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 Activity-dependent regulation of prestin expression in mouse outer hair cells

2015 ◽  
Vol 113 (10) ◽  
pp. 3531-3542 ◽  
Author(s):  
Yohan Song ◽  
Anping Xia ◽  
Hee Yoon Lee ◽  
Rosalie Wang ◽  
Anthony J. Ricci ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Information Transfer ◽  
Outer Hair Cell ◽  
Endocochlear Potential ◽  
Outer Hair Cells ◽  
Tectorial Membrane ◽  
Inner Hair Cell ◽  
Activity Dependent

Prestin is a membrane protein necessary for outer hair cell (OHC) electromotility and normal hearing. Its regulatory mechanisms are unknown. Several mouse models of hearing loss demonstrate increased prestin, inspiring us to investigate how hearing loss might feedback onto OHCs. To test whether centrally mediated feedback regulates prestin, we developed a novel model of inner hair cell loss. Injection of diphtheria toxin (DT) into adult CBA mice produced significant loss of inner hair cells without affecting OHCs. Thus, DT-injected mice were deaf because they had no afferent auditory input despite OHCs continuing to receive normal auditory mechanical stimulation and having normal function. Patch-clamp experiments demonstrated no change in OHC prestin, indicating that loss of information transfer centrally did not alter prestin expression. To test whether local mechanical feedback regulates prestin, we used TectaC1509G mice, where the tectorial membrane is malformed and only some OHCs are stimulated. OHCs connected to the tectorial membrane had normal prestin levels, whereas OHCs not connected to the tectorial membrane had elevated prestin levels, supporting an activity-dependent model. To test whether the endocochlear potential was necessary for prestin regulation, we studied TectaC1509G mice at different developmental ages. OHCs not connected to the tectorial membrane had lower than normal prestin levels before the onset of the endocochlear potential and higher than normal prestin levels after the onset of the endocochlear potential. Taken together, these data indicate that OHC prestin levels are regulated through local feedback that requires mechanoelectrical transduction currents. This adaptation may serve to compensate for variations in the local mechanical environment.

scholarly journals Unmyelinated type II afferent neurons report cochlear damage

2015 ◽  
Vol 112 (47) ◽  
pp. 14723-14727 ◽  
Author(s):  
Chang Liu ◽  
Elisabeth Glowatzki ◽  
Paul Albert Fuchs
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Outer Hair Cell ◽  
Cell Damage ◽  
Large Diameter ◽  
Outer Hair Cells ◽  
Type I ◽  
Type Ii ◽  
Inner Hair Cell ◽  
Hair Cell Damage

In the mammalian cochlea, acoustic information is carried to the brain by the predominant (95%) large-diameter, myelinated type I afferents, each of which is postsynaptic to a single inner hair cell. The remaining thin, unmyelinated type II afferents extend hundreds of microns along the cochlear duct to contact many outer hair cells. Despite this extensive arbor, type II afferents are weakly activated by outer hair cell transmitter release and are insensitive to sound. Intriguingly, type II afferents remain intact in damaged regions of the cochlea. Here, we show that type II afferents are activated when outer hair cells are damaged. This response depends on both ionotropic (P2X) and metabotropic (P2Y) purinergic receptors, binding ATP released from nearby supporting cells in response to hair cell damage. Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term “noxacusis” to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber’s response to hair cell damage. Type II afferents may be the cochlea’s nociceptors, prompting avoidance of further damage to the irreparable inner ear.

scholarly journals Codeficiency of Lysosomal Mucolipins 3 and 1 in Cochlear Hair Cells Diminishes Outer Hair Cell Longevity and Accelerates Age-Related Hearing Loss

2018 ◽  
Vol 38 (13) ◽  
pp. 3177-3189 ◽  
Author(s):  
Teerawat Wiwatpanit ◽  
Natalie N. Remis ◽  
Aisha Ahmad ◽  
Yingjie Zhou ◽  
John C. Clancy ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Outer Hair Cell ◽  
Cochlear Hair Cells ◽  
Age Related ◽  
Age Related Hearing Loss ◽  
Cell Longevity

Psychophysical Tuning Curves in Subjects with Tinnitus Suggest Outer Hair Cell Lesions

1995 ◽  
Vol 113 (3) ◽  
pp. 223-233 ◽  
Author(s):  
Curtin R. Mitchell ◽  
Thomas A. Creedon
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Outer Hair Cell ◽  
Tuning Curve ◽  
Control Design ◽  
Nerve Fibers ◽  
Outer Hair Cells ◽  
Tuning Curves ◽  
Hearing Thresholds

A study by Penner (J Speech Hear Res 1980;23:779–86) found evidence for Impaired lateral suppression in subjects with tinnitus and sensorineural hearing loss. If lateral suppression is related to tuning curve sharpness and lateral suppression is impaired, the shape of the tuning curve should be affected. The purpose of this study was to determine whether subjects with tinnitus have psychophysical tuning curves that are different from those of subjects without tinnitus. Psychophysical tuning curves and hearing thresholds were obtained from 18 subjects, 7 with tinnitus and 11 without tinnitus. Only subjects with normal audiograms (through 8 kHz) were selected for this study. In subjects with tinnitus psychophysical tuning curves were obtained in the region pitch-matched to their tinnitus. In nontinnitus subjects psychophysical tuning curves were determined at the same frequencies as for the tinnitus subjects in a yoked-control design. The slopes of the tails and tips and the Q10 and other measures were calculated for each tuning curve. The psychophysical tuning curves in subjects with tinnitus were significantly different (0.01 level) from those of control subjects and often had hypersensitive tails and some elevated tips. These shapes of tuning curves are consistent with cochlear lesions involving the loss of outer hair cells without damage to the Inner hair cells or nerve fibers.

scholarly journals Inner Hair Cell and Neuron Degeneration Contribute to Hearing Loss in a Dfna2-Like Mouse Model

2018 ◽  
Author(s):  
Camila Carignano ◽  
Esteban Pablo Barila ◽  
Ezequiel Ignacio Rías ◽  
Leonardo Dionisio ◽  
Eugenio Aztiria ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Spiral Ganglion ◽  
Outer Hair Cells ◽  
Ganglion Neuron ◽  
Spiral Ganglion Neuron ◽  
Inner Hair Cell ◽  
Neuron Degeneration ◽  
Knock Out

HIGHLIGHTSKCNQ4 knock-out mouse shows hair cells and spiral ganglion neuron degeneration.Inner hair cells and spiral ganglion neuron loss begin 30 weeks later than outer hair cells in Kcnq4-/- mice.Inner hair cell loss kinetic is faster than that of outer hair cells in cochlear basal turn in Kcnq4-/-.Outer hair cells from Kcnq4-/- mice degenerate slower in apical than in basal turn.Kcnq4 knock-out allele expressed in C3H/HeJ strain reproduces the two phases of DFNA2 hearing loss.GRAPHICAL ABSTRACT

scholarly journals Noise-induced and age-related hearing loss:  new perspectives and potential therapies

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 927 ◽  
Author(s):  
M Charles Liberman
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Auditory Nerve ◽  
Cell Loss ◽  
Sensorineural Hearing ◽  
Hair Cell Loss ◽  
Age Related ◽  
Age Related Hearing Loss

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

Early Evidence of Cochlear Damage in a Large Sample of Percussionists

2005 ◽  
Vol 20 (3) ◽  
pp. 135-139
Author(s):  
Jodee A Pride ◽  
David R Cunningham
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Otoacoustic Emissions ◽  
Outer Hair Cell ◽  
Cell Damage ◽  
Normal Hearing ◽  
Outer Hair Cells ◽  
Sensory Loss ◽  
Distortion Product ◽  
Hair Cell Damage

Percussionists can be exposed to intermittent sound stimuli that exceed 145 dB SPL, although damage may occur to the outer hair cells at levels of 120 dB SPL. The present study measured distortion-product otoacoustic emissions (DPOAEs) in a group of 86 normal-hearing percussionists and 39 normal-hearing nonpercussionists. Results indicate that normal-hearing percussionists have lower DPOAE amplitudes than normal-hearing nonpercussionists. DPOAE amplitudes were significantly lower at 6000 Hz in both the left and right ears for percussionists. Percussionists also more frequently had absent DPOAEs, with the greatest differences occurring at 6000 Hz (absent DPOAEs in 25% of percussionists vs 10% of nonpercussionists). When all frequencies are considered as a group, 33% of the percussionists had an absent DPOAE in either ear at some frequency, compared to only 23% of the nonpercussionists. Otoacoustic emissions are more sensitive to outer hair cell damage than pure-tone threshold measurements and can serve as an important measurement of sensory loss (i.e., outer hair cell damage) in musicians before the person perceives the hearing loss. DPOAE monitoring for musicians, along with appropriate education and intervention, might help prevent or minimize music-induced hearing loss.

scholarly journals Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Pengcheng Xu ◽  
Longhao Wang ◽  
Hu Peng ◽  
Huihui Liu ◽  
Hongchao Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Mitochondrial Dysfunction ◽  
Hair Cells ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Inner Hair Cells

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

scholarly journals Enhancing the sensitivity of the envelope-following response for cochlear synaptopathy screening in humans: the role of stimulus envelope

2020 ◽  
Author(s):  
Viacheslav Vasilkov ◽  
Markus Garrett ◽  
Manfred Mauermann ◽  
Sarah Verhulst
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Nerve ◽  
Outer Hair Cell ◽  
Cell Damage ◽  
Modulation Depth ◽  
Auditory Evoked Potential ◽  
Sensorineural Hearing ◽  
Age Related

AbstractAuditory de-afferentation, a permanent reduction in the number of innerhair-cells and auditory-nerve synapses due to cochlear damage or synaptopathy, can reliably be quantified using temporal bone histology and immunostaining. However, there is an urgent need for non-invasive markers of synaptopathy to study its perceptual consequences in live humans and to develop effective therapeutic interventions. While animal studies have identified candidate auditory-evoked-potential (AEP) markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or lack of measurement sensitivity. To render AEP-based markers of synaptopathy more sensitive and differential to the synaptopathy aspect of sensorineural hearing loss, we followed a combined computational and experimental approach. Starting from the known characteristics of auditory-nerve physiology, we optimized the stimulus envelope to stimulate the available auditory-nerve population optimally and synchronously to generate strong envelope-following-responses (EFRs). We further used model simulations to explore which stimuli evoked a response that was sensitive to synaptopathy, while being maximally insensitive to possible co-existing outer-hair-cell pathologies. We compared the model-predicted trends to AEPs recorded in younger and older listeners (N=44, 24f) who had normal or impaired audiograms with suspected age-related synaptopathy in the older cohort. We conclude that optimal stimulation paradigms for EFR-based quantification of synaptopathy should have sharply rising envelope shapes, a minimal plateau duration of 1.7-2.1 ms for a 120-Hz modulation rate, and inter-peak intervals which contain near-zero amplitudes. From our recordings, the optimal EFR-evoking stimulus had a rectangular envelope shape with a 25% duty cycle and a 95% modulation depth. Older listeners with normal or impaired audiometric thresholds showed significantly reduced EFRs, which were consistent with how (age-induced) synaptopathy affected these responses in the model.Significance StatementCochlear synaptopathy was in 2009 identified as a new form of sensorineural hearing loss (SNHL) that also affects primates and humans. However, clinical practice does not routinely screen for synaptopathy, and hence its consequences for degraded sound and speech perception remain unclear. Cochlear synaptopathy may thus remain undiagnosed and untreated in the aging population who often report self-reported hearing difficulties. To enable an EEG-based differential diagnosis of synaptopathy in humans, it is crucial to develop a recording method that evokes a robust response and emphasizes inter-individual differences. These differences should reflect the synaptopathy aspect of SNHL, while being insensitive to other aspects of SNHL (e.g. outer-hair-cell damage). This study uniquely combines computational modeling with experiments in normal and hearing-impaired listeners to design an EFR stimulation and recording paradigm that can be used for the diagnosis of synaptopathy in humans.

scholarly journals Inner hair cell dysfunction in Klhl18 mutant mice leads to low frequency progressive hearing loss

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258158
Author(s):  
Neil J. Ingham ◽  
Navid Banafshe ◽  
Clarisse Panganiban ◽  
Julia L. Crunden ◽  
Jing Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Cell Function ◽  
Low Frequency ◽  
Mutant Mice ◽  
Auditory Brainstem Responses ◽  
Distortion Product Otoacoustic Emission ◽  
Inner Hair Cell ◽  
Distortion Product ◽  
Age Related

Age-related hearing loss in humans (presbycusis) typically involves impairment of high frequency sensitivity before becoming progressively more severe at lower frequencies. Pathologies initially affecting lower frequency regions of hearing are less common. Here we describe a progressive, predominantly low-frequency recessive hearing impairment in two mutant mouse lines carrying different mutant alleles of the Klhl18 gene: a spontaneous missense mutation (Klhl18lowf) and a targeted mutation (Klhl18tm1a(KOMP)Wtsi). Both males and females were studied, and the two mutant lines showed similar phenotypes. Threshold for auditory brainstem responses (ABR; a measure of auditory nerve and brainstem neural activity) were normal at 3 weeks old but showed progressive increases from 4 weeks onwards. In contrast, distortion product otoacoustic emission (DPOAE) sensitivity and amplitudes (a reflection of cochlear outer hair cell function) remained normal in mutants. Electrophysiological recordings from the round window of Klhl18lowf mutants at 6 weeks old revealed 1) raised compound action potential thresholds that were similar to ABR thresholds, 2) cochlear microphonic potentials that were normal compared with wildtype and heterozygous control mice and 3) summating potentials that were reduced in amplitude compared to control mice. Scanning electron microscopy showed that Klhl18lowf mutant mice had abnormally tapering of the tips of inner hair cell stereocilia in the apical half of the cochlea while their synapses appeared normal. These results suggest that Klhl18 is necessary to maintain inner hair cell stereocilia and normal inner hair cell function at low frequencies.

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