and possibly mediated by otoferlin.


Figure 1. Schematic of the sound transmission pathway from the eardrum to the cochlea. Sound stimuli impinge on the tympanum (t), or eardrum, at the end of the ear canal and the vibrations (denoted by red arrows) are transmitted through the three bones of the middle ear: malleus (m), incus (i), and stapes (s). The footplate of the stapes behaves like a piston in the oval window and initiates pressure waves in the cochlear fluids so setting in vibration the basilar membrane. The pressure is relieved at the round window (rw). The cochlea, here depicted as straight, is in situ coiled like a snail's shell and embedded in the petrous temporal bone. It is subdivided into three compartments containing perilymph or endolymph fluid, the two outer compartment being connected by the helicotrema. The total length of the cochlea is 35 mm (humans), 26 mm (cat), 18 mm (guinea pig), and 6 mm (mice).


Figure 2. Cross section though the cochlear duct showing the cellular structure. The scala media is delimited by Reissner's membrane, the spiral ligament, and the basilar membrane, which is surmounted by the organ of Corti. The width of the basilar membrane ranges from approximately 100 to 500 μm in humans. The scala media is filled with a K+‐based endolymph, here colored pink. The organ of Corti contains the sensory hair cells embedded in assorted supporting cells of distinct shape. The hair‐cell stereociliary bundles are covered in an acellular tectorial sheet and the cells are innervated by the cochlear branch of the VIIIth cranial nerve. Inner hair cells are contacted by afferents (orange) whereas outer hair cells are innervated mainly by efferent fibers (yellow). The stria vascularis is an epithelial strip on the lateral wall that is specialized for secreting endolymph.


Figure 3. Schematic of the stria vascularis. The stria comprises two cellular layers separated by an intrastrial space. Marginal cells face the endolymph and intermediate/basal cells, interconnected by gap junctions (blue pairs of lines), are exposed to fibrocytes of the strial ligament and perilymph; adjacent cells in each layer are linked by tight junctions (purple). (Note that the orientation is reversed with regard to that shown in Fig. 2.) Flow of K+ ions is facilitated by the inwardly rectifying KCNJ10 K+ channel on intermediate cells and the KCNQ1/KCNE1 K+ channel on the endolymphatic aspect of the marginal cells. Ionic balance is maintained by Na/K ATPase, Na‐2Cl‐K and Cl transporters. The voltages given (+90, +100, and +10 mV) refer to the static potentials of the extracellular spaces with respect to the scala tympani. The endolymphatic potential of +90 mV is attributable to a Nernst K+ equilibrium potential of ∼100 mV across the highly K+ selective apical membrane of intermediate cells. The intrastrial space has low K+ due to uptake of the ion by the Na‐2Cl‐K cotransporter and the Na/K ATPase and K+ is then secreted into endolymph across the K+‐selective membrane of marginal cell.


Figure 4. Stereociliary bundles and the transduction apparatus. Scanning electron micrographs of stereociliary bundles of (A) an outer hair cell and (B) an inner hair cell, showing the staircase in heights of the rows. (C) Transmission electron micrograph of an outer hair cell showing a tip link connecting two stereocilia; the insertion sites of the tip link (TL) are heavily electron dense suggesting dense protein densities. (D) Schematic of the molecular structure of the tip link apparatus deduced from various mutations. USH‐1 and USH‐2 denote different Usher type 1 and type 2 mutations. The association between the N‐termini of protocadherin‐15 and cadherin‐23 is Ca2+ dependent. Two MET channels (red) are situated at the lower end of the tip link and are present as complexes with TMIE, LHFPL5, TMC1, and possibly other proteins. Modified, with permission, from ().


Figure 5. Mechanoelectrical transducer (MET) currents in outer hair cells. (A) Schematic of the stimulating and recording techniques. OHCs are patch clamped and the stereociliary bundle is deflected either by a glass probe attached to a piezoelectric device or by a fluid jet. Displacement of the bundle are calibrated by projection of image onto a photodiode array (). (B) MET currents for family of step displacements, X, of a hair bundle, displaying rapid rise to peak and then adaptive decline to a steady level. (C) Plot of peak MET current against bundle displacement with an operating range of ∼0.25 μm. (D) Expanded scale of MET current onset showing that it develops as quickly as the displacement step (shown above) but then adapts with a time constant, τA, of 100 μs. (E) MET currents in OHCs from the apex and base of the cochlea for sinusoidal modulation of hair bundle position (top). Bundle motion was calibrated by projecting its image on to a pair of photodiodes, the noisy grey trace denoting the photocurrent. (F) MET current increases from apex to base of cochlea; current amplitude was 50% larger in the reduced Ca2+ of the endolymph solution‐bathing bundle. All currents measured at a holding potential of −84 mV. Modified, with permission, from ().


Figure 6. Single MET channels in mouse hair cells. (A) Apical outer hair cell: four representative single channel records for 150 nm hair bundle displacement steps; middle, ensemble average of 10 responses; bottom amplitude histograms giving mean single‐channel current of 6.2 pA. (B) Basal outer hair cell: four representative single channel records for 150 nm hair bundle stimuli; middle, ensemble average of 10 responses; bottom, amplitude histograms giving mean single‐channel current of 12 pA. (C) Single‐channel current and conductance (mean ± 1 SD) as a function of position in the cochlea, expressed as relative distance from the apical end. Total length of cochlea is 6 mm. All measurements made at room temperature and −84 mV holding potential. Modified, with permission, from ().


Figure 7. Adaptation assayed with two‐pulse experiment. (A) MET currents for two series of brief bundle displacements, the first are control steps and the second are test steps, which are preceded by a long adapting step. Note the current decay during the adapting step. (B) Current‐displacement relationships for first (control) pulse and for second (test) pulse after adapting step. The current I is scaled to its maximum value, Imax. Note the positive shift, ΔX0.5, in the current‐displacement relationship. (C) Schematic of experiment where the amplitude of the adapting step was varied. (D) Plot of shift in current‐displacement relation, ΔX0.5, as a function of the size of the adapting step. The slope is typically 0.5–0.6. All currents measured in outer hair cells at a holding potential of −84 mV. Results, with permission, from reference ().


Figure 8. Tonotopic variations in membrane properties of rodent outer hair cells. (A) Principal membrane currents determining potential of outer hair cell. MET current, IMT, carried mainly by K+ ions, flows in through MET channels down a potential gradient determined by the positive endolymphatic potential (EP, 90 mV) and the resting potential (VR, ∼ −50 mV); the K+ current exits mainly via GK,n channels in lateral wall, down a K+ concentration gradient into the perilymph. (B) MET conductance, GMT, increases with the characteristic frequency at the location of the hair cell. (C) Voltage‐dependent K+ conductance, GK,n, increases with hair‐cell characteristic frequency. (D) Membrane capacitance decreases with hair‐cell characteristic frequency, signifying a progressive decrease in the size, mainly the length, of the outer hair cell. Combining results in B, C, and D, implies a significant reduction in the membrane time constant determined by C/(GMET + GKn). Results are combined measurements from gerbils (filled circles) and rats (filled squares) and were taken, with permission, from (). (E) OHC length (and hence membrane area and electrical capacitance) decreases with increase in characteristic frequency in different mammals: (a) chinchilla, human; (b) guinea pig; (c) chinchilla, gerbil; (d) guinea pig, chinchilla; (e) gerbil, rat; (f) chinchilla, mouse, rat; (g) guinea pig, rat, human; (h) rat, bat; (i) mouse; (j) bat. Data, with permission, from [(); rat, bat, guinea pig, and gerbil], [(); chinchilla], [(); human], and from author's laboratory (rat, mouse, and gerbil).


Figure 9. Filtering of receptor potentials by inner hair cell. (A) Changes in IHC membrane potential elicited by current pulses of magnitudes given next to each trace in isolated guinea pig inner hair cell. Note the voltage inactivation for larger responses. (B) Schematic of organ of Corti showing the IHC and innervation by multiple afferents. The medial and lateral sides of the IHC are often referred to as “modiolar” and “pillar,” the orientation of which is shown beneath the schematic. (C) Receptor potentials in an inner hair cell of an anesthetized guinea pig for tones of different frequencies, given in Hz alongside the traces. At low frequencies, the response is purely sinusoidal, reflecting the sound stimulus. At frequencies above 1000 Hz, the periodic (AC) component is filtered by the membrane time constant leaving a sustained depolarizing (DC) component. (D) Synchronization index, indicating phase‐locking in auditory nerve discharge, as a function of the frequency of the sound stimulus in auditory nerve fibers of cats (crosses) and guinea pigs (filled and open squares). An index of 1.0 denotes perfect synchronization of the spikes to a specific phase on every cycle of the tone, whereas an index of 0 denotes no relationship between the spike firing and the sound cycle. Records in (A) modified, with permission, from () and (C) and (D), with permission, from (). See also Figure 14 for examples of phase locking.


Figure 10. Tonotopic organization of the turtle auditory papilla. Left, medial view with the hair‐cell papilla on the right‐hand side of the basilar membrane; scale bar = 100 μm. Right, examples of electrical resonance in hair cells at different positions along the epithelium. Resonant frequency, given beside traces, increases from apex to base. Each record is the voltage response to a small depolarizing current step, the timing of which is shown at top; cells had resting potentials in the range −44 to −51 mV. Figure taken, with permission, from ().


Figure 11. Mechanical and electrical tuning curves in the mammalian cochlea. (A) Solid curves are frequency‐threshold tuning curves for two auditory nerve fibers in the chinchilla cochlea, with characteristic frequencies of 0.4 and 9.5 kHz. Superimposed on each nerve‐fiber tuning curve at similar locations are the basilar membrane vibrations: iso‐displacement response (dotted curves, 1‐nm left and 2.7 nm right) and isovelocity response (dashed curves, 2.5 μm/s left, and 164 μm/s right). The results indicate almost all of the frequency tuning is present in the basilar membrane vibrations, with isovelocity responses giving better fits to the nerve fiber frequency‐threshold curve; from (). (B) Schematic of auditory nerve fiber tuning curves for the cat cochlea based on results in references (). Similar sets of tuning curves are also available for other mammals including the Mongolian gerbil () and the mouse ().


Figure 12. Outer hair cell contractility mediated by prestin. (A) Schematic of outer hair cell with prestin molecules in lateral wall. Force applied to hair bundle open MET channels, causing depolarization and cell contraction due to change in conformation of prestin. (B) Transmission electron micrograph of rat outer hair cell immunolabeled for prestin shows gold particles in the lateral wall; abbreviations: st, stereociliary bundle; cp cuticular plate; cy, cytoplasm; jc junctional complex. (C) Contractions of outer hair cell evoked by voltage steps from −120 mV to +50 mV; length change measured with dual photodiode; (D) plots of length change in outer hair cell recorded with chloride‐based and sulfate‐based intracellular solutions. With chloride, the prestin was half‐activated at −50 mV, but sulfate shifted the activation relationship ∼150 mV positive. B taken, with permission, from (); C and D taken, with permission, from ().


Figure 13. Deformation of organ of Corti during stimulation. (A) Excitatory (rarefaction) sound stimulus causes upward deflection of basilar membrane and organ of Corti. On conventional view, the entire organ moves upward without changing shape and causes abneural displacement of hair bundles; brown background denotes resting position and black outline new stimulated position. (B) Electrical stimulation elicits contraction of outer hair cells and compression of the organ of Corti, with the reticular lamina being pulled down and basilar membrane pulled up. During normal stimulation it is envisage that both processes in A and B will occur sequentially but the exact timing is still uncertain.


Figure 14. Synaptic potentials and action potentials in an auditory afferent. (A) Microelectrode recordings from an auditory nerve terminal in the turtle cochlea showing the spontaneous synaptic potentials and action potentials in the absence of a sound stimulus (top) and the response evoked by a tone at 265 Hz, 54 dB SPL (bottom). (B) Peristimulus histograms showing phase locking of action potentials to a 265 Hz tone (top) and a 520 Hz tone (bottom) from cell in (A); modified, with permission, from reference ().


Figure 15. The synapse between the inner hair cell and cochlear afferent fiber. (A) Inner hair cell makes synaptic contacts with multiple (10‐20) afferent fibers on its basolateral aspect, each synapse having one presynaptic ribbon (blue) and release site onto one afferent. Fibers synapsing on the pillar side are thought to have low thresholds and high resting spontaneous firing; fibers synapsing on the modiolar side have high threshold and low spontaneous discharge. The ribbons are smaller and the postsynaptic glutamate receptor densities (blue strip) are larger for the low threshold fibers. (B) Enlargement of the (blue) ribbon surrounded by halo of (yellow) synaptic vesicles. The ribbon is composed of ribeye and piccolo proteins and anchored to the membrane of the release site by bassoon. Vesicles are exocytosed by Ca2+ influx through Cav1.3 Ca2+ channels on presynaptic membrane and glutamate neurotransmitter binds to GluA2/3 receptors on the postsynaptic membrane. (C) High power view of synaptic vesicle, glutamate transporter Vglut3, and Ca2+ sensor otoferlin with six #c2 domains. (D) Conventional view of the life cycle of the synaptic vesicle, from docking at the release site, interaction of vesicular and target SNARE proteins and priming for release, fusion and reuptake. Several of these processes are thought to be Ca2+‐sensitive and possibly mediated by otoferlin.
References
 1.Occupational Noise Exposure Cincinnati, OH: DHHS (NIOSH) Publication No. 98–126, 1998, p. 2‐3.
 2.Ahmed ZM, Goodyear R, Riazuddin S, Lagziel A, Legan PK, Behra M, Burgess SM, Lilley KS, Wilcox ER, Riazuddin S, Griffith AJ, Frolenkov GI, Belyantseva IA, Richardson GP, Friedman TB. The tip‐link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin‐15. J Neurosci 26: 7022‐7034, 2006.
 3.Akinpelu OV, Peleva E, Funnell WR, Daniel SJ. Otoacoustic emissions in newborn hearing screening: A systematic review of the effects of different protocols on test outcomes. Int J Pediatr Otorhinolaryngol 78: 711‐717, 2014.
 4.Andrade LR, Salles FT, Grati M, Manor U, Kachar B. Tectorins crosslink type II collagen fibrils and connect the tectorial membrane to the spiral limbus. J Struct Biol 194: 139‐146, 2016.
 5.Art JJ, Fettiplace R. Variation of membrane properties in hair cells isolated from the turtle cochlea. J Physiol 385: 207‐242, 1987.
 6.Ashmore J. Cochlear outer hair cell motility. Physiol Rev 88: 173‐210, 2008.
 7.Ashmore JF. A fast motile response in guinea‐pig outer hair cells: The cellular basis of the cochlear amplifier. J Physiol 388: 323‐347, 1987.
 8.Assad JA, Hacohen N, Corey DP. Voltage dependence of adaptation and active bundle movement in bullfrog saccular hair cells. Proc Natl Acad Sci U S A 86: 2918‐2922, 1989.
 9.Assad JA, Shepherd GM, Corey DP. Tip‐link integrity and mechanical transduction in vertebrate hair cells. Neuron 7: 985‐994, 1991.
 10.Atkinson PJ, Huarcaya Najarro E, Sayyid ZN, Cheng AG. Sensory hair cell development and regeneration: Similarities and differences. Development 142: 1561‐1571, 2015.
 11.Bae C, Sachs F, Gottlieb PA. The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4. Biochemistry 50: 6295‐6300, 2011.
 12.Barr‐Gillespie PG. Assembly of hair bundles, an amazing problem for cell biology. Mol Biol Cell 26: 2727‐2732, 2015.
 13.Bekesy Gv. Experiments in Hearing. New York: McGraw‐Hill, 1960.
 14.Belyantseva IA, Boger ET, Naz S, Frolenkov GI, Sellers JR, Ahmed ZM, Griffith AJ, Friedman TB. Myosin‐XVa is required for tip localization of whirlin and differential elongation of hair‐cell stereocilia. Nat Cell Biol 7: 148‐156, 2005.
 15.Ben‐Yosef T, Belyantseva IA, Saunders TL, Hughes ED, Kawamoto K, Van Itallie CM, Beyer LA, Halsey K, Gardner DJ, Wilcox ER, Rasmussen J, Anderson JM, Dolan DF, Forge A, Raphael Y, Camper SA, Friedman TB. Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 12: 2049‐2061, 2003.
 16.Beurg M, Evans MG, Hackney CM, Fettiplace R. A large‐conductance calcium‐selective mechanotransducer channel in mammalian cochlear hair cells. J Neurosci 26: 10992‐11000, 2006.
 17.Beurg M, Fettiplace R, Nam JH, Ricci AJ. Localization of inner hair cell mechanotransducer channels using high‐speed calcium imaging. Nat Neurosci 12: 553‐558, 2009.
 18.Beurg M, Goldring AC, Fettiplace R. The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells. J Gen Physiol 146: 233‐243, 2015.
 19.Beurg M, Kim KX, Fettiplace R. Conductance and block of hair‐cell mechanotransducer channels in transmembrane channel‐like protein mutants. J Gen Physiol 144: 55‐69, 2014.
 20.Beurg M, Nam JH, Chen Q, Fettiplace R. Calcium balance and mechanotransduction in rat cochlear hair cells. J Neurophysiol 104: 18‐34, 2010.
 21.Beurg M, Nam JH, Crawford A, Fettiplace R. The actions of calcium on hair bundle mechanics in mammalian cochlear hair cells. Biophys J 94: 2639‐2653, 2008.
 22.Beurg M, Tan X, Fettiplace R. A prestin motor in chicken auditory hair cells: Active force generation in a nonmammalian species. Neuron 79: 69‐81, 2013.
 23.Beurg M, Xiong W, Zhao B, Muller U, Fettiplace R. Subunit determination of the conductance of hair‐cell mechanotransducer channels. Proc Natl Acad Sci U S A 112: 1589‐1594, 2015.
 24.Beutner D, Voets T, Neher E, Moser T. Calcium dependence of exocytosis and endocytosis at the cochlear inner hair cell afferent synapse. Neuron 29: 681‐690, 2001.
 25.Bohne BA, Carr CD. Morphometric analysis of hair cells in the chinchilla cochlea. J Acoust Soc Am 77: 153‐158, 1985.
 26.Borst JG, Soria van Hoeve J. The calyx of Held synapse: From model synapse to auditory relay. Annu Rev Physiol 74: 199‐224, 2012.
 27.Bosher SK. The nature of the negative endocochlear potentials produced by anoxia and ethacrynic acid in the rat and guinea‐pig. J Physiol 293: 329‐345, 1979.
 28.Bosher SK, Warren RL. Very low calcium content of cochlear endolymph, an extracellular fluid. Nature 273: 377‐378, 1978.
 29.Brandt A, Striessnig J, Moser T. CaV1.3 channels are essential for development and presynaptic activity of cochlear inner hair cells. J Neurosci 23: 10832‐10840, 2003.
 30.Brown MC, Nuttall AL. Efferent control of cochlear inner hair cell responses in the guinea‐pig. J Physiol 354: 625‐646, 1984.
 31.Brown MC, Nuttall AL, Masta RI, Lawrence M. Cochlear inner hair cells: Effects of transient asphyxia on intracellular potentials. Hear Res 9: 131‐144, 1983.
 32.Brownell WE, Bader CR, Bertrand D, de Ribaupierre Y. Evoked mechanical responses of isolated cochlear outer hair cells. Science 227: 194‐196, 1985.
 33.Chan DK, Hudspeth AJ. Ca2+ current‐driven nonlinear amplification by the mammalian cochlea in vitro. Nat Neurosci 8: 149‐155, 2005.
 34.Chapman ER. How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem 77: 615‐641, 2008.
 35.Chapochnikov NM, Takago H, Huang CH, Pangrsic T, Khimich D, Neef J, Auge E, Gottfert F, Hell SW, Wichmann C, Wolf F, Moser T. Uniquantal release through a dynamic fusion pore is a candidate mechanism of hair cell exocytosis. Neuron 83: 1389‐1403, 2014.
 36.Chatzigeorgiou M, Bang S, Hwang SW, Schafer WR. tmc‐1 encodes a sodium‐sensitive channel required for salt chemosensation in C. elegans. Nature 494: 95‐99, 2013.
 37.Cheatham MA, Goodyear RJ, Homma K, Legan PK, Korchagina J, Naskar S, Siegel JH, Dallos P, Zheng J, Richardson GP. Loss of the tectorial membrane protein CEACAM16 enhances spontaneous, stimulus‐frequency, and transiently evoked otoacoustic emissions. J Neurosci 34: 10325‐10338, 2014.
 38.Chen F, Zha D, Fridberger A, Zheng J, Choudhury N, Jacques SL, Wang RK, Shi X, Nuttall AL. A differentially amplified motion in the ear for near‐threshold sound detection. Nat Neurosci 14: 770‐774, 2011.
 39.Chen Q, Mahendrasingam S, Tickle JA, Hackney CM, Furness DN, Fettiplace R. The development, distribution and density of the plasma membrane calcium ATPase 2 calcium pump in rat cochlear hair cells. Eur J Neurosci 36: 2302‐2310, 2012.
 40.Cheung EL, Corey DP. Ca2+ changes the force sensitivity of the hair‐cell transduction channel. Biophys J 90: 124‐139, 2006.
 41.Clark GM. The multichannel cochlear implant for severe‐to‐profound hearing loss. Nat Med 19: 1236‐1239, 2013.
 42.Clark GM. The multi‐channel cochlear implant: Multi‐disciplinary development of electrical stimulation of the cochlea and the resulting clinical benefit. Hear Res 322: 4‐13, 2015.
 43.Cohen‐Salmon M, Ott T, Michel V, Hardelin JP, Perfettini I, Eybalin M, Wu T, Marcus DC, Wangemann P, Willecke K, Petit C. Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr Biol 12: 1106‐1111, 2002.
 44.Cooper NP. An improved heterodyne laser interferometer for use in studies of cochlear mechanics. J Neurosci Methods 88: 93‐102, 1999.
 45.Cooper NP, Rhode WS. Basilar membrane mechanics in the hook region of cat and guinea‐pig cochleae: Sharp tuning and nonlinearity in the absence of baseline position shifts. Hear Res 63: 163‐190, 1992.
 46.Cooper NP, Rhode WS. Nonlinear mechanics at the apex of the guinea‐pig cochlea. Hear Res 82: 225‐243, 1995.
 47.Corey DP, Hudspeth AJ. Kinetics of the receptor current in bullfrog saccular hair cells. J Neurosci 3: 962‐976, 1983.
 48.Corns LF, Johnson SL, Kros CJ, Marcotti W. Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells. Proc Natl Acad Sci U S A 111: 14918‐14923, 2014.
 49.Corns LF, Johnson SL, Kros CJ, Marcotti W. Tmc1 point mutation affects Ca2+ sensitivity and block by dihydrostreptomycin of the mechanoelectrical transducer current of mouse outer hair cells. J Neurosci 36: 336‐349, 2016.
 50.Coste B, Murthy SE, Mathur J, Schmidt M, Mechioukhi Y, Delmas P, Patapoutian A. Piezo1 ion channel pore properties are dictated by C‐terminal region. Nat Commun 6: 7223, 2015.
 51.Crawford AC, Evans MG, Fettiplace R. Activation and adaptation of transducer currents in turtle hair cells. J Physiol 419: 405‐434, 1989.
 52.Crawford AC, Evans MG, Fettiplace R. The actions of calcium on the mechano‐electrical transducer current of turtle hair cells. J Physiol 434: 369‐398, 1991.
 53.Crawford AC, Fettiplace R. The frequency selectivity of auditory nerve fibres and hair cells in the cochlea of the turtle. J Physiol 306: 79‐125, 1980.
 54.Crawford AC, Fettiplace R. An electrical tuning mechanism in turtle cochlear hair cells. J Physiol 312: 377‐412, 1981.
 55.Crawford AC, Fettiplace R. The mechanical properties of ciliary bundles of turtle cochlear hair cells. J Physiol 364: 359‐379, 1985.
 56.Dallos P. Peripheral mechanisms of hearing. In: Handbook of Physiology, The Nervous System, Sensory Processes: American Physiological Society, pp. 595‐637, 1984.
 57.Dallos P. Response characteristics of mammalian cochlear hair cells. J Neurosci 5: 1591‐1608, 1985.
 58.Dallos P, He DZ, Lin X, Sziklai I, Mehta S, Evans BN. Acetylcholine, outer hair cell electromotility, and the cochlear amplifier. J Neurosci 17: 2212‐2226, 1997.
 59.Dallos P, Wu X, Cheatham MA, Gao J, Zheng J, Anderson CT, Jia S, Wang X, Cheng WH, Sengupta S, He DZ, Zuo J. Prestin‐based outer hair cell motility is necessary for mammalian cochlear amplification. Neuron 58: 333‐339, 2008.
 60.Dannhof BJ, Roth B, Bruns V. Length of hair cells as a measure of frequency representation in the mammalian inner ear? Naturwissenschaften 78: 570‐573, 1991.
 61.Davis H. An active process in cochlear mechanics. Hear Res 9: 79‐90, 1983.
 62.Delprat B, Michel V, Goodyear R, Yamasaki Y, Michalski N, El‐Amraoui A, Perfettini I, Legrain P, Richardson G, Hardelin JP, Petit C. Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly. Hum Mol Genet 14: 401‐410, 2005.
 63.Dick O, Hack I, Altrock WD, Garner CC, Gundelfinger ED, Brandstatter JH. Localization of the presynaptic cytomatrix protein Piccolo at ribbon and conventional synapses in the rat retina: Comparison with Bassoon. J Comp Neurol 439: 224‐234, 2001.
 64.Dixon MJ, Gazzard J, Chaudhry SS, Sampson N, Schulte BA, Steel KP. Mutation of the Na‐K‐Cl co‐transporter gene Slc12a2 results in deafness in mice. Hum Mol Genet 8: 1579‐1584, 1999.
 65.Doll JC, Peng AW, Ricci AJ, Pruitt BL. Faster than the speed of hearing: Nanomechanical force probes enable the electromechanical observation of cochlear hair cells. Nano Lett 12: 6107‐6111, 2012.
 66.Dong W, Cooper NP. An experimental study into the acousto‐mechanical effects of invading the cochlea. J R Soc Interface 3: 561‐571, 2006.
 67.Dong W, Olson ES. Detection of cochlear amplification and its activation. Biophys J 105: 1067‐1078, 2013.
 68.Dumont RA, Lins U, Filoteo AG, Penniston JT, Kachar B, Gillespie PG. Plasma membrane Ca2+‐ATPase isoform 2a is the PMCA of hair bundles. J Neurosci 21: 5066‐5078, 2001.
 69.Eatock RA. Adaptation in hair cells. Annu Rev Neurosci 23: 285‐314, 2000.
 70.Eatock RA, Corey DP, Hudspeth AJ. Adaptation of mechanoelectrical transduction in hair cells of the bullfrog's sacculus. J Neurosci 7: 2821‐2836, 1987.
 71.Ebrahim S, Avenarius MR, Grati M, Krey JF, Windsor AM, Sousa AD, Ballesteros A, Cui R, Millis BA, Salles FT, Baird MA, Davidson MW, Jones SM, Choi D, Dong L, Raval MH, Yengo CM, Barr‐Gillespie PG, Kachar B. Stereocilia‐staircase spacing is influenced by myosin III motors and their cargos espin‐1 and espin‐like. Nat Commun 7: 10833, 2016.
 72.Elgoyhen AB, Katz E, Fuchs PA. The nicotinic receptor of cochlear hair cells: A possible pharmacotherapeutic target? Biochem Pharmacol 78: 712‐719, 2009.
 73.Emadi G, Richter CP, Dallos P. Stiffness of the gerbil basilar membrane: Radial and longitudinal variations. J Neurophysiol 91: 474‐488, 2004.
 74.Evans EF, Klinke R. The effects of intracochlear and systemic furosemide on the properties of single cochlear nerve fibres in the cat. J Physiol 331: 409‐427, 1982.
 75.Everett LA, Morsli H, Wu DK, Green ED. Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear. Proc Natl Acad Sci U S A 96: 9727‐9732, 1999.
 76.Farris HE, LeBlanc CL, Goswami J, Ricci AJ. Probing the pore of the auditory hair cell mechanotransducer channel in turtle. J Physiol 558: 769‐792, 2004.
 77.Fay RR. Hearing in Vertebrates: A Psychophysics Databook. Winnetka, IL: Hill‐Fay Associates, 1988.
 78.Fettiplace R. Is TMC1 the hair cell mechanotransducer channel? Biophys J 111: 3‐9, 2016.
 79.Fettiplace R, Fuchs PA. Mechanisms of hair cell tuning. Annu Rev Physiol 61: 809‐834, 1999.
 80.Fettiplace R, Kim KX. The physiology of mechanoelectrical transduction channels in hearing. Physiol Rev 94: 951‐986, 2014.
 81.Fettiplace R, Ricci AJ. Mechanoelectrical transduction in auditory hair cells. In: Vertebrate Hair Cells, edited by Eatock RA, Fay RR and Popper AN. New York: Springer, pp. 154‐203, 2006.
 82.Fisher JA, Nin F, Reichenbach T, Uthaiah RC, Hudspeth AJ. The spatial pattern of cochlear amplification. Neuron 76: 989‐997, 2012.
 83.Flagella M, Clarke LL, Miller ML, Erway LC, Giannella RA, Andringa A, Gawenis LR, Kramer J, Duffy JJ, Doetschman T, Lorenz JN, Yamoah EN, Cardell EL, Shull GE. Mice lacking the basolateral Na‐K‐2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem 274: 26946‐26955, 1999.
 84.Frank G, Hemmert W, Gummer AW. Limiting dynamics of high‐frequency electromechanical transduction of outer hair cells. Proc Natl Acad Sci U S A 96: 4420‐4425, 1999.
 85.Frank T, Rutherford MA, Strenzke N, Neef A, Pangrsic T, Khimich D, Fejtova A, Gundelfinger ED, Liberman MC, Harke B, Bryan KE, Lee A, Egner A, Riedel D, Moser T. Bassoon and the synaptic ribbon organize Ca(2)+ channels and vesicles to add release sites and promote refilling. Neuron 68: 724‐738, 2010.
 86.Fridberger A, Tomo I, Ulfendahl M, Boutet de Monvel J. Imaging hair cell transduction at the speed of sound: dynamic behavior of mammalian stereocilia. Proc Natl Acad Sci U S A 103: 1918‐1923, 2006.
 87.Frolenkov GI. Regulation of electromotility in the cochlear outer hair cell. J Physiol 576: 43‐48, 2006.
 88.Fuchs PA. A ‘calcium capacitor’ shapes cholinergic inhibition of cochlear hair cells. J Physiol 592: 3393‐3401, 2014.
 89.Fuchs PA, Glowatzki E. Synaptic studies inform the functional diversity of cochlear afferents. Hear Res 330: 18‐25, 2015.
 90.Furman AC, Kujawa SG, Liberman MC. Noise‐induced cochlear neuropathy is selective for fibers with low spontaneous rates. J Neurophysiol 110: 577‐586, 2013.
 91.Furness DN, Katori Y, Nirmal Kumar B, Hackney CM. The dimensions and structural attachments of tip links in mammalian cochlear hair cells and the effects of exposure to different levels of extracellular calcium. Neuroscience 154: 10‐21, 2008.
 92.Gale JE, Marcotti W, Kennedy HJ, Kros CJ, Richardson GP. FM1‐43 dye behaves as a permeant blocker of the hair‐cell mechanotransducer channel. J Neurosci 21: 7013‐7025, 2001.
 93.Geisler CD, Sang C. A cochlear model using feed‐forward outer‐hair‐cell forces. Hear Res 86: 132‐146, 1995.
 94.Geleoc GS, Lennan GW, Richardson GP, Kros CJ. A quantitative comparison of mechanoelectrical transduction in vestibular and auditory hair cells of neonatal mice. Proc Biol Sci 264: 611‐621, 1997.
 95.Ghaffari R, Aranyosi AJ, Richardson GP, Freeman DM. Tectorial membrane travelling waves underlie abnormal hearing in Tectb mutant mice. Nat Commun 1: 96, 2010.
 96.Gill SS, Salt AN. Quantitative differences in endolymphatic calcium and endocochlear potential between pigmented and albino guinea pigs. Hear Res 113: 191‐197, 1997.
 97.Gillespie PG, Cyr JL. Myosin‐1c, the hair cell's adaptation motor. Annu Rev Physiol 66: 521‐545, 2004.
 98.Gleason MR, Nagiel A, Jamet S, Vologodskaia M, Lopez‐Schier H, Hudspeth AJ. The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish. Proc Natl Acad Sci U S A 106: 21347‐21352, 2009.
 99.Glowatzki E, Fuchs PA. Transmitter release at the hair cell ribbon synapse. Nat Neurosci 5: 147‐154, 2002.
 100.Goodyear RJ, Marcotti W, Kros CJ, Richardson GP. Development and properties of stereociliary link types in hair cells of the mouse cochlea. J Comp Neurol 485: 75‐85, 2005.
 101.Gorbunov D, Sturlese M, Nies F, Kluge M, Bellanda M, Battistutta R, Oliver D. Molecular architecture and the structural basis for anion interaction in prestin and SLC26 transporters. Nat Commun 5: 3622, 2014.
 102.Goutman JD. Transmitter release from cochlear hair cells is phase locked to cyclic stimuli of different intensities and frequencies. J Neurosci 32: 17025‐17035a, 2012.
 103.Goutman JD, Glowatzki E. Time course and calcium dependence of transmitter release at a single ribbon synapse. Proc Natl Acad Sci U S A 104: 16341‐16346, 2007.
 104.Gow A, Davies C, Southwood CM, Frolenkov G, Chrustowski M, Ng L, Yamauchi D, Marcus DC, Kachar B. Deafness in Claudin 11‐null mice reveals the critical contribution of basal cell tight junctions to stria vascularis function. J Neurosci 24: 7051‐7062, 2004.
 105.Grati M, Kachar B. Myosin VIIa and sans localization at stereocilia upper tip‐link density implicates these Usher syndrome proteins in mechanotransduction. Proc Natl Acad Sci U S A 108: 11476‐11481, 2011.
 106.Graydon CW, Cho S, Li GL, Kachar B, von Gersdorff H. Sharp Ca(2)(+) nanodomains beneath the ribbon promote highly synchronous multivesicular release at hair cell synapses. J Neurosci 31: 16637‐16650, 2011.
 107.Guinan JJ. Efferent Physiology. In: The Cochlea, edited by Dallos P, Popper AN and Fay RR. New York: Springer Verlag, pp. 435‐502, 1996.
 108.Gummer AW, Hemmert W, Zenner HP. Resonant tectorial membrane motion in the inner ear: Its crucial role in frequency tuning. Proc Natl Acad Sci U S A 93: 8727‐8732, 1996.
 109.Guo Y, Wang Y, Zhang W, Meltzer S, Zanini D, Yu Y, Li J, Cheng T, Guo Z, Wang Q, Jacobs JS, Sharma Y, Eberl DF, Gopfert MC, Jan LY, Jan YN, Wang Z. Transmembrane channel‐like (tmc) gene regulates Drosophila larval locomotion. Proc Natl Acad Sci U S A 113: 7243‐7248, 2016.
 110.Hackney CM, Mahendrasingam S, Penn A, Fettiplace R. The concentrations of calcium buffering proteins in mammalian cochlear hair cells. J Neurosci 25: 7867‐7875, 2005.
 111.Hacohen N, Assad JA, Smith WJ, Corey DP. Regulation of tension on hair‐cell transduction channels: Displacement and calcium dependence. J Neurosci 9: 3988‐3997, 1989.
 112.He DZ, Jia S, Dallos P. Mechanoelectrical transduction of adult outer hair cells studied in a gerbil hemicochlea. Nature 429: 766‐770, 2004.
 113.He DZ, Jia S, Sato T, Zuo J, Andrade LR, Riordan GP, Kachar B. Changes in plasma membrane structure and electromotile properties in prestin deficient outer hair cells. Cytoskeleton (Hoboken) 67: 43‐55, 2010.
 114.Hille B. Ion Channels of Excitable Membranes (3rd ed.). Sunderland, MA: Sinauer, 2001.
 115.Holley MC, Ashmore JF. On the mechanism of a high‐frequency force generator in outer hair cells isolated from the guinea pig cochlea. Proc R Soc Lond B Biol Sci 232: 413‐429, 1988.
 116.Holton T, Hudspeth AJ. The transduction channel of hair cells from the bull‐frog characterized by noise analysis. J Physiol 375: 195‐227, 1986.
 117.Housley GD, Ashmore JF. Ionic currents of outer hair cells isolated from the guinea‐pig cochlea. J Physiol 448: 73‐98, 1992.
 118.Howard J, Hudspeth AJ. Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bullfrog's saccular hair cell. Proc Natl Acad Sci U S A 84: 3064‐3068, 1987.
 119.Howard J, Hudspeth AJ. Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog's saccular hair cell. Neuron 1: 189‐199, 1988.
 120.Hudspeth AJ. Integrating the active process of hair cells with cochlear function. Nat Rev Neurosci 15: 600‐614, 2014.
 121.Hudspeth AJ, Lewis RS. A model for electrical resonance and frequency tuning in saccular hair cells of the bull‐frog, Rana catesbeiana. J Physiol 400: 275‐297, 1988.
 122.Huth ME, Ricci AJ, Cheng AG. Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Int J Otolaryngol 2011: 937861, 2011.
 123.Ikeda K, Kusakari J, Takasaka T, Saito Y. The Ca2+ activity of cochlear endolymph of the guinea pig and the effect of inhibitors. Hear Res 26: 117‐125, 1987.
 124.Iwasa KH, Adachi M. Force generation in the outer hair cell of the cochlea. Biophys J 73: 546‐555, 1997.
 125.Javel E. Shapes of cat auditory nerve fiber tuning curves. Hear Res 81: 167‐188, 1994.
 126.Jentsch TJ. Neuronal KCNQ potassium channels: Physiology and role in disease. Nat Rev Neurosci 1: 21‐30, 2000.
 127.Jia S, Dallos P, He DZ. Mechanoelectric transduction of adult inner hair cells. J Neurosci 27: 1006‐1014, 2007.
 128.Johnson CP, Chapman ER. Otoferlin is a calcium sensor that directly regulates SNARE‐mediated membrane fusion. J Cell Biol 191: 187‐197, 2010.
 129.Johnson SL, Beurg M, Marcotti W, Fettiplace R. Prestin‐driven cochlear amplification is not limited by the outer hair cell membrane time constant. Neuron 70: 1143‐1154, 2011.
 130.Johnson SL, Kennedy HJ, Holley MC, Fettiplace R, Marcotti W. The resting transducer current drives spontaneous activity in prehearing mammalian cochlear inner hair cells. J Neurosci 32: 10479‐10483, 2012.
 131.Johnson SL, Marcotti W, Kros CJ. Increase in efficiency and reduction in Ca2 +dependence of exocytosis during development of mouse inner hair cells. J Physiol 563: 177‐191, 2005.
 132.Jones GP, Elliott SJ, Russell IJ, Lukashkin AN. Modified protein expression in the tectorial membrane of the cochlea reveals roles for the striated sheet matrix. Biophys J 108: 203‐210, 2015.
 133.Joris P, Yin TC. A matter of time: Internal delays in binaural processing. Trends Neurosci 30: 70‐78, 2007.
 134.Karavitaki KD, Mountain DC. Imaging electrically evoked micromechanical motion within the organ of corti of the excised gerbil cochlea. Biophys J 92: 3294‐3316, 2007.
 135.Kawashima Y, Geleoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel‐like genes. J Clin Invest 121: 4796‐4809, 2011.
 136.Kazmierczak P, Sakaguchi H, Tokita J, Wilson‐Kubalek EM, Milligan RA, Muller U, Kachar B. Cadherin 23 and protocadherin 15 interact to form tip‐link filaments in sensory hair cells. Nature 449: 87‐91, 2007.
 137.Keen EC, Hudspeth AJ. Transfer characteristics of the hair cell's afferent synapse. Proc Natl Acad Sci U S A 103: 5537‐5542, 2006.
 138.Kemp DT. Otoacoustic emissions, their origin in cochlear function, and use. Br Med Bull 63: 223‐241, 2002.
 139.Kennedy HJ, Crawford AC, Fettiplace R. Force generation by mammalian hair bundles supports a role in cochlear amplification. Nature 433: 880‐883, 2005.
 140.Kennedy HJ, Evans MG, Crawford AC, Fettiplace R. Fast adaptation of mechanoelectrical transducer channels in mammalian cochlear hair cells. Nat Neurosci 6: 832‐836, 2003.
 141.Kennedy HJ, Evans MG, Crawford AC, Fettiplace R. Depolarization of cochlear outer hair cells evokes active hair bundle motion by two mechanisms. J Neurosci 26: 2757‐2766, 2006.
 142.Kharkovets T, Dedek K, Maier H, Schweizer M, Khimich D, Nouvian R, Vardanyan V, Leuwer R, Moser T, Jentsch TJ. Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness. Embo j 25: 642‐652, 2006.
 143.Khimich D, Nouvian R, Pujol R, Tom Dieck S, Egner A, Gundelfinger ED, Moser T. Hair cell synaptic ribbons are essential for synchronous auditory signalling. Nature 434: 889‐894, 2005.
 144.Kiang NYS. Peripheral neural processing of auditory information. In: Handbook of Physiology, The Nervous System, Sensory Processes: American Physiological Society, pp. 639‐674, 1984.
 145.Kim KX, Beurg M, Hackney CM, Furness DN, Mahendrasingam S, Fettiplace R. The role of transmembrane channel‐like proteins in the operation of hair cell mechanotransducer channels. J Gen Physiol 142: 493‐505, 2013.
 146.Kim KX, Fettiplace R. Developmental changes in the cochlear hair cell mechanotransducer channel and their regulation by transmembrane channel‐like proteins. J Gen Physiol 141: 141‐148, 2013.
 147.Kitajiri S, Miyamoto T, Mineharu A, Sonoda N, Furuse K, Hata M, Sasaki H, Mori Y, Kubota T, Ito J, Furuse M, Tsukita S. Compartmentalization established by claudin‐11‐based tight junctions in stria vascularis is required for hearing through generation of endocochlear potential. J Cell Sci 117: 5087‐5096, 2004.
 148.Kitajiri S, Sakamoto T, Belyantseva IA, Goodyear RJ, Stepanyan R, Fujiwara I, Bird JE, Riazuddin S, Riazuddin S, Ahmed ZM, Hinshaw JE, Sellers J, Bartles JR, Hammer JA, III, Richardson GP, Griffith AJ, Frolenkov GI, Friedman TB. Actin‐bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing. Cell 141: 786‐798, 2010.
 149.Kong JH, Adelman JP, Fuchs PA. Expression of the SK2 calcium‐activated potassium channel is required for cholinergic function in mouse cochlear hair cells. J Physiol 586: 5471‐5485, 2008.
 150.Kozel PJ, Friedman RA, Erway LC, Yamoah EN, Liu LH, Riddle T, Duffy JJ, Doetschman T, Miller ML, Cardell EL, Shull GE. Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+‐ATPase isoform 2. J Biol Chem 273: 18693‐18696, 1998.
 151.Kozlov AS, Risler T, Hudspeth AJ. Coherent motion of stereocilia assures the concerted gating of hair‐cell transduction channels. Nat Neurosci 10: 87‐92, 2007.
 152.Kros CJ. How to build an inner hair cell: Challenges for regeneration. Hear Res 227: 3‐10, 2007.
 153.Kros CJ, Crawford AC. Potassium currents in inner hair cells isolated from the guinea‐pig cochlea. J Physiol 421: 263‐291, 1990.
 154.Kros CJ, Marcotti W, van Netten SM, Self TJ, Libby RT, Brown SD, Richardson GP, Steel KP. Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations. Nat Neurosci 5: 41‐47, 2002.
 155.Kros CJ, Rusch A, Richardson GP. Mechano‐electrical transducer currents in hair cells of the cultured neonatal mouse cochlea. Proc Biol Sci 249: 185‐193, 1992.
 156.Kujawa SG, Liberman MC. Adding insult to injury: Cochlear nerve degeneration after “temporary” noise‐induced hearing loss. J Neurosci 29: 14077‐14085, 2009.
 157.Kurima K, Ebrahim S, Pan B, Sedlacek M, Sengupta P, Millis BA, Cui R, Nakanishi H, Fujikawa T, Kawashima Y, Choi BY, Monahan K, Holt JR, Griffith AJ, Kachar B. TMC1 and TMC2 localize at the site of mechanotransduction in mammalian inner ear hair cell stereocilia. Cell Rep 12: 1606‐1617, 2015.
 158.Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, Arnaud D, Drury S, Mo J, Makishima T, Ghosh M, Menon PS, Deshmukh D, Oddoux C, Ostrer H, Khan S, Riazuddin S, Deininger PL, Hampton LL, Sullivan SL, Battey JF, Jr., Keats BJ, Wilcox ER, Friedman TB, Griffith AJ. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair‐cell function. Nat Genet 30: 277‐284, 2002.
 159.Labay V, Weichert RM, Makishima T, Griffith AJ. Topology of transmembrane channel‐like gene 1 protein. Biochemistry 49: 8592‐8598, 2010.
 160.Lee HY, Raphael PD, Park J, Ellerbee AK, Applegate BE, Oghalai JS. Noninvasive in vivo imaging reveals differences between tectorial membrane and basilar membrane traveling waves in the mouse cochlea. Proc Natl Acad Sci U S A 112: 3128‐3133, 2015.
 161.Legan PK, Lukashkina VA, Goodyear RJ, Kossi M, Russell IJ, Richardson GP. A targeted deletion in alpha‐tectorin reveals that the tectorial membrane is required for the gain and timing of cochlear feedback. Neuron 28: 273‐285, 2000.
 162.Li GL, Keen E, Andor‐Ardo D, Hudspeth AJ, von Gersdorff H. The unitary event underlying multiquantal EPSCs at a hair cell's ribbon synapse. J Neurosci 29: 7558‐7568, 2009.
 163.Liberman LD, Wang H, Liberman MC. Opposing gradients of ribbon size and AMPA receptor expression underlie sensitivity differences among cochlear‐nerve/hair‐cell synapses. J Neurosci 31: 801‐808, 2011.
 164.Liberman MC. Noise‐induced hearing loss: Permanent versus temporary threshold shifts and the effects of hair cell versus neuronal degeneration. Adv Exp Med Biol 875: 1‐7, 2016.
 165.Liberman MC. Auditory‐nerve response from cats raised in a low‐noise chamber. J Acoust Soc Am 63: 442‐455, 1978.
 166.Liberman MC. Morphological differences among radial afferent fibers in the cat cochlea: An electron‐microscopic study of serial sections. Hear Res 3: 45‐63, 1980.
 167.Liberman MC. The cochlear frequency map for the cat: Labeling auditory‐nerve fibers of known characteristic frequency. J Acoust Soc Am 72: 1441‐1449, 1982.
 168.Liberman MC, Dodds LW. Single‐neuron labeling and chronic cochlear pathology. III. Stereocilia damage and alterations of threshold tuning curves. Hear Res 16: 55‐74, 1984.
 169.Liberman MC, Gao J, He DZ, Wu X, Jia S, Zuo J. Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier. Nature 419: 300‐304, 2002.
 170.Lim DJ. Functional structure of the organ of Corti: A review. Hear Res 22: 117‐146, 1986.
 171.Liu Y, Gracewski SM, Nam JH. Consequences of location‐dependent organ of corti micro‐mechanics. PLoS One 10: e0133284, 2015.
 172.Liu YP, Zhao HB. Cellular characterization of Connexin26 and Connnexin30 expression in the cochlear lateral wall. Cell Tissue Res 333: 395‐403, 2008.
 173.Longo‐Guess CM, Gagnon LH, Cook SA, Wu J, Zheng QY, Johnson KR. A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry‐scurry (hscy) mice. Proc Natl Acad Sci U S A 102: 7894‐7899, 2005.
 174.Lv C, Stewart WJ, Akanyeti O, Frederick C, Zhu J, Santos‐Sacchi J, Sheets L, Liao JC, Zenisek D. Synaptic ribbons require ribeye for electron density, proper synaptic localization, and recruitment of calcium channels. Cell Rep 15: 2784‐2795, 2016.
 175.Maeda R, Kindt KS, Mo W, Morgan CP, Erickson T, Zhao H, Clemens‐Grisham R, Barr‐Gillespie PG, Nicolson T. Tip‐link protein protocadherin 15 interacts with transmembrane channel‐like proteins TMC1 and TMC2. Proc Natl Acad Sci U S A 111: 12907‐12912, 2014.
 176.Mahendrasingam S, Beurg M, Fettiplace R, Hackney CM. The ultrastructural distribution of prestin in outer hair cells: A post‐embedding immunogold investigation of low‐frequency and high‐frequency regions of the rat cochlea. Eur J Neurosci 31: 1595‐1605, 2010.
 177.Maison SF, Pyott SJ, Meredith AL, Liberman MC. Olivocochlear suppression of outer hair cells in vivo: Evidence for combined action of BK and SK2 channels throughout the cochlea. J Neurophysiol 109: 1525‐1534, 2013.
 178.Maison SF, Usubuchi H, Liberman MC. Efferent feedback minimizes cochlear neuropathy from moderate noise exposure. J Neurosci 33: 5542‐5552, 2013.
 179.Mammano F. Ca2+ homeostasis defects and hereditary hearing loss. Biofactors 37: 182‐188, 2011.
 180.Mammano F, Ashmore JF. Differential expression of outer hair cell potassium currents in the isolated cochlea of the guinea‐pig. J Physiol 496(Pt 3): 639‐646, 1996.
 181.Mammano F, Ashmore JF. Reverse transduction measured in the isolated cochlea by laser Michelson interferometry. Nature 365: 838‐841, 1993.
 182.Manor U, Disanza A, Grati M, Andrade L, Lin H, Di Fiore PP, Scita G, Kachar B. Regulation of stereocilia length by myosin XVa and whirlin depends on the actin‐regulatory protein Eps8. Curr Biol 21: 167‐172, 2011.
 183.Marcotti W, Corns LF, Goodyear RJ, Rzadzinska AK, Avraham KB, Steel KP, Richardson GP, Kros CJ. The acquisition of mechano‐electrical transducer current adaptation in auditory hair cells requires myosin VI. J Physiol 594: 3667‐3681, 2016.
 184.Marcotti W, Johnson SL, Holley MC, Kros CJ. Developmental changes in the expression of potassium currents of embryonic, neonatal and mature mouse inner hair cells. J Physiol 548: 383‐400, 2003.
 185.Marcotti W, Johnson SL, Kros CJ. Effects of intracellular stores and extracellular Ca(2+) on Ca(2+)‐activated K(+) currents in mature mouse inner hair cells. J Physiol 557: 613‐633, 2004.
 186.Marcotti W, Johnson SL, Rusch A, Kros CJ. Sodium and calcium currents shape action potentials in immature mouse inner hair cells. J Physiol 552: 743‐761, 2003.
 187.Marcotti W, Kros CJ. Developmental expression of the potassium current IK,n contributes to maturation of mouse outer hair cells. J Physiol 520(Pt 3): 653‐660, 1999.
 188.Marcotti W, van Netten SM, Kros CJ. The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano‐electrical transducer channels. J Physiol 567: 505‐521, 2005.
 189.Marcus DC, Wu T, Wangemann P, Kofuji P. KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential. Am J Physiol Cell Physiol 282: C403‐407, 2002.
 190.Markin VS, Hudspeth AJ. Gating‐spring models of mechanoelectrical transduction by hair cells of the internal ear. Annu Rev Biophys Biomol Struct 24: 59‐83, 1995.
 191.Martin P, Bozovic D, Choe Y, Hudspeth AJ. Spontaneous oscillation by hair bundles of the bullfrog's sacculus. J Neurosci 23: 4533‐4548, 2003.
 192.Martin P, Hudspeth AJ. Active hair‐bundle movements can amplify a hair cell's response to oscillatory mechanical stimuli. Proc Natl Acad Sci U S A 96: 14306‐14311, 1999.
 193.Matthews G, Fuchs P. The diverse roles of ribbon synapses in sensory neurotransmission. Nat Rev Neurosci 11: 812‐822, 2010.
 194.Mburu P, Mustapha M, Varela A, Weil D, El‐Amraoui A, Holme RH, Rump A, Hardisty RE, Blanchard S, Coimbra RS, Perfettini I, Parkinson N, Mallon AM, Glenister P, Rogers MJ, Paige AJ, Moir L, Clay J, Rosenthal A, Liu XZ, Blanco G, Steel KP, Petit C, Brown SD. Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet 34: 421‐428, 2003.
 195.Meaud J, Grosh K. The effect of tectorial membrane and basilar membrane longitudinal coupling in cochlear mechanics. J Acoust Soc Am 127: 1411‐1421, 2010.
 196.Meaud J, Grosh K. Coupling active hair bundle mechanics, fast adaptation, and somatic motility in a cochlear model. Biophys J 100: 2576‐2585, 2011.
 197.Meyers JR, MacDonald RB, Duggan A, Lenzi D, Standaert DG, Corwin JT, Corey DP. Lighting up the senses: FM1‐43 loading of sensory cells through nonselective ion channels. J Neurosci 23: 4054‐4065, 2003.
 198.Mistrik P, Mullaley C, Mammano F, Ashmore J. Three‐dimensional current flow in a large‐scale model of the cochlea and the mechanism of amplification of sound. J R Soc Interface 6: 279‐291, 2009.
 199.Mohrmann R, de Wit H, Connell E, Pinheiro PS, Leese C, Bruns D, Davletov B, Verhage M, Sorensen JB. Synaptotagmin interaction with SNAP‐25 governs vesicle docking, priming, and fusion triggering. J Neurosci 33: 14417‐14430, 2013.
 200.Muller M. Developmental changes of frequency representation in the rat cochlea. Hear Res 56: 1‐7, 1991.
 201.Muller M. The cochlear place‐frequency map of the adult and developing Mongolian gerbil. Hear Res 94: 148‐156, 1996.
 202.Muller M, von Hunerbein K, Hoidis S, Smolders JW. A physiological place‐frequency map of the cochlea in the CBA/J mouse. Hear Res 202: 63‐73, 2005.
 203.Naidu RC, Mountain DC. Measurements of the stiffness map challenge a basic tenet of cochlear theories. Hear Res 124: 124‐131, 1998.
 204.Nam JH, Fettiplace R. Force transmission in the organ of Corti micromachine. Biophys J 98: 2813‐2821, 2010.
 205.Nam JH, Fettiplace R. Optimal electrical properties of outer hair cells ensure cochlear amplification. PLoS One 7: e50572, 2012.
 206.Nam JH, Peng AW, Ricci AJ. Underestimated sensitivity of mammalian cochlear hair cells due to splay between stereociliary columns. Biophys J 108: 2633‐2647, 2015.
 207.Naraghi M, Neher E. Linearized buffered Ca2+ diffusion in microdomains and its implications for calculation of [Ca2+] at the mouth of a calcium channel. J Neurosci 17: 6961‐6973, 1997.
 208.Narayan SS, Temchin AN, Recio A, Ruggero MA. Frequency tuning of basilar membrane and auditory nerve fibers in the same cochleae. Science 282: 1882‐1884, 1998.
 209.Neef J, Gehrt A, Bulankina AV, Meyer AC, Riedel D, Gregg RG, Strenzke N, Moser T. The Ca2+ channel subunit beta2 regulates Ca2+ channel abundance and function in inner hair cells and is required for hearing. J Neurosci 29: 10730‐10740, 2009.
 210.Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange‐Nielsen cardioauditory syndrome. Nat Genet 15: 186‐189, 1997.
 211.Nie L. KCNQ4 mutations associated with nonsyndromic progressive sensorineural hearing loss. Curr Opin Otolaryngol Head Neck Surg 16: 441‐444, 2008.
 212.Nin F, Hibino H, Doi K, Suzuki T, Hisa Y, Kurachi Y. The endocochlear potential depends on two K+ diffusion potentials and an electrical barrier in the stria vascularis of the inner ear. Proc Natl Acad Sci U S A 105: 1751‐1756, 2008.
 213.Nouvian R, Neef J, Bulankina AV, Reisinger E, Pangrsic T, Frank T, Sikorra S, Brose N, Binz T, Moser T. Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins. Nat Neurosci 14: 411‐413, 2011.
 214.Nowotny M, Gummer AW. Nanomechanics of the subtectorial space caused by electromechanics of cochlear outer hair cells. Proc Natl Acad Sci U S A 103: 2120‐2125, 2006.
 215.Ohlemiller KK, Echteler SM. Functional correlates of characteristic frequency in single cochlear nerve fibers of the Mongolian gerbil. J Comp Physiol A 167: 329‐338, 1990.
 216.Ohmori H. Mechano‐electrical transduction currents in isolated vestibular hair cells of the chick. J Physiol 359: 189‐217, 1985.
 217.Ohn TL, Rutherford MA, Jing Z, Jung S, Duque‐Afonso CJ, Hoch G, Picher MM, Scharinger A, Strenzke N, Moser T. Hair cells use active zones with different voltage dependence of Ca2+ influx to decompose sounds into complementary neural codes. Proc Natl Acad Sci U S A 113: E4716‐4725, 2016.
 218.Oliver D, He DZ, Klocker N, Ludwig J, Schulte U, Waldegger S, Ruppersberg JP, Dallos P, Fakler B. Intracellular anions as the voltage sensor of prestin, the outer hair cell motor protein. Science 292: 2340‐2343, 2001.
 219.Oliver D, Taberner AM, Thurm H, Sausbier M, Arntz C, Ruth P, Fakler B, Liberman MC. The role of BKCa channels in electrical signal encoding in the mammalian auditory periphery. J Neurosci 26: 6181‐6189, 2006.
 220.Overstreet EH, III, Temchin AN, Ruggero MA. Basilar membrane vibrations near the round window of the gerbil cochlea. J Assoc Res Otolaryngol 3: 351‐361, 2002.
 221.Padmanarayana M, Hams N, Speight LC, Petersson EJ, Mehl RA, Johnson CP. Characterization of the lipid binding properties of Otoferlin reveals specific interactions between PI(4,5)P2 and the #c2C and #c2F domains. Biochemistry 53: 5023‐5033, 2014.
 222.Palmer AR, Russell IJ. Phase‐locking in the cochlear nerve of the guinea‐pig and its relation to the receptor potential of inner hair‐cells. Hear Res 24: 1‐15, 1986.
 223.Pan B, Geleoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 79: 504‐515, 2013.
 224.Pangrsic T, Gabrielaitis M, Michanski S, Schwaller B, Wolf F, Strenzke N, Moser T. EF‐hand protein Ca2+ buffers regulate Ca2+ influx and exocytosis in sensory hair cells. Proc Natl Acad Sci U S A 112: E1028‐1037, 2015.
 225.Pangrsic T, Lasarow L, Reuter K, Takago H, Schwander M, Riedel D, Frank T, Tarantino LM, Bailey JS, Strenzke N, Brose N, Muller U, Reisinger E, Moser T. Hearing requires otoferlin‐dependent efficient replenishment of synaptic vesicles in hair cells. Nat Neurosci 13: 869‐876, 2010.
 226.Pangrsic T, Reisinger E, Moser T. Otoferlin: A multi‐C2 domain protein essential for hearing. Trends Neurosci 35: 671‐680, 2012.
 227.Peng AW, Effertz T, Ricci AJ. Adaptation of mammalian auditory hair cell mechanotransduction is independent of calcium entry. Neuron 80: 960‐972, 2013.
 228.Peng AW, Gnanasambandam R, Sachs F, Ricci AJ. Adaptation independent modulation of auditory hair cell mechanotransduction channel open probability implicates a role for the lipid bilayer. J Neurosci 36: 2945‐2956, 2016.
 229.Peng AW, Salles FT, Pan B, Ricci AJ. Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction. Nat Commun 2: 523, 2011.
 230.Pepermans E, Michel V, Goodyear R, Bonnet C, Abdi S, Dupont T, Gherbi S, Holder M, Makrelouf M, Hardelin JP, Marlin S, Zenati A, Richardson G, Avan P, Bahloul A, Petit C. The CD2 isoform of protocadherin‐15 is an essential component of the tip‐link complex in mature auditory hair cells. EMBO Mol Med 6: 984‐992, 2014.
 231.Petit C, Richardson GP. Linking genes underlying deafness to hair‐bundle development and function. Nat Neurosci 12: 703‐710, 2009.
 232.Pickles JO, Comis SD, Osborne MP. Cross‐links between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction. Hear Res 15: 103‐112, 1984.
 233.Platzer J, Engel J, Schrott‐Fischer A, Stephan K, Bova S, Chen H, Zheng H, Striessnig J. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L‐type Ca2+ channels. Cell 102: 89‐97, 2000.
 234.Pollock LM, McDermott BM, Jr. The cuticular plate: A riddle, wrapped in a mystery, inside a hair cell. Birth Defects Res C Embryo Today 105: 126‐139, 2015.
 235.Pujol R L‐RM, Lenoir M. Development of sensory and neural structures in the mammalian cochlea In: Development of the Auditory System, edited by Rubel EW PA, Fay RR. New York: Springer pp. 146‐192, 1998.
 236.Pyott SJ, Glowatzki E, Trimmer JS, Aldrich RW. Extrasynaptic localization of inactivating calcium‐activated potassium channels in mouse inner hair cells. J Neurosci 24: 9469‐9474, 2004.
 237.Pyott SJ, Meredith AL, Fodor AA, Vazquez AE, Yamoah EN, Aldrich RW. Cochlear function in mice lacking the BK channel alpha, beta1, or beta4 subunits. J Biol Chem 282: 3312‐3324, 2007.
 238.Rabbitt RD, Clifford S, Breneman KD, Farrell B, Brownell WE. Power efficiency of outer hair cell somatic electromotility. PLoS Comput Biol 5: e1000444, 2009.
 239.Rask‐Andersen H, Erixon E, Kinnefors A, Lowenheim H, Schrott‐Fischer A, Liu W. Anatomy of the human cochlea—implications for cochlear implantation. Cochlear Implants Int 12(Suppl 1): S8‐S13, 2011.
 240.Reichenbach T, Hudspeth AJ. A ratchet mechanism for amplification in low‐frequency mammalian hearing. Proc Natl Acad Sci U S A 107: 4973‐4978, 2010.
 241.Ren T, He W, Kemp D. Reticular lamina and basilar membrane vibrations in living mouse cochleae. Proc Natl Acad Sci U S A 113: 9910‐9915, 2016.
 242.Rhode W, Cooper NP. Nonlinear mechanics in the apical turn of the chinchilla cochlea in vivo. Auditory Neurosci 3: 101‐121, 1996.
 243.Ricci AJ, Crawford AC, Fettiplace R. Active hair bundle motion linked to fast transducer adaptation in auditory hair cells. J Neurosci 20: 7131‐7142, 2000.
 244.Ricci AJ, Crawford AC, Fettiplace R. Tonotopic variation in the conductance of the hair cell mechanotransducer channel. Neuron 40: 983‐990, 2003.
 245.Ricci AJ, Fettiplace R. Calcium permeation of the turtle hair cell mechanotransducer channel and its relation to the composition of endolymph. J Physiol 506(Pt 1): 159‐173, 1998.
 246.Ricci AJ, Gray‐Keller M, Fettiplace R. Tonotopic variations of calcium signalling in turtle auditory hair cells. J Physiol 524(Pt 2): 423‐436, 2000.
 247.Ricci AJ, Kennedy HJ, Crawford AC, Fettiplace R. The transduction channel filter in auditory hair cells. J Neurosci 25: 7831‐7839, 2005.
 248.Ricci AJ, Wu YC, Fettiplace R. The endogenous calcium buffer and the time course of transducer adaptation in auditory hair cells. J Neurosci 18: 8261‐8277, 1998.
 249.Richardson GP, de Monvel JB, Petit C. How the genetics of deafness illuminates auditory physiology. Annu Rev Physiol 73: 311‐334, 2011.
 250.Richardson GP, Lukashkin AN, Russell IJ. The tectorial membrane: One slice of a complex cochlear sandwich. Curr Opin Otolaryngol Head Neck Surg 16: 458‐464, 2008.
 251.Richter CP, Emadi G, Getnick G, Quesnel A, Dallos P. Tectorial membrane stiffness gradients. Biophys J 93: 2265‐2276, 2007.
 252.Roberts WM. Localization of calcium signals by a mobile calcium buffer in frog saccular hair cells. J Neurosci 14: 3246‐3262, 1994.
 253.Roberts WM, Jacobs RA, Hudspeth AJ. Colocalization of ion channels involved in frequency selectivity and synaptic transmission at presynaptic active zones of hair cells. J Neurosci 10: 3664‐3684, 1990.
 254.Robles L, Ruggero MA. Mechanics of the mammalian cochlea. Physiol Rev 81: 1305‐1352, 2001.
 255.Rose JE, Brugge JF, Anderson DJ, Hind JE. Phase‐locked response to low‐frequency tones in single auditory nerve fibers of the squirrel monkey. J Neurophysiol 30: 769‐793, 1967.
 256.Roth B, Bruns V. Postnatal development of the rat organ of Corti. II. Hair cell receptors and their supporting elements. Anat Embryol (Berl) 185: 571‐581, 1992.
 257.Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A, Perfettini I, Le Gall M, Rostaing P, Hamard G, Triller A, Avan P, Moser T, Petit C. Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 127: 277‐289, 2006.
 258.Ruel J, Emery S, Nouvian R, Bersot T, Amilhon B, Van Rybroek JM, Rebillard G, Lenoir M, Eybalin M, Delprat B, Sivakumaran TA, Giros B, El Mestikawy S, Moser T, Smith RJ, Lesperance MM, Puel JL. Impairment of SLC17A8 encoding vesicular glutamate transporter‐3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am J Hum Genet 83: 278‐292, 2008.
 259.Ruggero MA, Rich NC. Furosemide alters organ of corti mechanics: Evidence for feedback of outer hair cells upon the basilar membrane. J Neurosci 11: 1057‐1067, 1991.
 260.Ruggero MA, Rich NC, Recio A, Narayan SS, Robles L. Basilar‐membrane responses to tones at the base of the chinchilla cochlea. J Acoust Soc Am 101: 2151‐2163, 1997.
 261.Russell IJ, Drexl M, Foeller E, Vater M, Kossl M. Synchronization of a nonlinear oscillator: Processing the cf component of the echo‐response signal in the cochlea of the mustached bat. J Neurosci 23: 9508‐9518, 2003.
 262.Russell IJ, Legan PK, Lukashkina VA, Lukashkin AN, Goodyear RJ, Richardson GP. Sharpened cochlear tuning in a mouse with a genetically modified tectorial membrane. Nat Neurosci 10: 215‐223, 2007.
 263.Safieddine S, El‐Amraoui A, Petit C. The auditory hair cell ribbon synapse: From assembly to function. Annu Rev Neurosci 35: 509‐528, 2012.
 264.Safieddine S, Wenthold RJ. SNARE complex at the ribbon synapses of cochlear hair cells: Analysis of synaptic vesicle‐ and synaptic membrane‐associated proteins. Eur J Neurosci 11: 803‐812, 1999.
 265.Salt AN, Inamura N, Thalmann R, Vora A. Calcium gradients in inner ear endolymph. Am J Otolaryngol 10: 371‐375, 1989.
 266.Salt AN, Melichar I, Thalmann R. Mechanisms of endocochlear potential generation by stria vascularis. Laryngoscope 97: 984‐991, 1987.
 267.Santos‐Sacchi J, Song L, Zheng J, Nuttall AL. Control of mammalian cochlear amplification by chloride anions. J Neurosci 26: 3992‐3998, 2006.
 268.Schaechinger TJ, Oliver D. Nonmammalian orthologs of prestin (SLC26A5) are electrogenic divalent/chloride anion exchangers. Proc Natl Acad Sci U S A 104: 7693‐7698, 2007.
 269.Schmitz F, Konigstorfer A, Sudhof TC. RIBEYE, a component of synaptic ribbons: A protein's journey through evolution provides insight into synaptic ribbon function. Neuron 28: 857‐872, 2000.
 270.Schnee ME, Lawton DM, Furness DN, Benke TA, Ricci AJ. Auditory hair cell‐afferent fiber synapses are specialized to operate at their best frequencies. Neuron 47: 243‐254, 2005.
 271.Schnee ME, Santos‐Sacchi J, Castellano‐Munoz M, Kong JH, Ricci AJ. Calcium‐dependent synaptic vesicle trafficking underlies indefatigable release at the hair cell afferent fiber synapse. Neuron 70: 326‐338, 2011.
 272.Schneider ME, Dose AC, Salles FT, Chang W, Erickson FL, Burnside B, Kachar B. A new compartment at stereocilia tips defined by spatial and temporal patterns of myosin IIIa expression. J Neurosci 26: 10243‐10252, 2006.
 273.Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E, Lustig LR, Edwards RH. Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 57: 263‐275, 2008.
 274.Sellick PM, Patuzzi R, Johnstone BM. Measurement of basilar membrane motion in the guinea pig using the Mossbauer technique. J Acoust Soc Am 72: 131‐141, 1982.
 275.Sellick PM, Patuzzi R, Johnstone BM. Modulation of responses of spiral ganglion cells in the guinea pig cochlea by low frequency sound. Hear Res 7: 199‐221, 1982.
 276.Sewell WF. The effects of furosemide on the endocochlear potential and auditory‐nerve fiber tuning curves in cats. Hear Res 14: 305‐314, 1984.
 277.Shera CA. Laser amplification with a twist: Traveling‐wave propagation and gain functions from throughout the cochlea. J Acoust Soc Am 122: 2738‐2758, 2007.
 278.Spiden SL, Bortolozzi M, Di Leva F, de Angelis MH, Fuchs H, Lim D, Ortolano S, Ingham NJ, Brini M, Carafoli E, Mammano F, Steel KP. The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss. PLoS Genet 4: e1000238, 2008.
 279.Steel KP, Barkway C. Another role for melanocytes: Their importance for normal stria vascularis development in the mammalian inner ear. Development 107: 453‐463, 1989.
 280.Street VA, McKee‐Johnson JW, Fonseca RC, Tempel BL, Noben‐Trauth K. Mutations in a plasma membrane Ca2+‐ATPase gene cause deafness in deafwaddler mice. Nat Genet 19: 390‐394, 1998.
 281.Strenzke N, Chakrabarti R, Al‐Moyed H, Muller A, Hoch G, Pangrsic T, Yamanbaeva G, Lenz C, Pan KT, Auge E, Geiss‐Friedlander R, Urlaub H, Brose N, Wichmann C, Reisinger E. Hair cell synaptic dysfunction, auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants. Embo j, 2016.
 282.Suchyna TM, Johnson JH, Hamer K, Leykam JF, Gage DA, Clemo HF, Baumgarten CM, Sachs F. Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation‐selective stretch‐activated channels. J Gen Physiol 115: 583‐598, 2000.
 283.Taberner AM, Liberman MC. Response properties of single auditory nerve fibers in the mouse. J Neurophysiol 93: 557‐569, 2005.
 284.Tan X, Beurg M, Hackney C, Mahendrasingam S, Fettiplace R. Electrical tuning and transduction in short hair cells of the chicken auditory papilla. J Neurophysiol 109: 2007‐2020, 2013.
 285.Temchin AN, Rich NC, Ruggero MA. Threshold tuning curves of chinchilla auditory‐nerve fibers. I. Dependence on characteristic frequency and relation to the magnitudes of cochlear vibrations. J Neurophysiol 100: 2889‐2898, 2008.
 286.Temchin AN, Ruggero MA. Phase‐locked responses to tones of chinchilla auditory nerve fibers: Implications for apical cochlear mechanics. J Assoc Res Otolaryngol 11: 297‐318, 2010.
 287.Teudt IU, Richter CP. Basilar membrane and tectorial membrane stiffness in the CBA/CaJ mouse. J Assoc Res Otolaryngol 15: 675‐694, 2014.
 288.Tritsch NX, Yi E, Gale JE, Glowatzki E, Bergles DE. The origin of spontaneous activity in the developing auditory system. Nature 450: 50‐55, 2007.
 289.Tucker T, Fettiplace R. Confocal imaging of calcium microdomains and calcium extrusion in turtle hair cells. Neuron 15: 1323‐1335, 1995.
 290.van der Heijden M, Versteegh CP. Energy flux in the cochlea: Evidence against power amplification of the traveling wave. J Assoc Res Otolaryngol 16: 581‐597, 2015.
 291.Verpy E, Leibovici M, Michalski N, Goodyear RJ, Houdon C, Weil D, Richardson GP, Petit C. Stereocilin connects outer hair cell stereocilia to one another and to the tectorial membrane. J Comp Neurol 519: 194‐210, 2011.
 292.Versteegh CP, Meenderink SW, van der Heijden M. Response characteristics in the apex of the gerbil cochlea studied through auditory nerve recordings. J Assoc Res Otolaryngol 12: 301‐316, 2011.
 293.Vogl C, Cooper BH, Neef J, Wojcik SM, Reim K, Reisinger E, Brose N, Rhee JS, Moser T, Wichmann C. Unconventional molecular regulation of synaptic vesicle replenishment in cochlear inner hair cells. J Cell Sci 128: 638‐644, 2015.
 294.Vollrath MA, Eatock RA. Time course and extent of mechanotransducer adaptation in mouse utricular hair cells: Comparison with frog saccular hair cells. J Neurophysiol 90: 2676‐2689, 2003.
 295.Vu AA, Nadaraja GS, Huth ME, Luk L, Kim J, Chai R, Ricci AJ, Cheng AG. Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. PLoS One 8: e54794, 2013.
 296.Wang HC, Bergles DE. Spontaneous activity in the developing auditory system. Cell Tissue Res 361: 65‐75, 2015.
 297.Wangemann P. Supporting sensory transduction: Cochlear fluid homeostasis and the endocochlear potential. J Physiol 576: 11‐21, 2006.
 298.Wangemann P. The role of pendrin in the development of the murine inner ear. Cell Physiol Biochem 28: 527‐534, 2011.
 299.Wangemann P, Itza EM, Albrecht B, Wu T, Jabba SV, Maganti RJ, Lee JH, Everett LA, Wall SM, Royaux IE, Green ED, Marcus DC. Loss of KCNJ10 protein expression abolishes endocochlear potential and causes deafness in Pendred syndrome mouse model. BMC Med 2: 30, 2004.
 300.Wangemann P, Liu J, Marcus DC. Ion transport mechanisms responsible for K+ secretion and the transepithelial voltage across marginal cells of stria vascularis in vitro. Hear Res 84: 19‐29, 1995.
 301.Wangemann P, Nakaya K, Wu T, Maganti RJ, Itza EM, Sanneman JD, Harbidge DG, Billings S, Marcus DC. Loss of cochlear HCO3‐ secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model. Am J Physiol Renal Physiol 292: F1345‐1353, 2007.
 302.Webb SW, Grillet N, Andrade LR, Xiong W, Swarthout L, Della Santina CC, Kachar B, Muller U. Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain. Development 138: 1607‐1617, 2011.
 303.Wersinger E, McLean WJ, Fuchs PA, Pyott SJ. BK channels mediate cholinergic inhibition of high frequency cochlear hair cells. PLoS One 5: e13836, 2010.
 304.Wiederhold ML. Variations in the effects of electric stimulation of the crossed olivocochlear bundle on cat single auditory‐nerve‐fiber responses to tone bursts. J Acoust Soc Am 48: 966‐977, 1970.
 305.Willemin JF, Dandliker R, Khanna SM. Heterodyne interferometer for submicroscopic vibration measurements in the inner ear. J Acoust Soc Am 83: 787‐795, 1988.
 306.Wingard JC, Zhao HB. Cellular and deafness mechanisms underlying connexin mutation‐induced hearing loss—a common hereditary deafness. Front Cell Neurosci 9: 202, 2015.
 307.Wong AB, Rutherford MA, Gabrielaitis M, Pangrsic T, Gottfert F, Frank T, Michanski S, Hell S, Wolf F, Wichmann C, Moser T. Developmental refinement of hair cell synapses tightens the coupling of Ca2+ influx to exocytosis. Embo j 33: 247‐264, 2014.
 308.Wood JD, Muchinsky SJ, Filoteo AG, Penniston JT, Tempel BL. Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance. J Assoc Res Otolaryngol 5: 99‐110, 2004.
 309.Wu DK, Kelley MW. Molecular mechanisms of inner ear development. Cold Spring Harb Perspect Biol 4: a008409, 2012.
 310.Wu YC, Art JJ, Goodman MB, Fettiplace R. A kinetic description of the calcium‐activated potassium channel and its application to electrical tuning of hair cells. Prog Biophys Mol Biol 63: 131‐158, 1995.
 311.Wu YC, Ricci AJ, Fettiplace R. Two components of transducer adaptation in auditory hair cells. J Neurophysiol 82: 2171‐2181, 1999.
 312.Xiong W, Grillet N, Elledge HM, Wagner TF, Zhao B, Johnson KR, Kazmierczak P, Muller U. TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells. Cell 151: 1283‐1295, 2012.
 313.Yamoah EN, Lumpkin EA, Dumont RA, Smith PJ, Hudspeth AJ, Gillespie PG. Plasma membrane Ca2+‐ATPase extrudes Ca2+ from hair cell stereocilia. J Neurosci 18: 610‐624, 1998.
 314.Yan Z, Zhang W, He Y, Gorczyca D, Xiang Y, Cheng LE, Meltzer S, Jan LY, Jan YN. Drosophila NOMPC is a mechanotransduction channel subunit for gentle‐touch sensation. Nature 493: 221‐225, 2013.
 315.Yasunaga S, Grati M, Cohen‐Salmon M, El‐Amraoui A, Mustapha M, Salem N, El‐Zir E, Loiselet J, Petit C. A mutation in OTOF, encoding otoferlin, a FER‐1‐like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet 21: 363‐369, 1999.
 316.Yoon YJ, Steele CR, Puria S. Feed‐forward and feed‐backward amplification model from cochlear cytoarchitecture: An interspecies comparison. Biophys J 100: 1‐10, 2011.
 317.Zhang L, Gualberto DG, Guo X, Correa P, Jee C, Garcia LR. TMC-1 attenuates C. elegans development and sexual behavior in a chemically defined food environment. Nature Comm 6: 6345, 2015.
 318.Zhao B, Muller U. The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol 34: 172‐179, 2015.
 319.Zhao B, Wu Z, Grillet N, Yan L, Xiong W, Harkins‐Perry S, Muller U. TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84: 954‐967, 2014.
 320.Zheng J, Shen W, He DZ, Long KB, Madison LD, Dallos P. Prestin is the motor protein of cochlear outer hair cells. Nature 405: 149‐155, 2000.
 321.Zheng L, Sekerkova G, Vranich K, Tilney LG, Mugnaini E, Bartles JR. The deaf jerker mouse has a mutation in the gene encoding the espin actin‐bundling proteins of hair cell stereocilia and lacks espins. Cell 102: 377‐385, 2000.
 322.Zidanic M, Brownell WE. Fine structure of the intracochlear potential field. I. The silent current. Biophys J 57: 1253‐1268, 1990.
 323.Zwislocki JJ, Kletsky EJ. Tectorial membrane: A possible effect on frequency analysis in the cochlea. Science 204: 639‐641, 1979.

Teaching Material

R. Fettiplace. Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea. Compr Physiol 7:2017, 1197-1227. doi:10.1002/cphy.c160049

Didactic Synopsis

Major Teaching Points:

  • Sound is detected by hair cells, the mechanoreceptors of the cochlea, the spiral cavity of the inner ear. Hair cells are excited by submicrometer vibrations of their stereociliary (hair) bundles, which are converted into changes in membrane potential graded with sound intensity.
  • Hair bundles are bathed in an extracellular fluid, high in potassium and low in calcium and at a positive 100 mV potential, which optimizes the transduction process.
  • There are two types of hair cell with disparate functions: outer hair cells contain prestin, a piezoelectric motor protein that generates force to amplify the mechanical stimulus, inner hair cells communicate with auditory nerve fibers via a ribbon synapse at the cochlear output.
  • The frequency of a sound is analyzed by both passive and active tuning mechanisms, with subsets of hair cells along the cochlear being tuned to different frequencies.
  • Transduction can be disrupted by mutations in single genes leading to permanent deafness; many of these genes are linked to the hair bundle structure.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. This figure shows the pathway for conducting sound waves from the eardrum via three small bones of the middle ear to the cochlea. The stapes acts like a piston, generating pressure waves in the cochlear fluid, which result in small displacements of the basilar membrane synchronized to the sound stimulus. A pure tone (sinusoidal) sound stimulus will produce a traveling wave on the basilar membrane that peaks at a position characteristic of the stimulus frequency. The properties of the cochlea vary from one end to the other, which causes the frequency components in the sound to be separated along it length like an acoustic prism. Thus, low frequencies are most effective at the distal apex near the helicotrema, whereas high frequencies elicit vibrations, which are confined to the proximal base. This is referred to as a tonotopic organization. The cochlea is divided into three compartments, with the central compartment containing endolymph fluid having an ionic composition which, with its high K+ concentration, differs from that in most extracellular spaces.

Figure 2. This figure depicts a slice through the cochlear tube of Figure 1 showing the location of the sensory hair cells (in green), which detect the sound stimulus. The hair cells are embedded in an array of specially named supporting cells in the organ of Corti. There are two types of hair cell: inner hair cells and outer hair cells. Inner hair cells produce the major output of the cochlea, and synapse on afferent neurons of the VIIIth cranial nerve, which generate action potentials. Outer hair cells contract and amplify the sound-evoked motion. Both types of hair cell are covered in a gelatinous structure termed the tectorial membrane, and they detect vibrations of this membrane relative to the basilar membrane. Bundles of modified microvilli, referred to as stereocilia, project from the tops of each hair cell, and are the site of mechanically sensitive ion channels where transduction occurs. The stereociliary bundles are immersed in a fluid of special ionic composition known as endolymph that fills the scala media (indicated in pink).

Figure 3. This shows a schematic of the stria vascularis, an epithelial strip on the side wall of the cochlea, which secretes the K+-based endolymph and generates ~100 mV endocochlear potential (EP). Both features facilitate hair cell transduction. These properties are achieved by two layers of cells, each tightly interconnected, with membranes containing K+ ion channels (KCNQ1, KCNJ10) and transporters (NKCC), that participate in the secretion of endolymph. Ion channels are proteins with a central pore that are embedded in the lipid bilayer of the plasma membrane, through which ions traverse. The voltages given (+90, +100, and +10 mV) refer to the static potentials of the extracellular spaces with respect to the scala tympani.

Figure 4. Details of the ultrastructure and protein composition of the stereociliary bundles and the transduction apparatus. Scanning electron micrographs of stereociliary bundles of an outer hair cell and an inner hair cell illustrate the staircase in heights of the rows. Deflection towards the taller row of stereocilia is excitatory. The rows are interconnected by various extracellular filaments, the most important of which is the tip link connecting the tip of one stereocilium with the side wall of its taller neighbor. A number of proteins form the tip link and the transduction apparatus, which includes two mechanoelectrical transducer (MET) ion channels situated at the lower end of the tip link. Much of this information has been gleaned from study of genetic mutations, especially those that occur in the deafness-blindness Usher syndrome.

Figure 5. This figure illustrates the properties of the electrical currents evoked in outer hair cells in response to displacement of their stereociliary bundles. The electrical currents are measured by patch clamping hair cells during a series displacement steps to the bundles. Mechanoelectrical transducer (MET) currents show a rapid rise to a peak followed by a subsequent decline in a process known as adaptation. As in other sensory receptors, adaptation optimizes transducer sensitivity around the resting state. The peak MET current encodes bundle displacements over a fraction of a micron. The maximum amplitude of the MET current depends on the location of the hair cell in the cochlea, and increases from the low-frequency apex to the high-frequency base. The systematic change in the amplitude of the macroscopic current along the cochlea is largely accounted for by a changes in the single-channel conductance. Its role may be to enhance the sensitivity in high frequency cells.

Figure 6. As shown in Figure 4, the ion channels underlying the macroscopic transducer current in hair cells are localized to the tips of the shorter stereocilia where they are activated by tension in tip links. Channels can be isolated by severing almost all of the tip links with exposure to submicromolar Ca2+. The figure shows examples of single MET ion channel events. The currents look square, with the channel being either closed (C) or open (O). The amplitude of the current events is larger in outer hair cells at the base than at the apex. The gradient in channel conductance largely accounts for the systematic change in macroscopic current shown and it implies that the molecular composition of the MET channel varies along the cochlea.

Figure 7. This figure shows one method of quantifying the adaptation of the MET current. This is done by presenting two sets of brief displacement stimuli, the second of which is preceded by a long adapting step. Adaptation is manifested by a shift in the sigmoidal current-displacement relationship along the displacement axis. Varying the amplitude of the adapting step shows that the positive shift, DX0.5, in the current-displacement relationship increases as a function of the adapting amplitude.

Figure 8. Multiple properties of the basilar membrane and the hair cells change along the cochlea to enable the distribution of frequency components in a sound stimulus. The figure shows how both structural and ionic properties of the outer hair cells vary systematically along the cochlea, each location being identified with a characteristic sound frequency. Factors increasing with characteristic frequency include the magnitude of the MET conductance, the number of K+ channels that determine the resting membrane potential, and the electrical capacitance. The electrical capacitance is attributable to the plasma membrane, and its magnitude reflects the surface area of the outer hair cell. Systematic variation is produced mainly by a change in outer hair cell length which varies in different mammals between 8 and 80 microns.

Figure 9. Inner hair cells are the main output of the cochlea and are innervated by multiple auditory afferent fibers. A sinusoidal sound stimulus produces a receptor potential in an inner hair cell, and action potentials are first generated in the auditory nerve fibers. This figure summarizes the change in the IHC receptor potential and in the firing of action potentials for different sound frequencies. At low frequencies, the IHC response is purely sinusoidal, reflecting the sound stimulus. At frequencies above 1000 Hz, the periodic (AC) component of the receptor potential is filtered by the membrane time constant leaving a sustained depolarizing (DC) component. The periodic component is also manifest in the phase locking of auditory nerve action potentials synchronized to the cycles of the sound at low frequencies but phase locking is lost at high frequencies.

Figure 10. In all vertebrate cochleas, a hair cell’s characteristic frequency changes systematically along the organ. The figure illustrates this tonotopic organization in the turtle cochlea, where the membrane potential of each hair cell resonates when the cell is stimulated electrically. In most nonmammals, frequency tuning is accomplished by an electrical resonance achieved by the interplay of K+ and Ca2+ channels in the hair cell membrane. These channels tune the receptor potential, with different resonant frequencies being generated by altering the density and kinetics of the K+ channels. Although the frequency range (60 to 400 Hz) is much lower than in mammals, the orientation of the frequency map is the same.

Figure 11. This figure shows frequency tuning curves in the mammalian cochlea. For each plot, the sound level required to elicit a threshold response is an approximately V-shaped function of the sound frequency, with the tip of the “V” being referred to as the characteristic frequency (CF). The sound threshold is expressed in decibels (dB), which is a logarithmic measure, 20 dBs being a ten-fold pressure change. Comparison of the frequency-threshold tuning curves for two auditory nerve fibers with the frequency tuning in the basilar membrane vibrations indicates that almost all of the tuning is present in the basilar membrane motion. The figure also shows multiple frequency tuning curves for auditory nerve fibers in the cat cochlea, illustrating how the shape of the tuning curves changes across the frequency spectrum.

Figure 12. There has been uncertainty about the mechanisms involved in producing the narrow frequency tuning curves in Figure 11. It is well established that the passive mechanical properties of the basilar membrane generate some frequency tuning but another metabolically sensitive (active) mechanism is needed to augment the selectivity and produce narrow tuning curves. The active mechanism is mediated by a piezoelectric motor protein known as prestin in the outer hair cell membrane, which is activated by changes in membrane potential. This figure shows some features of prestin. Localization of prestin to the OHC lateral membrane can be demonstrated by antibody labeling and electron microscopy. Depolarization of the OHC causes the outer hair cell to contract, with the cell length showing a sigmoidal dependence on membrane potential around a resting potential of about -50 mV. Correct operation of the prestin mechanism requires the presence of chloride ions.

Figure 13. This figure shows that the organ of Corti is deformed during a sound stimulus. A reduction in sound pressure at the eardrum (a rarefaction) causes an upward displacement of the basilar membrane and organ of Corti. On the conventional view, the entire organ moves upward without changing its shape, and results in lateral displacement of hair bundles and hair cell excitation. The brown background indicates the organ of Corti at rest, and the black outline the new position when stimulated. This view of a rigid organ of Corti cannot be completely accurate because, upon stimulation, outer hair cells contract and cause the organ of Corti to compress, bringing the reticular lamina and basilar membrane closer together. The latter effect can be studied in the absence of a sound stimulus by electrically stimulating the organ of Corti to elicit outer hair cell contraction. During normal a stimulus, both processes in A and B will occur sequentially but their relative timing is still not precisely known.

Figure 14. This figure shows microelectrode recordings of the excitatory synaptic potentials and action potentials in an auditory afferent terminal. These recordings indicate that there are spontaneous synaptic potentials and action potentials in the absence of a sound stimulus. However, in response to a tone, the action potentials become synchronized, or phase locked, to the cycles of tones at 265 and 520 Hz. Not all synaptic potentials evoke action potentials.

Figure 15. This figure shows the schematic structure of the synapse between the inner hair cell and cochlear afferent fiber derived from transmission electron micrographs and antibody labeling against specific protein components. An inner hair cell makes synaptic contacts with multiple (10-20) afferent fibers, which have different sensitivities. This glutamatergic synapse is unusual in a number of respects. It is characterized by an electron dense presynaptic structure known as a ribbon, which is surrounded by a halo of synaptic vesicles containing the neurotransmitter. Fusion of the synaptic vesicles with the plasma membrane is triggered by an increase in cytoplasmic Ca2+. Unlike most synapses, Ca2+ influx occurs via L-type Ca2+ channels, whereas at other synapses in the central nervous system N-type and P-type Ca2+ channels are more common. Furthermore, exocytosis is not regulated by the Ca2+ binding protein synaptotagmin, which is absent. Instead, several of the steps in synaptic vesicle docking, fusion and reuptake are thought mediated by the Ca2+-binding protein otoferlin. The glutamate neurotransmitter released into the synaptic cleft binds to AMPA receptors on the postsynaptic membrane.


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How to Cite

Robert Fettiplace. Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea. Compr Physiol 2017, 7: 1197-1227. doi: 10.1002/cphy.c160049