scholarly journals The frequency limit of outer hair cell motility measured in vivo

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Anna Vavakou ◽  
Nigel P Cooper ◽  
Marcel van der Heijden
Keyword(s):  
Outer Hair Cell ◽  
Gain Control ◽  
Outer Hair Cells ◽  
Corner Frequency ◽  
Cochlear Function ◽  
Cycle Basis ◽  
Low Pass ◽  
Cochlear Hearing Loss ◽  
Length Changes

Outer hair cells (OHCs) in the mammalian ear exhibit electromotility, electrically driven somatic length changes that are thought to mechanically amplify sound-evoked vibrations. For this amplification to work, OHCs must respond to sounds on a cycle-by-cycle basis even at frequencies that exceed the low-pass corner frequency of their cell membranes. Using in vivo optical vibrometry we tested this theory by measuring sound-evoked motility in the 13–25 kHz region of the gerbil cochlea. OHC vibrations were strongly rectified, and motility exhibited first-order low-pass characteristics with corner frequencies around 3 kHz– more than 2.5 octaves below the frequencies the OHCs are expected to amplify. These observations lead us to suggest that the OHCs operate more like the envelope detectors in a classical gain-control scheme than like high-frequency sound amplifiers. These findings call for a fundamental reconsideration of the role of the OHCs in cochlear function and the causes of cochlear hearing loss.

scholarly journals Overexpression of SK2 Channels Enhances Efferent Suppression of Cochlear Responses Without Enhancing Noise Resistance

2007 ◽  
Vol 97 (4) ◽  
pp. 2930-2936 ◽  
Author(s):  
Stéphane F. Maison ◽  
Lisan L. Parker ◽  
Lucy Young ◽  
John P. Adelman ◽  
Jian Zuo ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Hair Cells ◽  
Otoacoustic Emissions ◽  
Outer Hair Cell ◽  
Outer Hair Cells ◽  
Sk Channels ◽  
Cochlear Function ◽  
Cochlear Hair Cells ◽  
Efferent Suppression

Cochlear hair cells express SK2, a small-conductance Ca2+-activated K+ channel thought to act in concert with Ca2+-permeable nicotinic acetylcholine receptors (nAChRs) α9 and α10 in mediating suppressive effects of the olivocochlear efferent innervation. To probe the in vivo role of SK2 channels in hearing, we examined gene expression, cochlear function, efferent suppression, and noise vulnerability in mice overexpressing SK2 channels. Cochlear thresholds, as measured by auditory brain stem responses and otoacoustic emissions, were normal in overexpressers as was overall cochlear morphology and the size, number, and distribution of efferent terminals on outer hair cells. Cochlear expression levels of SK2 channels were elevated eightfold without striking changes in other SK channels or in the α9/α10 nAChRs. Shock-evoked efferent suppression of cochlear responses was significantly enhanced in overexpresser mice as seen previously in α9 overexpresser mice; however, in contrast to α9 overexpressers, SK2 overexpressers were not protected from acoustic injury. Results suggest that efferent-mediated cochlear protection is mediated by other downstream effects of ACh-mediated Ca2+ entry different from those involving SK2-mediated hyperpolarization and the associated reduction in outer hair cell electromotility.

The location and mechanism of electromotility in guinea pig outer hair cells

1993 ◽  
Vol 70 (2) ◽  
pp. 549-558 ◽  
Author(s):  
R. Hallworth ◽  
B. N. Evans ◽  
P. Dallos
Keyword(s):  
Guinea Pig ◽  
Hair Cells ◽  
Outer Hair Cell ◽  
Length Change ◽  
Opposite Polarity ◽  
Outer Hair Cells ◽  
Response Amplitude ◽  
Change Function ◽  
Length Changes ◽  
Diameter Change

1. The microchamber method was used to examine the motile responses of isolated guinea pig outer hair cells to electrical stimulation. In the microchamber method, an isolated cell is drawn partway into a suction pipette and stimulated transcellularly. The relative position of the cell in the microchamber is referred to as the exclusion fraction. 2. The length changes of the included and excluded segments were compared for constant sinusoidal stimulus amplitude as functions of the exclusion fraction. Both included and excluded segments showed maximal responses when the cell was excluded approximately halfway. Both segments showed smaller or absent responses when the cell was almost fully excluded or almost fully included. 3. When the cell was near to, but not at, the maximum exclusion, the included segment response amplitude was zero, whereas the excluded segment response amplitude was nonzero. In contrast, when the cell was nearly fully included, the excluded segment response amplitude was zero, but the included segment response amplitude was still detectable. A simple model of outer hair cell motility based on these results suggests that the cell has finite-resistance terminations and that the motors are restricted to a region above the nucleus and below its ciliated apex (cuticular plate). 4. The function describing length change as a function of command voltage was measured for each segment as the exclusion fraction was varied. The functions were similar at midrange exclusions (i.e., when the segments were about equal length), showing nonlinearity and saturability. The functions were strikingly different when the segment lengths were different. The effects of exclusion on the voltage to length-change functions suggested that the nonlinearity and saturability are local properties of the motility mechanism. 5. The diameter changes of both segments were examined. The segment diameter changes were always antiphasic to the length changes. This finding implies that the motility mechanism has an active antiphasic diameter component. The diameter change amplitude was a monotonically increasing function of exclusion for the included segment, and a decreasing function for the excluded segment. 6. The voltage to length-change and voltage to diameter-change functions were measured for the same cell and exclusion fraction. The voltage to diameter-change function was smaller in amplitude than the voltage to length-change function. The functions were of opposite polarity to each other, but were otherwise similar in character. Thus it is likely that the same motor mechanism is responsible for both axial and diameter deformations.

scholarly journals In Vivo Outer Hair Cell Length Changes Expose the Active Process in the Cochlea

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e32757 ◽  
Author(s):  
Dingjun Zha ◽  
Fangyi Chen ◽  
Sripriya Ramamoorthy ◽  
Anders Fridberger ◽  
Niloy Choudhury ◽  
...  
Keyword(s):  
Hair Cell ◽  
Outer Hair Cell ◽  
Cell Length ◽  
Active Process ◽  
Length Changes

Effectiveness, Active Energy Produced by Molecular Motors, and Nonlinear Capacitance of the Cochlear Outer Hair Cell

2005 ◽  
Vol 127 (3) ◽  
pp. 391-399 ◽  
Author(s):  
Alexander A. Spector
Keyword(s):  
Hair Cell ◽  
Molecular Motors ◽  
Outer Hair Cell ◽  
Molecular Motor ◽  
Force Production ◽  
Outer Hair Cells ◽  
Nonlinear Capacitance ◽  
Effective Capacitance ◽  
Capacitive Properties ◽  
Length Changes

Cochlear outer hair cells are crucial for active hearing. These cells have a unique form of motility, named electromotility, whose main features are the cell’s length changes, active force production, and nonlinear capacitance. The molecular motor, prestin, that drives outer hair cell electromotility has recently been identified. We reveal relationships between the active energy produced by the outer hair cell molecular motors, motor effectiveness, and the capacitive properties of the cell membrane. We quantitatively characterize these relationships by introducing three characteristics: effective capacitance, zero-strain capacitance, and zero-resultant capacitance. We show that zero-strain capacitance is smaller than zero-resultant capacitance, and that the effective capacitance is between the two. It was also found that the differences between the introduced capacitive characteristics can be expressed in terms of the active energy produced by the cell’s molecular motors. The effectiveness of the cell and its molecular motors is introduced as the ratio of the motors’ active energy to the energy of the externally applied electric field. It is shown that the effectiveness is proportional to the difference between zero-strain and zero-resultant capacitance. We analyze the cell and motor’s effectiveness within a broad range of cellular parameters and estimate it to be within a range of 12%–30%.

Spontaneous reversibility of damage to outer hair cells after sodium salicylate induced ototoxicity

2011 ◽  
Vol 125 (8) ◽  
pp. 786-794 ◽  
Author(s):  
I de Almeida-Silva ◽  
J A A de Oliveira ◽  
M Rossato ◽  
F Fiacadori Salata ◽  
M A Hyppolito
Keyword(s):  
Hair Cell ◽  
Drug Administration ◽  
Outer Hair Cell ◽  
Cell Function ◽  
Sodium Salicylate ◽  
Cell Structure ◽  
Outer Hair Cells ◽  
Cochlear Function ◽  
Action Function ◽  
High Sodium

AbstractBackground:High sodium salicylate doses can cause reversible hearing loss and tinnitus, possibly due to reduced outer hair cell electromotility. Sodium salicylate is known to alter outer hair cell structure and function. This study determined the reversibility and cochlear recovery time after administration of an ototoxic sodium salicylate dose to guinea pigs with normal cochlear function.Study design:Prospective experimental investigation.Methods:All animals received a single 500 mg sodium salicylate dose, but with different durations of action. Function was evaluated before drug administration and immediately before sacrifice. Cochleae were processed and viewed using scanning electron microscopy.Results:Changes in outer hair cell function were observed to be present 2 hours after drug administration, with recovery of normal anatomy beginning after 24 hours. Subsequently, derangement and distortion of cilia reduced, with effects predominantly in row three. At 168 hours, cilia were near-normal but with mild distortions which interfered with normal cochlear physiology.Conclusions:Ciliary changes persisted for up to 168 hours after ototoxic sodium salicylate administration.

Theory of electrically driven shape changes of cochlear outer hair cells

1993 ◽  
Vol 70 (1) ◽  
pp. 299-323 ◽  
Author(s):  
P. Dallos ◽  
R. Hallworth ◽  
B. N. Evans
Keyword(s):  
Cell Membrane ◽  
Hair Cell ◽  
Outer Hair Cell ◽  
Linear Motor ◽  
Outer Hair Cells ◽  
Pressure Effects ◽  
Model Parameters ◽  
Minor Importance ◽  
Length Changes ◽  
Shape Changes

1. A theory of cochlear outer hair cell electromotility is developed and specifically applied to somatic shape changes elicited in a microchamber. The microchamber permits the arbitrary electrical and mechanical partitioning of the outer hair cell along its length. This means that the two partitioned segments are stimulated with different input voltages and undergo different shape changes. Consequently, by imposing more constraints than other methods, experiments in the microchamber are particularly suitable for testing different theories of outer hair cell motility. 2. The present model is based on simple hypotheses. They include a distributed motor associated with the cell membrane or cortex and the assumption that the displacement generated by the motor is related to the transmembrane voltage across the associated membrane element. It is expected that the force generated by the motor is counterbalanced by an elastic restoring force indigenous to the cell membrane and cortex, and a tensile force due to intracellular pressure. It is assumed that all changes take place while total cell volume is conserved. The above elements of the theory taken together permit the development of qualitative and quantitative predictions about the expected motile responses of both partitioned segments of the cell. Only a DC treatment is offered here. 3. Both a linear motor and an expanded treatment that incorporates a stochastic molecular motor model are considered. The latter is represented by a two-state Boltzmann process. We show that the linear motor treatment is an appropriate extrapolation of the stochastic motor theory for the case of small voltage driving signals. Comparison of experimental results with model responses permits the estimation of model parameters. Good match of data is obtained if it is assumed that the molecular motors undergo conformational length changes of 0.7-1.0 nm, that they have an effective displacement vector at approximately -20 degrees with the long axis of the cell, and that their linear density is approximately 80/microns. 4. An effort is made to parcel out motile response components that are a direct consequence of the motor action from those that are mediated by cytoplasmic pressure changes brought about by the concerted action of the motors. We show that pressure effects are of minor importance, and thus rule out models that rely on radial constriction/expansion-mediated internal pressure change as the primary cause of longitudinal motility. 5. As a consequence of the interaction between the Boltzmann process and the mechanical characteristics of the cell, the electromotile response is asymmetric.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals In vivo gene editing of outer hair cells prevents progressive hearing loss in a dominant-negative KCNQ4 murine model

2021 ◽  
Author(s):  
Byunghwa Noh ◽  
John Hoon Rim ◽  
Ramu Gopalappa ◽  
Haiyue Lin ◽  
Kyu Min Kim ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Targeted Therapy ◽  
Gene Editing ◽  
Outer Hair Cell ◽  
Outer Hair Cells ◽  
Dominant Negative ◽  
Therapeutic Window ◽  
Round Window Membrane ◽  
Progressive Hearing Loss

Abstract Adult-onset hearing loss (AHL)—including presbycusis—caused by outer hair cell (OHC) degeneration is the most common sensorial disorder. Despite the high prevalence of AHL and wide therapeutic window, no targeted therapy is currently available. Here, we generated a mouse model harboring Kcnq4W276S/+ to recapitulate DFNA2, a common genetic form of progressive hearing loss caused by degenerating OHCs. By comprehensively optimizing guide RNAs, Cas9s, vehicles, and delivery routes, we found that in vivo gene editing using dual adeno-associated virus packaging in OHCs via the round window membrane significantly improved auditory function. We developed a new technique using live-cell imaging to measure the membrane potential of the OHCs and demonstrated that our approach resulted in more hyperpolarized, steady-state OHCs, indicative of elevated KCNQ4 channel activity. These findings can help develop targeted therapy for AHL and support the use of CRISPR-based gene therapy to rectify defects in OHCs.

scholarly journals Synaptic contributions to cochlear outer hair cell Ca2+ homeostasis

2020 ◽  
Author(s):  
Marcelo J. Moglie ◽  
Diego L. Wengier ◽  
A. Belén Elgoyhen ◽  
Juan D. Goutman
Keyword(s):  
Outer Hair Cell ◽  
Control Function ◽  
Basolateral Membrane ◽  
Ryanodine Receptors ◽  
Outer Hair Cells ◽  
Synaptic Activity ◽  
Cochlear Function ◽  
Intracellular Ca ◽  
Regulation Mechanisms ◽  
Different Origins

AbstractFor normal cochlear function, outer hair cells (OHCs) require a precise regulation of intracellular Ca2+ levels. Influx of Ca2+ occurs both at the stereocillia tips and through the basolateral membrane. In this latter compartment, two different origins for Ca2+ influx have been poorly explored: voltage-gated Ca2+ channels (VGCC) at synapses with type II afferent neurons, and α9α10 cholinergic nicotinic receptors at synapses with medio-olivochlear complex (MOC) neurons. Using functional imaging in rodent OHCs, we report that these two Ca2+ entry sites are closely positioned, but present different regulation mechanisms. Ca2+ spread from MOC synapses is contained by cisternal Ca2+-ATPases. Considered a weak drive for transmitter release, we unexpectedly found that VGCC Ca2+ signals are comparable in size to those elicited by α9α10 and can be potentiated by ryanodine receptors. Finally, we showed that sorcin, a highly expressed gene product in OHCs with reported Ca2+ control function in cardiomy-ocytes, regulates basal Ca2+ levels and MOC synaptic activity in OHCs.

Dissociation between the calcium-induced and voltage-driven motility in cochlear outer hair cells from the waltzing guinea pig

1993 ◽  
Vol 104 (4) ◽  
pp. 1137-1143
Author(s):  
B. Canlon ◽  
D. Dulon
Keyword(s):  
Guinea Pig ◽  
Hair Cells ◽  
Guinea Pigs ◽  
Outer Hair Cell ◽  
Calcium Ionophore ◽  
Organ Of Corti ◽  
Length Change ◽  
Outer Hair Cells ◽  
Permeabilized Cells ◽  
Length Changes

The waltzing guinea pig, possessing an hereditary progressive deafness, shows pathology to the actin-bearing structures within the hair cells of the organ of Corti. In particular, the affected structures include the stereocilia, the cuticular plate and, as shown in the present study, swollen and disorganized subsurface cisternae. To test whether this pathology affected outer hair cell motility, cells were isolated from waltzing guinea pigs and their age-matched controls and were subjected to either electrical or chemical stimulation. Visual detection thresholds and the magnitude of the electrically-induced length changes were equivalent for both groups. However, when intracellular calcium was increased with either the calcium ionophore, ionomycin or Ca2+/ATP (under permeabilized conditions with DMSO), length changes were significantly reduced for the outer hair cells from waltzing guinea pigs compared to the controls. The average percent length increase induced by 10 microM ionomycin for the outer hair cells from control animals was 2.3 +/- 1.7 whereas for postnatal day 4 waltzing guinea pigs it was 1.3 +/- 1.7. Postnatal day 7 and 10 waltzing guinea pigs responded with significantly smaller percent length changes. The intracellular concentration of ionic calcium increased similarly for both groups after the application of ionomycin as revealed with the indicator fluo-3. In the permeabilized cells in the presence of Ca2+/ATP, control cells responded with a percent length change of 3.5, whereas, age-matched waltzing outer hair cells responded with barely detectable length changes.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Outer hair cell electromotility is low-pass filtered relative to the molecular conformational changes that produce nonlinear capacitance

2019 ◽  
Vol 151 (12) ◽  
pp. 1369-1385 ◽  
Author(s):  
Joseph Santos-Sacchi ◽  
Kuni H. Iwasa ◽  
Winston Tan
Keyword(s):  
Guinea Pig ◽  
Hair Cell ◽  
Frequency Response ◽  
Time Constant ◽  
Outer Hair Cell ◽  
Resting Potential ◽  
Nonlinear Capacitance ◽  
Cochlear Amplification ◽  
Low Pass ◽  
Length Changes

The outer hair cell (OHC) of the organ of Corti underlies a process that enhances hearing, termed cochlear amplification. The cell possesses a unique voltage-sensing protein, prestin, that changes conformation to cause cell length changes, a process termed electromotility (eM). The prestin voltage sensor generates a capacitance that is both voltage- and frequency-dependent, peaking at a characteristic membrane voltage (Vh), which can be greater than the linear capacitance of the OHC. Accordingly, the OHC membrane time constant depends upon resting potential and the frequency of AC stimulation. The confounding influence of this multifarious time constant on eM frequency response has never been addressed. After correcting for this influence on the whole-cell voltage clamp time constant, we find that both guinea pig and mouse OHC eM is low pass, substantially attenuating in magnitude within the frequency bandwidth of human speech. The frequency response is slowest at Vh, with a cut-off, approximated by single Lorentzian fits within that bandwidth, near 1.5 kHz for the guinea pig OHC and near 4.3 kHz for the mouse OHC, each increasing in a U-shaped manner as holding voltage deviates from Vh. Nonlinear capacitance (NLC) measurements follow this pattern, with cut-offs about double that for eM. Macro-patch experiments on OHC lateral membranes, where voltage delivery has high fidelity, confirms low pass roll-off for NLC. The U-shaped voltage dependence of the eM roll-off frequency is consistent with prestin’s voltage-dependent transition rates. Modeling indicates that the disparity in frequency cut-offs between eM and NLC may be attributed to viscoelastic coupling between prestin’s molecular conformations and nanoscale movements of the cell, possibly via the cytoskeleton, indicating that eM is limited by the OHC’s internal environment, as well as the external environment. Our data suggest that the influence of OHC eM on cochlear amplification at higher frequencies needs reassessment.

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