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.

scholarly journals A modified adenovirus can transfect cochlear hair cells in vivo without compromising cochlear function

Gene Therapy ◽  
2001 ◽  
Vol 8 (10) ◽  
pp. 789-794 ◽  
Author(s):  
A E Luebke ◽  
J D Steiger ◽  
B L Hodges ◽  
A Amalfitano
Keyword(s):  
Hair Cells ◽  
Cochlear Function ◽  
Cochlear Hair Cells

scholarly journals Olivocochlear suppression of outer hair cells in vivo: evidence for combined action of BK and SK2 channels throughout the cochlea

2013 ◽  
Vol 109 (6) ◽  
pp. 1525-1534 ◽  
Author(s):  
Stéphane F. Maison ◽  
Sonja J. Pyott ◽  
Andrea L. Meredith ◽  
M. Charles Liberman
Keyword(s):  
Hair Cells ◽  
In Vitro Study ◽  
Bk Channels ◽  
Outer Hair Cells ◽  
Cochlear Hair Cells ◽  
Α Subunit ◽  
Combined Action ◽  
Cholinergic Effects

Cholinergic inhibition of cochlear hair cells via olivocochlear (OC)-efferent feedback is mediated by Ca2+ entry through α9-/α10-nicotinic receptors, but the nature of the K+ channels activated by this Ca2+ entry has been debated (Yoshida N, Hequembourg SJ, Atencio CA, Rosowski JJ, Liberman MC. J Neurophysiol 85: 84–88, 2001). A recent in vitro study (Wersinger E, McLean WJ, Fuchs PA, Pyott SJ. PLoS One 5: e13836, 2010) suggests that small-conductance (SK2) channels mediate cholinergic effects in the apical turn, whereas large-conductance (BK) channels mediate basal turn effects. Here, we measure, as a function of cochlear frequency, the magnitude of BK and SK2 expression in outer hair cells and the strength of in vivo OC suppression in BK+/+ mice vs. BK−/− lacking the obligatory α-subunit (Meredith AL, Thorneloe KS, Werner ME, Nelson MT, Aldrich RW. J Biol Chem 279: 36746–36752, 2004). Except at the extreme apical tip, we see immunostaining for both BK and SK2 in BK+/+. Correspondingly, at all testable frequencies (8–45 kHz), we see evidence for both SK2 and BK contributions to OC effects evoked by electrically stimulating the OC bundle: OC-mediated suppression was reduced, but not eliminated, at all frequencies in the BK−/− ears. The suppression remaining in BK nulls was blocked by strychnine, suggesting involvement of α9-/α10-cholinergic receptors, coupled to activation of the remaining SK2 channels.

scholarly journals Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Rescue the Loss of Outer Hair Cells and Repair Cochlear Damage in Cisplatin-Injected Mice

2021 ◽  
Vol 22 (13) ◽  
pp. 6664
Author(s):  
Stella Chin-Shaw Tsai ◽  
Kuender D. Yang ◽  
Kuang-Hsi Chang ◽  
Frank Cheau-Feng Lin ◽  
Ruey-Hwang Chou ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Umbilical Cord ◽  
Hair Cells ◽  
Round Window ◽  
Outer Hair Cells ◽  
Protective Effects ◽  
Cochlear Hair Cells ◽  
Potential Applications ◽  
Round Window Niche

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 μg/μL) injection at the same time point; and (ii) UCMSC exosome (1.2 μg/μL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.

scholarly journals Calcium Balance and Mechanotransduction in Rat Cochlear Hair Cells

2010 ◽  
Vol 104 (1) ◽  
pp. 18-34 ◽  
Author(s):  
Maryline Beurg ◽  
Jong-Hoon Nam ◽  
Qingguo Chen ◽  
Robert Fettiplace
Keyword(s):  
Time Constant ◽  
Hair Cells ◽  
Pump Current ◽  
Outer Hair Cells ◽  
Hair Bundle ◽  
Calcium Balance ◽  
Cochlear Hair Cells ◽  
Fluorescent Indicators ◽  
Intracellular Ca

Auditory transduction occurs by opening of Ca2+-permeable mechanotransducer (MT) channels in hair cell stereociliary bundles. Ca2+ clearance from bundles was followed in rat outer hair cells (OHCs) using fast imaging of fluorescent indicators. Bundle deflection caused a rapid rise in Ca2+ that decayed after the stimulus, with a time constant of about 50 ms. The time constant was increased by blocking Ca2+ uptake into the subcuticular plate mitochondria or by inhibiting the hair bundle plasma membrane Ca2+ ATPase (PMCA) pump. Such manipulations raised intracellular Ca2+ and desensitized the MT channels. Measurement of the electrogenic PMCA pump current, which saturated at 18 pA with increasing Ca2+ loads, indicated a maximum Ca2+ extrusion rate of 3.7 fmol·s−1. The amplitude of the Ca2+ transient decreased in proportion to the Ca2+ concentration bathing the bundle and in artificial endolymph (160 mM K+, 20 μM Ca2+), Ca2+ carried 0.2% of the MT current. Nevertheless, MT currents in endolymph displayed fast adaptation with a submillisecond time constant. In endolymph, roughly 40% of the MT current was activated at rest when using 1 mM intracellular BAPTA compared with 12% with 1 mM EGTA, which enabled estimation of the in vivo Ca2+ load as 3 pA at rest. The results were reproduced by a model of hair bundle Ca2+ diffusion, showing that the measured PMCA pump density could handle Ca2+ loads incurred from resting and maximal MT currents in endolymph. The model also indicated the endogenous mobile buffer was equivalent to 1 mM BAPTA.

scholarly journals Estimation of outer hair cells function in chronic bilateral tinnitus patients with normal hearing using distortion product otoacoustic emissions

2021 ◽  
Author(s):  
Aras Karimiani ◽  
Nematollah Rouhbakhsh ◽  
Farzaneh Zamiri Abdollahi ◽  
Shohreh Jalaie
Keyword(s):  
Hair Cells ◽  
Otoacoustic Emissions ◽  
Normal Hearing ◽  
Outer Hair Cells ◽  
Distortion Product Otoacoustic Emissions ◽  
Control Group ◽  
Distortion Product Otoacoustic Emission ◽  
Frequency Range ◽  
Cochlear Function ◽  
Distortion Product

Background and Aim: It is not clear if the measurement of distortion product otoacoustic emissions (DPOAE) at frequencies above 8 kHz adds any value in determining the differences in the cochlear function between patients with and without tinnitus. This study aimed to compare DPOAE in the frequency range of 0.5−10 kHz in patients with normal hearing with and without tinnitus. Methods: This comparative cross-sectional study was conducted on 20 individuals with tinnitus and normal hearing as a study group (SG) and a control group (CG) of 20 normal-hearing individuals without tinnitus. The DPOAE was measured with F1/F2 = 1.22 and intensities of F1 = 65 dB SPL and F2 =55 dB SPL in the frequency range of 0.5−10 kHz, moreover in the frequency of tinnitus in SG and corresponding frequency in CG. Results: DPOAE level at 10 kHz did not differ significantly between SG and CG (p = 0.491). However, the mean of overall DPOAE level, DPOAE level at the frequency of tinnitus, and F2 values of 2.5, 5, and 6.298 kHz were significantly lower in SG than CG (p < 0.05). Conclusion: Measurement of DPOAE at 10 kHz did not seem to add any value in determining the differences in the cochlear function between patients with and without tinnitus. However, decreased DPOAE levels at 2.5, 5, and 6.298 kHz which were observed among patients who have tinnitus and normal hearing, indicates some outer hair cells damage that was not detectable by conventional audiometry. Keywords: Tinnitus; normal hearing; outer hair cell; distortion product otoacoustic emission

scholarly journals THE STUDY OF MATURATION OF THE AUDITORY ANALYZER RABBIT ACCORDING DISTORTION-PRODUCT OTOACOUSTIC EMISSIONS

2013 ◽  
Vol 68 (11) ◽  
pp. 94-97
Author(s):  
I. N. D'yakonova ◽  
Yu. S. Ishanova ◽  
I. V. Rakhmanova
Keyword(s):  
Hair Cells ◽  
Otoacoustic Emissions ◽  
Normative Data ◽  
Outer Hair Cell ◽  
Rabbit Model ◽  
Outer Hair Cells ◽  
Distortion Product Otoacoustic Emissions ◽  
Acoustic Response ◽  
Auditory Analyzer ◽  
Distortion Product

Aim: In our chronic experiment to  register changes of acoustic response of Distortion-Product Otoacoustic Emissions (DPOAE) of intact rabbits in postnatal ontogenesis for the purpose of getting normative data which can be used for studying impact of pathological factors on auditory function and maturation of activity of outer hair cell in ontogenesis. Materials and methods: Study of otoacoustic emissions used mature chinchilla rabbits with a 19 day life of up to 3 months. Results: in the course of ripening were obtained functional activity of outer hair cells of the cochlea. Conclusion: normative data obtained allow us to study using a rabbit model, the pathological effects of agents on the maturation of the outer hair cells of the cochlea in the experiment.

scholarly journals Characterization of HA-tagged α9 and α10 nAChRs in the mouse cochlea

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Pankhuri Vyas ◽  
Megan Beers Wood ◽  
Yuanyuan Zhang ◽  
Adam C. Goldring ◽  
Fatima-Zahra Chakir ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Hair Cells ◽  
Outer Hair Cells ◽  
Synaptic Function ◽  
Auditory Brainstem Responses ◽  
Wild Type ◽  
Cochlear Hair Cells ◽  
Heterozygous Condition ◽  
Adult Mice ◽  
Efferent Neurons

AbstractNeurons of the medial olivary complex inhibit cochlear hair cells through the activation of α9α10-containing nicotinic acetylcholine receptors (nAChRs). Efforts to study the localization of these proteins have been hampered by the absence of reliable antibodies. To overcome this obstacle, CRISPR-Cas9 gene editing was used to generate mice in which a hemagglutinin tag (HA) was attached to the C-terminus of either α9 or α10 proteins. Immunodetection of the HA tag on either subunit in the organ of Corti of adult mice revealed immunopuncta clustered at the synaptic pole of outer hair cells. These puncta were juxtaposed to immunolabeled presynaptic efferent terminals. HA immunopuncta also occurred in inner hair cells of pre-hearing (P7) but not in adult mice. These immunolabeling patterns were similar for both homozygous and heterozygous mice. All HA-tagged genotypes had auditory brainstem responses not significantly different from those of wild type littermates. The activation of efferent neurons in heterozygous mice evoked biphasic postsynaptic currents not significantly different from those of wild type hair cells. However, efferent synaptic responses were significantly smaller and less frequent in the homozygous mice. We show that HA-tagged nAChRs introduced in the mouse by a CRISPR knock-in are regulated and expressed like the native protein, and in the heterozygous condition mediate normal synaptic function. The animals thus generated have clear advantages for localization studies.

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 Cy3-RgIA-5727 Labels and Inhibits α9-Containing nAChRs of Cochlear Hair Cells

2021 ◽  
Vol 15 ◽  
Author(s):  
Fernando Fisher ◽  
Yuanyuan Zhang ◽  
Philippe F. Y. Vincent ◽  
Joanna Gajewiak ◽  
Thomas J. Gordon ◽  
...  
Keyword(s):  
Hair Cell ◽  
Nicotinic Acetylcholine Receptors ◽  
Hair Cells ◽  
Acetylcholine Receptors ◽  
Tight Binding ◽  
Cholinergic Neurons ◽  
Outer Hair Cells ◽  
Cyanine Dye ◽  
Cochlear Hair Cells ◽  
Calcium Dependent

Efferent cholinergic neurons inhibit sensory hair cells of the vertebrate inner ear through the combined action of calcium-permeable α9α10-containing nicotinic acetylcholine receptors (nAChRs) and associated calcium-dependent potassium channels. The venom of cone snails is a rich repository of bioactive peptides, many with channel blocking activities. The conopeptide analog, RgIA-5474, is a specific and potent antagonist of α9α10-containing nAChRs. We added an alkyl functional group to the N-terminus of the RgIA-5474, to enable click chemistry addition of the fluorescent cyanine dye, Cy3. The resulting peptide, Cy3-RgIA-5727, potently blocked mouse α9α10 nAChRs expressed in Xenopus oocytes (IC50 23 pM), with 290-fold less activity on α7 nAChRs and 40,000-fold less activity on all other tested nAChR subtypes. The tight binding of Cy3-RgIA-5727 provided robust visualization of hair cell nAChRs juxtaposed to cholinergic efferent terminals in excised, unfixed cochlear tissue from mice. Presumptive postsynaptic sites on outer hair cells (OHCs) were labeled, but absent from inner hair cells (IHCs) and from OHCs in cochlear tissue from α9-null mice and in cochlear tissue pre-incubated with non-Cy3-conjugated RgIA-5474. In cochlear tissue from younger (postnatal day 10) mice, Cy3-RgIA-5727 also labeled IHCs, corresponding to transient efferent innervation at that age. Cy3 puncta in Kölliker’s organ remained in the α9-null tissue. Pre-exposure with non-Cy3-conjugated RgIA-5474 or bovine serum albumin reduced this non-specific labeling to variable extents in different preparations. Cy3-RgIA-5727 and RgIA-5474 blocked the native hair cell nAChRs, within the constraints of application to the excised cochlear tissue. Cy3-RgIA-5727 or RgIA-5474 block of efferent synaptic currents in young IHCs was not relieved after 50 min washing, so effectively irreversible.

Computational Modeling of Spontaneous Otoacoustic Emissions by the Mammalian Cochlea

2018 ◽  
Author(s):  
Julien Meaud ◽  
Thomas Bowling ◽  
Charlsie Lemons
Keyword(s):  
Hair Cells ◽  
Otoacoustic Emissions ◽  
Outer Hair Cell ◽  
Dynamic Range ◽  
Micromechanical Model ◽  
Outer Hair Cells ◽  
Cell Biophysics ◽  
Three Dimensional Model ◽  
Spontaneous Otoacoustic Emissions ◽  
Broad Dynamic Range

The mammalian cochlea is a sensory system with high sensitivity, sharp frequency selectivity and a broad dynamic range. These characteristics are due to the active nonlinear feedback by outer hair cells. Because it is an active nonlinear system, the cochlea sometimes emits spontaneous otoacoustic emissions (SOAEs) that are generated in the absence of any external stimulus due to the emergence of limit cycle oscillations. In this work, we use a computational physics-based model of the mammalian cochlea to investigate the generation of SOAEs. This model includes a three-dimensional model of the fluid mechanics in the cochlear ducts, a micromechanical model for the vibrations of the cochlear structures, and a realistic model of outer hair cell biophysics. Direct simulations of SOAEs in the time-domain demonstrate that the model is able to capture key experimental observations regarding SOAEs. Parametric studies and analysis of model simulations are used to demonstrate that SOAEs are a global phenomenon that arises due to the collective action of a distributed region of the cochlea rather than from spontaneous oscillations from individual outer hair cells.

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