Victoria A Lukashkina

University of Sussex, Brighton, ENG, United Kingdom

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Publications (16)97.48 Total impact

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    ABSTRACT: 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.
    Biophysical Journal 03/2013; 104(6):1357-66. · 3.67 Impact Factor
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    ABSTRACT: The gene causative for the human nonsyndromic recessive form of deafness DFNB22 encodes otoancorin, a 120-kDa inner ear-specific protein that is expressed on the surface of the spiral limbus in the cochlea. Gene targeting in ES cells was used to create an EGFP knock-in, otoancorin KO (Otoa(EGFP/EGFP)) mouse. In the Otoa(EGFP/EGFP) mouse, the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to the spiral limbus and lies over the organ of Corti, retains its general form, and remains in close proximity to the organ of Corti, but is detached from the limbal surface. Measurements of cochlear microphonic potentials, distortion product otoacoustic emissions, and basilar membrane motion indicate that the TM remains functionally attached to the electromotile, sensorimotor outer hair cells of the organ of Corti, and that the amplification and frequency tuning of the basilar membrane responses to sounds are almost normal. The compound action potential masker tuning curves, a measure of the tuning of the sensory inner hair cells, are also sharply tuned, but the thresholds of the compound action potentials, a measure of inner hair cell sensitivity, are significantly elevated. These results indicate that the hearing loss in patients with Otoa mutations is caused by a defect in inner hair cell stimulation, and reveal the limbal attachment of the TM plays a critical role in this process.
    Proceedings of the National Academy of Sciences 11/2012; · 9.81 Impact Factor
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    ABSTRACT: It has been predicted that a nonfunctional prestin in the mammalian cochlea would produce a basilar membrane response at lower characteristic frequency, as we see in the prestin knock-out mouse, but with a reduced sensitivity that would reflect an enhanced coupling between basilar membrane and reticular lamina and inner hair cell stereocilia. We demonstrate here that this is the case in measurements from the 499 mouse where prestin in the lateral membrane of the outer hair cells is present but effectively silenced.
    11/2011;
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    ABSTRACT: We demonstrate that in Otoa−∕− mice, in which the inner-ear-specific protein otoancorin is absent, excitation of the outer hair cells and cochlear amplification is normal. This finding is remarkable because the tectorial membrane (TM), although remaining functionally attached to the outer hair cell bundles, is completely detached from the spiral limbus. Therefore, as in ancestral vertebrate auditory organs, where inertia provides the excitatory force to the hair cells, it is the inertia of the TM that must be important for exciting the outer hair cells, setting the sensitivity of their transducer conductance, and determining the precise timing of cochlear amplification.
    11/2011;
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    ABSTRACT: The sensory hair cells of amniote hearing organs are usually distributed in tonotopic array from low to high frequencies and are very sensitively and sharply tuned to acoustic stimulation. Frequency tuning and tonotopicity of non-mammalian auditory hair cells is due largely to intrinsic properties of the hair cells [1], but frequency tuning and tonotopic organisation of the mammalian cochlea has an extrinsic basis in the basilar membrane (BM); a spiralling ribbon of collagen-rich extracellular matrix that decreases in stiffness from the high-frequency base of the cochlea to the low-frequency apex [2,3]. Sensitive frequency tuning is due to amplification, which specifically boosts low-level input to the mechanosensitive hair cells at their tonotopic location to overcome viscous damping [1-3]. In non-mammalian hearing organs, at least, amplification is attributed to calcium-mediated hair bundle motion [1]. In the mammalian cochlea, amplification is the remit of the sensory-motor outer hair cells (OHCs), located within the organ of Corti to exercise maximum mechanical effect on the motion of the BM and transmit cochlear responses to the adjacent sensory inner hair cells (IHCs) and, consequently, to the auditory nerve [1-3] (Figure 1A). OHCs behave like piezoelectric actuators, developing forces along their long axis in response to changes in membrane potential [2]. These forces are due to voltage-dependent conformational changes in the motor molecule prestin, which is densely distributed in the OHC lateral membranes [2].
    Current biology: CB 09/2011; 21(18):R682-3. · 10.99 Impact Factor
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    ABSTRACT: The mammalian inner ear contains sense organs responsible for detecting sound, gravity and linear acceleration, and angular acceleration. Of these organs, the cochlea is involved in hearing, while the sacculus and utriculus serve to detect linear acceleration. Recent evidence from birds and mammals, including humans, has shown that the sacculus, a hearing organ in many lower vertebrates, has retained some of its ancestral acoustic sensitivity. Here we provide not only more evidence for the retained acoustic sensitivity of the sacculus, but we also found that acoustic stimulation of the sacculus has behavioral significance in mammals. We show that the amplitude of an elicited auditory startle response is greater when the startle stimuli are presented simultaneously with a low-frequency masker, including masker tones that are outside the sensitivity range of the cochlea. Masker-enhanced auditory startle responses were also observed in otoconia-absent Nox3 mice, which lack otoconia but have no obvious cochlea pathology. However, masker enhancement was not observed in otoconia-absent Nox3 mice if the low-frequency masker tones were outside the sensitivity range of the cochlea. This last observation confirms that otoconial organs, most likely the sacculus, contribute to behavioral responses to low-frequency sounds in mice.
    Journal of the Association for Research in Otolaryngology 12/2010; 11(4):725-32. · 2.95 Impact Factor
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    ABSTRACT: Recent observations have changed our understanding of tectorial membrane function. Transgenic mice have shown that the tectorial membrane is a structure that can influence the sensitivity and tuning properties of the cochlea in several ways. It ensures that the gain and timing of cochlear feedback are optimal; that the hair bundles of the inner hair cells are driven efficiently by the outer hair cells, and it may influence the extent to which different elements are coupled along the length of the cochlea. KeywordsCochlea-Deafness genes-Hearing loss-TECTA-Tectorial membrane-Cochlear amplification
    12/2009: pages 69-77;
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    ABSTRACT: 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 approximately 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 alpha-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.
    Genes Brain and Behavior 07/2009; 8(7):699-713. · 3.60 Impact Factor
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    ABSTRACT: The sensitivity, large dynamic range and narrow frequency tuning of the mammalian cochlea is determined by the passive mechanical properties of the basilar membrane (BM) and active feedback from the outer hair cells (OHCs). Two mechanisms have been proposed to provide amplification: Hair bundle motility, and OHC somatic-motility. Acoustically- and electrically-elicited mechanical responses were measured from the BMs of the cochleae of wild type and genetically modified mice where the hair bundles are freestanding and cannot react against the tectorial membrane (TM) to contribute to amplification. We found the electrically elicited responses in mutant mice, where only somatic motility can provide amplification, to be remarkably similar to acoustical and electrical responses in the wild type animals. We, therefore, conclude that somatic, not stereocilia motility is the basis of the cochlear amplifier.
    02/2009;
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    ABSTRACT: A tenet of cochlear physiology is that sharp tuning and sensitivity are directly interrelated. Here we show a reciprocal interdependence between tuning and sensitivity in the mammalian cochlea from measurements of basilar membrane (BM) mechanical tuning and neural suppression tuning curves of wild-type (Tectb+/+) and beta-tectorin mutant (Tectb-/-) mice. The tectorial membrane (TM) of the mutants lacks striated-sheet matrix, which is likely to decrease longitudinal elastic coupling. Mechanical and neural tuning curves recorded in mutants are slightly less sensitive, although more sharply tuned. The inverse relationship between sensitivity and tuning observed in the mutants could be attributed to smaller numbers of the outer hair cells responding in synchrony due to reduced longitudinal coupling in the TM. We suggest that frequency tuning and high sensitivity are not necessarily concomitant but reciprocal properties of the cochlea.
    02/2009;
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    ABSTRACT: Sensitivity, dynamic range and frequency tuning of the cochlea are attributed to amplification involving outer hair cell stereocilia and/or somatic motility. We measured acoustically and electrically elicited basilar membrane displacements from the cochleae of wild-type and Tecta(DeltaENT/DeltaENT) mice, in which stereocilia are unable to contribute to amplification near threshold. Electrically elicited responses from Tecta(DeltaENT/DeltaENT) mice were markedly similar to acoustically and electrically elicited responses from wild-type mice. We conclude that somatic, and not stereocilia, motility is the basis of cochlear amplification.
    Nature Neuroscience 08/2008; 11(7):746-8. · 15.25 Impact Factor
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    ABSTRACT: Frequency tuning in the cochlea is determined by the passive mechanical properties of the basilar membrane and active feedback from the outer hair cells, sensory-effector cells that detect and amplify sound-induced basilar membrane motions. The sensory hair bundles of the outer hair cells are imbedded in the tectorial membrane, a sheet of extracellular matrix that overlies the cochlea's sensory epithelium. The tectorial membrane contains radially organized collagen fibrils that are imbedded in an unusual striated-sheet matrix formed by two glycoproteins, alpha-tectorin (Tecta) and beta-tectorin (Tectb). In Tectb(-/-) mice the structure of the striated-sheet matrix is disrupted. Although these mice have a low-frequency hearing loss, basilar-membrane and neural tuning are both significantly enhanced in the high-frequency regions of the cochlea, with little loss in sensitivity. These findings can be attributed to a reduction in the acting mass of the tectorial membrane and reveal a new function for this structure in controlling interactions along the cochlea.
    Nature Neuroscience 03/2007; 10(2):215-23. · 15.25 Impact Factor
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    ABSTRACT: 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.
    Nature Neuroscience 09/2005; 8(8):1035-42. · 15.25 Impact Factor
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    ABSTRACT: Distortion product otoacoustic emissions (DPOAE) were recorded from wild-type mice and mutant Tecta(deltaENT/deltaENT) mice with detached tectorial membranes (TM) under combined ketamine/xylaxine anesthesia. In Tecta(deltaENT/deltaENT) mice, DPOAEs could be detected above the noise floor only when the levels of the primary tones exceeded 65 dB SPL. DPOAE amplitude decreased with increasing frequency of the primaries in Tecta(deltaENT/deltaENT) mice. This was attributed to hair cell excitation via viscous coupling to the surrounding fluid and not by interaction with the TM as in the wild-type mice. Local minima and corresponding phase transitions in the DPOAE growth functions occurred at higher DPOAE levels in wild-type than in Tecta(deltaENT/deltaENT) mice. In less-sensitive Tecta(deltaENT/deltaENT) mice, the position of the local minima varied nonsystematically with frequency or no minima were observed. A bell-like dependence of the DPOAE amplitude on the ratio of the primaries was recorded in both wild-type and Tecta(deltaENT/deltaENT) mice. However, the pattern of this dependence was different in the wild-type and Tecta(deltaENT/deltaENT) mice, an indication that the bell-like shape of the DPOAE was produced by a combination of different mechanisms. A nonlinear low-frequency resonance, revealed by nonmonotonicity of the phase behavior, was seen in the wild-type but not in Tecta(deltaENT/deltaENT) mice.
    Journal of Neurophysiology 02/2004; 91(1):163-71. · 3.30 Impact Factor
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    Andrei N Lukashkin, Victoria A Lukashkina, Ian J Russell
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    ABSTRACT: Distortion product otoacoustic emissions (DPOAE) elicited by tones below 60-70 dB sound pressure level (SPL) are significantly more sensitive to cochlear insults. The vulnerable, low-level DPOAE have been associated with the postulated active cochlear process, whereas the relatively robust high-level DPOAE component has been attributed to the passive, nonlinear macromechanical properties of the cochlea. However, it is proposed that the differences in the vulnerability of DPOAEs to high and low SPLs is a natural consequence of the way the cochlea responds to high and low SPLs. An active process boosts the basilar membrane (BM) vibrations, which are attenuated when the active process is impaired. However, at high SPLs the contribution of the active process to BM vibration is small compared with the dominating passive mechanical properties of the BM. Consequently, reduction of active cochlear amplification will have greatest effect on BM vibrations and DPOAEs at low SPLs. To distinguish between the "two sources" and the "single source" hypotheses we analyzed the level dependence of the notch and corresponding phase discontinuity in plots of DPOAE magnitude and phase as functions of the level of the primaries. In experiments where furosemide was used to reduce cochlear amplification, an upward shift of the notch supports the conclusion that both the low- and high-level DPOAEs are generated by a single source, namely a nonlinear amplifier with saturating I/O characteristic.
    The Journal of the Acoustical Society of America 07/2002; 111(6):2740-8. · 1.65 Impact Factor
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    ABSTRACT: alpha-tectorin is an extracellular matrix molecule of the inner ear. Mice homozygous for a targeted deletion in a-tectorin have tectorial membranes that are detached from the cochlear epithelium and lack all noncollagenous matrix, but the architecture of the organ of Corti is otherwise normal. The basilar membranes of wild-type and alpha-tectorin mutant mice are tuned, but the alpha-tectorin mutants are 35 dB less sensitive. Basilar membrane responses of wild-type mice exhibit a second resonance, indicating that the tectorial membrane provides an inertial mass against which outer hair cells can exert forces. Cochlear microphonics recorded in alpha-tectorin mutants differ in both phase and symmetry relative to those of wild-type mice. Thus, the tectorial membrane ensures that outer hair cells can effectively respond to basilar membrane motion and that feedback is delivered with the appropriate gain and timing required for amplification.
    Neuron 11/2000; 28(1):273-85. · 15.77 Impact Factor