一般在哺乳類動物耳蝸之外毛細胞造成耳蝸放大的機制有兩種[1]：其一為毛細胞上之毛叢受到曲折(hair-bundle motility)而產生力電轉換(mechano-electrical transduction)的過程產生；其二由毛細胞上之快速蛋白prestin所產生之細胞體之電動性(somatic motility)，兩者機制皆為非線性。本論文第一部分以Liu and Neely於2009與2010年提出的中耳至內耳耳蝸及外毛細胞模型為基礎，利用數學運算模擬外毛細胞受到內側橄欖－耳蝸中繼神經元(Medial Olivocochlear Interneurons, MOC)傳出所產生之「快反應」(fast effect) [2]；第二部分：隨著分子生物實驗技術的進步，利用重新接合(knock-in)外毛細胞上之基因方式[3]，造成外毛細胞上快速蛋白prestin數量的改變，本論文以此模型模擬此基因改變造成聽力之頻率響應的影響，模擬結果在耳蝸高頻區域頻率響應與文獻相符，外毛細胞之非線性電容[4]及電動性與耳蝸放大之增益並非為線性相關，最後並提出耳蝸低頻區域之頻率響應猜測。

Two mechanisms have been proposed for outer hair cells(OHCs) mediated amplification in mammalian cochlea : a hair-bundle(HB) motility generated during mechano-electrial transduction(MET) and a somatic motility generated by motor protein prestin in the outer hair cell lateral membrane. Both mechanisms are nonlinear. In the first section, this thesis uses computer models to simulate the outer hair cell fast effect by efferent control from medial olivocochlea interneuron. The middle-ear to inner ear and outer hair cell model proposed by Liu and Neely in 2009 and 2010 were adopted for this purpose. In the second section, with recent advance in molecular biology, the amount of prestin can be changed in all outer hair cells in the cochlea using novel knock-in techniques. This thesis simulated the effects on hearing curves with altered gene expression. The results of simulation in high frequency region of the cochlea are consistent with literature in that the outer hair cell nonlinear capacitance and somatic motility are not linearly correlated with the gain of the cochlea amplifier. Base on the computer model, insight regarding the cochlea frequency responses at low frequency region is also provided.

[1] Liu, Y. W. and S. T. Neely (2009). "Outer hair cell electromechanical properties in a nonlinear piezoelectric model." Journal of the Acoustical Society of America 126(2): 751-761.
[2] Sridhar, T. S., M. C. Liberman, et al. (1995). "A novel cholinergic slow effect of efferent stimulation on cochlear potentials in the guinea-pig." Journal of Neuroscience 15(5): 3667-3678.
[3] Zuo, J., T. Yamashita, et al. (2011). "Normal hearing sensitivity at low to middle frequencies with ~ 25% prestin." What Fire Is in Mine Ears: Progress in Auditory Biomechanics 1403.
[4] Fang, J. and K. H. Iwasa (2007). "Effects of chlorpromazine and trinitrophenol on the membrane motor of outer hair cells." Biophysical Journal 93(5): 1809-1817.
[5] Liu, Y. W. and S. T. Neely (2010). "Distortion product emissions from a cochlear model with nonlinear mechanoelectrical transduction in outer hair cells." Journal of the Acoustical Society of America 127(4): 2420-2432.
[6] Patuzzi, R. B., G. K. Yates, et al. (1989). "Outer hair cell-receptor current and sensorineural hearing-loss." Hearing Research 42(1): 47-72.
[7] Guinan, J. J. (2007). "Olivocochlear efferents: Anatomy, physiology, function, and the measurement of efferent effects in humans (vol 27, pg 589, 2006)." Ear and Hearing 28(1): 129-129.
[8] Flanagan, J. L., Allen, J. B., Hasegawa-Johnson M. A. (2008), Chap. 6 The Ear and Hearing. Speech Analysis Synthesis and Perception(pp.147-189), The third edition.
[9] Liberman, M. C. and J. J. Guinan (1998). "Feedback control of the auditory periphery: Anti-masking effects of middle ear muscles vs. olivocochlear efferents." Journal of Communication Disorders 31(6): 471-483.
[10] Gleich, O., R. J. Dooling, et al. (1995). "Evidence for continuous hair cell regeneration in a song bird with hereditary cochlear hearing-loss." Hno 43(5): 287-293.
[11] Manoussaki, D., E. K. Dimitriadis, et al. (2006). "Cochlea's graded curvature effect on low frequency waves." Physical Review Letters 96(8).
[12] Ku, E. M. (2008) "Modelling the Human Cochlea," University of Southampton Faculty of Engineering, Science and Mathematics, Institute of Sound and Vibration Research. Fulbright Scholar.
[13] von Bekesy, G. (1949). "The vibration of the cochlear partition in anatomical preparations and in models of the inner ear." Journal of the Acoustical Society of America 21(3): 233-245.
[14] Squire, L. R. (2008). Fundamental neuroscience. Amsterdam ; Boston, Elsevier / Academic Press.
[15] Young, E. D. and D. oertel (2004). Chap.4 The cochlear nucleus. In Shepherd, G .M., The synaptic organization of the brain(pp.125-171). Oxford ; New York, Oxford University Press.
[16] Fettiplace, R. (2006). "Active hair bundle movements in auditory hair cells." Journal of Physiology-London 576(1): 29-36.
[17] Raphael, Y. and R. A. Altschuler (2003). "Structure and innervation of the cochlea." Brain Research Bulletin 60(5-6): 397-422.
[18] Fuchs, P. A., E. Glowatzki, et al. (2003). "The afferent synapse of cochlear hair cells." Current Opinion in Neurobiology 13(4): 452-458.
[19] Guinan J. J. (2011). Chap. 3 physiology of the Medial and Lateral Olivocochlear System. In Ryugo, D. K., R. R. Fay, et al. Auditory and vestibular efferent(pp39-81). New York, Springer
[20] William W. F. (2011). Chap. 4 Pharmacology and Neurochemistry of olivocochlear efferents. In Ryugo, D. K., R. R. Fay, et al. Auditory and vestibular efferent(pp83-101). New York, Springer
[21] Elgoyhen, A. B., D. E. Vetter, et al. (2001). "alpha 10: A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells." Proc Natl Acad Sci U S A 98(6): 3501-3506.
[22] Gisselsson, L. (1950). "Experimental investigation into the problem of humoral transmission in the cochlea." Acta Otolaryngol Suppl 82: 9-78.
[23] Nenov, A. P., C. Norris, et al. (1996). "Acetylcholine response in guinea pig outer hair cells .2. Activation of a small conductance Ca2+-activated K+ channel." Hearing Research 101(1-2): 149-172.
[24] Jasser, A. and P. S. Guth (1973). "The synthesis of acetylcholine by the olivo-cochlear bundle." J Neurochem 20(1): 45-53.
[25] Frolenkov, G. I. (2006). "Regulation of electromotility in the cochlear outer hair cell." Journal of Physiology-London 576(1): 43-48.
[26] Appler, J. M. and L. V. Goodrich (2011). "Connecting the ear to the brain: Molecular mechanisms of auditory circuit assembly." Progress in Neurobiology 93(4): 488-508.
[27] Munirathinam, S., E. M. Ostapoff, et al. (2004). "Organization of inhibitory feed-forward synapses from the dorsal to the ventral cochlear nucleus in the cat: a quantitative analysis of endings by vesicle morphology." Hearing Research 198(1-2): 99-115.
[28] Brown, M. C., R. K. de Venecia, et al. (2003). "Responses of medial olivocochlear neurons - Specifying the central pathways of the medial olivocochlear reflex." Experimental Brain Research 153(4): 491-498.
[29] Dallos, P., D. Z. Z. He, et al. (1997). "Acetylcholine, outer hair cell electromotility, and the cochlear amplifier." Journal of Neuroscience 17(6): 2212-2226.
[30] Cooper, N. P. and J. J. Guinan (2006). "Medial olivocochlear efferent effects on basilar membrane responses to sound." Auditory Mechanisms: Processes and Models: 86-92.
[31] Russell, I. J. and E. Murugasu (1997). "Medial efferent inhibition suppresses basilar membrane responses to near characteristic frequency tones of moderate to high intensities." Journal of the Acoustical Society of America 102(3): 1734-1738.
[32] Dolan, D. F., M. H. Guo, et al. (1997). "Frequency-dependent enhancement of basilar membrane velocity during olivocochlear bundle stimulation." Journal of the Acoustical Society of America 102(6): 3587-3596.
[33] Cooper, N. P. and J. J. Guinan (2003). "Separate mechanical processes underlie fast and slow effects of medial olivocochlear efferent activity." Journal of Physiology-London 548(1): 307-312.
[34] Allen, J. B. (1990). "Modeling the Noise Damaged Cochlea." Mechanics and Biophysics of Hearing 87: 324-332.
[35] Kolston, P. J., E. Deboer, et al. (1990). "What type of force does the cochlear amplifier produce." Journal of the Acoustical Society of America 88(4): 1794-1801.
[36] He, D. Z. Z., S. P. Jia, et al. (2003). "Prestin and the dynamic stiffness of cochlear outer hair cells." Journal of Neuroscience 23(27): 9089-9096.
[37] de Boer, J., A. R. D. Thornton, et al. (2012). "What is the role of the medial olivocochlear system in speech-in-noise processing?" J Neurophysiol 107(5): 1301-1312.
[38] Hawkey, D. J. C., S. Amitay, et al. (2004). "Early and rapid perceptual learning." Nature Neuroscience 7(10): 1055-1056.
[39] Burkard, R. and K. Hecox (1983). "The effect of broadband noise on the human brainstem auditory evoked response. I. Rate and intensity effects." Journal of the Acoustical Society of America 74(4): 1204-1213.
[40] Chandrasekaran, B. and N. Kraus (2010). "The scalp-recorded brainstem response to speech: neural origins and plasticity." Psychophysiology 47(2): 236-246.
[41] Micheyl, C. and L. Collet (1996). "Involvement of the olivocochlear bundle in the detection of tones in noise." Journal of the Acoustical Society of America 99(3): 1604-1610.
[42] Maison, S., C. Micheyl, et al. (2001). "Influence of focused auditory attention on cochlear activity in humans." Psychophysiology 38(1): 35-40.
[43] Winer, J. A. (2006). "Decoding the auditory corticofugal systems (vol 207, pg 1, 2005)." Hearing Research 212(1-2): 1-8.
[44] Darbon, P., D. J. Wright, et al. (2011). "Conductance properties of the acetylcholine receptor current of guinea pig outer hair cells." Jaro-Journal of the Association for Research in Otolaryngology 12(1): 59-70.
[45] Gomez-Casati, M. E., P. A. Fuchs, et al. (2005). "Biophysical and pharmacological characterization of nicotinic cholinergic receptors in rat cochlear inner hair cells." J Physiol 566(Pt 1): 103-118.
[46] Weisstaub, N., D. E. Vetter, et al. (2002). "The alpha 9 alpha 10 nicotinic acetylcholine receptor is permeable to and is modulated by divalent cations." Hearing Research 167(1-2): 122-135.
[47] Yazejian, B. and G. L. Fain (1993). "Whole-cell currents activated at nicotinic acetylcholine-receptors on ganglion-cells isolated from goldfish retina." Visual Neuroscience 10(2): 353-361.
[48] He, D. Z. Z. and P. Dallos (2000). "Properties of voltage-dependent somatic stiffness of cochlear outer hair cells." Jaro-Journal of the Association for Research in Otolaryngology 1(1): 64-81.
[49] Santos-Sacchi, J. (1991). "Reversible Inhibition of Voltage-Dependent Outer Hair Cell Motility and Capacitance." Journal of Neuroscience 11(10): 3096-3110.
[50] Kakehata, S. and J. Santos-Sacchi (1996). "Effects of salicylate and lanthanides on outer hair cell motility and associated gating charge." Journal of Neuroscience 16(16): 4881-4889.
[51] He, D. Z. Z. and P. Dallos (1999). "Development of acetylcholine-induced responses in neonatal gerbil outer hair cells." J Neurophysiol 81(3): 1162-1170.
[52] Hallworth, R. (2007). "Absence of voltage-dependent compliance in high-frequency cochlear outer hair cells." Jaro-Journal of the Association for Research in Otolaryngology 8(4): 464-473.
[53] Liberman, M. C., J. G. Gao, et al. (2002). "Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier." Nature 419(6904): 300-304.
[54] Lagarde, M. M. M., M. Drexl, et al. (2008). "Prestin's role in cochlear frequency tuning and transmission of mechanical responses to neural excitation." Current Biology 18(3): 200-202.
[55] Ursick, J. and H. Staecker (2007). "An overview of animal models of tinnitus." B-Ent: 23-25.
[56] Geven, L. I., E. de Kleine, et al. (2011). "Contralateral suppression of otoacoustic emissions in tinnitus patients." Otology & Neurotology 32(2): 315-321.
[57] Ceranic, B. J., D. K. Prasher, et al. (1998). "Tinnitus after head injury: evidence from otoacoustic emissions." Journal of Neurology Neurosurgery and Psychiatry 65(4): 523-529.
[58] Shera, C. A. (2007). "Laser amplification with a twist: Traveling-wave propagation and gain functions from throughout the cochlea." Journal of the Acoustical Society of America 122(5): 2738-2758.
[59] Hudspeth, A. J. (1997). "Mechanical amplification of stimuli by hair cells." Current Opinion in Neurobiology 7(4): 480-486.
[60] Brownell, W. E., C. R. Bader, et al. (1985). "Evoked mechanical responses of isolated cochlear outer hair-cells." Science 227(4683): 194-196.
[61] Ashmore, J. F. (1987). "A fast motile response in guinea-pig outer hair-cells - the cellular basis of the cochlear amplifier." Journal of Physiology-London 388: 323-347.
[62] Kemp, D. T. (1978). "Stimulated acoustic emissions from within human auditory-system." Journal of the Acoustical Society of America 64(5): 1386-1391.
[63] Zweig, G. and C. A. Shera (1995). "The origin of periodicity in the spectrum of evoked otoacoustic emissions." Journal of the Acoustical Society of America 98(4): 2018-2047.
[64] Matthews, J. W. (1983). "Modeling reverse middle ear transmission of acoustic distortion signals," in Mechanics of Hearing, edited by E. de Boer and M. A. Viergever Delft University Press, Delft, pp. 11–18.
[65] Zwislocki, J. (1962). "Analysis of the middle-ear function. Part I: Input impedance. " J. Acoust. Soc. Am. 34, 1514–1523.
[66] Santos-Sacchi, J. (1991). "Reversible inhibition of voltage-dependent outer hair cell motility and capacitance." J. Neurosci. 11, 3096–3110.
[67] Mountain, D. C., and Hubbard, A. E. (1994). "A piezoelectric model of outer hair cell function." J. Acoust. Soc. Am. 95(1), 350–354.
[68] Kennedy, H. J., A. C. Crawford, et al. (2005). "Force generation by mammalian hair bundles supports a role in cochlear amplification." Nature 433(7028): 880-883.
[69] Dallos, P. (1973). The Auditory Periphery: Biophysics and Physiology . New York, Academic Press..
[70] Sachs, M. B. and P. J. Abbas (1974). "Rate versus level functions for auditory-nerve fibers in cats - tone-burst stimuli." Journal of the Acoustical Society of America 56(6): 1835-1847.
[71] A. van Schaik, E. Fragniere and E. Vittoz (1996) "An analogue electronic model of ventral cochlear nucleus neurons," IEEE Int. Conf. Microelectronics for Neural Networks: 52-59.
[72] W. S. Rhode and S. Greenberg (1992) The Mammalian Auditory Pathway: Neurophysiology, Edited by Popper, A.N., and Fay, R.R., Springer-Verlag, New York.
[73] Katz, E. Elgoyhen, A. B. and Fuchs, P. A. (2011). Chap. 5 Cholinergic Inhibition of Hair Cells. In Ryugo, D. K., R. R. Fay, et al. Auditory and vestibular efferent(pp39-81). New York, Springer
[74] Fuchs, P. A. and B. W. Murrow (1992). "A novel cholinergic receptor mediates inhibition of chick cochlear hair cells." Proc Biol Sci 248(1321): 35-40.
[75] Fuchs, P. A. and B. W. Murrow (1992). "Cholinergic inhibition of short (outer) hair cells of the chick's cochlea." Journal of Neuroscience 12(3): 800-809.
[76] Fettiplace, R., A. C. Crawford, et al. (2006). "Signal transformation by mechanotransducer channels of mammalian outer hair cells." Auditory Mechanisms: Processes and Models: 245-253.
[77] Mountain, D. C. and A. E. Hubbard (1994). "A piezoelectric model of outer hair cell function." Journal of the Acoustical Society of America 95(1): 350-354.