Carboplatin ototoxicity: an animal model

1993 ◽  
Vol 107 (7) ◽  
pp. 585-589 ◽  
Author(s):  
Mark Wake ◽  
Sachio Takeno ◽  
Danyl Ibrahim ◽  
Robert Harrison ◽  
Richard Mount
Keyword(s):  
Animal Model ◽  
Light Microscopy ◽  
Hair Cell ◽  
Brain Stem ◽  
Auditory System ◽  
Hair Cells ◽  
Afferent Input ◽  
Evoked Responses ◽  
Auditory Thresholds ◽  
Scanning Electronmicroscopy

A new animal model of ototoxicity is presented using intravenous carboplatin in adult chinchillas. A range of physiological and morphological effects was produced using doses calculated from the recommended therapeutic range (200–400 mg/m2). Auditory thresholds to tone pips stimuli were monitored using brain stem evoked responses (ABR). Cochlear histopathology was studied by light microscopy (LM) and ultrstructural hair cell abnormalities investigated with scanning electronmicroscopy (SEM). Carboplatin in this animal model predominantly affected the inner hair cells. This may provide an important model for the study of selective loss of the main afferent input in the auditory system.

scholarly journals Efferent Control of Hair Cell and Afferent Responses in the Semicircular Canals

2009 ◽  
Vol 102 (3) ◽  
pp. 1513-1525 ◽  
Author(s):  
Richard Boyle ◽  
Richard D. Rabbitt ◽  
Stephen M. Highstein
Keyword(s):  
Hair Cell ◽  
Brain Stem ◽  
Hair Cells ◽  
Intracellular Signaling ◽  
Dynamic Range ◽  
Reversal Potential ◽  
Semicircular Canals ◽  
Resting Potential ◽  
Efferent Neurons ◽  
The Brain

The sensations of sound and motion generated by the inner ear are controlled by the brain through extensive centripetal innervation originating within the brain stem. In the semicircular canals, brain stem efferent neurons make synaptic contacts with mechanosensory hair cells and with the dendrites of afferent neurons. Here, we examine the relative contributions of efferent action on hair cells and afferents. Experiments were performed in vivo in the oyster toadfish, Opsanus tau. The efferent system was activated via electrical pulses to the brain stem and sensory responses to motion stimuli were quantified by simultaneous voltage recording from afferents and intracellular current- and/or voltage-clamp recordings from hair cells. Results showed synaptic inputs to both afferents and hair cells leading to relatively long-latency intracellular signaling responses: excitatory in afferents and inhibitory in hair cells. Generally, the net effect of efferent action was an increase in afferent background discharge and a simultaneous decrease in gain to angular motion stimuli. Inhibition of hair cells was likely the result of a ligand-gated opening of a major basolateral conductance. The reversal potential of the efferent-evoked current was just below the hair cell resting potential, thus resulting in a small hyperpolarization. The onset latency averaged about 90 ms and latency to peak response was 150–400 ms. Hair cell inhibition often outlasted afferent excitation and, in some cases, latched hair cells in the “off” condition for >1 s following cessation of stimulus. These features endow the animal with a powerful means to adjust the sensitivity and dynamic range of motion sensation.

Recovery of the Vestibulocolic Reflex After Aminoglycoside Ototoxicity in Domestic Chickens

1999 ◽  
Vol 81 (3) ◽  
pp. 1025-1035 ◽  
Author(s):  
Christopher T. Goode ◽  
John P. Carey ◽  
Albert F. Fuchs ◽  
Edwin W Rubel
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Afferent Input ◽  
Open Loop ◽  
Cell Regeneration ◽  
Type I ◽  
Neural Pathways ◽  
Hair Cell Regeneration ◽  
Vestibular Hair Cells ◽  
Aminoglycoside Ototoxicity

Recovery of the vestibulocolic reflex after aminoglycoside ototoxicity in domestic chickens. Avian auditory and vestibular hair cells regenerate after damage by ototoxic drugs, but until recently there was little evidence that regenerated vestibular hair cells function normally. In an earlier study we showed that the vestibuloocular reflex (VOR) is eliminated with aminoglycoside antibiotic treatment and recovers as hair cells regenerate. The VOR, which stabilizes the eye in the head, is an open-loop system that is thought to depend largely on regularly firing afferents. Recovery of the VOR is highly correlated with the regeneration of type I hair cells. In contrast, the vestibulocolic reflex (VCR), which stabilizes the head in space, is a closed-loop, negative-feedback system that seems to depend more on irregularly firing afferent input and is thought to be subserved by different circuitry than the VOR. We examined whether this different reflex also of vestibular origin would show similar recovery after hair cell regeneration. Lesions of the vestibular hair cells of 10-day-old chicks were created by a 5-day course of streptomycin sulfate. One day after completion of streptomycin treatment there was no measurable VCR gain, and total hair cell density was ∼35% of that in untreated, age-matched controls. At 2 wk postlesion there was significant recovery of the VCR; at this time two subjects showed VCR gains within the range of control chicks. At 3 wk postlesion all subjects showed VCR gains and phase shifts within the normal range. These data show that the VCR recovers before the VOR. Unlike VOR gain, recovering VCR gain correlates equally well with the density of regenerating type I and type II vestibular hair cells, except at high frequencies. Several factors other than hair cell regeneration, such as length of stereocilia, reafferentation of hair cells, and compensation involving central neural pathways, may be involved in behavioral recovery. Our data suggest that one or more of these factors differentially affect the recovery of these two vestibular reflexes.

scholarly journals Autophagy: A Novel Horizon for Hair Cell Protection

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Chang Liu ◽  
Zhiwei Zheng ◽  
Pengjun Wang ◽  
Shuangba He ◽  
Yingzi He
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Auditory System ◽  
Hair Cells ◽  
Acoustic Trauma ◽  
Hearing Protection ◽  
Cellular Reaction ◽  
Cell Protection ◽  
Ototoxic Drugs ◽  
Potential Measure

As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs.

scholarly journals Assessment of cochlear toxicity in response to chronic 3,3′-iminodipropionitrile in mice reveals early and reversible functional loss that precedes overt histopathology

2021 ◽  
Vol 95 (3) ◽  
pp. 1003-1021
Author(s):  
Erin A. Greguske ◽  
Jordi Llorens ◽  
Sonja J. Pyott
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Auditory System ◽  
Hair Cells ◽  
Time Course ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Brainstem Response ◽  
Peripheral Auditory System

AbstractThe peripheral auditory and vestibular systems rely on sensorineural structures that are vulnerable to ototoxic agents that cause hearing loss and/or equilibrium deficits. Although attention has focused on hair cell loss as the primary pathology underlying ototoxicity, evidence from the peripheral vestibular system indicates that hair cell loss during chronic exposure is preceded by synaptic uncoupling from the neurons and is potentially reversible. To determine if synaptic pathology also occurs in the peripheral auditory system, we examined the extent, time course, and reversibility of functional and morphological alterations in cochleae from mice exposed to 3,3′-iminodipropionitrile (IDPN) in drinking water for 2, 4 or 6 weeks. Functionally, IDPN exposure caused progressive high- to low-frequency hearing loss assessed by measurement of auditory brainstem response wave I absolute thresholds and amplitudes. The extent of hearing loss scaled with the magnitude of vestibular dysfunction assessed behaviorally. Morphologically, IDPN exposure caused progressive loss of outer hair cells (OHCs) and synapses between the inner hair cells (IHCs) and primary auditory neurons. In contrast, IHCs were spared from ototoxic damage. Importantly, hearing loss consistent with cochlear synaptopathy preceded loss of OHCs and synapses and, moreover, recovered if IDPN exposure was stopped before morphological pathology occurred. Our observations suggest that synaptic uncoupling, perhaps as an early phase of cochlear synaptopathy, also occurs in the peripheral auditory system in response to IDPN exposure. These findings identify novel mechanisms that contribute to the earliest stages of hearing loss in response to ototoxic agents and possibly other forms of acquired hearing loss.

scholarly journals Neuroplastin expression is essential for hearing and hair cell PMCA expression

2021 ◽  
Author(s):  
Xiao Lin ◽  
Michael G. K. Brunk ◽  
Pingan Yuanxiang ◽  
Andrew W. Curran ◽  
Enqi Zhang ◽  
...  
Keyword(s):  
Hair Cell ◽  
White Noise ◽  
Hair Cells ◽  
Normal Development ◽  
Single Photon ◽  
Photon Emission ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Emission Computed Tomography ◽  
Cell Degeneration

AbstractHearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn−/−) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn−/− mice. Adult Nptn−/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn−/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn−/− mice. Conditional ablation of neuroplastin in Nptnlox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult NptnΔlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

scholarly journals Development in the Mammalian Auditory System Depends on Transcription Factors

2021 ◽  
Vol 22 (8) ◽  
pp. 4189
Author(s):  
Karen L. Elliott ◽  
Gabriela Pavlínková ◽  
Victor V. Chizhikov ◽  
Ebenezer N. Yamoah ◽  
Bernd Fritzsch
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Auditory System ◽  
Hair Cells ◽  
System Development ◽  
Neuronal Cell ◽  
Spiral Ganglion Neuron ◽  
Cochlear Hair Cells ◽  
Cochlear Nuclei ◽  
Bhlh Genes

We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix–loop–helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons’ fate into “hair cells”, highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of “intraganglionic” HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

scholarly journals Inner hair cell stereocilia are embedded in the tectorial membrane

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pierre Hakizimana ◽  
Anders Fridberger
Keyword(s):  
Electron Microscopy ◽  
Hair Cell ◽  
Mechanical Stimulation ◽  
Hair Cells ◽  
Viscous Drag ◽  
Tectorial Membrane ◽  
Inner Hair Cell ◽  
Inner Hair Cells ◽  
Inward Currents

AbstractMammalian 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.

Sign in / Sign up

Export Citation Format

Share Document