Proc. Natl. Acad. Sci. USA Vol. 90, pp.

8347-8351, September 1993 Neurobiology

Stereocilia displacement induced somatic motility of cochlear outer hair cells
BURT N. EVANS AND PETER DALLOS
Auditory Physiology Laboratory (The Hugh Knowles Center) and Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208

Communicated by A. J. Hudspeth, June 2, 1993 (received for review February 4, 1993)

ABSTRACT Outer hair cells, isolated from mammalian cochleas, are known to respond to electrical stimulation with elongation or contraction of the cell's cylindrical soma. It is assumed that such shape changes, when driven by the cell's receptor potential in vivo, are a part of the feedback process that underlies cochlear amplification. To date it has not been possible to demonstrate somatic shape changes upon normal mechanical stimulation of the cell-i.e., the deflection of its hair bundle. We show here that mechanically induced hairbundle deflection produces somatic motiliy of the cell. Such motility is dependent upon a functioning forward trnsucer process and disappears upon interference with trnsduction. The motile response also reflects the hair bundle's known directional sensitivity. This demonstration of mechanically driven motility indicates that the cell may possess capabilities to affect its mechanical environment under control of its own receptor potential and, thereby, participate in a local cochlear feedback process. It is commonly accepted that normal operation of the mammalian cochlea is dependent on amplification, in the form of mechanical feedback, from outer hair ceils (OHCs) to the basilar membrane-tectorial membrane complex (for reviews, see refs. 1-4). OHCs are considered to be mechanical effectors, and inner hair cells, possessing 90-95% of afferent innervation (5), are thought of as the true sensory receptors. In this scheme, receptor potentials produced by OHCs in response to acoustic stimulation provide the input to the cell's motor activity. Consequently, the OHC is thought to perform two transducer functions (6), a conventional mechanoelectrical or forward transduction and a specialized electromechanical or reverse transduction. The capability of OHCs to change their length under voltage control (7-11) is assumed to be a possible means whereby OHCs deliver a force to the cochlear partition.* The above construct is based on two sets of separate observations. (i) It is known that OHCs produce a receptor potential in response to acoustic stimulation in vivo (14). (ii) Electrical stimulation results in somatic motility in vitro, so-called electromotility (7). To date, however, a direct link between the appropriate stimulus to OHCs, stereocilia (hair bundle) deflection, and somatic motility has not been demonstrated. To discriminate a somatic motile response evoked by a mechanical stimulus, hair-bundle deflection, from simple electromotility and to avoid the repetitive use of the correct but long descriptive term, "hair-bundle displacement-evoked somatic motility," we designate this complete response mechanomotility. We seek the existence of this response in the present experiments. We have studied (15) OHC electromotility with the aid of a wide-bore rapidly tapering glass suction pipette, the microchamber (15, 16), which was also used here. Cells were fully inserted into the chamber (Fig. 1A) so that only their cuticular
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plate and stereocilia bundle protruded into the surrounding bathing medium. Experiments consisted of recording the axial extension and contraction of the cell by measuring the motion of its synaptic pole. Two types of stimuli were delivered: mechanical and electrical. The first of these was the induction of sinusoidal hair-bundle motion by a fluid jet. The second was the delivery of a step-voltage command of either polarity across the cell while continuing mechanical stimulation of the hair bundle and measuring somatic length changes. We first examined whether stimulation of the stereocilia elicited somatic motility and whether the amplitude of the response was dependent on electrical polarization of the cell. We further investigated the dependence of this somatic motile response upon the integrity of the cell's transducer apparatus. To study transduction-related events, and particularly transduction-controlled motile events, it is advantageous to confine mechanical stimulation to the stereociliary bundle. It has been reported that there are stretch-activated channels in the OHC basolateral membrane (19, 20) and that direct mechanical stimulation of the basolateral membrane may result in somatic motility (21). In the microchamber configuration, the cell's soma is fully insulated from the mechanical input that is directed at the hair bundle. Consequently, the microchamber provides a platform for the study of transduction-related electrical and mechanical events without likely contamination by other factors.

MATERIALS AND METHODS OHCs were obtained from the cochleas of young (150-250 g) anesthetized albino guinea pigs. Cells were harvested only from the third and fourth turns of the cochlea; their lengths ranged between 55 and 75 ,um and their diameter was uniform, 8-9 pm. After removing segments of the organ of Corti, cells were transferred after enzymatic incubation (type IV collagenase, Sigma; 0.5 mg/ml) to the experimental bath containing either Leibovitz's L-15 medium (GIBCO) or Medium 199 (GIBCO), supplemented with 15 mM Hepes and S mM bovine serum albumin (Sigma), and adjusted to 300 milliosmolal and pH 7.35. The perfusion medium for low Ca2+ experiments consisted of a modified calcium-deficient Medium 199 (83-0063; GIBCO), supplemented with 20 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA, A 4926; Sigma), adjusted to 300 milliosmolal and
pH 7.35. The bath medium was replaced every 60 sec by using a Holter (Extracorporeal, King of Prussia, PA) (RL-175) peristaltic pump. Experiments were done on a Labovert (Leitz) inverted microscope. By extending the technique of Santos-Sacchi (17), the somatic and stereociliary displacements were meaAbbreviations: OHC, outer hair cell; BAPTA, bis(2-aminophenoxy)-

ethane-N,N,N',N'-tetraacetate. *Alteration of ciliary stiffness under stimulus control may be another effective means whereby OHCs modify cochlear micromechanics (12, 13).

8347

8348 A

Neurobiology: Evans and Dallos

Proc. Natl. Acad. Sci. USA 90 (1993)
FIG. 1. (A) Fully inserted OHC held within the microchamber. During data acquisition, the stereociliary bundle and the cell's synaptic pole are further magnified and imaged onto photodiodes for measuring displacements. (B) Schematic diagram of the cell in the microchamber with an equivalent electrical circuit superimposed. Hair-bundle deflection modulates the cell's apical membrane resistance Ra. Voltage drop on the basolateral membrane resistance Rb, due to the receptor current i, drives putative voltage-to-displacement converter motors. (Inset) Characteristic function of electromotility (17, 18). Note that as the operating point on the function moves toward a more depolarized region, the slope (gain) first increases and then decreases.

B
LDepolari7e
-y
E ;4

cou

-0.6
-1.6

1(00 -80

hO0

40

n,. IXIV

f

Vb
sured using a pair of photosensitive elements (555-HS; United Detector Technology, Santa Monica, CA) that were mounted to the video display. Microchambers that held the cells were fabricated from borosilicate glass (Friedrich & Dimmock, Vineland, NJ; 2011-L) having aperture diameters similar to those of OHCs. Cells were drawn into siliconized (Hills, Bristol, PA) microchambers by gentle suction. Inserted cells were inspected at high magnification and discarded upon any sign of induced trauma such as swelling of cell soma, nuclear translation, Brownian motion of organelles, or disruption of the stereociliary bundle. The manipulator holding the microchamber allowed for axial rotation and proper alignment of the hair bundle with respect to an oscillating fluid jet that stimulated bundle displacement. The fluid jet was driven from a small loudspeaker driving a piston through an air column (22), yielding an oscillating flow at a rate of 5 Hz. The aperture of the glass pipette that provided the jet was 10 ,um in diameter and was placed at a distance of -10 ,um from the stereocilia. The stimulator was initially oriented so that the force upon the hair bundle was in the direction of the hair bundle's axis of symmetry and, consequently, its axis of optimal stimulation (23). By rotating the microchamber, and thus the cell, along its axis, different orientations of the stimulus relative to the hair bundle were possible. Calibration of the fluid jet apparatus was not necessary inasmuch as we measured the actual stereociliary bundle motion resulting from the mechanical stimulation. A high-intensity xenon light source (Karl Storz, Culver City, CA) was used to illuminate the specimen by a 0.5-inch fiber optic coupler (1 inch = 2.54 cm). The optics (Zeiss 63 x, 0.9 n.a. Neofluar) were modified for contrast enhancement (Modulation Optics, Greenvale, NY). The edges of the stereociliary hair bundle and the cell's synaptic pole provided marked light-dark transitions. Such images were projected through additional relay lenses and then to a multiimage module (Nikon), allowing simultaneous high-magnification (x35,000) imaging of the cell's hair bundle and synaptic pole. Real-time digital and analog processing (Hamamatsu, Middlesex, NJ) of the video signal further enhanced edgedetection capability. The images were finally displayed on black and white monitor screens upon which the calibrated diode sensors were affixed. By using a piezoelectric actuator, calibrated displacements of the microchamber and cell, in toto, indicated that subpixel motion (10 nm peak-to-peak) could be resolved. By employing signal averaging, time-locked movements on the order of 1 nm could be routinely recorded. Calibration factors were obtained for each experimental run under program control by electronically displacing the live video image in front of the diode sensors by known amounts (+1 pixel = ±58 nm) after the system itself was calibrated by measuring the image size of microbeads (Polyscience) 1.0 ,um in diameter. The above technique was found to be equivalent to other calibration

procedures previously implemented including the optical lever technique (24). The linearity of the charge-coupled device camera was verified by interrogating pixel intensity profiles generated in response to test patterns after disabling the camera's automatic gain control circuitry. Finally, it was verified that the small displacements were not distorted by automatic gain control features resident in the display monitor itself. The linearity ofthe entire measurement system was tested by electronically displacing the image around its center position under computer control. It was found that the linear range for dc and ac displacements encompassed ±5 pixels, which was sufficiently wide to assure undistorted reproduction of ac displacements of the stereocilia and synaptic pole. The amplified diode signals were digitized at a rate of 3 kHz, averaged (usually 20 trials), and low-pass-filtered at 10 Hz. Video images of the cell and hair-bundle segment were stored on an optical laser disk. Electrical command signals were generated in voltageclamp mode (model 8900; Dagen Instruments, Minneapolis) and delivered between the electrolytes surrounding and filling the microchamber (Fig. 1B). The cell and the chamber form a resistive seal between electrolytes inside and surrounding the microchamber with an access resistance of =10 MQl. Making the fluid within the microchamber positive hyperpolarizes the included membrane segment and depolarizes the excluded membrane (18). When the cell is fully inserted (as in Fig. 1), the command voltage is divided on a voltage divider formed by the cell's ciliated apical membrane (Ra; outside the chamber) and its basolateral membrane (Rb; inside the chamber). The electrical resistances of these two membrane regions are likely very different both in vivo and in vitro (25, 26), with Ra >> Rb. It has been estimated that the electrical resistance of the excluded membrane of a fully inserted cell in the absence of mechanical stimulation is at least 10 times greater than that of the included membrane (25). Consequently, at least 90% ofthe applied voltage should appear across Ra, the excluded (stereociliary) membrane segment for a fully inserted cell. While the microchamber method does not permit us to measure the cell's resting potential directly, as the above consideration indicates for the excluded membrane segment the command voltage well approximates the change in membrane potential. Furthermore, the asymmetry of the electromotile response is indicative of the cell's resting potential. Cells that are likely to have relatively high resting potentials produce larger shortening than extension-directed responses (Fig. 1B; refs. 18 and 27). Conversely, depolarized cells generate either a symmetrical electromotile response or a response with extension dominance (18, 27). Note, for example, the electromotile response of the cell in Fig. 2B: contraction exceeds expansion; hence, the membrane potential is unlikely to have been less negative than approximately -40 mV. The current passing through the microchamber is the sum of the receptor

Neurobiology: Evans and Dallos

Proc. Natl. Acad. Sci. USA 90 (1993)

8349

_s

B
11 0 0

voltage- and time-dependent conductances of the cell's basolateral membrane are omitted from this elementary model (28). Fig. 1B Inset shows the cell's reverse transducer function, i.e., motility vs. membrane voltage change (17, 18). Hair-bundle deflection modulates the cell's apical resistance by opening and closing of transducer channels in the stereocilia (29). Denote the ratio ofresting (no stimulus) basolateral and apical membrane resistances as ao = Rb/Rao, whereas the dynamic stimulus-controlled value is a(t) = Rb/Ra(t) = aoftt), wheref(t) is some function oftime. The voltage across the cell's basolateral membrane that drives motility is Vb(t). Assume that the cell membrane's electromotive force (Thdvenin-equivalent or open-circuit voltage) is E, a dc command voltage Vis placed across the cell, the microchamber's series resistance is Ro, and the access resistance between external and internal fluid media is Rsh. Define (3 = Ro/Rsh (as we have indicated, B << 1). Analysis of the circuit yields the receptor current, i.

co

(1 + f3)E + V

C) 11

(Ra + Rb)[1 + ( + RO/(Ra + Rb)]
aof(t)
v
_

I
1-

[1 + aof(t)]Rb

(1 + O

[1]

AA/

W0JAAWVV\A/W\YWVVV

Il
0
2 4

The above simplification makes use of Ro << Ra + Rb. The series resistance of the cell's apical and basolateral membranes is in excess of the input resistance, known to exceed 100 MQl for the long cells used in our experiments (17, 30). The basolateral membrane voltage, Vb is as follows.

6

Time, sec

Vb=E-iRb

[i]b [ aof(t)J
[ +

E

Vaof(t)1

(I +

)

[2]

FIG. 2. (A) Computed model response (solid line) to a combination of ac (mechanical) modulation of apical resistance and dc (electrical) polarization of the cell. Basolateral membrane voltage is computed from Eq. 2 using V = +100 mV, ao = 0.1, and ( = 0.1. Motile response is obtained from the function in Fig. 1B Inset, with Vb as the input. For reference, the time courses of the command voltage V (dashed line) and the mechanical stimulus (dotted line) are also shown. Vertical projection lines aid in determining the phase of the response during the two polarities of the command voltage. (B) Demonstration of mechanomotile response. The axial displacement of the cell's synaptic pole, inside the microchamber, is measured (upper trace). Cell extension is plotted upward. During these measurements, the stereocilia are displaced sinusoidally by the fluid jet (5-10 nm, peak-to-peak, corresponding to 0.03-0.08° angular amplitude). A voltage change (±100 mV) is applied across the cell. The first change from baseline corresponds to hyperpolarization of the excluded portion (and corresponding depolarization of the included portion) of the cell membrane. The second change is a shift to the opposite polarity. The dc voltage changes elicit tonic electromotile responses. Note that with zero electrical command there is a sinusoidal somatic motile response related to the displacement ofthe stereocilia. During negative command, the mechanomotility is enhanced, whereas during positive command, it is depressed. The measured current through the microchamber and the sinusoidal mechanical and dc electrical stimuli are also shown (lower two traces). The current trace is dominated by current through Rsh. Vertical lines are drawn to aid in determining the phase of the mechanomotile response. The apparent time delay ofthe response in this and subsequent figures is due to the 10-Hz low-pass filtering of the photodiode output.

The resting dc current through the cell is

aoE
t0

=(1 + ao)Rb

[3]

The resting membrane potential of the cell is

current and a dominant shunt current through Rsh. In these experiments the receptor current is not measured.

RESULTS Theory. In Fig. 1B an electrical circuit that represents the OHC-microchamber system is shown. For simplicity, all

[4] Note that Vbo, the cell's membrane potential, is approximately equal to E, the electromotive force that probably reflects a potassium conductance (28). If V is negative, it hyperpolarizes the apical membrane and increases the receptor current. At the same time, a negative Vdepolarizes the basolateral membrane. There are three consequences. (i) If the receptor current increases for a given input, f(t), then the gain of the forward transducer is enhanced. (ii) Fig. 1B Inset shows that, as the basolateral membrane is depolarized, the operating point on the nonlinear function describing the electromotile response moves toward a steeper slope region; hence, the gain of electromotility is increased. (iii) Depolarization of the basolateral membrane may activate some voltage-dependent conductances (10, 17, 28, 30), probably producing a complex effect. Conversely, a positive command, V, decreases the forward transducer gain and also decreases the reverse transducer gain due to the shift of the operating point toward a shallower slope region on the electromotility function. Hyperpolarization ofthe basolateral membrane may also activate inward rectifying channels (31, 32) and also turn off outward rectifying voltage-gated channels (28). Once again, the effects are expected to be complex. As depolarization of the basolateral membrane increases at larger values of - V, the operating point moves beyond the maximum slope region and the reverse transducer gain begins to decrease. The linear effect of voltage bias (varying V) upon

Vbo= E - ioRb = E/(1 + ao).

8350

Neurobiology: Evans and Dallos

forward gain appears to dominate the changes in response, resulting in a monotonic response magnitude function. Finally, it can be shown that the phasic mechanomotile response goes through a null and reverses phase when the dc command voltage is approximately equal to the cell's membrane potential, Vbo. Specifically, the response reverses its phase when i = 0, at a command voltage V = Vr,v:
[5] Vrev = -(1 + 3)E = -(1 + 0)(1 + ao)Vo. Consequently, by using the microchamber technique, the cell's membrane potential can be estimated without the

0 0 Ce
6I

CZ -4)

.0
0 0

necessity of impalement. In Fig. 2A we demonstrate a simple model calculation based on the above concepts. The model assumesthatE= -70mV, ao = 0.1, ,B= 0.1, V= ±100mV, the input f(t) is a simple sinusoid, and the electromotility function is as shown in Fig. 1B. Note that the baseline response represents mechanomotility with zero electrical command. When V = -100 mV, the mechanomotile response is significantly increased, while it is decreased in amplitude during the application of V = +100 mV. Since V > Vre., the model predicts phase reversal of the mechanomotile response during the depolarizing command. Experimental Results. In Fig. 2B we demonstrate the axial displacement of the cell's synaptic pole. In this case the stimulus consisted of the fluid jet driving the stereociliary bundle and an electrical command signal applied across the cell. The data demonstrate that hair-bundle deflection produces somatic motility, and consequently, mechanomotility does exist. Phasic mechanomotile displacement of the cell's synaptic pole was discernible on the video monitor at the stimulus frequency of 5 Hz. The baseline mechanomotile response in this example was ;5.5 nm from peak to peak. When the basolateral membrane of the cell was depolarized, the mechanomotile response increased to "25 nm, and when the basolateral membrane was hyperpolarized, the mechanomotile response decreased to --2.5 nm. After the cessation of the electrical stimulus, the mechanomotility returned to the baseline value, =z5.5 nm. The response also contained a large asymmetrical dc electromotile component due to the direct effect of the electrical stimulation upon the basolateral membrane and the putative motor molecules therein. We note the similarity of the measured response to that predicted by the model (Fig. 2A). Included among similar features is the phase reversal of the mechanomotile response during depolarization of the ciliary membrane and an increase in the ac gain during -100 mV and its decrease during +100 mV. By keeping the fluid jet stimulus invariant, it is possible to rotate the microchamber, and thus the OHC, around the cell's long axis. This permits the delivery of mechanical stimulation to the hair bundle at different orientations vis-a-vis its morphological polarization. We ascertained that hair-bundle movement toward the tall hairs always produced mechanomotile response in the shortening direction. As Fig. 3A shows, when the cell is rotated 90°, mechanomotility disappears, whereas rotation by 1800 produces responses in opposite phase. This response character is invariant from cell to cell. Thus, as shown in Fig. 3B, any two cells that are oriented with their hairbundles facing the fluid jet with short vs. tall stereociliary rows produce mechanomotile responses in opposite phase. Mechanically induced somatic motility directly depends upon basolateral membrane voltage changes produced by the forward transducer current. It is known that very low Ca2+ levels in the medium surrounding the hair bundle irreversibly eliminate transduction (33-36). Upon replacing the external bath with Ca2+-free culture medium containing 20 mM BAPTA, cells responded to electrical stimulation with undiminished electromotility, whereas the mechanomotile responses were entirely abolished within 1 min. Mechanomotility is clearly dependent upon functioning mechanoelectric

700

B
0

E.E..E
Proc. Natl. Acad. Sci. USA 90 (1993)
180°
900
1300 Poststimulus onset, msec

1900

'0 ce
10

CC

z

0

2
Time, sec

4

6

FIG. 3. (A) Three successive response traces obtained at three orientations of the same hair bundle with respect to the stimulating fluid jet. Solid line, orientation such that shortest stereociliary row faces tojet (0') (this is the same orientation as in Fig. 2B); dashed line, bundle is rotated 90'; dotted line, bundle is rotated an additional 90'. To clearly show the response phases, only a portion of the response time course is presented. (B) Mechanomotile responses of two cells, one at 0' and the other at 180' stereocilia bundle orientation. Note that the ac response phases are opposite throughout the records, whereas the dc electromotile responses are the same. Combined mechanical (ac) and electrical (dc, ±100 mV) stimulation.

transduction. Another means of demonstrating this is to take advantage of the known capacity of aminoglycosides to block transducer channels in hair cells (37-39). We observed a complete elimination of mechanomotility upon replacing the external bathing medium with medium containing 200 pM dihydrostreptomycin sulfate. The effect was partially reversible upon washing out the drug. Finally, mechanomotility was not seen in all cells tested. In fact, the majority of cells (78 of 110 cells), despite excellent light microscopic appearance of the hair bundle and full ability to produce electromotile responses, failed to generate mechanically induced somatic motility. Apparently, the transducer channels or their input linkages to cilia (40) often failed to survive the cell isolation procedure or subsequent mechanical manipulations.

DISCUSSION
These experiments demonstrate a direct link between "natural" mechanical stimulation of the transducer organelle of outer hair cells, their hair (or ciliary) bundle, and somatic shape changes of these cells. Deflection of the bundle toward the tallest row of cilia is known to be excitatory, producing depolarization of the cell (29, 41, 42). Deflection in the opposite direction generates hyperpolarization, whereas orthogonal displacement is largely ineffective (29, 41). Deflection of the bundle toward the tallest ciliary row yields somatic shortening; deflection in the opposite direction produces lengthening. These polarities are as expected, for it is known

Neurobiology: Evans and Dallos
that electrical depolarization of these cells generates contraction whereas hyperpolarization generates expansion (9, 10). Apparently the expected sequence of events takes place in which sinusoidal hair-bundle deflection produces an alternating receptor current via the opening and closing of transducer channels (40). Current-induced voltage drops on the cell's basolateral membrane activate their putative molecular motors (43, 44), thereby producing cell motility. For simplicity, this complete sequence of events is now termed "mechanomotility." We have begun to systematically examine the gain of mechanomotility-i.e., the ratio of somatic displacement and bundle displacement (or angle). Preliminary indication is that the gain is close to unity, at least for cells with a length of 55-75 ,um, having bundle heights of 3-5 ,um, and at least at the very low frequencies tested. The marked change in the mechanomotile response with electrical polarization of the cell is explained by noting that two synergistic effects accentuate the change. When an electrical signal is applied in the microchamber that hyperpolarizes the excluded apical membrane and simultaneously depolarizes the included basolateral membrane, the effects are reinforcing in favoring a large mechanomotile response as we have discussed above. The pronounced effects demonstrated in the mechanomotile response due to electrical polarization of the cell (Fig. 2B) are a consequence of the unique ability ofthe microchamber technique to impart opposite-polarity voltage commands onto the two membrane segments (apical and basolateral) of the cell. In addition, the microchamber provides a stable mechanical platform, partially simulating the cell's in vivo condition. One result ofthis stability, not readily achievable by other means, is to permit mechanical stimulation of the stereocilia without transmission of mechanical forces to the cell body, and thus without a likelihood of opening stretch-activated channels therein (19, 20). The method may also be suited for the measurement of receptor currents (16) without contamination by currents due to stretch-activated channels, a conceivable problem with previous attempts (39). Our various control experiments effectively demonstrate that the motile response is the result of transducer channel activation and not derived from some mechanoelectrical artifact such as modulation of the access resistance or direct deformation of the cell.t Specifically, rotation of the cell and its consequence of changing mechanomotile response in accordance with the bundle's directional sensitivity are not reconcilable with a mechanical artifact. The profound effects seen upon mechanomotility as a consequence of the application of agents known to impair transduction, such as streptomycin and Ca2+-free medium, are also irreconcilable with an artifactual basis for this response. This is especially so since all of these agents affected only the phasic mechanomotile responses but not the tonic electromotile responses due to the voltage-step commands. We conclude that a mechanomotile response occurs in isolated OHCs and, thus, the proposition that such a response operates in vivo as a part of the putative cochlear amplifier appears tenable.
tBy assuming that a significant modulation of the access resistance (R.h) occurs, such that ,B = og(t), we could express Eq. 2 in the form:
E
Vb

Proc. Natl. Acad. Sci. USA 90 (1993)

8351

We thank our colleague Brian Clark for software and hardware development; Ralph Willen (Technical Products, Inc.), Ron Overaker (Research Instruments, Inc.), and Ron Lepinski (Northwestern University) for development of mechanical instrumentation; and Robert Hughes (Nuhsbaum, Inc.) for technical assistance. Drs. M. A. Cheatham, S. M. Echteler, J. H. Siegel, and I. Sziklai are thanked for helpful suggestions. This work was supported by National Institutes of Health Grant DC00708 and the American Hearing Research Foundation.
1. Dallos, P. (1985) in Contemporary Sensory Neurobiology, eds. Correia, M. J. & Peracchio, A. A. (Liss, New York), pp. 207-230. 2. Kim, D. 0. (1986) Hearing Res. 22, 105-114. 3. Dalos, P. (1988) in Functions of the Auditory System, eds. Edelman, G. M., Gall, E. W. & Cowan, W. M. (Wiley, New York), pp. 153-188. 4. Dalos, P. (1992) J. Neurosci. 12, 4575-4585. 5. Spoendlin, H. (1969) Acta Oto-Laryngol. 67, 239-254. 6. Weiss, T. F. (1982) Hearing Res. 7, 353-360. 7. Brownell, W. E., Bader, C. R., Bertrand, D. & de Ribaupierre, Y. (1985) Science 227, 194-196. 8. Kachar, B., Brownell, W. E., Altschuler, R. A. & Fex, J. (1986) Nature (London) 322, 365-368. 9. Ashmore, J. F. (1987) J. Physiol. (London) 388, 323-347. 10. Santos-Sacchi, J. & Dilger, D. P. (1988) Hearing Res. 35, 143-150. 11. Zenner, H. P. (1986) Hearing Res. 22, 83-90. 12. Mountain, D. C., Hubbard, A. E. & McMullen, T. A. (1983) in Mechanics of Hearing, eds. de Boer, E. & Viergever, M. A. (Delft Univ. Press, Delft, The Netherlands), pp. 119-126. 13. Evans, B. N. & Dallos, P. (1993) Abstr. Assoc. Res. Otolaryngol. 16, 116. 14. Dallos, P., Santos-Sacchi, J. & Flock, A. (1982) Science 218, 582-585. 15. Evans, B. N., Dalos, P. & Hallworth, R. (1989) in Cochlear Mechanisms, eds. Wilson, J. P. & Kemp, D. T. (Plenum, London), pp. 205-206. 16. Baylor, D. A., Lamb, T. D. & Yau, K.-w. (1979) J. Physiol. (London) 288, 589-611. 17. Santos-Sacchi, J. (1992) J. Neurosci. 12, 1906-1916. 18. Evans, B. N., Hallworth, R. & Dabos, P. (1991) Hearing Res. 52, 288-304. 19. Ding, J. P., Salvi, R. J. & Sachs, F. (1991) Hearing Res. 56, 19-28. 20. Iwasa, K. H., Li, M., Jia, M. & Kachar, B. (1991) Neurosci. Lett. 133, 171-174. 21. Brundin, L., Flock, A. & Canlon, B. (1989) Nature (London) 342, 814-816. 22. Saunders, J. C. & Szymko, Y. M. (1989) in Cochlear Mechanisms, eds. Wilson, J. P. & Kemp, D. T. (Plenum, London), pp. 135-142. 23. Hudspeth, A. J. & Jacobs, R. (1979) Proc. Natl. Acad. Sci. USA 76, 1506-1509. 24. Clark, B. A., Hallworth, R. & Evans, B. (1990) Pflagers Arch. 415, 490-493. 25. Dallos, P. (1983) Hearing Res. 12, 89-119. 26. Roberts, W. M., Jacobs, R. A. & Hudspeth, A. J. (1990) J. Neurosci. 10, 3664-3684. 27. Santos-Sacchi, J. (1989) J. Neurosci. 9, 2954-2962. 28. Ashmore, J. F. & Meech, R. W. (1986) Nature (London) 322, 368-371. 29. Hudspeth, A. J. & Corey, D. P. (1977) Proc. Natl. Acad. Sci. USA 74, 2407-2411. 30. Housley, G. D. & Ashmore, J. F. (1992) J. Physiol. (London) 448, 73-98. 31. Ohmori, H. (1984) J. Physiol. (London) 350, 561-581. 32. Eatock, R. A., Saeki, M. & Hutzler, M. J. (1993) J. Neurosci. 13, 1767-1783. 33. Sand, 0. (1975) J. Comp. Physiol. 102, 27-42. 34. Corey, D. P. & Hudspeth, A. J. (1979) Nature (London) 281, 675-677. 35. Crawford, A. C., Evans, M. G. & Fettiplace, R. (1991) J. Physiol. (London) 434, 369-398. 36. Assad, J. A., Shepherd, G. M. G. & Corey, D. P. (1991) Neuron 7, 985-994. 37. Ohmori, H. (1985) J. Physiol. (London) 359, 189-217. 38. Kroese, A. B. A., Das, A. & Hudspeth, A. J. (1989) Hearing Res. 37, 203-217. 39. Ashmore, J. F. (1990) Neurosci. Res. 12, (Suppl.), 39-50. 40. Hudspeth, A. J. (1989) Nature (London) 341, 397-404. 41. Flock, A. (1964) J. Cell Biol. 22, 413-432. 42. Russell, I. J. & Richardson, G. P. (1987) Hearing Res. 31, 9-24. 43. Ashmore, J. F. (1991) in Sensory Transduction, eds. Corey, D. P. & Roper, S. D. (Rockefeller Univ. Press, New York), pp. 396-412. 44. Dallos, P., Evans, B. N. & Hallworth, R. (1991) Nature (London) 350, 155-157.

Vaof(t)

1 + aof(t)

[1 + aof(t)][1 + Po g(t)]

[2aJ

The important observation is that a time-dependent response component due to this artifact could occur only during the application of the dc bias voltage V. Observation of all data clearly indicates the presence of a mechanomotile response in the absence of V. Estimation of shunt current magnitudes required to artifactually produce the ac responses seen is also incompatible with our measurements.

Related Interests

W0JAAWVV\A/W\YWVVV

Il
0
2 4

The above simplification makes use of Ro << Ra + Rb. The series resistance of the cell's apical and basolateral membranes is in excess of the input resistance, known to exceed 100 MQl for the long cells used in our experiments (17, 30). The basolateral membrane voltage, Vb is as follows.

6

Time, sec

Vb=E-iRb

[i]b [ aof(t)J
[ +

E

Vaof(t)1

(I +

)

[2]

FIG. 2. (A) Computed model response (solid line) to a combination of ac (mechanical) modulation of apical resistance and dc (electrical) polarization of the cell. Basolateral membrane voltage is computed from Eq. 2 using V = +100 mV, ao = 0.1, and ( = 0.1. Motile response is obtained from the function in Fig. 1B Inset, with Vb as the input. For reference, the time courses of the command voltage V (dashed line) and the mechanical stimulus (dotted line) are also shown. Vertical projection lines aid in determining the phase of the response during the two polarities of the command voltage. (B) Demonstration of mechanomotile response. The axial displacement of the cell's synaptic pole, inside the microchamber, is measured (upper trace). Cell extension is plotted upward. During these measurements, the stereocilia are displaced sinusoidally by the fluid jet (5-10 nm, peak-to-peak, corresponding to 0.03-0.08° angular amplitude). A voltage change (±100 mV) is applied across the cell. The first change from baseline corresponds to hyperpolarization of the excluded portion (and corresponding depolarization of the included portion) of the cell membrane. The second change is a shift to the opposite polarity. The dc voltage changes elicit tonic electromotile responses. Note that with zero electrical command there is a sinusoidal somatic motile response related to the displacement ofthe stereocilia. During negative command, the mechanomotility is enhanced, whereas during positive command, it is depressed. The measured current through the microchamber and the sinusoidal mechanical and dc electrical stimuli are also shown (lower two traces). The current trace is dominated by current through Rsh. Vertical lines are drawn to aid in determining the phase of the mechanomotile response. The apparent time delay ofthe response in this and subsequent figures is due to the 10-Hz low-pass filtering of the photodiode output.

The resting dc current through the cell is

aoE
t0

=(1 + ao)Rb

[3]

The resting membrane potential of the cell is

current and a dominant shunt current through Rsh. In these experiments the receptor current is not measured.

RESULTS Theory. In Fig. 1B an electrical circuit that represents the OHC-microchamber system is shown. For simplicity, all

[4] Note that Vbo, the cell's membrane potential, is approximately equal to E, the electromotive force that probably reflects a potassium conductance (28). If V is negative, it hyperpolarizes the apical membrane and increases the receptor current. At the same time, a negative Vdepolarizes the basolateral membrane. There are three consequences. (i) If the receptor current increases for a given input, f(t), then the gain of the forward transducer is enhanced. (ii) Fig. 1B Inset shows that, as the basolateral membrane is depolarized, the operating point on the nonlinear function describing the electromotile response moves toward a steeper slope region; hence, the gain of electromotility is increased. (iii) Depolarization of the basolateral membrane may activate some voltage-dependent conductances (10, 17, 28, 30), probably producing a complex effect. Conversely, a positive command, V, decreases the forward transducer gain and also decreases the reverse transducer gain due to the shift of the operating point toward a shallower slope region on the electromotility function. Hyperpolarization ofthe basolateral membrane may also activate inward rectifying channels (31, 32) and also turn off outward rectifying voltage-gated channels (28). Once again, the effects are expected to be complex. As depolarization of the basolateral membrane increases at larger values of - V, the operating point moves beyond the maximum slope region and the reverse transducer gain begins to decrease. The linear effect of voltage bias (varying V) upon

Vbo= E - ioRb = E/(1 + ao).

8350

Neurobiology: Evans and Dallos

forward gain appears to dominate the changes in response, resulting in a monotonic response magnitude function. Finally, it can be shown that the phasic mechanomotile response goes through a null and reverses phase when the dc command voltage is approximately equal to the cell's membrane potential, Vbo. Specifically, the response reverses its phase when i = 0, at a command voltage V = Vr,v:
[5] Vrev = -(1 + 3)E = -(1 + 0)(1 + ao)Vo. Consequently, by using the microchamber technique, the cell's membrane potential can be estimated without the

0 0 Ce
6I

CZ -4)

.0
0 0

necessity of impalement. In Fig. 2A we demonstrate a simple model calculation based on the above concepts. The model assumesthatE= -70mV, ao = 0.1, ,B= 0.1, V= ±100mV, the input f(t) is a simple sinusoid, and the electromotility function is as shown in Fig. 1B. Note that the baseline response represents mechanomotility with zero electrical command. When V = -100 mV, the mechanomotile response is significantly increased, while it is decreased in amplitude during the application of V = +100 mV. Since V > Vre., the model predicts phase reversal of the mechanomotile response during the depolarizing command. Experimental Results. In Fig. 2B we demonstrate the axial displacement of the cell's synaptic pole. In this case the stimulus consisted of the fluid jet driving the stereociliary bundle and an electrical command signal applied across the cell. The data demonstrate that hair-bundle deflection produces somatic motility, and consequently, mechanomotility does exist. Phasic mechanomotile displacement of the cell's synaptic pole was discernible on the video monitor at the stimulus frequency of 5 Hz. The baseline mechanomotile response in this example was ;5.5 nm from peak to peak. When the basolateral membrane of the cell was depolarized, the mechanomotile response increased to "25 nm, and when the basolateral membrane was hyperpolarized, the mechanomotile response decreased to --2.5 nm. After the cessation of the electrical stimulus, the mechanomotility returned to the baseline value, =z5.5 nm. The response also contained a large asymmetrical dc electromotile component due to the direct effect of the electrical stimulation upon the basolateral membrane and the putative motor molecules therein. We note the similarity of the measured response to that predicted by the model (Fig. 2A). Included among similar features is the phase reversal of the mechanomotile response during depolarization of the ciliary membrane and an increase in the ac gain during -100 mV and its decrease during +100 mV. By keeping the fluid jet stimulus invariant, it is possible to rotate the microchamber, and thus the OHC, around the cell's long axis. This permits the delivery of mechanical stimulation to the hair bundle at different orientations vis-a-vis its morphological polarization. We ascertained that hair-bundle movement toward the tall hairs always produced mechanomotile response in the shortening direction. As Fig. 3A shows, when the cell is rotated 90°, mechanomotility disappears, whereas rotation by 1800 produces responses in opposite phase. This response character is invariant from cell to cell. Thus, as shown in Fig. 3B, any two cells that are oriented with their hairbundles facing the fluid jet with short vs. tall stereociliary rows produce mechanomotile responses in opposite phase. Mechanically induced somatic motility directly depends upon basolateral membrane voltage changes produced by the forward transducer current. It is known that very low Ca2+ levels in the medium surrounding the hair bundle irreversibly eliminate transduction (33-36). Upon replacing the external bath with Ca2+-free culture medium containing 20 mM BAPTA, cells responded to electrical stimulation with undiminished electromotility, whereas the mechanomotile responses were entirely abolished within 1 min. Mechanomotility is clearly dependent upon functioning mechanoelectric

700

B
0

E.E..E
Proc. Natl. Acad. Sci. USA 90 (1993)
180°
900
1300 Poststimulus onset, msec

1900

'0 ce
10

CC

z

0

2
Time, sec

4

6

FIG. 3. (A) Three successive response traces obtained at three orientations of the same hair bundle with respect to the stimulating fluid jet. Solid line, orientation such that shortest stereociliary row faces tojet (0') (this is the same orientation as in Fig. 2B); dashed line, bundle is rotated 90'; dotted line, bundle is rotated an additional 90'. To clearly show the response phases, only a portion of the response time course is presented. (B) Mechanomotile responses of two cells, one at 0' and the other at 180' stereocilia bundle orientation. Note that the ac response phases are opposite throughout the records, whereas the dc electromotile responses are the same. Combined mechanical (ac) and electrical (dc, ±100 mV) stimulation.

transduction. Another means of demonstrating this is to take advantage of the known capacity of aminoglycosides to block transducer channels in hair cells (37-39). We observed a complete elimination of mechanomotility upon replacing the external bathing medium with medium containing 200 pM dihydrostreptomycin sulfate. The effect was partially reversible upon washing out the drug. Finally, mechanomotility was not seen in all cells tested. In fact, the majority of cells (78 of 110 cells), despite excellent light microscopic appearance of the hair bundle and full ability to produce electromotile responses, failed to generate mechanically induced somatic motility. Apparently, the transducer channels or their input linkages to cilia (40) often failed to survive the cell isolation procedure or subsequent mechanical manipulations.

DISCUSSION
These experiments demonstrate a direct link between "natural" mechanical stimulation of the transducer organelle of outer hair cells, their hair (or ciliary) bundle, and somatic shape changes of these cells. Deflection of the bundle toward the tallest row of cilia is known to be excitatory, producing depolarization of the cell (29, 41, 42). Deflection in the opposite direction generates hyperpolarization, whereas orthogonal displacement is largely ineffective (29, 41). Deflection of the bundle toward the tallest ciliary row yields somatic shortening; deflection in the opposite direction produces lengthening. These polarities are as expected, for it is known

Neurobiology: Evans and Dallos
that electrical depolarization of these cells generates contraction whereas hyperpolarization generates expansion (9, 10). Apparently the expected sequence of events takes place in which sinusoidal hair-bundle deflection produces an alternating receptor current via the opening and closing of transducer channels (40). Current-induced voltage drops on the cell's basolateral membrane activate their putative molecular motors (43, 44), thereby producing cell motility. For simplicity, this complete sequence of events is now termed "mechanomotility." We have begun to systematically examine the gain of mechanomotility-i.e., the ratio of somatic displacement and bundle displacement (or angle). Preliminary indication is that the gain is close to unity, at least for cells with a length of 55-75 ,um, having bundle heights of 3-5 ,um, and at least at the very low frequencies tested. The marked change in the mechanomotile response with electrical polarization of the cell is explained by noting that two synergistic effects accentuate the change. When an electrical signal is applied in the microchamber that hyperpolarizes the excluded apical membrane and simultaneously depolarizes the included basolateral membrane, the effects are reinforcing in favoring a large mechanomotile response as we have discussed above. The pronounced effects demonstrated in the mechanomotile response due to electrical polarization of the cell (Fig. 2B) are a consequence of the unique ability ofthe microchamber technique to impart opposite-polarity voltage commands onto the two membrane segments (apical and basolateral) of the cell. In addition, the microchamber provides a stable mechanical platform, partially simulating the cell's in vivo condition. One result ofthis stability, not readily achievable by other means, is to permit mechanical stimulation of the stereocilia without transmission of mechanical forces to the cell body, and thus without a likelihood of opening stretch-activated channels therein (19, 20). The method may also be suited for the measurement of receptor currents (16) without contamination by currents due to stretch-activated channels, a conceivable problem with previous attempts (39). Our various control experiments effectively demonstrate that the motile response is the result of transducer channel activation and not derived from some mechanoelectrical artifact such as modulation of the access resistance or direct deformation of the cell.t Specifically, rotation of the cell and its consequence of changing mechanomotile response in accordance with the bundle's directional sensitivity are not reconcilable with a mechanical artifact. The profound effects seen upon mechanomotility as a consequence of the application of agents known to impair transduction, such as streptomycin and Ca2+-free medium, are also irreconcilable with an artifactual basis for this response. This is especially so since all of these agents affected only the phasic mechanomotile responses but not the tonic electromotile responses due to the voltage-step commands. We conclude that a mechanomotile response occurs in isolated OHCs and, thus, the proposition that such a response operates in vivo as a part of the putative cochlear amplifier appears tenable.
tBy assuming that a significant modulation of the access resistance (R.h) occurs, such that ,B = og(t), we could express Eq. 2 in the form:
E
Vb

Proc. Natl. Acad. Sci. USA 90 (1993)

8351

We thank our colleague Brian Clark for software and hardware development; Ralph Willen (Technical Products, Inc.), Ron Overaker (Research Instruments, Inc.), and Ron Lepinski (Northwestern University) for development of mechanical instrumentation; and Robert Hughes (Nuhsbaum, Inc.) for technical assistance. Drs. M. A. Cheatham, S. M. Echteler, J. H. Siegel, and I. Sziklai are thanked for helpful suggestions. This work was supported by National Institutes of Health Grant DC00708 and the American Hearing Research Foundation.
1. Dallos, P. (1985) in Contemporary Sensory Neurobiology, eds. Correia, M. J. & Peracchio, A. A. (Liss, New York), pp. 207-230. 2. Kim, D. 0. (1986) Hearing Res. 22, 105-114. 3. Dalos, P. (1988) in Functions of the Auditory System, eds. Edelman, G. M., Gall, E. W. & Cowan, W. M. (Wiley, New York), pp. 153-188. 4. Dalos, P. (1992) J. Neurosci. 12, 4575-4585. 5. Spoendlin, H. (1969) Acta Oto-Laryngol. 67, 239-254. 6. Weiss, T. F. (1982) Hearing Res. 7, 353-360. 7. Brownell, W. E., Bader, C. R., Bertrand, D. & de Ribaupierre, Y. (1985) Science 227, 194-196. 8. Kachar, B., Brownell, W. E., Altschuler, R. A. & Fex, J. (1986) Nature (London) 322, 365-368. 9. Ashmore, J. F. (1987) J. Physiol. (London) 388, 323-347. 10. Santos-Sacchi, J. & Dilger, D. P. (1988) Hearing Res. 35, 143-150. 11. Zenner, H. P. (1986) Hearing Res. 22, 83-90. 12. Mountain, D. C., Hubbard, A. E. & McMullen, T. A. (1983) in Mechanics of Hearing, eds. de Boer, E. & Viergever, M. A. (Delft Univ. Press, Delft, The Netherlands), pp. 119-126. 13. Evans, B. N. & Dallos, P. (1993) Abstr. Assoc. Res. Otolaryngol. 16, 116. 14. Dallos, P., Santos-Sacchi, J. & Flock, A. (1982) Science 218, 582-585. 15. Evans, B. N., Dalos, P. & Hallworth, R. (1989) in Cochlear Mechanisms, eds. Wilson, J. P. & Kemp, D. T. (Plenum, London), pp. 205-206. 16. Baylor, D. A., Lamb, T. D. & Yau, K.-w. (1979) J. Physiol. (London) 288, 589-611. 17. Santos-Sacchi, J. (1992) J. Neurosci. 12, 1906-1916. 18. Evans, B. N., Hallworth, R. & Dabos, P. (1991) Hearing Res. 52, 288-304. 19. Ding, J. P., Salvi, R. J. & Sachs, F. (1991) Hearing Res. 56, 19-28. 20. Iwasa, K. H., Li, M., Jia, M. & Kachar, B. (1991) Neurosci. Lett. 133, 171-174. 21. Brundin, L., Flock, A. & Canlon, B. (1989) Nature (London) 342, 814-816. 22. Saunders, J. C. & Szymko, Y. M. (1989) in Cochlear Mechanisms, eds. Wilson, J. P. & Kemp, D. T. (Plenum, London), pp. 135-142. 23. Hudspeth, A. J. & Jacobs, R. (1979) Proc. Natl. Acad. Sci. USA 76, 1506-1509. 24. Clark, B. A., Hallworth, R. & Evans, B. (1990) Pflagers Arch. 415, 490-493. 25. Dallos, P. (1983) Hearing Res. 12, 89-119. 26. Roberts, W. M., Jacobs, R. A. & Hudspeth, A. J. (1990) J. Neurosci. 10, 3664-3684. 27. Santos-Sacchi, J. (1989) J. Neurosci. 9, 2954-2962. 28. Ashmore, J. F. & Meech, R. W. (1986) Nature (London) 322, 368-371. 29. Hudspeth, A. J. & Corey, D. P. (1977) Proc. Natl. Acad. Sci. USA 74, 2407-2411. 30. Housley, G. D. & Ashmore, J. F. (1992) J. Physiol. (London) 448, 73-98. 31. Ohmori, H. (1984) J. Physiol. (London) 350, 561-581. 32. Eatock, R. A., Saeki, M. & Hutzler, M. J. (1993) J. Neurosci. 13, 1767-1783. 33. Sand, 0. (1975) J. Comp. Physiol. 102, 27-42. 34. Corey, D. P. & Hudspeth, A. J. (1979) Nature (London) 281, 675-677. 35. Crawford, A. C., Evans, M. G. & Fettiplace, R. (1991) J. Physiol. (London) 434, 369-398. 36. Assad, J. A., Shepherd, G. M. G. & Corey, D. P. (1991) Neuron 7, 985-994. 37. Ohmori, H. (1985) J. Physiol. (London) 359, 189-217. 38. Kroese, A. B. A., Das, A. & Hudspeth, A. J. (1989) Hearing Res. 37, 203-217. 39. Ashmore, J. F. (1990) Neurosci. Res. 12, (Suppl.), 39-50. 40. Hudspeth, A. J. (1989) Nature (London) 341, 397-404. 41. Flock, A. (1964) J. Cell Biol. 22, 413-432. 42. Russell, I. J. & Richardson, G. P. (1987) Hearing Res. 31, 9-24. 43. Ashmore, J. F. (1991) in Sensory Transduction, eds. Corey, D. P. & Roper, S. D. (Rockefeller Univ. Press, New York), pp. 396-412. 44. Dallos, P., Evans, B. N. & Hallworth, R. (1991) Nature (London) 350, 155-157.

Vaof(t)

1 + aof(t)

[1 + aof(t)][1 + Po g(t)]

[2aJ

The important observation is that a time-dependent response component due to this artifact could occur only during the application of the dc bias voltage V. Observation of all data clearly indicates the presence of a mechanomotile response in the absence of V. Estimation of shunt current magnitudes required to artifactually produce the ac responses seen is also incompatible with our measurements.

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