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Integrating the active process of hair cells with cochlear function

Key Points

  • Hearing benefits from an active process that amplifies acoustic inputs by more than a hundred-fold, sharpens frequency discrimination to facilitate the comprehension of speech and the recognition of sound sources, and compresses responses so that we can resolve sounds over a million-fold range in amplitude.

  • The gating of transduction channels endows a mechanically sensitive hair bundle with negative stiffness, an instability that interacts with the motor protein myosin 1c to produce a mechanical amplifier and oscillator. This active hair-bundle motility constitutes the active process of some non-mammalian tetrapods.

  • An outer hair cell of the mammalian cochlea displays somatic motility, in which changes in the transmembrane voltage alter the membrane area occupied by the piezoelectric protein prestin. Depolarization causes the cell body to contract and hyperpolarization causes it to extend at frequencies that can exceed 100 kHz.

  • Acoustic stimulation evokes on the elastic basilar membrane a travelling wave that progresses from the cochlear base towards the apex, peaking at a specific position determined by the stimulus frequency. As this wave advances, the active process of successive hair cells adds energy to counter viscous dissipation.

  • The active process of the mammalian cochlea combines active hair-bundle motility and somatic motility; the former mechanism probably regulates the phase of responsiveness, whereas the latter provides most of the mechanical power.

  • The characteristics of the active process reflect the operation of hair cells near a dynamical instability, the Hopf bifurcation, the generic properties of which explain various phenomena associated with hearing. When extreme quiet excites the active process sufficiently, hair cells traverse the bifurcation and — even in most individuals with normal hearing — produce spontaneous oscillations that emerge from the ears.

Abstract

Uniquely among human senses, hearing is not simply a passive response to stimulation. Our auditory system is instead enhanced by an active process in cochlear hair cells that amplifies acoustic signals several hundred-fold, sharpens frequency selectivity and broadens the ear's dynamic range. Active motility of the mechanoreceptive hair bundles underlies the active process in amphibians and some reptiles; in mammals, this mechanism operates in conjunction with prestin-based somatic motility. Both individual hair bundles and the cochlea as a whole operate near a dynamical instability, the Hopf bifurcation, which accounts for the cardinal features of the active process.

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Figure 1: The cochlea and organ of Corti.
Figure 2: The hair cell and hair bundle.
Figure 3: Gating of transduction channels.
Figure 4: Non-linearity associated with channel gating.
Figure 5: Slow adaptation.
Figure 6: Hair-bundle oscillation.

References

  1. 1

    Dalhoff, E., Turcanu, D., Zenner, H.-P. & Gummer, A. W. Distortion product otoacoustic emissions measured as vibration on the eardrum of human subjects. Proc. Natl Acad. Sci. USA 104, 1546–1551 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Harris, G. G. Brownian motion in the cochlear partition. J. Acoust. Soc. Am. 44, 176–186 (1968).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Sek, A. & Moore, B. C. Frequency discrimination as a function of frequency, measured in several ways. J. Acoust. Soc. Am. 97, 2479–2486 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Reichenbach, T. & Hudspeth, A. J. Discrimination of low-frequency tones employs temporal fine structure. PLoS ONE 7, e45579 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Yost, W. A. & Killion, M. C. in Encyclopedia of Acoustics Vol.3, Ch. 123 (ed. Crocker, M. J.) 1545–1554 (Wiley-Interscience, 1997).

    Google Scholar 

  6. 6

    Davis, H. An active process in cochlear mechanics. Hear. Res. 9, 79–90 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Manley, G. A. Cochlear mechanisms from a phylogenetic viewpoint. Proc. Natl Acad. Sci. USA 97, 11736–11743 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Manley, G. A. Evidence for an active process and a cochlear amplifier in nonmammals. J. Neurophysiol. 86, 541–549 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Pickles, J. O. An Introduction to the Physiology of Hearing 4th edn (Emerald Group Publishing, 2012).

    Google Scholar 

  10. 10

    Hudspeth, A. J. in Principles of Neural Science 5th edn (eds Kandel, E. R., Schwartz, J. H., Jessel, T. M., Siegelbaum, S. A. & Hudspeth, A. J.) 654–681 (McGraw-Hill Medical, 2013).

    Google Scholar 

  11. 11

    Retzius, G. Das Gehörorgan der Wirbelthiere. II. Das Gehörorgan der Reptilien, der Vögel und der Säugethiere 354 (Samson & Wallin, 1884).

    Google Scholar 

  12. 12

    Fettiplace, R. & Fuchs, P. A. Mechanisms of hair cell tuning. Annu. Rev. Physiol. 61, 809–834 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Spiegel, M. F. Performance on frequency-discrimination tasks by musicians and nonmusicians. J. Acoust. Soc. Am. 76, 1690 (1984).

    Article  Google Scholar 

  14. 14

    De Boer, E. No sharpening? A challenge for cochlear mechanics. J. Acoust. Soc. Am. 73, 567–573 (1983).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Reichenbach, T. & Hudspeth, A. J. Dual contribution to amplification in the mammalian inner ear. Phys. Rev. Lett. 105, 118102 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Fisher, J. A. N., Nin, F., Reichenbach, T., Uthaiah, R. C. & Hudspeth, A. J. The spatial pattern of cochlear amplification. Neuron 76, 989–997 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Camalet, S., Duke, T., Jülicher, F. & Prost, J. Auditory sensitivity provided by self-tuned critical oscillations of hair cells. Proc. Natl Acad. Sci. USA 97, 3183–3188 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. 18

    Brownell, W. E., Bader, C. R., Bertrand, D. & de Ribaupierre, Y. Evoked mechanical responses of isolated cochlear outer hair cells. Science 227, 194–196 (1985).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Ashmore, J. F. A fast motile response in guinea-pig outer hair cells: the cellular basis of the cochlear amplifier. J. Physiol. 388, 323–347 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Brownell, W. E., Spector, A. A., Raphael, R. M. & Popel, A. S. Micro- and nanomechanics of the cochlear outer hair cell. Annu. Rev. Biomed. Eng. 3, 169–194 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Dallos, P., Zheng, J. & Cheatham, M. A. Prestin and the cochlear amplifier. J. Physiol. 576, 37–42 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Dallos, P. Cochlear amplification, outer hair cells and prestin. Curr. Opin. Neurobiol. 18, 370–376 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ashmore, J. Cochlear outer hair cell motility. Physiol. Rev. 88, 173–210 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    Beurg, M., Tan, X. & Fettiplace, R. A prestin motor in chicken auditory hair cells: active force generation in a nonmammalian species. Neuron 79, 69–81 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Zheng, J. et al. Prestin is the motor protein of cochlear outer hair cells. Nature 405, 149–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Zheng, J. et al. Analysis of the oligomeric structure of the motor protein prestin. J. Biol. Chem. 281, 19916–19924 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Wang, X., Yang, S., Jia, S. & He, D. Z. Z. Prestin forms oligomer with four mechanically independent subunits. Brain Res. 1333, 28–35 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Hallworth, R. & Nichols, M. G. Prestin in HEK cells is an obligate tetramer. J. Neurophysiol. 107, 5–11 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    He, D. Z. Z., Lovas, S., Ai, Y., Li, Y. & Beisel, K. W. Prestin at year 14: progress and prospect. Hear. Res. http://dx.doi.org/10.1016/j.heares.2013.12.002 (2013).

  30. 30

    Scherer, M. P. & Gummer, A. W. Vibration pattern of the organ of Corti up to 50 kHz: evidence for resonant electromechanical force. Proc. Natl Acad. Sci. USA 101, 17652–17657 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Frank, G., Hemmert, W. & Gummer, A. W. Limiting dynamics of high-frequency electromechanical transduction of outer hair cells. Proc. Natl Acad. Sci. USA 96, 4420–4425 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Liberman, M. C. et al. Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier. Nature 419, 300–304 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Cheatham, M. A., Huynh, K. H., Gao, J., Zuo, J. & Dallos, P. Cochlear function in prestin knockout mice. J. Physiol. 560, 821–830 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Dallos, P. et al. Prestin-based outer hair cell motility is necessary for mammalian cochlear amplification. Neuron 58, 333–339 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Liberman, M. C., Zuo, J. & Guinan, J. J. Jr. Otoacoustic emissions without somatic motility: can stereocilia mechanics drive the mammalian cochlea? J. Acoust. Soc. Am. 116, 1649–1655 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Chan, D. K. & Hudspeth, A. J. Mechanical responses of the organ of corti to acoustic and electrical stimulation in vitro. Biophys. J. 89, 4382–4395 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Kennedy, H. J., Crawford, A. C. & Fettiplace, R. Force generation by mammalian hair bundles supports a role in cochlear amplification. Nature 433, 880–883 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Kennedy, H. J., Evans, M. G., Crawford, A. C. & Fettiplace, R. Depolarization of cochlear outer hair cells evokes active hair bundle motion by two mechanisms. J. Neurosci. 26, 2757–2766 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Chan, D. K. & Hudspeth, A. J. Ca2+ current-driven nonlinear amplification by the mammalian cochlea in vitro. Nature Neurosci. 8, 149–155 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Nin, F., Reichenbach, T., Fisher, J. A. N. & Hudspeth, A. J. Contribution of active hair-bundle motility to nonlinear amplification in the mammalian cochlea. Proc. Natl Acad. Sci. USA 109, 21076–21080 (2012).

    Article  PubMed  Google Scholar 

  41. 41

    Markin, V. S. & Hudspeth, A. J. Modeling the active process of the cochlea: phase relations, amplification, and spontaneous oscillation. Biophys. J. 69, 138–147 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Ó Maoiléidigh, D. & Jülicher, F. The interplay between active hair bundle motility and electromotility in the cochlea. J. Acoust. Soc. Am. 128, 1175–1190 (2010).

    Article  PubMed  Google Scholar 

  43. 43

    Meaud, J. & Grosh, K. Coupling active hair bundle mechanics, fast adaptation, and somatic motility in a cochlear model. Biophys. J. 100, 2576–2585 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Hudspeth, A. J. Making an effort to listen: mechanical amplification in the ear. Neuron 59, 530–545 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Peng, A. W. & Ricci, A. J. Somatic motility and hair bundle mechanics, are both necessary for cochlear amplification? Hear. Res. 273, 109–122 (2011).

    Article  PubMed  Google Scholar 

  46. 46

    Ó Maoiléidigh, D. & Hudspeth, A. J. Effects of cochlear loading on the motility of active outer hair cells. Proc. Natl Acad. Sci. USA 110, 5474–5479 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Hudspeth, A. J. & Corey, D. P. Sensitivity, polarity, and conductance change in the response of vertebrate hair cells to controlled mechanical stimuli. Proc. Natl Acad. Sci. USA 74, 2407–2411 (1977).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Fettiplace, R. & Hackney, C. M. The sensory and motor roles of auditory hair cells. Nature Rev. Neurosci. 7, 19–29 (2006).

    Article  CAS  Google Scholar 

  49. 49

    Gillespie, P. G. & Müller, U. Mechanotransduction by hair cells: models, molecules, and mechanisms. Cell 139, 33–44 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Hudspeth, A. J., Jülicher, F. & Martin, P. A critique of the critical cochlea: Hopf—a bifurcation—is better than none. J. Neurophysiol. 104, 1219–1229 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Richardson, G. P., de Monvel, J. B. & Petit, C. How the genetics of deafness illuminates auditory physiology. Annu. Rev. Physiol. 73, 311–334 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Corey, D. P. & Hudspeth, A. J. Kinetics of the receptor current in bullfrog saccular hair cells. J. Neurosci. 3, 962–976 (1983).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Crawford, A. C., Evans, M. G. & Fettiplace, R. The actions of calcium on the mechano-electrical transducer current of turtle hair cells. J. Physiol. 434, 369–398 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Patuzzi, R. & Rajan, R. Does electrical stimulation of the crossed olivo-cochlear bundle produce movement of the organ of Corti? Hear. Res. 45, 15–32 (1990).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Kirk, D. L., Moleirinho, A. & Patuzzi, R. B. Microphonic and DPOAE measurements suggest a micromechanical mechanism for the 'bounce' phenomenon following low-frequency tones. Hear. Res. 112, 69–86 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Bobbin, R. P. & Salt, A. N. ATP-γ-S shifts the operating point of outer hair cell transduction towards scala tympani. Hear. Res. 205, 35–43 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Legan, P. K. et al. A targeted deletion in α-tectorin reveals that the tectorial membrane is required for the gain and timing of cochlear feedback. Neuron 28, 273–285 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Farris, H. E., Wells, G. B. & Ricci, A. J. Steady-state adaptation of mechanotransduction modulates the resting potential of auditory hair cells, providing an assay for endolymph [Ca2+]. J. Neurosci. 26, 12526–12536 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Evans, M. G. & Fuchs, P. A. Tetrodotoxin-sensitive, voltage-dependent sodium currents in hair cells from the alligator cochlea. Biophys. J. 52, 649–652 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Marcotti, W., Johnson, S. L., Rusch, A. & Kros, C. J. Sodium and calcium currents shape action potentials in immature mouse inner hair cells. J. Physiol. 552, 743–761 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Rutherford, M. A. & Roberts, W. M. Spikes and membrane potential oscillations in hair cells generate periodic afferent activity in the frog sacculus. J. Neurosci. 9, 10025–10037 (2009).

    Article  CAS  Google Scholar 

  62. 62

    Tritsch, N. X. et al. Calcium action potentials in hair cells pattern auditory neuron activity before hearing onset. Nature Neurosci. 13, 1050–1052 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Martin, P., Mehta, A. D. & Hudspeth, A. J. Negative hair-bundle stiffness betrays a mechanism for mechanical amplification by the hair cell. Proc. Natl Acad. Sci. USA 97, 12026–12031 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    He, D. Z. Z., Jia, S. & Dallos, P. Mechanoelectrical transduction of adult outer hair cells studied in a gerbil hemicochlea. Nature 429, 766–770 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Johnson, S. L., Beurg, M., Marcotti, W. & Fettiplace, R. Prestin-driven cochlear amplification is not limited by the outer hair cell membrane time constant. Neuron 70, 1143–1154 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Corey, D. P. & Hudspeth, A. J. Response latency of vertebrate hair cells. Biophys. J. 26, 499–506 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Pickles, J. O., Comis, S. D. & Osborne, M. P. Cross-links between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction. Hear. Res. 15, 103–112 (1984).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Kachar, B., Parakkal, M., Kurc, M., Zhao, Y. & Gillespie, P. G. High-resolution structure of hair-cell tip links. Proc. Natl Acad. Sci. USA 97, 13336–13341 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Auer, M. et al. Three-dimensional architecture of hair-bundle linkages revealed by electron-microscopic tomography. J. Assoc. Res. Otolaryngol. 9, 215–224 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Siemens, J. et al. Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature 428, 950–955 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Söllner, C. et al. Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells. Nature 428, 955–959 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Ahmed, Z. M. et al. The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15. J. Neurosci. 26, 7022–7034 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Kazmierczak, P. et al. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449, 87–91 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Sotomayor, M., Weihofen, W. A., Gaudet, R. & Corey, D. P. Structural determinants of cadherin-23 function in hearing and deafness. Neuron 66, 85–100 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Sotomayor, M., Weihofen, W. A., Gaudet, R. & Corey, D. P. Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction. Nature 492, 128–132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Assad, J. A., Shepherd, G. M. & Corey, D. P. Tip-link integrity and mechanical transduction in vertebrate hair cells. Neuron 7, 985–994 (1991).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Zhao, Y., Yamoah, E. N. & Gillespie, P. G. Regeneration of broken tip links and restoration of mechanical transduction in hair cells. Proc. Natl Acad. Sci. USA 93, 15469–15474 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Indzhykulian, A. A. et al. Molecular remodeling of tip links underlies mechanosensory regeneration in auditory hair cells. PLoS Biol. 11, e1001583 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Howard, J. & Hudspeth, A. J. Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bullfrog's saccular hair cell. Proc. Natl Acad. Sci. USA 84, 3064–3068 (1987).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Howard, J. & Spudich, J. A. Is the lever arm of myosin a molecular elastic element? Proc. Natl Acad. Sci. USA 93, 4462–4464 (1996).

    CAS  PubMed  Google Scholar 

  81. 81

    Bozovic, D. & Hudspeth, A. J. Hair-bundle movements elicited by transepithelial electrical stimulation of hair cells in the sacculus of the bullfrog. Proc. Natl Acad. Sci. USA 100, 958–963 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Powers, R. J. et al. Stereocilia membrane deformation: implications for the gating spring and mechanotransduction channel. Biophys. J. 102, 201–210 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Bosher, S. K. & Warren, R. L. Very low calcium content of cochlear endolymph, an extracellular fluid. Nature 273, 377–378 (1978).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Ikeda, K., Kusakari, J., Takasaka, T. & Saito, Y. The Ca2+ activity of cochlear endolymph of the guinea pig and the effect of inhibitors. Hear. Res. 26, 117–125 (1987).

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Marquis, R. E. & Hudspeth, A. J. Effects of extracellular Ca2+ concentration on hair-bundle stiffness and gating-spring integrity in hair cells. Proc. Natl Acad. Sci. USA 94, 11923–11928 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Kozlov, A. S., Andor-Ardó, D. & Hudspeth, A. J. Anomalous Brownian motion discloses viscoelasticity in the ear's mechanoelectrical-transduction apparatus. Proc. Natl Acad. Sci. USA 109, 2896–2901 (2012).

    Article  PubMed  Google Scholar 

  87. 87

    Shotwell, S. L., Jacobs, R. & Hudspeth, A. J. Directional sensitivity of individual vertebrate hair cells to controlled deflection of their hair bundles. Ann. NY Acad. Sci. 374, 1–10 (1981).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Hudspeth, A. J. Extracellular current flow and the site of transduction by vertebrate hair cells. J. Neurosci. 2, 1–10 (1982).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Lumpkin, E. A. & Hudspeth, A. J. Detection of Ca2+ entry through mechanosensitive channels localizes the site of mechanoelectrical transduction in hair cells. Proc. Natl Acad. Sci. USA 92, 10297–10301 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Jaramillo, F. & Hudspeth, A. J. Localization of the hair cell's transduction channels at the hair bundle's top by iontophoretic application of a channel blocker. Neuron 7, 409–420 (1991).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Denk, W., Holt, J. R., Shepherd, G. M. & Corey, D. P. Calcium imaging of single stereocilia in hair cells: localization of transduction channels at both ends of tip links. Neuron 15, 1311–1321 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Beurg, M., Fettiplace, R., Nam, J.-H. & Ricci, A. J. Localization of inner hair cell mechanotransducer channels using high-speed calcium imaging. Nature Neurosci. 12, 553–558 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Hudspeth, A. J. Transduction and tuning by vertebrate hair cells. Trends Neurosci. 6, 366–369 (1983).

    Article  Google Scholar 

  94. 94

    Holton, T. & Hudspeth, A. J. The transduction channel of hair cells from the bull-frog characterized by noise analysis. J. Physiol. 375, 195–227 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Shin, J.-B. et al. Molecular architecture of the chick vestibular hair bundle. Nature Neurosci. 16, 365–374 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Christensen, A. P. & Corey, D. P. TRP channels in mechanosensation: direct or indirect activation? Nature Rev. Neurosci. 8, 510–521 (2007).

    Article  CAS  Google Scholar 

  97. 97

    Chalfie, M. Neurosensory mechanotransduction. Nature Rev. Mol. Cell Biol. 10, 44–52 (2009).

    Article  CAS  Google Scholar 

  98. 98

    Arnadóttir, J. & Chalfie, M. Eukaryotic mechanosensitive channels. Annu. Rev. Biophys. 39, 111–137 (2010).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Martinac, B. Bacterial mechanosensitive channels as a paradigm for mechanosensory transduction. Cell. Physiol. Biochem. 28, 1051–1060 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Marshall, K. L. & Lumpkin, E. A. The molecular basis of mechanosensory transduction. Adv. Exp. Med. Biol. 739, 142–155 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Sukharev, S. & Sachs, F. Molecular force transduction by ion channels: diversity and unifying principles. J. Cell Sci. 125, 3075–3083 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Delmas, P. & Coste, B. Mechano-gated ion channels in sensory systems. Cell 155, 278–284 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Wilson, M. E., Maksaev, G. & Haswell, E. S. MscS-like mechanosensitive channels in plants and microbes. Biochemistry 52, 5708–5722 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Kurima, K. et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nature Genet. 30, 277–284 (2002).

    Article  PubMed  Google Scholar 

  105. 105

    Labay, V., Weichert, R. M., Makishima, T. & Griffith, A. J. Topology of transmembrane channel-like gene 1 protein. Biochemistry 49, 8592–8598 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Holt, J. R., Pan, B., Koussa, M. A. & Asai, Y. TMC function in hair cell transduction. Hear. Res. http://dx.doi.org/10.1016/j.heares.2014.01.001 (2014).

  107. 107

    Kawashima, Y. et al. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J. Clin. Invest. 121, 4796–4809 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Kim, K. X. & Fettiplace, R. Developmental changes in the cochlear hair cell mechanotransducer channel and their regulation by transmembrane channel-like proteins. J. Gen. Physiol. 141, 141–148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Pan, B. et al. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 79, 504–515 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. 110

    Kim, K. X. et al. The role of transmembrane channel-like proteins in the operation of hair cell mechanotransducer channels. J. Gen. Physiol. 142, 493–505 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Kindt, K. S., Finch, G. & Nicolson, T. Kinocilia mediate mechanosensitivity in developing zebrafish hair cells. Dev. Cell 23, 329–341 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Alagramam, K. N. et al. Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells. PLoS ONE 6, e19183 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Marcotti, W. et al. Transduction without tip links in cochlear hair cells is mediated by ion channels with permeation properties distinct from those of the mechano-electrical transducer channel. J. Neurosci. 34, 5505–5514 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Keresztes, G., Mutai, H. & Heller, S. TMC and EVER genes belong to a larger novel family, the TMC gene family encoding transmembrane proteins. BMC Genomics 4, 24 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Mitchem, K. L. et al. Mutation of the novel gene Tmie results in sensory cell defects in the inner ear of spinner, a mouse model of human hearing loss DFNB6. Hum. Mol. Genet. 11, 1887–1898 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Naz, S. et al. Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am. J. Hum. Genet. 71, 632–636 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Gleason, M. R. et al. The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish. Proc. Natl Acad. Sci. USA 106, 21347–21352 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Longo-Guess, C. M. et al. A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice. Proc. Natl Acad. Sci. USA 102, 7894–7899 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Shabbir, M. I. et al. Mutations of human TMHS cause recessively inherited non-syndromic hearing loss. J. Med. Genet. 43, 634–640 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Xiong, W. et al. TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells. Cell 151, 1283–1295 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Coste, B. et al. Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483, 176–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Woo, S.-H. et al. Piezo2 is required for Merkel-cell mechanotransduction. Nature 509, 622–626 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Howard, J., Roberts, W. M. & Hudspeth, A. J. Mechanoelectrical transduction by hair cells. Annu. Rev. Biophys. Biophys. Chem. 17, 99–124 (1988).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Howard, J. & Hudspeth, A. J. Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog's saccular hair cell. Neuron 1, 189–199 (1988).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    Denk, W., Keolian, R. M. & Webb, W. W. Mechanical response of frog saccular hair bundles to the aminoglycoside block of mechanoelectrical transduction. J. Neurophysiol. 68, 927–932 (1992).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    Le Goff, L., Bozovic, D. & Hudspeth, A. J. Adaptive shift in the domain of negative stiffness during spontaneous oscillation by hair bundles from the internal ear. Proc. Natl Acad. Sci. USA 102, 16996–17001 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. 128

    Eatock, R. A., Corey, D. P. & Hudspeth, A. J. Adaptation of mechanoelectrical transduction in hair cells of the bullfrog's sacculus. J. Neurosci. 7, 2821–2836 (1987).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Hacohen, N., Assad, J. A., Smith, W. J. & Corey, D. P. Regulation of tension on hair-cell transduction channels: displacement and calcium dependence. J. Neurosci. 9, 3988–3997 (1989).

    Article  CAS  PubMed  Google Scholar 

  130. 130

    Assad, J. A. & Corey, D. P. An active motor model for adaptation by vertebrate hair cells. J. Neurosci. 12, 3291–3309 (1992).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Assad, J. A., Hacohen, N. & Corey, D. P. Voltage dependence of adaptation and active bundle movement in bullfrog saccular hair cells. Proc. Natl Acad. Sci. USA 86, 2918–2922 (1989).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    Holt, J. R., Corey, D. P. & Eatock, R. A. Mechanoelectrical transduction and adaptation in hair cells of the mouse utricle, a low-frequency vestibular organ. J. Neurosci. 17, 8739–8748 (1997).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Peng, A. W., Effertz, T. & Ricci, A. J. Adaptation of mammalian auditory hair cell mechanotransduction is independent of calcium entry. Neuron 80, 960–972 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Gillespie, P. G. & Hudspeth, A. J. Adenine nucleoside diphosphates block adaptation of mechanoelectrical transduction in hair cells. Proc. Natl Acad. Sci. USA 90, 2710–2714 (1993).

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Yamoah, E. N. & Gillespie, P. G. Phosphate analogs block adaptation in hair cells by inhibiting adaptation-motor force production. Neuron 17, 523–533 (1996).

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Batters, C. et al. Myo1c is designed for the adaptation response in the inner ear. EMBO J. 23, 1433–1440 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Batters, C., Wallace, M. I., Coluccio, L. M. & Molloy, J. E. A model of stereocilia adaptation based on single molecule mechanical studies of myosin I. Phil. Trans. R. Soc. Lond. B 359, 1895–1905 (2004).

    Article  CAS  Google Scholar 

  138. 138

    Gillespie, P. G., Wagner, M. C. & Hudspeth, A. J. Identification of a 120 kd hair-bundle myosin located near stereociliary tips. Neuron 11, 581–594 (1993).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    Schneider, M. E. et al. A new compartment at stereocilia tips defined by spatial and temporal patterns of myosin IIIa expression. J. Neurosci. 26, 10243–10252 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    García, J. A., Yee, A. G., Gillespie, P. G. & Corey, D. P. Localization of myosin-Iβ near both ends of tip links in frog saccular hair cells. J. Neurosci. 18, 8637–8647 (1998).

    Article  PubMed  Google Scholar 

  141. 141

    Steyger, P. S., Gillespie, P. G. & Baird, R. A. Myosin Iβ is located at tip link anchors in vestibular hair bundles. J. Neurosci. 18, 4603–4615 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Holt, J. R. et al. A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells. Cell 108, 371–381 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Kros, C. J. et al. Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations. Nature Neurosci. 5, 41–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Grati, M. & Kachar, B. Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction. Proc. Natl Acad. Sci. USA 108, 11476–11481 (2011).

    Article  PubMed  Google Scholar 

  145. 145

    Ricci, A. J. & Fettiplace, R. The effects of calcium buffering and cyclic AMP on mechano-electrical transduction in turtle auditory hair cells. J. Physiol. 501, 111–124 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Kennedy, H. J., Evans, M. G., Crawford, A. C. & Fettiplace, R. Fast adaptation of mechanoelectrical transducer channels in mammalian cochlear hair cells. Nature Neurosci. 6, 832–836 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Benser, M. E., Marquis, R. E. & Hudspeth, A. J. Rapid, active hair bundle movements in hair cells from the bullfrog's sacculus. J. Neurosci. 16, 5629–5643 (1996).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    Ricci, A. J., Crawford, A. C. & Fettiplace, R. Active hair bundle motion linked to fast transducer adaptation in auditory hair cells. J. Neurosci. 20, 7131–7142 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. 149

    Choe, Y., Magnasco, M. O. & Hudspeth, A. J. A model for amplification of hair-bundle motion by cyclical binding of Ca2+ to mechanoelectrical-transduction channels. Proc. Natl Acad. Sci. USA 95, 15321–15326 (1998).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Tinevez, J.-Y., Jülicher, F. & Martin, P. Unifying the various incarnations of active hair-bundle motility by the vertebrate hair cell. Biophys. J. 93, 4053–4067 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Stauffer, E. A. et al. Fast adaptation in vestibular hair cells requires myosin-1c activity. Neuron 47, 541–553 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Kössl, M. Otoacoustic emissions from the cochlea of the 'constant frequency' bats, Pteronotus parnellii and Rhinolophus rouxi. Hear. Res. 72, 59–72 (1994).

    Article  PubMed  Google Scholar 

  153. 153

    Hudspeth, A. J. & Gillespie, P. G. Pulling springs to tune transduction: adaptation by hair cells. Neuron 12, 1–9 (1994).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Manley, G. A. & Gallo, L. Otoacoustic emissions, hair cells, and myosin motors. J. Acoust. Soc. Am. 102, 1049–1055 (1997).

    Article  CAS  PubMed  Google Scholar 

  155. 155

    Pringle, J. W. The contractile mechanism of insect fibrillar muscle. Prog. Biophys. Mol. Biol. 17, 1–60 (1967).

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Ó Maoiléidigh, D., Nicola, E. M. & Hudspeth, A. J. The diverse effects of mechanical loading on active hair bundles. Proc. Natl Acad. Sci. USA 109, 1943–1948 (2012).

    Article  PubMed  Google Scholar 

  157. 157

    Lumpkin, E. A., Marquis, R. E. & Hudspeth, A. J. The selectivity of the hair cell's mechanoelectrical-transduction channel promotes Ca2+ flux at low Ca2+ concentrations. Proc. Natl Acad. Sci. USA 94, 10997–11002 (1997).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Ricci, A. J. & Fettiplace, R. Calcium permeation of the turtle hair cell mechanotransducer channel and its relation to the composition of endolymph. J. Physiol. 506, 159–173 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Cheung, E. L. M. & Corey, D. P. Ca2+ changes the force sensitivity of the hair-cell transduction channel. Biophys. J. 90, 124–139 (2006).

    Article  CAS  PubMed  Google Scholar 

  160. 160

    Martin, P., Bozovic, D., Choe, Y. & Hudspeth, A. J. Spontaneous oscillation by hair bundles of the bullfrog's sacculus. J. Neurosci. 23, 4533–4548 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Kroese, A. B., Das, A. & Hudspeth, A. J. Blockage of the transduction channels of hair cells in the bullfrog's sacculus by aminoglycoside antibiotics. Hear. Res. 37, 203–217 (1989).

    Article  CAS  PubMed  Google Scholar 

  162. 162

    Doll, J. C., Peng, A. W., Ricci, A. J. & Pruitt, B. L. Faster than the speed of hearing: nanomechanical force probes enable the electromechanical observation of cochlear hair cells. Nano Lett. 12, 6107–6111 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Crawford, A. C. & Fettiplace, R. The mechanical properties of ciliary bundles of turtle cochlear hair cells. J. Physiol. 364, 359–379 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Roongthumskul, Y., Fredrickson-Hemsing, L., Kao, A. & Bozovic, D. Multiple-timescale dynamics underlying spontaneous oscillations of saccular hair bundles. Biophys. J. 101, 603–610 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Strimbu, C. E., Fredrickson-Hemsing, L. & Bozovic, D. Coupling and elastic loading affect the active response by the inner ear hair cell bundles. PLoS ONE 7, e33862 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Martin, P. & Hudspeth, A. J. Active hair-bundle movements can amplify a hair cell's response to oscillatory mechanical stimuli. Proc. Natl Acad. Sci. USA 96, 14306–14311 (1999).

    Article  CAS  PubMed  Google Scholar 

  167. 167

    Fredrickson-Hemsing, L., Ji, S., Bruinsma, R. & Bozovic, D. Mode-locking dynamics of hair cells of the inner ear. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 86, 021915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Dierkes, K., Lindner, B. & Jülicher, F. Enhancement of sensitivity gain and frequency tuning by coupling of active hair bundles. Proc. Natl Acad. Sci. USA 105, 18669–18674 (2008).

    Article  PubMed  Google Scholar 

  169. 169

    Barral, J., Dierkes, K., Lindner, B., Jülicher, F. & Martin, P. Coupling a sensory hair-cell bundle to cyber clones enhances nonlinear amplification. Proc. Natl Acad. Sci. USA 107, 8079–8084 (2010).

    Article  PubMed  Google Scholar 

  170. 170

    Vilfan, A. & Duke, T. Frequency clustering in spontaneous otoacoustic emissions from a lizard's ear. Biophys. J. 95, 4622–4630 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Gelfand, M., Piro, O., Magnasco, M. O. & Hudspeth, A. J. Interactions between hair cells shape spontaneous otoacoustic emissions in a model of the tokay gecko's cochlea. PLoS ONE 5, e11116 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Shera, C. A. Mammalian spontaneous otoacoustic emissions are amplitude-stabilized cochlear standing waves. J. Acoust. Soc. Am. 114, 244–262 (2003).

    Article  PubMed  Google Scholar 

  173. 173

    Eguíluz, V. M., Ospeck, M., Choe, Y., Hudspeth, A. J. & Magnasco, M. O. Essential nonlinearities in hearing. Phys. Rev. Lett. 84, 5232–5235 (2000).

    Article  PubMed  Google Scholar 

  174. 174

    Kern, A. & Stoop, R. Essential role of couplings between hearing nonlinearities. Phys. Rev. Lett. 91, 128101 (2003).

    Article  CAS  PubMed  Google Scholar 

  175. 175

    Martin, P. & Hudspeth, A. J. Compressive nonlinearity in the hair bundle's active response to mechanical stimulation. Proc. Natl Acad. Sci. USA 98, 14386–14391 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. 176

    Martin, P., Hudspeth, A. J. & Jülicher, F. Comparison of a hair bundle's spontaneous oscillations with its response to mechanical stimulation reveals the underlying active process. Proc. Natl Acad. Sci. USA 98, 14380–14385 (2001).

    Article  CAS  PubMed  Google Scholar 

  177. 177

    Overstreet, E. H. I. I. I., Temchin, A. N. & Ruggero, M. A. Basilar membrane vibrations near the round window of the gerbil cochlea. J. Assoc. Res. Otolaryngol. 3, 351–361 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  178. 178

    Ruggero, M. A., Rich, N. C., Recio, A., Narayan, S. S. & Robles, L. Basilar-membrane responses to tones at the base of the chinchilla cochlea. J. Acoust. Soc. Am. 101, 2151–2163 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Walker, D. P. Studies in Musical Science in the Late Renaissance (Warburg Institute, 1978).

    Google Scholar 

  180. 180

    Campbell, M. & Greated, C. A Musician's Guide to Acoustics (Oxford Univ. Press, 2002).

    Google Scholar 

  181. 181

    Robles, L., Ruggero, M. A. & Rich, N. C. Two-tone distortion in the basilar membrane of the cochlea. Nature 349, 413–414 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Robles, L., Ruggero, M. A. & Rich, N. C. Two-tone distortion on the basilar membrane of the chinchilla cochlea. J. Neurophysiol. 77, 2385–2399 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Kozlov, A. S., Risler, T., Hinterwirth, A. J. & Hudspeth, A. J. Relative stereociliary motion in a hair bundle opposes amplification at distortion frequencies. J. Physiol. 590, 301–308 (2012).

    Article  CAS  PubMed  Google Scholar 

  184. 184

    Jaramillo, F., Markin, V. S. & Hudspeth, A. J. Auditory illusions and the single hair cell. Nature 364, 527–529 (1993).

    Article  CAS  PubMed  Google Scholar 

  185. 185

    Barral, J. & Martin, P. Phantom tones and suppressive masking by active nonlinear oscillation of the hair-cell bundle. Proc. Natl Acad. Sci. USA 109, E1344–E1351 (2012).

    Article  PubMed  Google Scholar 

  186. 186

    Goldstein, J. L. Auditory nonlinearity. J. Acoust. Soc. Am. 41, 676–689 (1967).

    Article  CAS  PubMed  Google Scholar 

  187. 187

    Smoorenburg, G. F. Audibility region of combination tones. J. Acoust. Soc. Am. 52, 603 (1972).

    Article  Google Scholar 

  188. 188

    Jülicher, F., Andor, D. & Duke, T. Physical basis of two-tone interference in hearing. Proc. Natl Acad. Sci. USA 98, 9080–9085 (2001).

    Article  PubMed  Google Scholar 

  189. 189

    Stoop, R. & Kern, A. Two-tone suppression and combination tone generation as computations performed by the Hopf cochlea. Phys. Rev. Lett. 93, 268103 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. 190

    Anderson, D. J., Rose, J. E., Hind, J. E. & Brugge, J. F. Temporal position of discharges in single auditory nerve fibers within the cycle of a sine-wave stimulus: frequency and intensity effects. J. Acoust. Soc. Am. 49 (Suppl 2), 1131+ (1971).

    Article  Google Scholar 

  191. 191

    Köppl, C. Phase locking to high frequencies in the auditory nerve and cochlear nucleus magnocellularis of the barn owl, Tyto alba. J. Neurosci. 17, 3312–3321 (1997).

    Article  PubMed  Google Scholar 

  192. 192

    Izhikevich, E. M. Neural excitability, spiking and bursting. Int. J. Bifurc. Chaos 10, 1171–1266 (2000).

    Article  Google Scholar 

  193. 193

    Kemp, D. T. The evoked cochlear mechanical response and the auditory microstructure - evidence for a new element in cochlear mechanics. Scand. Audiol. Suppl. 35–47 (1979).

  194. 194

    Talmadge, C. L., Long, G. R., Murphy, W. J. & Tubis, A. New off-line method for detecting spontaneous otoacoustic emissions in human subjects. Hear. Res. 71, 170–182 (1993).

    Article  CAS  PubMed  Google Scholar 

  195. 195

    Penner, M. J. & Zhang, T. Prevalence of spontaneous otoacoustic emissions in adults revisited. Hear. Res. 103, 28–34 (1997).

    Article  CAS  PubMed  Google Scholar 

  196. 196

    Köppl, C. & Manley, G. A. Spontaneous otoacoustic emissions in the bobtail lizard. I: general characteristics. Hear. Res. 71, 157–169 (1993).

    Article  PubMed  Google Scholar 

  197. 197

    Manley, G. A. Spontaneous otoacoustic emissions from free-standing stereovillar bundles of ten species of lizard with small papillae. Hear. Res. 212, 33–47 (2006).

    Article  PubMed  Google Scholar 

  198. 198

    Izhikevich, E. M. Dynamical Systems in Neuroscience: The Geometry of Excitability and Bursting (MIT Press, 2010).

    Google Scholar 

  199. 199

    Oertel, D. & Doupe, A. J. in Principles of Neural Science 5th edn Ch. 31 (eds Kandel, E. R., Schwartz, J. H., Jessel, T. M., Siegelbaum, S. A. & Hudspeth, A. J.) 682–711 (McGraw-Hill Medical, 2013).

    Google Scholar 

  200. 200

    Fredrickson-Hemsing, L., Strimbu, C. E., Roongthumskul, Y. & Bozovic, D. Dynamics of freely oscillating and coupled hair cell bundles under mechanical deflection. Biophys. J. 102, 1785–1792 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Nadrowski, B., Martin, P. & Jülicher, F. Active hair-bundle motility harnesses noise to operate near an optimum of mechanosensitivity. Proc. Natl Acad. Sci. USA 101, 12195–12200 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

An investigator of Howard Hughes Medical Institute, the author thanks T. Reichenbach for the programme used to generate figure 1d and the members of his research group for comments on the manuscript.

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Glossary

Bifurcation

An abrupt, qualitative change in the character of a dynamical system in response to a continuous change in the value of a particular variable, the control parameter.

Transduction

In sensory neuroscience, the term refers to the representation of a physical stimulus — for example, light, sound, acceleration, touch and chemicals — as electrical activity in an appropriate receptor cell.

Hair bundles

Mechanically sensitive organelles of a hair cell, each consisting of an upright cluster of cylindrical stereocilia that extend from the cell's apical surface.

Basilar membrane

A flat strip of connective tissue that spirals along the mammalian cochlea and supports the organ of Corti, which is the receptor for acoustic stimuli.

Travelling wave

A mechanical disturbance that propagates along the basilar membrane from the base towards the apex of the cochlea in response to acoustic stimulation.

Piezoelectricity

The phenomenon whereby application of a mechanical force to a substance produces an electrical potential difference across that substance, or vice versa, such as the application of changes in voltage to the piezoelectric protein prestin, which causes it to undergo a conformational change that results in an elongation or contraction of the cell.

Gating compliance

A decrease in hair-bundle stiffness owing to the gating of transduction channels.

Adaptation

Resetting of the sensitivity in a sensory system. This involves an adjustment of the range of hair-bundle displacements over which a hair cell's electrical response varies.

Limit-cycle oscillation

A stable pattern of oscillation in a non-linear dynamical system to which the system will return even if started in a different configuration.

Distortion products

Oscillations at specific frequencies produced within a hearing organ by the non-linear properties of hair bundles exposed to acoustic stimuli at other frequencies. They are also called combination tones or phantom tones and are used in the medical diagnosis of hearing deficits.

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Hudspeth, A. Integrating the active process of hair cells with cochlear function. Nat Rev Neurosci 15, 600–614 (2014). https://doi.org/10.1038/nrn3786

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