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Edwin W Rubel - One of the best experts on this subject based on the ideXlab platform.
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The zebrafish merovingian mutant reveals a role for pH regulation in Hair Cell toxicity and function.
Disease models & mechanisms, 2014Co-Authors: Tamara M. Stawicki, Edwin W Rubel, Kelly N. Owens, Tor Linbo, Katherine E. Reinhart, David W RaibleAbstract:Control of the extraCellular environment of inner ear Hair Cells by ionic transporters is crucial for Hair Cell function. In addition to inner ear Hair Cells, aquatic vertebrates have Hair Cells on the surface of their body in the lateral line system. The ionic environment of these Cells also appears to be regulated, although the mechanisms of this regulation are less understood than those of the mammalian inner ear. We identified the merovingian mutant through genetic screening in zebrafish for genes involved in drug-induced Hair Cell death. Mutants show complete resistance to neomycin-induced Hair Cell death and partial resistance to cisplatin-induced Hair Cell death. This resistance is probably due to impaired drug uptake as a result of reduced mechanotransduction ability, suggesting that the mutants have defects in Hair Cell function independent of drug treatment. Through genetic mapping we found that merovingian mutants contain a mutation in the transcription factor gcm2. This gene is important for the production of ionocytes, which are Cells crucial for whole body pH regulation in fish. We found that merovingian mutants showed an acidified extraCellular environment in the vicinity of both inner ear and lateral line Hair Cells. We believe that this acidified extraCellular environment is responsible for the defects seen in Hair Cells of merovingian mutants, and that these mutants would serve as a valuable model for further study of the role of pH in Hair Cell function.
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functional mechanotransduction is required for cisplatin induced Hair Cell death in the zebrafish lateral line
The Journal of Neuroscience, 2013Co-Authors: Andrew J Thomas, Edwin W Rubel, David W Raible, Tamara M. Stawicki, Dale W Hailey, Allison B Coffin, Julian A SimonAbstract:Cisplatin, one of the most commonly used anticancer drugs, is known to cause inner ear Hair Cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced Hair Cell death, little is known about the mechanism whereby cisplatin is selectively toxic to Hair Cells. Using Hair Cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced Hair Cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced Hair Cell death. Using a fluorescent analog of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced Hair Cell death is dependent on functional mechanotransduction in the zebrafish lateral line.
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Hair Cell replacement in adult mouse utricles after targeted ablation of Hair Cells with diphtheria toxin
The Journal of Neuroscience, 2012Co-Authors: Justin S Golub, Edwin W Rubel, Ling Tong, Tot B Ngyuen, Cliff R Hume, Richard D Palmiter, Jennifer S StoneAbstract:We developed a transgenic mouse to permit conditional and selective ablation of Hair Cells in the adult mouse utricle by inserting the human diphtheria toxin receptor (DTR) gene into the Pou4f3 gene, which encodes a Hair Cell-specific transcription factor. In adult wild-type mice, administration of diphtheria toxin (DT) caused no significant Hair Cell loss. In adult Pou4f3(+/DTR) mice, DT treatment reduced Hair Cell numbers to 6% of normal by 14 days post-DT. Remaining Hair Cells were located primarily in the lateral extrastriola. Over time, Hair Cell numbers increased in these regions, reaching 17% of untreated Pou4f3(+/DTR) mice by 60 days post-DT. Replacement Hair Cells were morphologically distinct, with multiple cytoplasmic processes, and displayed evidence for active mechanotransduction channels and synapses characteristic of type II Hair Cells. Three lines of evidence suggest replacement Hair Cells were derived via direct (nonmitotic) transdifferentiation of supporting Cells: new Hair Cells did not incorporate BrdU, supporting Cells upregulated the pro-Hair Cell gene Atoh1, and supporting Cell numbers decreased over time. This study introduces a new method for efficient conditional Hair Cell ablation in adult mouse utricles and demonstrates that Hair Cells are spontaneously regenerated in vivo in regions where there may be ongoing Hair Cell turnover.
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identification of modulators of Hair Cell regeneration in the zebrafish lateral line
The Journal of Neuroscience, 2012Co-Authors: Parhum Namdaran, Kelly N. Owens, David W Raible, Katherine E. Reinhart, Edwin W RubelAbstract:The external location of the zebrafish lateral line makes it a powerful model for studying mechanosensory Hair Cell regeneration. We have developed a chemical screen to identify FDA-approved drugs and biologically active compounds that modulate Hair Cell regeneration in zebrafish. Of the 1680 compounds evaluated, we identified two enhancers and six inhibitors of regeneration. The two enhancers, dexamethasone and prednisolone, are synthetic glucocorticoids that potentiated Hair Cell numbers during regeneration and also induced Hair Cell addition in the absence of damage. BrdU analysis confirmed that the extra Hair Cells arose from mitotic activity. We found that dexamethasone and prednisolone, like other glucocorticoids, suppress zebrafish caudal fin regeneration, indicating that Hair Cell regeneration occurs by a distinctly different process. Further analyses of the regeneration inhibitors revealed that two of the six, flubendazole and topotecan, significantly suppress Hair Cell regeneration by preventing proliferation of Hair Cell precursors. Flubendazole halted support Cell division in M-phase, possibly by interfering with normal microtubule activity. Topotecan, a topoisomerase inhibitor, killed both Hair Cells and proliferating Hair Cell precursors. A third inhibitor, fulvestrant, moderately delayed Hair Cell regeneration by reducing support Cell proliferation. Our observation that Hair Cells do not regenerate when support Cell proliferation is impeded confirms previous observations that Cell division is the primary route for Hair Cell regeneration after neomycin treatment in zebrafish.
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cisplatin induced Hair Cell loss in zebrafish danio rerio lateral line
Hearing Research, 2007Co-Authors: David W Raible, Edwin W RubelAbstract:We have used time-lapse imaging to study cisplatin-induced Hair Cell death in lateral line neuromasts of zebrafish larvae in vivo. We found that cisplatin-induced Hair Cell death occurred much more slowly than had been shown to occur in aminoglycoside-induced Hair Cell death. By prelabeling Hair Cells with FM1-43FX, and assessing Hair Cell damage, it was established that cisplatin causes Hair Cell loss in the lateral line in a dose-dependent fashion. The kinetics of Hair Cell loss during exposure to different concentrations of cisplatin was also assessed and it was found that the onset of Hair Cell loss correlated with the accumulated dose of cisplatin. These data demonstrate the feasibility and repeatability of cisplatin damage protocols in the zebrafish lateral line and set the stage for future evaluations of modulation of cisplatin-induced Hair Cell death.
David W Raible - One of the best experts on this subject based on the ideXlab platform.
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ca2 permeable ampars mediate glutamatergic transmission and excitotoxic damage at the Hair Cell ribbon synapse
The Journal of Neuroscience, 2017Co-Authors: Joy Y Sebe, Soyoun Cho, Lavinia Sheets, Mark A Rutherford, Henrique Von Gersdorff, David W RaibleAbstract:We report functional and structural evidence for GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs) at the mature Hair Cell ribbon synapse. By using the methodological advantages of three species (of either sex), we demonstrate that CP-AMPARs are present at the Hair Cell synapse in an evolutionarily conserved manner. Via a combination of in vivo electrophysiological and Ca2+ imaging approaches in the larval zebrafish, we show that Hair Cell stimulation leads to robust Ca2+ influx into afferent terminals. Prolonged application of AMPA caused loss of afferent terminal responsiveness, whereas blocking CP-AMPARs protects terminals from excitotoxic swelling. Immunohistochemical analysis of AMPAR subunits in mature rat cochlea show regions within synapses lacking the GluA2 subunit. Paired recordings from adult bullfrog auditory synapses demonstrate that CP-AMPARs mediate a major component of glutamatergic transmission. Together, our results support the importance of CP-AMPARs in mediating transmission at the Hair Cell ribbon synapse. Further, excess Ca2+ entry via CP-AMPARs may underlie afferent terminal damage following excitotoxic challenge, suggesting that limiting Ca2+ levels in the afferent terminal may protect against cochlear synaptopathy associated with hearing loss.SIGNIFICANCE STATEMENT A single incidence of noise overexposure causes damage at the Hair Cell synapse that later leads to neurodegeneration and exacerbates age-related hearing loss. A first step toward understanding cochlear neurodegeneration is to identify the cause of initial excitotoxic damage to the postsynaptic neuron. Using a combination of immunohistochemical, electrophysiological, and Ca2+ imaging approaches in evolutionarily divergent species, we demonstrate that Ca2+-permeable AMPARs (CP-AMPARs) mediate glutamatergic transmission at the adult auditory Hair Cell synapse. Overexcitation of the terminal causes Ca2+ accumulation and swelling that can be prevented by blocking CP-AMPARs. We demonstrate that CP-AMPARs mediate transmission at this first-order sensory synapse and that limiting Ca2+ accumulation in the terminal may protect against hearing loss.
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The zebrafish merovingian mutant reveals a role for pH regulation in Hair Cell toxicity and function.
Disease models & mechanisms, 2014Co-Authors: Tamara M. Stawicki, Edwin W Rubel, Kelly N. Owens, Tor Linbo, Katherine E. Reinhart, David W RaibleAbstract:Control of the extraCellular environment of inner ear Hair Cells by ionic transporters is crucial for Hair Cell function. In addition to inner ear Hair Cells, aquatic vertebrates have Hair Cells on the surface of their body in the lateral line system. The ionic environment of these Cells also appears to be regulated, although the mechanisms of this regulation are less understood than those of the mammalian inner ear. We identified the merovingian mutant through genetic screening in zebrafish for genes involved in drug-induced Hair Cell death. Mutants show complete resistance to neomycin-induced Hair Cell death and partial resistance to cisplatin-induced Hair Cell death. This resistance is probably due to impaired drug uptake as a result of reduced mechanotransduction ability, suggesting that the mutants have defects in Hair Cell function independent of drug treatment. Through genetic mapping we found that merovingian mutants contain a mutation in the transcription factor gcm2. This gene is important for the production of ionocytes, which are Cells crucial for whole body pH regulation in fish. We found that merovingian mutants showed an acidified extraCellular environment in the vicinity of both inner ear and lateral line Hair Cells. We believe that this acidified extraCellular environment is responsible for the defects seen in Hair Cells of merovingian mutants, and that these mutants would serve as a valuable model for further study of the role of pH in Hair Cell function.
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functional mechanotransduction is required for cisplatin induced Hair Cell death in the zebrafish lateral line
The Journal of Neuroscience, 2013Co-Authors: Andrew J Thomas, Edwin W Rubel, David W Raible, Tamara M. Stawicki, Dale W Hailey, Allison B Coffin, Julian A SimonAbstract:Cisplatin, one of the most commonly used anticancer drugs, is known to cause inner ear Hair Cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced Hair Cell death, little is known about the mechanism whereby cisplatin is selectively toxic to Hair Cells. Using Hair Cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced Hair Cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced Hair Cell death. Using a fluorescent analog of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced Hair Cell death is dependent on functional mechanotransduction in the zebrafish lateral line.
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identification of modulators of Hair Cell regeneration in the zebrafish lateral line
The Journal of Neuroscience, 2012Co-Authors: Parhum Namdaran, Kelly N. Owens, David W Raible, Katherine E. Reinhart, Edwin W RubelAbstract:The external location of the zebrafish lateral line makes it a powerful model for studying mechanosensory Hair Cell regeneration. We have developed a chemical screen to identify FDA-approved drugs and biologically active compounds that modulate Hair Cell regeneration in zebrafish. Of the 1680 compounds evaluated, we identified two enhancers and six inhibitors of regeneration. The two enhancers, dexamethasone and prednisolone, are synthetic glucocorticoids that potentiated Hair Cell numbers during regeneration and also induced Hair Cell addition in the absence of damage. BrdU analysis confirmed that the extra Hair Cells arose from mitotic activity. We found that dexamethasone and prednisolone, like other glucocorticoids, suppress zebrafish caudal fin regeneration, indicating that Hair Cell regeneration occurs by a distinctly different process. Further analyses of the regeneration inhibitors revealed that two of the six, flubendazole and topotecan, significantly suppress Hair Cell regeneration by preventing proliferation of Hair Cell precursors. Flubendazole halted support Cell division in M-phase, possibly by interfering with normal microtubule activity. Topotecan, a topoisomerase inhibitor, killed both Hair Cells and proliferating Hair Cell precursors. A third inhibitor, fulvestrant, moderately delayed Hair Cell regeneration by reducing support Cell proliferation. Our observation that Hair Cells do not regenerate when support Cell proliferation is impeded confirms previous observations that Cell division is the primary route for Hair Cell regeneration after neomycin treatment in zebrafish.
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Feathers and Fins: Non-mammalian models for Hair Cell regeneration
Brain research, 2009Co-Authors: Heather R Brignull, David W Raible, Jennifer S StoneAbstract:Death of mechanosensory Cells in the inner ear results in two profound disabilities: hearing loss and balance disorders. Although mammals lack the capacity to regenerate Hair Cells, recent studies in mice and other rodents have offered valuable insight into strategies for stimulating Hair Cell regeneration in mammals. Investigations of model organisms that retain the ability to form new Hair Cells after embryogenesis, such as fish and birds, are equally important and have provided clues as to the Cellular and molecular mechanisms that may block Hair Cell regeneration in mammals. Here, we summarize studies on Hair Cell regeneration in the chicken and the zebrafish, discuss specific advantages of each model, and propose future directions for the use of non-mammalian models in understanding Hair Cell regeneration.
Andrew Forge - One of the best experts on this subject based on the ideXlab platform.
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Localized disorganization of the cochlear inner Hair Cell synaptic region after noise exposure.
Biology open, 2019Co-Authors: Anwen Bullen, Lucy A. Anderson, Warren Bakay, Andrew ForgeAbstract:The prevalence and importance of hearing damage caused by noise levels not previously thought to cause permanent hearing impairment has become apparent in recent years. The damage to, and loss of, afferent terminals of auditory nerve fibres at the cochlear inner Hair Cell has been well established, but the effects of noise exposure and terminal loss on the inner Hair Cell are less known. Using three-dimensional structural studies in mice we have examined the consequences of afferent terminal damage on inner Hair Cell morphology and intraCellular structure. We identified a structural phenotype in the pre-synaptic regions of these damaged Hair Cells that persists for four weeks after noise exposure, and demonstrates a specific dysregulation of the synaptic vesicle recycling pathway. We show evidence of a failure in regeneration of vesicles from small membrane cisterns in damaged terminals, resulting from a failure of separation of small vesicle buds from the larger cisternal membranes.
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Hair Cell regeneration in sensory epithelia from the inner ear of a urodele amphibian
The Journal of Comparative Neurology, 2005Co-Authors: Ruth Taylor, Andrew ForgeAbstract:The capacity of urodele amphibians to regenerate a variety of body parts is providing insight into mechanisms of tissue regeneration in vertebrates. In this study the ability of the newt, Notophthalmus viridescens, to regenerate inner ear Hair Cells in vitro was examined. Intact otic capsules were maintained in organotypic culture. Incubation in 2 mM gentamicin for 48 hours resulted in ablation of all Hair Cells from the saccular maculae. Thus, any Hair Cell recovery was not due to repair of damaged Hair Cells. Immature Hair Cells were subsequently observed at approximately 12 days posttreatment. Their number increased over the following 7-14 days to reach approximately 30% of the normal number. Following incubation of damaged tissue with bromodeoxyuridine (BrdU), labeled nuclei were confined strictly within regions of Hair Cell loss, indicating that supporting Cells entered S-phase. Double labeling of tissue with two different Hair Cell markers and three different antibodies to BrdU in various combinations, however, all showed that the nuclei of Cells that labeled with Hair Cell markers did not label for BrdU. This suggested that the new Hair Cells were not derived from those Cells that had undergone mitosis. When mitosis was blocked with aphidicolin, new Hair Cells were still generated. The results suggest that direct phenotypic conversion of supporting Cells into Hair Cells without an intervening mitotic event is a major mechanism of Hair Cell regeneration in the newt. A similar mechanism has been proposed for the Hair Cell recovery phenomenon observed in the vestibular organs of mammals.
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Hair Cell recovery in the vestibular sensory epithelia of mature guinea pigs
The Journal of Comparative Neurology, 1998Co-Authors: Andrew Forge, Graham NevillAbstract:The progression of recovery of the vestibular sensory epithelia of guinea pigs after gentamicin-induced Hair Cell injury was assessed quantitatively and qualitatively. Evaluations were made of the number of Cells bearing Hair bundles by using scanning electron microscopy (SEM) and of identifiable Hair Cells in thin sections. Both assessment procedures showed that an initial loss of Hair Cells in utricular maculae is followed by significant recovery in the number of Hair Cells present. SEM also showed recovery in saccules comparable to that in utricles. During the recovery, progressive maturation of Hair bundles, which exhibited features similar to those seen during normal ontogenetic development of Hair Cells, could be identified. The pattern and extent of Hair Cell loss and subsequent reappearance revealed by SEM corresponded with that derived from analysis of thin sections. This suggests that repair of nonlethally damaged Hair Cells is unlikely but, rather, that new Hair Cells are produced. An apparent decrease in supporting Cell numbers was observed coincident with the increase in Hair Cell numbers. This complements previous morphological observations, which have suggested new Hair Cells arise from direct, nonmitotic transdifferentiation of supporting Cells. The quantitative analyses indicate that more than half of the Hair Cells that are lost are replaced, but the recovery process does not result in complete restoration of the epithelium. Eight months after the end of drug treatment, the number of Hair Cells present was still significantly less than normal, and several other abnormalities persisted. There was also no evidence of any Hair Cell recovery in the organ of Corti. Thus, there appear to be limitations on the capacity for spontaneous replacement of lost Hair Cells in the mammalian inner ear.
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two modes of Hair Cell loss from the vestibular sensory epithelia of the guinea pig inner ear
The Journal of Comparative Neurology, 1995Co-Authors: Graham Nevill, Andrew ForgeAbstract:In the vestibular and auditory neurosensory epithelia of poikilothermic vertebrates and of birds, damaged sensory ''Hair'' Cells are often deleted by extrusion from the apical surface. In contrast, in the adult mammalian auditory epithelium (the organ of Corti), the bodies of damaged Hair Cells degenerate within the epithelium. To determine whether this apparent difference is species related or is associated with the differing structural organisation of the epithelia, Hair Cell deletion in the mammalian vestibular end-organs was examined. The structural organisation of these tissues is closer to that of the inner ear epithelia of lower vertebrates than to the organ of Corti. Hair Cell loss was induced by chronic, systemic treatment of guinea pigs with the ototoxic aminoglycoside antibiotic gentamicin. The vestibular sensory epithelia were examined at various times after treatment via scanning electron microscopy, thin sectioning, and staining f-actin with fluorescently labelled phalloidin. Two distinct modes of Hair Cell loss were identified: 1) degeneration of Hair Cells within the epithelium, which often showed morphological features consistent with those described for apoptosis, and 2) extrusion of intact Cells from the apical surface. Neither process caused the formation of obvious lesions through the epithelial surfaces. Expansion of adjacent supporting Cells during Hair Cell deletion resulted in repair that appeared to preserve permeability barriers. There was also no evidence of inflammation accompanying Hair Cell removal. Thus, with both modes of Hair Cell loss, it appeared that deletion of Hair Cells was achieved without disruption of tissue architecture or integrity. This may be important for subsequent repair and regeneration processes to operate. (C) 1995 Wiley-Liss, Inc.
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ultrastructural evidence for Hair Cell regeneration in the mammalian inner ear
Science, 1993Co-Authors: Andrew Forge, Jeffrey T Corwin, Graham NevillAbstract:It has long been thought that Hair Cell loss from the inner ears of mammals is irreversible. This report presents scanning electron micrographs and thin sections of the utricles from the inner ears of guinea pigs that show that, after Hair Cell loss caused by treatment with the aminoglycoside gentamicin, Hair Cells reappeared. Four weeks after the end of treatment, a large number of Cells with immature Hair bundles in multiple stages of development could be identified in the utricle. Thin sections showed that lost type 1 Hair Cells were replaced by Cells with a morphology similar to that of type 2 Hair Cells. These results indicate an unexpected capacity for Hair Cell regeneration in vivo in the mature mammalian inner ear.
Richard Salvi - One of the best experts on this subject based on the ideXlab platform.
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insensitivity of the audiogram to carboplatin induced inner Hair Cell loss in chinchillas
Hearing Research, 2013Co-Authors: Edward Lobarinas, Richard Salvi, Dalian DingAbstract:Noise trauma, aging, and ototoxicity preferentially damage the outer Hair Cells of the inner ear, leading to increased hearing thresholds and poorer frequency resolution. Whereas outer Hair Cells make synaptic connections with less than 10% of afferent auditory nerve fibers (type-II), inner Hair Cells make connections with over 90% of afferents (type-I). Despite these extensive connections, little is known about how selective inner Hair Cell loss impacts hearing. In chinchillas, moderate to high doses of the anticancer compound carboplatin produce selective inner Hair Cell and type-I afferent loss with little to no effect on outer Hair Cells. To determine the effects of carboplatin-induced inner Hair Cell loss on the most widely used clinical measure of hearing, the audiogram, pure-tone thresholds were determined behaviorally before and after 75 mg/kg carboplatin. Following carboplatin treatment, small effects on audiometric thresholds were observed even with extensive inner Hair Cell losses that exceed 80%. These results suggest that conventional audiometry is insensitive to inner Hair Cell loss and that only small populations of inner Hair Cells appear to be necessary for detecting tonal stimuli in a quiet background.
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up regulation of gap 43 in the chinchilla ventral cochlear nucleus after carboplatin induced hearing loss correlations with inner Hair Cell loss and outer Hair Cell loss
Hearing Research, 2013Co-Authors: Kari Suzanne Kraus, Dalian Ding, Haiyan Jiang, Mohammad Habiby Kermany, S Mitra, Richard SalviAbstract:Inner ear damage leads to nerve fiber growth and synaptogenesis in the ventral cochlear nucleus (VCN). In this study, we documented the relationship between Hair Cell loss patterns and synaptic plasticity in the chinchilla VCN using immunolabeling of the growth associated protein-43 (GAP-43), a protein associated with axon outgrowth and modification of presynaptic endings. Unilateral round window application of carboplatin caused Hair Cell degeneration in which inner Hair Cells (IHC) were more vulnerable than outer Hair Cells (OHC). One month after carboplatin treatment (0.5-5 mg/ml), we observed varying patterns of cochlear Hair Cell loss and GAP-43 expression in VCN. Both IHC loss and OHC loss were strongly correlated with increased GAP-43 immunolabeling in the ipsilateral VCN. We speculate that two factors might promote the expression of GAP-43 in the VCN; one is the loss of afferent input through IHC or the associated type I auditory nerve fibers. The other occurs when the medial olivocochlear efferent neurons lose their cochlear targets, the OHC, and may as compensation increase their synapse numbers in the VCN.
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age related cochlear Hair Cell loss is enhanced in mice lacking copper zinc superoxide dismutase
Neurobiology of Aging, 1999Co-Authors: Sandra L Mcfadden, Dalian Ding, Andrew G Reaume, Dorothy G Flood, Richard SalviAbstract:Age-related hearing loss in humans and many strains of mice is associated with a base-to-apex gradient of cochlear Hair Cell loss. To determine if copper/zinc superoxide dismutase (Cu/Zn SOD) deficiency influences age-related cochlear pathology, we compared Hair Cell losses in cochleas obtained from 2-, 7-, and 17- to 19-month-old wild type (WT) mice with normal levels of Cu/Zn SOD and mutant knockout (KO) mice with a targeted deletion of Sod1, the gene that codes for Cu/Zn SOD. WT and KO mice exhibited similar patterns of Hair Cell loss with age, i.e., a baso-apical progression of Hair Cell loss, with greater loss of outer Hair Cells than inner Hair Cells. Within each age group, the magnitude of loss was much greater in KO mice compared to WT mice. The results indicate that Cu/Zn SOD deficiency potentiates cochlear Hair Cell degeneration, presumably through metabolic pathways involving the superoxide radical.
William E. Brownell - One of the best experts on this subject based on the ideXlab platform.
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Sound-induced length changes in outer Hair Cell stereocilia
Nature communications, 2012Co-Authors: Pierre Hakizimana, William E. Brownell, Stefan Jacob, Anders FridbergerAbstract:Hearing relies on mechanical stimulation of stereocilia bundles on the sensory Cells of the inner ear. When sound hits the ear, each stereocilium pivots about a neck-like taper near their base. More than three decades of research have established that sideways deflection of stereocilia is essential for converting mechanical stimuli into electrical signals. Here we show that mammalian outer Hair Cell stereocilia not only move sideways but also change length during sound stimulation. Currents that enter stereocilia through mechanically sensitive ion channels control the magnitude of both length changes and bundle deflections in a reciprocal manner: the smaller the length change, the larger is the bundle deflection. Thus, the transduction current is important for maintaining the resting mechanical properties of stereocilia. Hair Cell stimulation is most effective when bundles are in a state that ensures minimal length change.
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micro and nanomechanics of the cochlear outer Hair Cell
Annual Review of Biomedical Engineering, 2001Co-Authors: William E. Brownell, Alexander A Spector, Robert M Raphael, Aleksander S PopelAbstract:▪ Abstract Outer Hair Cell electromotility is crucial for the amplification, sharp frequency selectivity, and nonlinearities of the mammalian cochlea. Current modeling efforts based on morphological, physiological, and biophysical observations reveal transmembrane potential gradients and membrane tension as key independent variables controlling the passive and active mechanics of the Cell. The Cell's mechanics has been modeled on the microscale using a continuum approach formulated in terms of effective (Cellular level) mechanical and electric properties. Another modeling approach is nanostructural and is based on the molecular organization of the Cell's membranes and cytoskeleton. It considers interactions between the components of the composite Cell wall and the molecular elements within each of its components. The methods and techniques utilized to increase our understanding of the central role outer Hair Cell mechanics plays in hearing are also relevant to broader research questions in Cell mechanics,...
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contribution of membrane cholesterol to outer Hair Cell lateral wall stiffness
Otolaryngology-Head and Neck Surgery, 1998Co-Authors: Thanhvan N Nguyen, William E. BrownellAbstract:The outer Hair Cell can be divided into three domains: the apex, the base, and the lateral wall. With the use of filipin, a polyene fluorescent antibiotic that binds to cholesterol, we found under fluorescence microscopy that the lateral wall membranes were less intensely stained than the apical and basal membranes. This difference in filipin fluorescence between the lateral walls and the ends diminished when Cells were incubated in water-soluble cholesterol before staining, suggesting that exogenous cholesterol enters the lateral wall. Under confocal microscopy, we studied the incorporation pattern of a fluorescent cholesterol analogue, NBD-cholesterol. NBD-cholesterol did not stain the apical membranes whereas it intensely labeled the lateral wall. The micropipette aspiration technique was used to assess the effect of cholesterol on lateral wall stiffness. The lateral wall stiffness parameter of Cells treated with water-soluble cholesterol (n = 23) was significantly higher than that of controls (n = 27): 0.76 ± 0.24 (mean ± SD) versus 0.46 ± 0.10 (Student’s t test, p < 0.001). In conclusion, cholesterol has different distributions among outer Hair Cell membranes, and when water-soluble cholesterol is incorporated into the Cells, the outer Hair Cell lateral wall stiffness parameter increases. (Otolaryngol Head Neck Surg 1998;119:14-20.)
