The remarkable sensitivity, frequency selectivity, and dynamic range of the mammalian cochlea relies on longitudinal transmission of minuscule amounts of energy as passive, pressure-driven, basilar ...membrane (BM) traveling waves. These waves are actively amplified at frequency-specific locations by a mechanism that involves interaction between the BM and another extracellular matrix, the tectorial membrane (TM). From mechanical measurements of isolated segments of the TM, we made the important new (to our knowledge) discovery that the stiffness of the TM is reduced when it is mechanically stimulated at physiologically relevant magnitudes and at frequencies below their frequency place in the cochlea. The reduction in stiffness functionally uncouples the TM from the organ of Corti, thereby minimizing energy losses during passive traveling-wave propagation. Stiffening and decreased viscosity of the TM at high stimulus frequencies can potentially facilitate active amplification, especially in the high-frequency, basal turn, where energy loss due to internal friction within the TM is less than in the apex. This prediction is confirmed by neural recordings from several frequency regions of the cochlea.
The remarkable power amplifier 1 of the cochlea boosts low-level and compresses high-level vibrations of the basilar membrane (BM) 2. By contributing maximally at the characteristic frequency (CF) of ...each point along its length, the amplifier ensures the exquisite sensitivity, narrow frequency tuning, and enormous dynamic range of the mammalian cochlea. The motor protein prestin in the outer hair cell (OHC) lateral membrane is a prime candidate for the cochlear power amplifier 3. The other contender for this role is the ubiquitous calcium-mediated motility of the hair cell stereocilia, which has been demonstrated in vitro and is based on fast adaptation of the mechanoelectrical transduction channels 4, 5. Absence of prestin 6 from OHCs results in a 40–60 dB reduction in cochlear neural sensitivity 7. Here we show that sound-evoked BM vibrations in the high-frequency region of prestin−/− mice cochleae are, surprisingly, as sensitive as those of their prestin+/+ siblings. The BM vibrations of prestin−/− mice are, however, broadly tuned to a frequency approximately a half octave below the CF of prestin+/+ mice at similar BM locations. The peak sensitivity of prestin+/+ BM tuning curves matches the neural thresholds. In contrast, prestin−/− BM tuning curves at their best frequency are >50 dB more sensitive than the neural responses. We propose that the absence of prestin from OHCs, and consequent reduction in stiffness of the cochlea partition, changes the passive impedance of the BM at high frequencies, including the CF. We conclude that prestin influences the cochlear partition's dynamic properties that permit transmission of its vibrations into neural excitation. Prestin is crucial for defining sharp and sensitive cochlear frequency tuning by reducing the sensitivity of the low-frequency tail of the tuning curve, although this necessitates a cochlear amplifier to determine the narrowly tuned tip.
Alpha-tectorin (encoded by Tecta) is a component of the tectorial membrane, an extracellular matrix of the cochlea. In humans, the Y1870C missense mutation in TECTA causes a 50- to 80-dB hearing ...loss. In transgenic mice with the Y1870C mutation in Tecta, the tectorial membrane's matrix structure is disrupted, and its adhesion zone is reduced in thickness. These abnormalities do not seriously influence the tectorial membrane's known role in ensuring that cochlear feedback is optimal, because the sensitivity and frequency tuning of the mechanical responses of the cochlea are little changed. However, neural thresholds are elevated, neural tuning is broadened, and a sharp decrease in sensitivity is seen at the tip of the neural tuning curve. Thus, using Tecta(Y1870C/+) mice, we have genetically isolated a second major role for the tectorial membrane in hearing: it enables the motion of the basilar membrane to optimally drive the inner hair cells at their best frequency.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Sensory hair cells, including the sensorimotor outer hair cells, which enable the sensitive, sharply tuned responses of the mammalian cochlea, are excited by radial shear between the organ of Corti ...and the overlying tectorial membrane. It is not currently possible to measure directly in vivo mechanical responses in the narrow cleft between the tectorial membrane and organ of Corti over a wide range of stimulus frequencies and intensities. The mechanical responses can, however, be derived by measuring hair cell receptor potentials. We demonstrate that the seemingly complex frequency- and intensity-dependent behavior of outer hair cell receptor potentials could be qualitatively explained by a two degrees of freedom system with local cochlear partition and tectorial membrane resonances strongly coupled by the outer hair cell stereocilia. A local minimum in the receptor potential below the characteristic frequency should always be observed at a frequency where the tectorial membrane mechanical impedance is minimal, i.e., at the presumed tectorial membrane resonance frequency. The tectorial membrane resonance frequency might, however, shift with stimulus intensity in accordance with a shift in the maximum of the tectorial membrane radial mechanical responses to lower frequencies, as observed in experiments.
Loud low-frequency sounds can induce temporary oscillatory changes in cochlear sensitivity, which have been termed the ‘bounce’ phenomenon. The origin of these sensitivity changes has been attributed ...to slow fluctuations in cochlear homeostasis, causing changes in the operating points of the outer hair cell mechano-electrical and electro-mechanical transducers. Here, we acquired three objective and subjective measures resulting in a comprehensive dataset of the bounce phenomenon in each of 22 normal-hearing human subjects. We analysed the level and phase of cubic and quadratic distortion product otoacoustic emissions and the auditory thresholds before and after presentation of a low-frequency stimulus (30 Hz sine wave, 120 dB SPL, 90 s) as a function of time. In addition, the perceived loudness of temporary, tinnitus-like sensations occurring in all subjects after cessation of the low-frequency stimulus was tracked over time. The majority of the subjects (70 %) showed a significant, biphasic change of quadratic, but not cubic, distortion product otoacoustic emissions of about 3–4 dB. Eighty-six percent of the tested subjects showed significant alterations of hearing thresholds after low-frequency stimulation. Four different types of threshold changes were observed, namely monophasic desensitisations (the majority of cases), monophasic sensitisations, biphasic alterations with initial sensitisation and biphasic alterations with initial desensitisation. The similar duration of the three bounce phenomenon measures indicates a common origin. The current findings are consistent with the hypothesis that slow oscillations of homeostatic control mechanisms and associated operating point shifts within the cochlea are the source of the bounce phenomenon.
The review is both timely and relevant, as recent findings have shown the tectorial membrane plays a more dynamic role in hearing than hitherto suspected, and that many forms of deafness can result ...from mutations in tectorial membrane proteins.
Main themes covered are the molecular composition, the structural organization and properties of the tectorial membrane, the role of the tectorial membrane as a second resonator and a structure within which there is significant longitudinal coupling, and how mutations in tectorial membrane proteins cause deafness in mice and men.
Findings from experimental models imply that the tectorial membrane plays multiple, critical roles in hearing. These include coupling elements along the length of the cochlea, supporting a travelling wave and ensuring the gain and timing of cochlear feedback are optimal. The clinical findings suggest stable, moderate-to-severe forms of hereditary hearing loss may be diagnostic of a mutation in TECTA, a gene encoding one of the major, noncollagenous proteins of the tectorial membrane.
Cochlear amplification enables the enormous dynamic range of hearing through amplifying cochlear responses to low- to moderate-level sounds and compressing them to loud sounds. Amplification is ...attributed to voltage-dependent electromotility of mechanosensory outer hair cells (OHCs) driven by changing voltages developed across their cell membranes. At low frequencies, these voltage changes are dominated by intracellular receptor potentials (RPs). However, OHC membranes have electrical low-pass filter properties that attenuate high-frequency RPs, which should potentially attenuate amplification of high-frequency cochlear responses and impede high-frequency hearing. We made
intracellular and extracellular electrophysiological measurements from the organ of Corti of male and female mice of the CBA/J strain, with excellent high-frequency hearing, and from the CD-1 mouse strain, which has sensitive hearing below 12 kHz but loses high-frequency hearing within a few weeks postpartum. The CD-1 mouse strain was transfected with an A88V mutation of the connexin 30 gap-junction protein. By blocking the action of the GJ protein to reduce input resistance, the mutation increased the OHC extracellular RP (ERP) magnitude and rescued high-frequency hearing. However, by increasing the organ of Corti resistance, the mutation rescued high-frequency hearing through preserving the OHC extracellular RP (ERP) magnitude. We measured the voltage developed across the basolateral membranes of OHCs, which controls their electromotility, for low- to high-frequency sounds in male and female mice of the CD-1 strain that expressed the A88V mutation. We demonstrate that ERPs, not RPs, drive OHC motility and cochlear amplification at high frequencies because at high frequencies, ERPs are not frequency attenuated, exceed RPs in magnitude, and are appropriately timed to provide cochlear amplification.
Cochlear amplification, which enables the enormous dynamic range of hearing, is attributed to voltage-dependent electromotility of the mechanosensory outer hair cells (OHCs) driven by sound-induced voltage changes across their membranes. OHC intracellular receptor potentials are electrically low-pass filtered, which should hinder high-frequency hearing. We measured the intracellular and extracellular voltages that control OHC electromotility
in a mouse strain with impaired high-frequency hearing. A gap-junction mutation of the strain rescued high-frequency hearing, increased organ of Corti resistance, and preserved large OHC extracellular receptor potentials but reduced OHC intracellular receptor potentials and impaired low-frequency hearing. We concluded intracellular potentials drive OHC motility at low frequencies and extracellular receptor potentials drive OHC motility and cochlear amplification at high frequencies.
The cochlea's inaccessibility and complex nature provide significant challenges to delivering drugs and other agents uniformly, safely and efficiently, along the entire cochlear spiral. Large drug ...concentration gradients are formed along the cochlea when drugs are administered to the middle ear. This undermines the major goal of attaining therapeutic drug concentration windows along the whole cochlea. Here, utilizing a well-known physiological effect of salicylate, we demonstrate a proof of concept in which drug distribution along the entire cochlea is enhanced by applying round window membrane low-frequency micro vibrations with a probe that only partially covers the round window. We provide evidence of enhanced drug influx into the cochlea and cochlear apical drug distribution without breaching cochlear boundaries. It is further suggested that ossicular functionality is not required for the effective drug distribution we report. The novel method presented here of local drug delivery to the cochlea could be implemented when ossicular functionality is absent or impeded and can be incorporated in clinically approved auditory protheses for patients who suffer with conductive, sensorineural or mixed hearing loss.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Accelerated age-related hearing loss disrupts high-frequency hearing in inbred CD-1 mice. The p.Ala88Val (A88V) mutation in the gene coding for the gap-junction protein connexin30 (Cx30) protects the ...cochlear basal turn of adult CD-1Cx30
mice from degeneration and rescues hearing. Here we report that the passive compliance of the cochlear partition and active frequency tuning of the basilar membrane are enhanced in the cochleae of CD-1Cx30
compared to CBA/J mice with sensitive high-frequency hearing, suggesting that gap junctions contribute to passive cochlear mechanics and energy distribution in the active cochlea. Surprisingly, the endocochlear potential that drives mechanoelectrical transduction currents in outer hair cells and hence cochlear amplification is greatly reduced in CD-1Cx30
mice. Yet, the saturating amplitudes of cochlear microphonic potentials in CD-1Cx30
and CBA/J mice are comparable. Although not conclusive, these results are compatible with the proposal that transmembrane potentials, determined mainly by extracellular potentials, drive somatic electromotility of outer hair cells.
Deafness is the most common sensory disorder in humans and the aetiology of genetic deafness is complex. Mouse mutants have been crucial in identifying genes involved in hearing. However, many ...deafness genes remain unidentified. Using N‐ethyl N−nitrosourea (ENU) mutagenesis to generate new mouse models of deafness, we identified a novel semi‐dominant mouse mutant, Cloth‐ears (Clth). Cloth‐ears mice show reduced acoustic startle response and mild hearing loss from ∼30 days old. Auditory‐evoked brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) analyses indicate that the peripheral neural auditory pathway is impaired in Cloth‐ears mice, but that cochlear function is normal. In addition, both Clth/Clth and Clth/+ mice display paroxysmal tremor episodes with behavioural arrest. Clth/Clth mice also show a milder continuous tremor during movement and rest. Longitudinal phenotypic analysis showed that Clth/+ and Clth/Clth mice also have complex defects in behaviour, growth, neurological and motor function. Positional cloning of Cloth‐ears identified a point mutation in the neuronal voltage‐gated sodium channel α‐subunit gene, Scn8a, causing an aspartic acid to valine (D981V) change six amino acids downstream of the sixth transmembrane segment of the second domain (D2S6). Complementation testing with a known Scn8a mouse mutant confirmed that this mutation is responsible for the Cloth‐ears phenotype. Our findings suggest a novel role for Scn8a in peripheral neural hearing loss and paroxysmal motor dysfunction.
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