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Hakizimana, P. & Fridberger, A. (2021). Inner hair cell stereocilia are embedded in the tectorial membrane. Nature Communications, 12, Article ID 2604.
Open this publication in new window or tab >>Inner hair cell stereocilia are embedded in the tectorial membrane
2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, article id 2604Article in journal (Refereed) Published
Abstract [en]

Mammalian hearing depends on sound-evoked displacements of the stereocilia of inner hair cells (IHCs), which cause the endogenous mechanoelectrical transducer channels to conduct inward currents of cations including Ca2+. Due to their presumed lack of contacts with the overlaying tectorial membrane (TM), the putative stimulation mechanism for these stereocilia is by means of the viscous drag of the surrounding endolymph. However, despite numerous efforts to characterize the TM by electron microscopy and other techniques, the exact IHC stereocilia-TM relationship remains elusive. Here we show that Ca2+-rich filamentous structures, that we call Ca2+ ducts, connect the TM to the IHC stereocilia to enable mechanical stimulation by the TM while also ensuring the stereocilia access to TM Ca2+. Our results call for a reassessment of the stimulation mechanism for the IHC stereocilia and the TM role in hearing.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-175758 (URN)10.1038/s41467-021-22870-1 (DOI)000687305500028 ()33972539 (PubMedID)2-s2.0-85105559630 (Scopus ID)
Note

Funding: Tysta Skolan Foundation; Swedish research councilSwedish Research CouncilEuropean Commission [2018-02692, 2017-06092]; US National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA

Available from: 2021-05-18 Created: 2021-05-18 Last updated: 2023-03-28Bibliographically approved
Prasad, S., Vona, B., Diñeiro, M., Costales, M., González-Aguado, R., Fontalba, A., . . . Fridberger, A. (2020). Radixin modulates the function of outer hair cell stereocilia. Communications Biology, 3(1), Article ID 792.
Open this publication in new window or tab >>Radixin modulates the function of outer hair cell stereocilia
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2020 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 3, no 1, article id 792Article in journal (Refereed) Published
Abstract [en]

The stereocilia of the inner ear sensory cells contain the actin-binding protein radixin, encoded by RDX. Radixin is important for hearing but remains functionally obscure. To determine how radixin influences hearing sensitivity, we used a custom rapid imaging technique to visualize stereocilia motion while measuring electrical potential amplitudes during acoustic stimulation. Radixin inhibition decreased sound-evoked electrical potentials. Other functional measures, including electrically induced sensory cell motility and sound-evoked stereocilia deflections, showed a minor amplitude increase. These unique functional alterations demonstrate radixin as necessary for conversion of sound into electrical signals at acoustic rates. We identified patients with RDX variants with normal hearing at birth who showed rapidly deteriorating hearing during the first months of life. This may be overlooked by newborn hearing screening and explained by multiple disturbances in postnatal sensory cells. We conclude radixin is necessary for ensuring normal conversion of sound to electrical signals in the inner ear.

Place, publisher, year, edition, pages
Nature Research, 2020
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-172295 (URN)10.1038/s42003-020-01506-y (DOI)000603063100002 ()
Note

Funding agencies: Linkoping University Library

Available from: 2021-01-05 Created: 2021-01-05 Last updated: 2021-12-29Bibliographically approved
Warren, R. L., Ramamoorthy, S., Ciganovic, N., Zhang, Y., Wilson, T. M., Petrie, T., . . . Fridberger, A. (2016). Minimal basilar membrane motion in low-frequency hearing. Proceedings of the National Academy of Sciences of the United States of America, 113(30), E4304-E4310
Open this publication in new window or tab >>Minimal basilar membrane motion in low-frequency hearing
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 30, p. E4304-E4310Article in journal (Refereed) Published
Abstract [en]

Low-frequency hearing is critically important for speech and music perception, but no mechanical measurements have previously been available from inner ears with intact low-frequency parts. These regions of the cochlea may function in ways different from the extensively studied high-frequency regions, where the sensory outer hair cells produce force that greatly increases the sound-evoked vibrations of the basilar membrane. We used laser interferometry in vitro and optical coherence tomography in vivo to study the low-frequency part of the guinea pig cochlea, and found that sound stimulation caused motion of a minimal portion of the basilar membrane. Outside the region of peak movement, an exponential decline in motion amplitude occurred across the basilar membrane. The moving region had different dependence on stimulus frequency than the vibrations measured near the mechanosensitive stereocilia. This behavior differs substantially from the behavior found in the extensively studied high-frequency regions of the cochlea.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2016
Keywords
hearing; basilar membrane; optical coherence tomography; hair cells
National Category
Biophysics
Identifiers
urn:nbn:se:liu:diva-130654 (URN)10.1073/pnas.1606317113 (DOI)000380346200009 ()27407145 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2014-63X-14061-14-5]; Torsten Soderberg Foundation; Stiftelsen Tysta Skolan; Strategic Research Area for Systems Neuroscience; NIH National Institute on Deafness and other Communication Disorders [DC 00141, 000105, DC 005983, NS 061800, R01 DC 010399]

Available from: 2016-08-22 Created: 2016-08-19 Last updated: 2021-12-29
Ramamoorthy, S., Zhang, Y., Petrie, T., Fridberger, A., Ren, T., Wang, R., . . . Nuttall, A. L. (2016). Minimally invasive surgical method to detect sound processing in the cochlear apex by optical coherence tomography. Journal of Biomedical Optics, 21(2), 025003
Open this publication in new window or tab >>Minimally invasive surgical method to detect sound processing in the cochlear apex by optical coherence tomography
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2016 (English)In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 21, no 2, p. 025003-Article in journal (Refereed) Published
Abstract [en]

Sound processing in the inner ear involves separation of the constituent frequencies along the length of the cochlea. Frequencies relevant to human speech (100 to 500 Hz) are processed in the apex region. Among mammals, the guinea pig cochlear apex processes similar frequencies and is thus relevant for the study of speech processing in the cochlea. However, the requirement for extensive surgery has challenged the optical accessibility of this area to investigate cochlear processing of signals without significant intrusion. A simple method is developed to provide optical access to the guinea pig cochlear apex in two directions with minimal surgery. Furthermore, all prior vibration measurements in the guinea pig apex involved opening an observation hole in the otic capsule, which has been questioned on the basis of the resulting changes to cochlear hydrodynamics. Here, this limitation is overcome by measuring the vibrations through the unopened otic capsule using phase-sensitive Fourier domain optical coherence tomography. The optically and surgically advanced method described here lays the foundation to perform minimally invasive investigation of speech-related signal processing in the cochlea. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.

Place, publisher, year, edition, pages
SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS, 2016
Keywords
optical coherence tomography; optical interferometry; phase-sensitive Fourier domain optical coherence tomography; cochlear vibration; speech; probe
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-126846 (URN)10.1117/1.JBO.21.2.025003 (DOI)000371735000006 ()26836207 (PubMedID)
Note

Funding Agencies|NIH NIDCD [R01DC000141]; NIH [R01DC004554, R01DC010201, R01DC011796]; Swedish Research Council [K2014-63X-14061-14-5]; Torsten Soderberg Foundation

Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2021-12-29
Bagger-Sjoback, D., Stromback, K., Hakizimana, P., Plue, J., Larsson, C., Hultcrantz, M., . . . Fridberger, A. (2015). A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery. PLOS ONE, 10(3), e0115657
Open this publication in new window or tab >>A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery
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2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 3, p. e0115657-Article in journal (Refereed) Published
Abstract [en]

Background Otosclerosis is a disorder that impairs middle ear function, leading to conductive hearing loss. Surgical treatment results in large improvement of hearing at low sound frequencies, but high-frequency hearing often suffers. A likely reason for this is that inner ear sensory cells are damaged by surgical trauma and loud sounds generated during the operation. Animal studies have shown that antioxidants such as N-Acetylcysteine can protect the inner ear from noise, surgical trauma, and some ototoxic substances, but it is not known if this works in humans. This trial was performed to determine whether antioxidants improve surgical results at high frequencies. Methods We performed a randomized, double-blind and placebo-controlled parallel group clinical trial at three Swedish university clinics. Using block-stratified randomization, 156 adult patients undergoing stapedotomy were assigned to intravenous N-Acetylcysteine (150 mg/kg body weight) or matching placebo (1:1 ratio), starting one hour before surgery. The primary outcome was the hearing threshold at 6 and 8 kHz; secondary outcomes included the severity of tinnitus and vertigo. Findings One year after surgery, high-frequency hearing had improved 2.7 +/- 3.8 dB in the placebo group (67 patients analysed) and 2.4 +/- 3.7 dB in the treated group (72 patients; means +/- 95% confidence interval, p = 0.54; linear mixed model). Surgery improved tinnitus, but there was no significant intergroup difference. Post-operative balance disturbance was common but improved during the first year, without significant difference between groups. Four patients receiving N-Acetylcysteine experienced mild side effects such as nausea and vomiting. Conclusions N-Acetylcysteine has no effect on hearing thresholds, tinnitus, or balance disturbance after stapedotomy.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117231 (URN)10.1371/journal.pone.0115657 (DOI)000351276300003 ()25763866 (PubMedID)
Note

Funding Agencies|AFA Forsakrings AB; Swedish Research Council [K2011-63X-14061-11-3]; Research Council for Working Life and Social Research [2006-1526]; Swedish National Association for Hard of Hearing People; Tysta Skolan foundation

Available from: 2015-04-22 Created: 2015-04-21 Last updated: 2021-12-29
Hakizimana, P. & Fridberger, A. (2015). Effects of salicylate on sound-evoked outer hair cell stereocilia deflections. Pflügers Archiv: European Journal of Physiology, 467(9), 2021-2029
Open this publication in new window or tab >>Effects of salicylate on sound-evoked outer hair cell stereocilia deflections
2015 (English)In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 467, no 9, p. 2021-2029Article in journal (Refereed) Published
Abstract [en]

Hearing depends on sound-evoked deflections of the stereocilia that protrude from the sensory hair cells in the inner ear. Although sound provides an important force driving stereocilia, forces generated through mechanically sensitive ion channels and through the motor protein prestin have been shown to influence stereocilia motion in solitary hair cells. While a possible influence of prestin on mechanically sensitive ion channels has not been systematically investigated, a decrease in transducer currents is evident in solitary hair cells when prestin is blocked with salicylate, raising the question of whether a reduced prestin activity or salicylate itself affected the mechanotransduction apparatus. We used two- and three-dimensional time-resolved confocal imaging to visualize outer hair cell stereocilia during sound stimulation in the apical turn of cochlear explant preparations from the guinea pig. Surprisingly, following application of salicylate, outer hair cell stereocilia deflections increased, while cochlear microphonic potentials decreased. However, when prestin activity was altered with the chloride ionophore tributyltin, both the cochlear microphonic potential and the stereocilia deflection amplitude decreased. Neither positive nor negative current stimulation abolished the bundle movements in the presence of salicylate, indicating that the observed effects did not depend on the endocochlear potential. These data suggest that salicylate may alter the mechanical properties of stereocilia, decreasing their bending stiffness.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2015
Keywords
Outer hair cells, Hearing, Salicylate, Tributyltin, Mechanotransduction, sound-evoked stereocilia movements
National Category
Health Sciences
Identifiers
urn:nbn:se:liu:diva-112088 (URN)10.1007/s00424-014-1646-4 (DOI)000359812600013 ()25392240 (PubMedID)
Funder
Swedish Research CouncilWenner-Gren Foundations
Note

Funders. Swedish Research Council [K2011-63X-14061-11-3]; Swedish Council for Working Life and Social Research [2006-1526]; Wallenberg foundations; Torsten Soderberg foundation; Tysta Skolan Foundation; Horselskadades Riksforbund; Wenner-Gren foundations

Available from: 2014-11-13 Created: 2014-11-13 Last updated: 2021-12-29
Bagger-Sjoback, D., Stromback, K., Hultcrantz, M., Papatziamos, G., Smeds, H., Danckwardt-Lilliestrom, N., . . . Fridberger, A. (2015). High-frequency hearing, tinnitus, and patient satisfaction with stapedotomy: A randomized prospective study. Scientific Reports, 5(13341)
Open this publication in new window or tab >>High-frequency hearing, tinnitus, and patient satisfaction with stapedotomy: A randomized prospective study
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2015 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, no 13341Article in journal (Refereed) Published
Abstract [en]

Otosclerosis is a common disorder that leads to conductive hearing loss. Most patients with otosclerosis also have tinnitus, and surgical treatment is known to improve hearing as well as tinnitus. Some patients however experience worsening of tinnitus after the operation, but there are no known factors that allow surgeons to predict who will be at risk. In this prospective observational study on 133 patients undergoing stapedotomy, we show that postoperative air conduction thresholds at very high stimulus frequencies predict improvement of tinnitus, as assessed with proportional odds logistic regression models. Young patients were significantly more likely to experience reduction of tinnitus and patients whose tinnitus became better were also more satisfied with the outcome of the operation. These findings have practical importance for patients and their surgeons. Young patients can be advised that surgery is likely to be beneficial for their tinnitus, but a less positive message should be conveyed to older patients.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121105 (URN)10.1038/srep13341 (DOI)000359839200001 ()26293121 (PubMedID)
Note

Funding Agencies|AFA Forsakrings AB; Swedish Research Council [K2014-63X-14061-14-5]; Stockholm County Council; Tysta Skolan foundation; Horselskadades Riksforbund; Swedish Research Council for Health, Working Life and Welfare [2006-1526]

Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2022-09-15
Grosh, K., Ren, T., He, W., Fridberger, A., Li, Y. & Nankali, A. (2015). Light-Induced Basilar Membrane Vibrations in the Sensitive Cochlea. In: MECHANICS OF HEARING: PROTEIN TO PERCEPTION: . Paper presented at 12th International Workshop on the Mechanics of Hearing. AMER INST PHYSICS, 1703(070005)
Open this publication in new window or tab >>Light-Induced Basilar Membrane Vibrations in the Sensitive Cochlea
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2015 (English)In: MECHANICS OF HEARING: PROTEIN TO PERCEPTION, AMER INST PHYSICS , 2015, Vol. 1703, no 070005Conference paper, Published paper (Refereed)
Abstract [en]

The exceptional sensitivity of mammalian hearing organ is attributed to an outer hair cell-mediated active process, where forces produced by sensory cells boost sound-induced vibrations, making soft sounds audible. This process is thought to be local, with each section of the hearing organ capable of amplifying sound-evoked movement, and nearly instantaneous, since amplification can work for sounds at frequencies up to 100 kHz in some species. To test these precepts, we developed a method for focally stimulating the living hearing organ with light. Light pulses caused intense and highly damped mechanical responses followed by traveling waves that developed with considerable delay. The delayed response was identical to movements evoked by click-like sounds. A physiologically based mathematical model shows that such waves engage the active process, enhancing hearing sensitivity. The experiments and the theoretical analysis show that the active process is neither local nor instantaneous, but requires mechanical waves traveling from the cochlear base toward its apex.

Place, publisher, year, edition, pages
AMER INST PHYSICS, 2015
Series
AIP Conference Proceedings, ISSN 0094-243X
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-127073 (URN)10.1063/1.4939379 (DOI)000372065400066 ()978-0-7354-1350-4 (ISBN)
Conference
12th International Workshop on the Mechanics of Hearing
Available from: 2016-04-13 Created: 2016-04-13 Last updated: 2021-12-29
Strimbu, C. E. & Fridberger, A. (2015). Noise Alters Hair-Bundle Mechanics at the Cochlear Apex. In: Mechanics of hearing: Protein to perception: . Paper presented at 12th International Workshop on the Mechanics of Hearing, Cape Sounio, Greece, 23–29 June 2014 (pp. 030014-1-030014-5). American Institute of Physics (AIP), 1703(030014)
Open this publication in new window or tab >>Noise Alters Hair-Bundle Mechanics at the Cochlear Apex
2015 (English)In: Mechanics of hearing: Protein to perception, American Institute of Physics (AIP), 2015, Vol. 1703, no 030014, p. 030014-1-030014-5Conference paper, Published paper (Refereed)
Abstract [en]

Exposure to loud sounds can lead to both permanent and short term changes in auditory sensitivity. Permanent hearing loss is often associated with gross changes in cochlear morphology including the loss of hair cells and auditory nerve fibers while the mechanisms of short term threshold shifts are much less well understood and may vary at different locations across the cochlea. Previous reports suggest that exposure to loud sounds leads to a decrease in the cochlear microphonic potential and in the stiffness of the organ of Corti. Because the cochlear microphonic reflects changes in the membrane potential of the hair cells, this suggests that hair-bundle motion should be reversibly altered following exposure to loud sounds. Using an in vitro preparation of the guinea pig temporal bone we investigate changes in the micro-mechanical response near the cochlear apex following a brief (up to 10 - 20 minutes) exposure to loud (similar to 120 dB) tones near the best frequency at this location. We use time-resolved confocal imaging to record the motion of outer hair cell bundles before and after acoustic overstimulation. We have also recorded larger-scale structural views of the organ of Corti before and after exposure to the loud sound. Conventional electrophysiological techniques are used measure the cochlear microphonic potential. As has been previously reported, following acoustic overexposure the cochlear microphonic declines in value and typically recovers on the order of 30 - 60 minutes. Hair-bundle trajectories are affected following the loud sound and typically recover on a somewhat faster time scale than the microphonic potential, although the results vary considerably across preparations. Preliminary results also suggest reversible changes in the hair cells resting potential following the loud sound.

Place, publisher, year, edition, pages
American Institute of Physics (AIP), 2015
Series
AIP Conference Proceedings, ISSN 0094-243X
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-127079 (URN)10.1063/1.4939329 (DOI)000372065400016 ()978-0-7354-1350-4 (ISBN)
Conference
12th International Workshop on the Mechanics of Hearing, Cape Sounio, Greece, 23–29 June 2014
Available from: 2016-04-13 Created: 2016-04-13 Last updated: 2021-12-29
Yamashita, T., Hakizimana, P., Wu, S., Hassan, A., Jacob, S., Temirov, J., . . . Zuo, J. (2015). Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins. PLOS Genetics, 11(9), Article ID e1005500.
Open this publication in new window or tab >>Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins
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2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 9, article id e1005500Article in journal (Refereed) Published
Abstract [en]

Nature's fastest motors are the cochlear outer hair cells (OHCs). These sensory cells use a membrane protein, Slc26a5 (prestin), to generate mechanical force at high frequencies, which is essential for explaining the exquisite hearing sensitivity of mammalian ears. Previous studies suggest that Slc26a5 continuously diffuses within the membrane, but how can a freely moving motor protein effectively convey forces critical for hearing? To provide direct evidence in OHCs for freely moving Slc26a5 molecules, we created a knockin mouse where Slc26a5 is fused with YFP. These mice and four other strains expressing fluorescently labeled membrane proteins were used to examine their lateral diffusion in the OHC lateral wall. All five proteins showed minimal diffusion, but did move after pharmacological disruption of membrane-associated structures with a cholesterol-depleting agent and salicylate. Thus, our results demonstrate that OHC lateral wall structure constrains the mobility of plasma membrane proteins and that the integrity of such membrane-associated structures are critical for Slc26a5's active and structural roles. The structural constraint of membrane proteins may exemplify convergent evolution of cellular motors across species. Our findings also suggest a possible mechanism for disorders of cholesterol metabolism with hearing loss such as Niemann-Pick Type C diseases.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-121278 (URN)10.1371/journal.pgen.1005500 (DOI)000362269000022 ()26352669 (PubMedID)
Note

Funding text: National Institutes of Health [DC006471, P30CA21765, DC00354, DC02775, P01GM051487]; Office of Naval Research [N000140911014, N000141210191, N000141210775]; Swedish Research Council [K2014-63X-14061-14-5]; Research Council for Working Life and Social Rese

Available from: 2015-09-11 Created: 2015-09-11 Last updated: 2021-12-29
Projects
Softer and thinner cochlear implants [2022-03339_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7960-1559

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