A mathematical model of the regulation of OHC basolateral permeability and transducer operating point

The cochlea presumably possesses a number of regulatory mechanisms to maintain cochlear sensitivity in the face of disturbances to its function. Evidence for such mechanisms can be found in the time-course of the recovery of CAP thresholds during experimental manipulations, and in observations of slow oscillations in cochlear micromechanics following exposure to LF tones (the 'bounce phenomenon') and other perturbations. To increase our understanding of the regulatory processes within the cochlea, and OHCs in particular, we have developed a mathematical model of the OHC that takes into account its known electrical properties, and includes the effect of fast and slow-motility of the cell body on transducer operating point and apical conductance. Central to the operation of the model is a putative intracellular 2nd-messenger system based on cytosolic Ca2+ concentration. Cytosolic Ca2+ is involved in regulation of i) the operating point of OHC MET channels via slow motility and axial stiffness; ii) the permeability of the basolateral wall to potassium via Ca2+-sensitive potassium channels; and iii) the cytosolic concentration of Ca2+ itself, via extrusion from the OHC (via the Ca2+-ATPases in the plasma membrane) and Ca2+-induced Ca2+-release (CICR) from intracellular Ca2+ storage organelles. The permeability of the OHC basolateral wall determines the standing current through the OHCs (and therefore a component of EP regulation), and in the presence of sound, affects the magnitude of the AC receptor potential that drives the prestin-mediated somatic electromotility and active gain. The mathematical model we have developed provides a physiologically-plausible and internally-consistent explanation for the time-courses of the cochlear changes observed during a number of different perturbations. We show how much of the oscillatory behaviour can be attributed to oscillations in cytosolic calcium concentration, and present results from the model for a number of simulations, including DC current injection into scala media, perilymphatic perfusions, and exposure to LF tones, and compare the results of these simulations to experimental data recorded from the guinea pig

In Vivo Effects of Reduced-Sodium Perilymph Perfusion on Hair Cell and Neural Potentials

To determine the functional significance of the sodium-transport mechanisms of the outer hair cells (OHCs) in vivo, the effect of reduced perilymphatic sodium on cochlear potentials was investigated in the guinea pig by perfusion of scala tympani with a modified artificial perilymph. The Na+ concentration of the artificial perilymph was reduced by almost 95% (from 150 mM to 8 mM) by substitution with choline, and resulted in an estimated 80% reduction in perilymphatic Na+ on perfusion through scala tympani. OHC function was assessed using Boltzmann analysis of the low-frequency cochlear microphonic (CM) and measurement of the high-frequency summating potential (SP) recorded at the round window. Compound action potential (CAP) thresholds and waveforms were monitored at multiple frequencies and the amplitude of the spectrum of the neural noise (SNN) in silence was measured as an indicator of spontaneous neural activity

Regulation of cochlear outer hair cells: Insights from mathematical modelling

The outer hair cells (OHCs) of the cochlea are the source of much of our exquisite auditory sensitivity, providing sharp mechanical tuning and increasing the vibration of the basilar membrane by up to a factor of 1000. They accomplish this by a combination of mechanoelectrical and electromechanical transduction – providing positive feedback to enhance sound-induced vibration and cancel friction. Because the OHCs are sensitive to displacements of molecular dimensions, and yet are motile themselves, they must employ a number of negative-feedback (homeostatic) mechanisms to regulate their sensitivity in the face of daily disturbances. To understand some of these mechanisms, we have created a mathematical model of OHC, focusing on the links between ion transport, electrophysiology and OHC motility. The model we present offers insights into the regulation of OHC membrane potential and mechanoelectrical transduction, and provides a physiologically-plausible and internally-consistent explanation for the time-courses of the cochlear changes we have observed during different experimental perturbations performed in the guinea pig cochlea. We show how the known ionic mechanisms within OHCs act to regulate membrane potential and hair bundle angle over a very wide range of electrical and hydrostatic conditions, and are responsible for a slow oscillatory behaviour (also present in humans) that we presume is due to oscillations in cytosolic calcium concentration

Application of force to the cochlear wall: effect on auditory thresholds, outer hair cell transduction, and distortion-product otoacoustic emissions

Abstracts published in The Journal of the Acoustical Society of AmericaDescribed are the changes in cochlear sensitivity and mechanoelectrical transduction during a novel cochlear perturbation: the application of force to the cochlear wall. While numerous methods exist to create transient shifts in the operating point of the outer hair cell (OHC) transducer, including low-frequency acoustic bias [G. Frank and M. Kössl, Hear. Res. 113, 57–68 (1997)] and hydrostatic bias [A. N. Salt and J. E. DeMott, Hear. Res. 123, 137–147 (1998)], attempts to create prolonged operating point shifts are largely thwarted by the numerous sources of ac coupling in the auditory system which prevent transmission of dc stimuli to the hair cells. The application of force sufficient to deform the otic capsule produced a consistent drop in neural thresholds and a sustained bias of the OHC operating point that did not rapidly adapt back to normal. Near-simultaneous measurements of compound action potential thresholds, distortion-product otoacoustic emissions, the OHC transfer curves derived from low-frequency cochlear microphonic waveforms, and the endocochlear potential were performed. The data provide ample evidence of the resistance of the cochlea to dc mechanical stimuli, particularly those which do not cause a large pressure differential across the basilar membrane. [The authors gratefully acknowledge the surgical assistance of Dr. Peter Sellick.

In vivo effects of hyperosmotic perilymph perfusion on hair cell and neural potentials

The effect of osmotic bias on cochlear potentials was investigated by perfusion of scala tympani with a modified artificial perilymph. The mean osmolality of the artificial perilymph was increased by around 15% (from 303 ± 6 mOsm/kg H2O to 349 ± 1 mOsm/kg H2O) by addition of sucrose. OHC function was assessed using Boltzmann analysis of the low-frequency CM. Neural thresholds and waveforms were monitored at multiple frequencies, and spontaneous neural noise was monitored via a round-window electrode. The 2-minute perfusions caused a 6 ± 4% increase in the maximal CM amplitude, indicating an increase in OHC basolateral permeability, and an 8 ± 1% increase in MET sensitivity, which may reflect a decrease in OHC axial stiffness. The operating-point shifts recorded were more variable: in healthy animals, the hyperosmotic perfusions caused initial operating point shifts towards scala vestibuli of around 1 – 2 meV that were either followed by a brief undershoot towards scala tympani, or initiated a longer-lasting scala tympani operating point shift. Nonetheless, these operating point shifts were smaller than expected, resulting in a less than ±2 meV deviation from the starting point. Neural thresholds during the perfusion fell (by 20 – 30 dB at 22 kHz), and recovered with a time course consistent with the predicted perilymphatic sucrose concentrations at the corresponding BM place for each frequency. The mechanism of the changes observed with these hyperosmotic perfusions is not known, but its effects were not consistent with a simple movement of the reticular lamina towards scala vestibuli. Other data (Marcon and Patuzzi, in preparation) indicate the CAP threshold shifts during these perfusions are most likely mechanical in origin. The experimental results from the guinea pig are compared with simulated perfusions carried out in a mathematical model of cochlear regulation based on the ionic transport mechanisms and motile properties of the outer hair cells

K+ currents produce P1 in the RW CAP: evidence from DC current bias, K+ channel blockade and recordings from cochlea and brainstem

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Transient focal cooling at the round window and cochlear nucleus shows round window CAP originates from cochlear neurones alone

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Identification of different subtypes of auditory neuropathy using electrocochleography

Currently, the physiological mechanisms underlying auditory neuropathy are unclear, and there are likely to be multiple sites of lesion. A better understanding of the disruption in individual cases may lead to more effective management and device selection. Frequency-specifi c round-window electrocochleography (ECochG) waveforms were used to assess local hair cell, dendritic, and axonal currents generated within the cochlea in 15 subjects with auditory neuropathy (16 ears). These results were compared with electrically evoked auditory brainstem response (EABR) measured after cochlear implantation. The results of this study demonstrate that predominantly two patterns of ECochG waveforms can be identifi ed: (i) a prolonged latency of the hair cell summating potential (SP) waveform with or without residual CAP activity and (ii) a normal latency SP, typically followed by a dendritic potential (DP). We show that seven of eight subjects with a prolonged SP showed a normal EABR waveform, consistent with a presynaptic lesion, whereas six of seven subjects with a normal latency SP showed poor morphology or absent EABR waveforms, consistent with a postsynaptic lesion. We suggest that a presynaptic and postsynaptic type of auditory neuropathy exist, which may have implications for the fi tting of cochlear implants.16 page(s