Making an effort to listen:
Mechanical amplification by novel molecular motors in the ear

A. J. Hudspeth,
The Rockefeller University, New York

Uniquely among vertebrate sensory receptors, the hair cell of the internal ear amplifies its inputs. An active process in auditory organs increases responsiveness to sound by over one-hundredfold and sharpens frequency selectivity. Two epiphenomena arise from the active process, nonlinearity in transduction and spontaneous otoacoustic emissions (SOAEs). Although changes in the length of outer hair cells are thought to mediate amplification in the mammalian cochlea, the auditory receptor organs of non-mammalian tetrapods, which lack electromotile hair cells, display essentially identical sensitivity, tuning, nonlinearity, and SOAEs. The active process necessary to explain the properties of hearing in these animals may therefore constitute part or all of the mammalian cochlear amplifier as well.

When bathed in a low?Ca2+ saline solution resembling endolymph, a hair bundle from the sacculus of the bullfrog's internal ear undergoes spontaneous oscillations of approximately 20 nm. The frequency of oscillation increases with the load applied to the hair bundle by a flexible stimulus fiber; the range of 5?100 Hz corresponds well to the characteristic frequencies of afferent neurons innervating the sacculus. Application of the fluctuation-dissipation theorem, which relates a system's mechanical responsiveness to stimulation to its reaction to thermal noise, confirms that spontaneous oscillations involve energy expenditure by the hair bundle. These oscillations may therefore supply the energy requisite for the production of SOAEs.

When a sinusoidal mechanical input as small as 1 nm is applied by a flexible stimulus fiber, the bundle's movement is entrained if the frequency lies near that of unstimulated oscillation. As judged by the amplitude of the response, the bundle appreciably amplifies its input. Moreover, the bundle exhibits power gain: an active energy source in the bundle is required to counter the power dissipated by viscous drag and that abstracted by the stimulus fiber. As the amplitude of stimulation is increased, the response grows as the one-third power of the input. This relation, which resembles that for basilar-membrane motion in the mammalian cochlea, is anticipated for an amplificatory process poised near a Hopf bifurcation. Active hair-bundle motility therefore constitutes the active process of hair cells in the bullfrog's sacculus.

Two processes power active hair-bundle motility, whether spontaneous or stimulus-evoked. Displacement-clamp measurements reveal that a hair bundle displays negative slope stiffness over a range of positions subtending roughly 10 nm. This phenomenon stems from the concerted gating of transduction channels: as each channel opens or closes, the change in gating-spring force encourages other channels to do likewise. Each time the adaptation process attempts to situate the hair bundle in the negative-stiffness region, the bundle lunges across this unstable domain, producing spontaneous oscillations. Stimuli trigger the bundle's progression through the same trajectory, thereby entraining amplified bundle movements. Active bundle movements are also driven by rapid, Ca2+?dependent reclosure of transduction channels, a phenomenon capable of mediating oscillation even at kilohertz frequencies. Because both the nonlinearity responsible for negative bundle stiffness and mechanical adaptation appear to occur in all hair cells, the same mechanisms may power the active processes of hair cells in general, including those of the mammalian cochlea.