scholarly journals A connexin30 mutation rescues hearing and reveals roles for gap junctions in cochlear amplification and micromechanics

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Victoria A. Lukashkina ◽  
Snezana Levic ◽  
Andrei N. Lukashkin ◽  
Nicola Strenzke ◽  
Ian J. Russell
Keyword(s):  
Gap Junctions ◽  
Hair Cells ◽  
High Frequency ◽  
Basilar Membrane ◽  
Frequency Tuning ◽  
Outer Hair Cells ◽  
Mechanoelectrical Transduction ◽  
Age Related ◽  
Junction Protein ◽  
Cochlear Amplification

Abstract Accelerated age-related hearing loss disrupts high-frequency hearing in inbred CD-1 mice. The p.Ala88Val (A88V) mutation in the gene coding for the gap-junction protein connexin30 (Cx30) protects the cochlear basal turn of adult CD-1Cx30 A88V/A88V mice from degeneration and rescues hearing. Here we report that the passive compliance of the cochlear partition and active frequency tuning of the basilar membrane are enhanced in the cochleae of CD-1Cx30 A88V/A88V compared to CBA/J mice with sensitive high-frequency hearing, suggesting that gap junctions contribute to passive cochlear mechanics and energy distribution in the active cochlea. Surprisingly, the endocochlear potential that drives mechanoelectrical transduction currents in outer hair cells and hence cochlear amplification is greatly reduced in CD-1Cx30 A88V/A88V mice. Yet, the saturating amplitudes of cochlear microphonic potentials in CD-1Cx30 A88V/A88V and CBA/J mice are comparable. Although not conclusive, these results are compatible with the proposal that transmembrane potentials, determined mainly by extracellular potentials, drive somatic electromotility of outer hair cells.

scholarly journals Amplification lags nonlinearity in the recovery from reduced endocochlear potential

2020 ◽  
Author(s):  
C. Elliott Strimbu ◽  
Yi Wang ◽  
Elizabeth S. Olson
Keyword(s):  
Hair Cells ◽  
Otoacoustic Emissions ◽  
Basilar Membrane ◽  
Frequency Tuning ◽  
Organ Of Corti ◽  
Endocochlear Potential ◽  
Outer Hair Cells ◽  
Frequency Resolution ◽  
Operating Condition ◽  
Distortion Product

ABSTRACTThe mammalian hearing organ, the cochlea, contains an active amplifier to boost the vibrational response to low level sounds. Hallmarks of this active process are sharp location-dependent frequency tuning and compressive nonlinearity over a wide stimulus range. The amplifier relies on outer hair cell (OHC) generated forces driven in part by the endocochlear potential (EP), the ~ +80 mV potential maintained in scala media, generated by the stria vascularis. We transiently eliminated the EP in vivo by an intravenous injection of furosemide and measured the vibrations of different layers in the cochlea’s organ of Corti using optical coherence tomography. Distortion product otoacoustic emissions (DPOAE) were monitored at the same times. Following the injection, the vibrations of the basilar membrane lost the best frequency (BF) peak and showed broad tuning similar to a passive cochlea. The intra-organ of Corti vibrations measured in the region of the OHCs lost their BF peak and showed low-pass responses, but retained nonlinearity, indicating that OHC electromotility was still operational. Thus, while electromotility is presumably necessary for amplification, its presence is not sufficient for amplification. The BF peak recovered nearly fully within 2 hours, along with a non-monotonic DPOAE recovery that suggests that physical shifts in operating condition are a final step in the recovery process.SIGNIFICANCEThe endocochlear potential, the +80 mV potential difference across the fluid filled compartments of the cochlea, is essential for normal mechanoelectrical transduction, which leads to receptor potentials in the sensory hair cells when they vibrate in response to sound. Intracochlear vibrations are boosted tremendously by an active nonlinear feedback process that endows the cochlea with its healthy sensitivity and frequency resolution. When the endocochlear potential was reduced by an injection of furosemide, the basilar membrane vibrations resembled those of a passive cochlea, with broad tuning and linear scaling. The vibrations in the region of the outer hair cells also lost the tuned peak, but retained nonlinearity at frequencies below the peak, and these sub-BF responses recovered fairly rapidly. Vibration responses at the peak recovered nearly fully over 2 hours. The staged vibration recovery and a similarly staged DPOAE recovery suggests that physical shifts in operating condition are a final step in the process of cochlear recovery.

Sensory transduction and frequency selectivity in the basal turn of the guinea-pig cochlea

1992 ◽  
Vol 336 (1278) ◽  
pp. 317-324 ◽  
Keyword(s):  
Guinea Pig ◽  
Hair Cells ◽  
High Frequency ◽  
Basilar Membrane ◽  
Receptor Potential ◽  
Outer Hair Cells ◽  
Sensory Transduction ◽  
Voltage Response ◽  
Operating Range ◽  
Dc Component

Receptor potentials recorded from outer hair cells (ohc ) and inner hair cells (ihc) in the basal highfrequency turn were com pared. The dc component of the ihc receptor potential is maximized to ensure that ihcs can signal a voltage response to high-frequency tones. The ohc dc component is minimized so that ohcs transduce in the most sensitive region of their operating range. The phase and magnitude of ohc receptor potentials were recorded as an indicator of the magnitude and phase of the energy which is fed back to the basilar membrane to provide the basis for the sharp tuning and fine sensitivity of the cochlea to tones. IHC receptor potentials were recorded to assess the net effect of the feedback on the mechanics of the cochlea. It was concluded that ohcs generate feedback which enhances the ihc responses only at the best frequency. At frequencies below cf, ihc dc responses are elicited only when the ohc ac responses begin to saturate.

scholarly journals All Three Rows of Outer Hair Cells Are Required for Cochlear Amplification

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Michio Murakoshi ◽  
Sho Suzuki ◽  
Hiroshi Wada
Keyword(s):  
Hair Cells ◽  
Noise Exposure ◽  
Dynamic Range ◽  
Basilar Membrane ◽  
Organ Of Corti ◽  
High Sensitivity ◽  
Element Model ◽  
Outer Hair Cells ◽  
Displacement Amplitude ◽  
Cochlear Amplification

In the mammalian auditory system, the three rows of outer hair cells (OHCs) located in the cochlea are thought to increase the displacement amplitude of the organ of Corti. This cochlear amplification is thought to contribute to the high sensitivity, wide dynamic range, and sharp frequency selectivity of the hearing system. Recent studies have shown that traumatic stimuli, such as noise exposure and ototoxic acid, cause functional loss of OHCs in one, two, or all three rows. However, the degree of decrease in cochlear amplification caused by such functional losses remains unclear. In the present study, a finite element model of a cross section of the gerbil cochlea was constructed. Then, to determine effects of the functional losses of OHCs on the cochlear amplification, changes in the displacement amplitude of the basilar membrane (BM) due to the functional losses of OHCs were calculated. Results showed that the displacement amplitude of the BM decreases significantly when a single row of OHCs lost its function, suggesting that all three rows of OHCs are required for cochlear amplification.

scholarly journals MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea

2021 ◽  
Vol 5 (2) ◽  
pp. e202101068
Author(s):  
Kuu Ikäheimo ◽  
Anni Herranen ◽  
Vilma Iivanainen ◽  
Tuuli Lankinen ◽  
Antti A Aarnisalo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Er Stress ◽  
Hair Cell ◽  
Hair Cells ◽  
High Frequency ◽  
Outer Hair Cell ◽  
Outer Hair Cells ◽  
Inner Hair Cell ◽  
Age Related ◽  
Er Homeostasis

Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of Manf (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeostasis-promoting protein. From hearing onset, Manf deficiency caused disarray of the outer hair cell stereocilia bundle and reduced cochlear sound amplification capability throughout the tonotopic axis. In high-frequency outer hair cells, the pathology ended in molecular changes in the stereocilia taper region and in strong stereocilia fusion. In high-frequency inner hair cells, Manf deficiency degraded ribbon synapses. The altered phenotype strongly depended on the mouse genetic background. Altogether, the failure in the ER homeostasis maintenance induced early-onset stereociliopathy and synaptopathy and accelerated the effect of genetic causes driving age-related hearing loss. Correspondingly, MANF mutation in a human patient induced severe sensorineural hearing loss from a young age onward. Thus, we present MANF as a novel protein and ER stress as a mechanism that regulate auditory hair cell maintenance in both mice and humans.

scholarly journals Assessing evidence for adaptive evolution in two hearing-related genes important for high-frequency hearing in echolocating mammals

2021 ◽  
Author(s):  
Hui Wang ◽  
Hanbo Zhao ◽  
Yujia Chu ◽  
Jiang Feng ◽  
Keping Sun
Keyword(s):  
Adaptive Evolution ◽  
Hair Cells ◽  
High Frequency ◽  
Phylogenetic Trees ◽  
Outer Hair Cells ◽  
Functional Domain ◽  
Coding Region ◽  
Selective Pressures ◽  
Wide Range ◽  
Different Parts

Abstract High-frequency hearing is particularly important for echolocating bats and toothed whales. Previously, studies of the hearing-related genes Prestin, KCNQ4, and TMC1 documented that adaptive evolution of high-frequency hearing has taken place in echolocating bats and toothed whales. In this study, we present two additional candidate hearing-related genes, Shh and SK2, that may also have contributed to the evolution of echolocation in mammals. Shh is a member of the vertebrate Hedgehog gene family and is required in the specification of the mammalian cochlea. SK2 is expressed in both inner and outer hair cells, and it plays an important role in the auditory system. The coding region sequences of Shh and SK2 were obtained from a wide range of mammals with and without echolocating ability. The topologies of phylogenetic trees constructed using Shh and SK2 were different; however, multiple molecular evolutionary analyses showed that those two genes experienced different selective pressures in echolocating bats and toothed whales compared to non-echolocating mammals. In addition, several nominally significant positively selected sites were detected in the non-functional domain of the SK2 gene, indicating that different selective pressures were acting on different parts of the SK2 gene. This study has expanded our knowledge of the adaptive evolution of high-frequency hearing in echolocating mammals.

scholarly journals Hearing at threshold intensities: by slow mechanical traveling waves or by fast cochlear fluid pressure waves

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Haim Sohmer
Keyword(s):  
Soft Tissue ◽  
Hair Cells ◽  
Traveling Wave ◽  
Basilar Membrane ◽  
Fluid Pressure ◽  
Low Frequency ◽  
Frequency Discrimination ◽  
Outer Hair Cells ◽  
Common Mechanism ◽  
Frequency Stimulation

The three modes of auditory stimulation (air, bone and soft tissue conduction) at threshold intensities are thought to share a common excitation mechanism: the stimuli induce passive displacements of the basilar membrane propagating from the base to the apex (slow mechanical traveling wave), which activate the outer hair cells, producing active displacements, which sum with the passive displacements. However, theoretical analyses and modeling of cochlear mechanics provide indications that the slow mechanical basilar membrane traveling wave may not be able to excite the cochlea at threshold intensities with the frequency discrimination observed. These analyses are complemented by several independent lines of research results supporting the notion that cochlear excitation at threshold may not involve a passive traveling wave, and the fast cochlear fluid pressures may directly activate the outer hair cells: opening of the sealed inner ear in patients undergoing cochlear implantation is not accompanied by threshold elevations to low frequency stimulation which would be expected to result from opening the cochlea, reducing cochlear impedance, altering hydrodynamics. The magnitude of the passive displacements at threshold is negligible. Isolated outer hair cells in fluid display tuned mechanical motility to fluid pressures which likely act on stretch sensitive ion channels in the walls of the cells. Vibrations delivered to soft tissue body sites elicit hearing. Thus, based on theoretical and experimental evidence, the common mechanism eliciting hearing during threshold stimulation by air, bone and soft tissue conduction may involve the fast-cochlear fluid pressures which directly activate the outer hair cells.

Tinnitus: some thoughts about its origin

1984 ◽  
Vol 98 (S9) ◽  
pp. 31-37 ◽  
Author(s):  
J. J. Eggermont
Keyword(s):  
Hair Cells ◽  
High Frequency ◽  
Basilar Membrane ◽  
Stimulus Frequency ◽  
Low Frequency ◽  
Nerve Fibers ◽  
Ear Ossicles ◽  
Stimulus Transduction ◽  
Low Levels ◽  
Inner Ear Fluids

An auditory sensation follows generally as the result of the sequence stimulus, transduction, coding, transformation and sensation. This is then optionally followed by perception and a reaction. The stimulus is usually airborne sound causing movements of the tympanic membrane, the middle ear ossicles, the inner ear fluids and the basilar membrane. The movements of the basilar membrane are dependent on stimulus frequency: high frequency tones excite only the basal part of the cochlea, regardless of the stimulus intensity; low frequency tones at low levels only excite the so-called place specific region at the apical end but at high levels (above 60–70 dB SPL) cause appreciable movement of the entire basilar membrane. Basilar membrane tuning is as sharp as that of inner hair cells or auditory nerve fibers (Sellick et al., 1982) at least in the basal turn of animals that have a cochlea in physiologically impeccable condition.

scholarly journals A Tmc1 mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells

2019 ◽  
Vol 116 (41) ◽  
pp. 20743-20749 ◽  
Author(s):  
Maryline Beurg ◽  
Amanda Barlow ◽  
David N. Furness ◽  
Robert Fettiplace
Keyword(s):  
Hair Cells ◽  
Single Channel ◽  
Maximum Amplitude ◽  
Outer Hair Cells ◽  
Single Amino Acid ◽  
Wild Type ◽  
Cochlear Hair Cells ◽  
Proximate Cause ◽  
Mechanoelectrical Transduction ◽  
Calcium Permeability

Mechanoelectrical transducer (MET) currents were recorded from cochlear hair cells in mice with mutations of transmembrane channel-like protein TMC1 to study the effects on MET channel properties. We characterized a Tmc1 mouse with a single-amino-acid mutation (D569N), homologous to a dominant human deafness mutation. Measurements were made in both Tmc2 wild-type and Tmc2 knockout mice. By 30 d, Tmc1 pD569N heterozygote mice were profoundly deaf, and there was substantial loss of outer hair cells (OHCs). MET current in OHCs of Tmc1 pD569N mutants developed over the first neonatal week to attain a maximum amplitude one-third the size of that in Tmc1 wild-type mice, similar at apex and base, and lacking the tonotopic size gradient seen in wild type. The MET-channel Ca2+ permeability was reduced 3-fold in Tmc1 pD569N homozygotes, intermediate deficits being seen in heterozygotes. Reduced Ca2+ permeability resembled that of the Tmc1 pM412K Beethoven mutant, a previously studied semidominant mouse mutation. The MET channel unitary conductance, assayed by single-channel recordings and by measurements of current noise, was unaffected in mutant apical OHCs. We show that, in contrast to the Tmc1 M412K mutant, there was reduced expression of the TMC1 D569N channel at the transduction site assessed by immunolabeling, despite the persistence of tip links. The reduction in MET channel Ca2+ permeability seen in both mutants may be the proximate cause of hair-cell apoptosis, but changes in bundle shape and protein expression in Tmc1 D569N suggest another role for TMC1 apart from forming the channel.

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