There are differences in electrical potential and chemical composition between the fluids of the inner ear and the insides of its cells. These electrochemical gradients are the battery providing power to a membrane-based motor essential for hearing. Systematic differences in the strength of the battery predict gradients in motor function within the inner ear. Recent findings have confirmed that the functional density decreases on going from high to low frequency regions of the inner ear and suggest gradients in motor function along the length of individual outer hair cells. We will investigate both the organ and cellular level gradients to achieve our goal of characterizing the mechanisms that maintain motor function and cochlear amplification at optimal performance. The membrane protein prestin is an integral part of the motor and its presence results in currents that are out of phase with the AC voltage that evokes them. Membrane voltage changes have similar effects on prestin-associated currents and outer hair cell length changes. The voltage of maximum gain for both the currents and length changes should be maintained close to the in vivo resting potential to assure that outer hair cell receptor potentials generate maximal electromechanical forces. A variety of external manipulations modify the voltage of maximum gain of both functions. Some modifiers act on the membrane directly;these include changes in holding potential, tension, and cholesterol as well as a variety of membrane reactive drugs such as salicylate and chlorpromazine. Changes of chloride ion concentration and the neurotransmitter acetylcholine also modify motor performance.
Aim 1 will determine whether there is a tonotopic gradient in the voltage of maximum gain by recording from cells isolated from all cochlear turns.
Aim 2 will measure the gradients in prestin-function along the length of individual outer hair cells and determine the contribution of the non-homogeneous motor distribution to the fine structure of whole cell currents. An aspiration pipette will mechanically deform the membrane at different locations along the lateral wall and the resulting charge movement will be measured with a whole-cell patch pipette.
Aim 3 will examine interactions between modifiers and compare the data to predictions of a systems based model of the outer hair cell.
Aims 1 &2 will reveal how the outer hair cell membrane potential is established under physiologic conditions and clarify the differences in prestin function between the high and low frequency regions of the inner ear. Data from all three aims will be used to clarify the role of prestin's transporter properties in the motr mechanism. Cell biophysics, neuroscience, chemical physics, and bioengineering approaches will be used. The studies will contribute to improved therapeutic interventions for the hearing impaired particularly loss resulting from decreased output or failure of the cochlear battery. The impact, if any, of maturation and sex on prestin-function will also be identified.
Aging and many deafness genes decrease the battery that powers the amplification of sound in the cochlea. Our studies characterize the cellular motor responsible for amplification and explore the mechanisms responsible for modulating its output. Knowing the limits of and interactions between these mechanisms will permit the design of strategies to maintain or restore hearing health.
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