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The ototoxic action of salicylate was investigated in the guinea pig by perfusion of both salicylate and bromosalicylate through scala tympani. The results qualitatively confirmed experiments using intravenous administration in cats (Stypulkowski, 1990), showing dose-dependent elevations in compound action potential (CAP) thresholds, increases in cochlear microphonics (CM) and level-dependent reductions in 2f1-f2 acoustic distortion products. The endocochlear potential was not significantly affected and iontophoretic injection of salicylate into scala media had no measurable effect on CAP thresholds, consistent with an action on the basolateral walls of the hair cells. Perfusion with indomethacin produced effects similar to those of the salicylates, but at non-physiological doses. Together with the great effectiveness of 5-bromosalicylate, this suggests that salicylate does not act by inhibiting prostaglandin synthesis. The results are qualitatively consistent with the proposition that salicylates act on the basolateral walls of the outer hair cells. However, the magnitude of the CM increases, particularly at high drug concentrations, and the fact that salicylate reduced, but did not eliminate the effects of olivocochlear efferent stimulation on CM amplitude indicate that a simple explanation for salicylate effects based solely on a conductance increase in the outer hair cell membranes may be inadequate.

f2-f1, but not 2f1-f2, was reduced in amplitude during continuous stimulation of the test ear with the primary tones, and with single tones near the primary frequencies. Stimulation of the contralateral ear, either with broad band noise or with single tones near the primary frequencies, also reduced f2-f1. Ipsilateral and contralateral effects were additive and were restricted to the frequency range between about 2 kHz and 7 kHz. Contralateral, but not ipsilateral suppression, was blocked after systemic administration of strychnine. Ipsilateral suppression was eliminated by perfusion of the cochlea with tetrodotoxin. Both contralateral and ipsilateral suppression were abolished after perfusion of the cochlea with bicuculline. The results are evidence for a role for a GABA-ergic efferent system in the modulation of outer hair cell mechanics in the apical cochlea.

The ototoxic mechanism of cisplatin was investigated. Potentiation of cisplatin ototoxicity by furosemide and amino-oxyacetic acid (AOAA) was observed. Substantial hearing loss in cisplatin-deafened animals was accompanied by normal values of the endocochlear potential and a reduction in the sensitivity of the 2f1-f2 distortion products. The loss in dB of the sensitivity of the distortion products correlated extremely well with the loss of the neural sensitivity in dB. There was also a relationship between the fractional reduction of the low frequency (1000 Hz) microphonic potential and hearing loss in dB. Iontophoresis of cisplatin into scala media resulting in the immediate loss of neural thresholds at the site of iontophoresis. It is concluded that cisplatin caused the hearing loss by blocking OHC transduction channels.

This report describes the effects of L-glutamate (Glu) introduced into the perilymph of scala tympani on the spontaneous and tone-evoked activity of guinea pig single primary auditory afferents. Concentrations below 2 mmol/l were in general ineffective, while a concentration of 5 mmol/l caused a marked decrease of the neural activity. At 2 mmol/l, roughly 60% of the Glu-perfusions were effective and produced a variety of changes. The most prominent effect was a reduction of the tone-evoked activity without a change in spontaneous rate. Indeed, in some cells, the tone-evoked activity could be almost totally abolished without affecting the spontaneous activity. More rarely observed was a moderate, generally transient increase of the spontaneous activity which was occasionally followed by a decrease in both tone-evoked and spontaneous firing rate. The increase in firing rate was always small relative to the maximum discharge rate evoked by tone stimuli. Desensitization of the Glu-evoked response without an obvious change in the spontaneous activity was also found. In a few cells Glu caused a reduction of the discharge rate below the spontaneous firing rate during loud tone presentation. Higher Glu doses generally caused a reduction of spontaneous and tone-evoked activity without any sign of a preceding increase. Thus, the effects of Glu in the mammalian cochlea appear to be complex and on balance seem inconsistent with the effects predicted for an excitatory transmitter. The findings argue against the hypothesis that Glu is the afferent transmitter released by inner hair-cells. However, the results do not exclude an involvement of Glu as a neuromodulator or co-transmitter.

In Nembutal- or Urethane-anaesthetised guinea pigs N1 audiograms and N1 input-output functions were measured as were compound action potential (CAP) tuning curves under forward masking and simultaneous masking conditions. Then the crossed olivocochlear bundle was lesioned at the floor of the fourth ventricle and the cochlear responses were re-measured. There were never any changes in the N1 audiograms, input-output functions, or the CAP tuning curves. Thus, the crossed efferent pathways do not appear to play any tonic role in determining cochlear threshold sensitivities, selectivities or masking phenomena in anaesthetised guinea pigs with normal hearing sensitivities.

Zwicker [Biol. Cybern. 35, 243-250, (1979); J. Acoust. Soc. Am. 80, 163-176 (1986)] has previously proposed that many nonlinear phenomena in the mammalian cochlea can be explained by saturation of a positive feedback process which enhances mechanical sensitivity, although the site of the nonlinearity producing this saturation has so far remained obscure. In this paper we present evidence suggesting that the nonlinearity of mechano-electrical transduction in the outer hair cells is the dominant nonlinearity producing two-tone suppression in the mammalian cochlea. In particular, we show that: (i) suppression of the extracellular summating potential (SP), recorded from a particular place within the organ of Corti, has characteristics similar to the suppression of activity in the auditory-nerve; (ii) that SP suppression occurs at approximately constant basilar membrane displacement, inferred from the SP iso-response contours; and that (iii) the onset of SP suppression with suppressor tones on the tail of the frequency tuning curve closely parallels the onset of nonlinearity in the local cochlear microphonic. Since previous studies (Patuzzi et al., 1989) have demonstrated that the vibration of the basilar membrane at its characteristic frequency is very sensitive to changes in outer hair cell receptor current, we consider that interference in outer hair cell currents caused by nonlinearity in mechano-electrical transduction is an adequate explanation of two-tone suppression. This requires that outer hair cell receptor currents deviate from linearity at a suppressor tone level below that required to produce a significant DC receptor potential within the inner hair cells, and that the active process within the cochlea is distributed along a local region of the cochlea, basal of the vibration peak.

The Mössbauer technique was used to measure displacements of the stapes footplate and adjacent temporal bone during bone conduction stimulation at frequencies from 250 to 400 Hz in anaesthetized guinea pigs. The stapes was found not to be driven at amplitudes or phases that differed significantly from those of the temporal bone. Measurement of stapes displacements during air conduction stimulation, and of temporal bone displacements during bone conduction stimulation producing matching cochlear microphonic amplitude, enabled calculation of limiting values of amplitude and phase difference necessary to produce the required relative displacement. The obtained values (less than 1 dB for amplitude and 1--4 degrees for phase) were beyond the resolution of the measurement system employed for reasonable nuclear counting times. The results provide quantitative estimates of the magnitude of inertial effects, but do not establish whether ossicular inertia is an important factor in bone conduction stimulation.

Guinea pigs were exposed to a 10 kHz pure tone and damage to the cochlea was investigated immediately after exposure, or after a recovery period ranging from 18-25 days. Structural damage was assessed using scanning electron microscopy and functional damage estimated using the N1 threshold audiogram. Exposure at 106 dB for 1 h caused obvious abnormalities of outer hair cell stereocilia. The location and extent of this damage was related to the immediate or long term deficits in the N1 threshold audiogram.

Cochleas of adult guinea pigs and rats, and 6-day-old rat pups, were injected, through the round window, with 2 microliters of artificial classical Konishi perilymph containing 1 nmol kainic acid (KA). 5 min later, they were fixed, removed, and processed for electron microscopy. In all KA-treated cochleas, the injection resulted in a severe swelling of auditory dendrites below the inner hair cells (IHCs). Below the outer hair cells (OHCs), the swelling appeared only in the 6-day-old rats, not in adult animals. These results are significant in three different ways: (1) They confirm the strong difference between afferents innervating the IHCs and the OHCs in adult cochleas. (2) They shed some light on the synaptic plasticity found at the OHC level during synaptogenesis. (3) They support the hypothesis that glutamate, or a related substance, is the IHC neurotransmitter.

By recording from single auditory neurons in the spiral ganglion of the guinea pig cochlea it was possible to monitor threshold changes to acoustic stimuli in the same neuron during acute exposures to continuous pure tones (100 dB SPL) delivered for periods of up to 180 min. Initial changes in the tuning curve were sensitivity losses at and above the characteristic frequency (CF). This asymmetric loss resulted in a shift in the CF to lower frequencies. Further exposure (up to 20 min) produced a complete loss of the sharply tuned portion of the tuning curve and the most sensitive area moved to lower frequencies by up to 0.75 of an actave when compared to the original CF. Sensitization of the low frequency section of the tuning curve could take place for short exposures (up to 20 min) but disappeared with further exposure, whether continuous or interrupted. Long term exposures (60--80 min) produced losses in the low frequency portion of the tuning curve until a point was reached when the unit no longer responded to stimuli at 110 dB SPL.

The simultaneous presentation of an intense low frequency tone and a moderate intensity high frequency tone produced modulation of the high frequency motion of the cochlear partition in the first turn of the guinea pig cochlea. This modulation was in synchrony with the displacement caused by the low frequency tone. Maximum reduction in mechanical sensitivity was observed for peak displacements towards scala tympani, whereas a less pronounced reduction was observed for peak displacements towards scala vestibuli. Modulation was reduced or absent for high frequency tones more than an octave below the characteristic frequency of the mechanical tuning curve and was absent post mortem.

Longitudinal endolymph flow rate in the guinea pig cochlea was measured by determining the rate of migration of extrinsic ions, tetraethylammonium chloride (TEA) or choline, with a potassium sensitive ion-selective microelectrode (ISM). Low concentrations of iontophoretically injected TEA were detected with the ISM at various distances from the injection electrode. The results were variable when the ISM was used to record spread of TEA from turn II to turn I and vice versa. However, consistent data were obtained when the TEA spread was measured at different electrode separations (0.2, 0.5, 0.7 mm) within turn II. Electrode locations were systematically exchanged without changing their distance, i.e. the ISM electrode was placed basally or apically with respect to the TEA electrode. Comparison of data with a model, which combines the bulk diffusion of TEA and the flow of endolymph, is consistent with a rate of endolymph flow in turn II of about 0.2 mm/min, apex to base. A similar value was also obtained with the iontophoretic injection of choline. The endolymph flow rate may be different in turn I as indicated by measurements of compound action potential (CAP) changes. However, the results of experiments when TEA spread is measured at large distances must be interpreted cautiously because TEA may enter cellular walls of the cochlear duct and alternative routes of transport may be involved.

The influence of direct current applied by round window stimulation on the whole nerve response of the auditory nerve of the cat has been studied. Effects on acoustically driven activity (CAP) and on the ensemble spontaneous activity of the nerve were observed. Stimulation with positive current suppressed driven and spontaneous activity. The strength and spread of suppressive effects was a function of the applied current level. After a period of positive electrical stimulation, driven and spontaneous activity rapidly returned to normal values. A rebound effect was sometimes observed, marked by a brief increase in spontaneous activity above the normal level. Negative current initially produced an increase in the amplitude of driven and spontaneous responses. Prolonged stimulation with negative current (greater than 30 s) resulted in a subsequent, graded reduction of neural activity, until a profound suppression of spontaneous and evoked neural activity was attained. The amplitude/latency relationship of CAPs was altered during passing of negative currents but not during passing of positive currents. Recovery from the suppression generated by negative currents was commonly prolonged for anything from a few seconds to many minutes; prolongation was dependent on stimulus amplitude, duration and duty cycles.

The presence of the 2f1-f2 combination distortion tone generated when two tones are presented to the cochlea, can be detected using a two-tone complex to forward mask a probe tone. The combination tone is the effective masking agent and the amplitude of the compound action potential response to the probe tone reflects the degree of masking. Excitation patterns, frequency relationships and intensity functions that are obtained with this procedure are consistent with previously published data.

We report a technique for activating the efferent nerve fibres to the cochlea by electrical stimulation at the round window. Such electrical stimulation caused a reduction in the amplitude of the gross nerve response (N1) to a click presented after the electrical stimulus but did not alter the latency of the response. The reduction increased with increasing current strength above 200 microA and increasing rate of electrical pulses above 50 Hz. The effect was also dependent on the duration of the shock train and the pulse width. The reduction in N1 was most pronounced at low click intensities. Recovery of the N1 was almost complete about 80 ms after the end of the electrical stimulus. The effect of electrical stimulation in reducing the N1 amplitude could almost always be blocked by intraperitoneal injections of strychnine. Recovery from the strychnine block was observed when animals were maintained for periods of more than 60 min after the administration of strychnine. The ease of this technique allows it to be used to examine the effects of efferent stimulation on various aspects of cochlear function in the guinea pig.

Glass micro-electrode recordings from the spiral ganglion of the basal turn of the guinea pig cochlea have been obtained before, during and after negative (cathodic) current injection into scala tympani. Electrical stimulation with currents between 100 microA and 900 microA produced a marked increase in firing rate of the afferent neurons for the first 3 min of electrical stimulation. This was followed by a fall in firing rate to rates near or below the pre-stimulatory spontaneous rate if stimulation continued. Continuous electrical stimulation lasting 5 or 10 min reduced neural sensitivity to acoustic stimulation. Although threshold elevation was greatest for sound frequencies near the characteristic frequency of each neuron, thresholds could also be elevated at lower frequencies on the tail of the frequency-threshold tuning curve. After electrical stimulation a fall in the amplitude of the low-frequency microphonic recorded at the round window was also observed, indicating a disruption of the outer hair cell transduction. These effects were highly localized in the basal turn near the site of current injection, and were not associated with any significant structural changes in the organ of Corti, except after stimulation with very high current intensities.

Scanning microscopy was used to examine guinea pig cochleas for structural damage immediately after exposure to a pure tone ranging from 96 to 129 dB SPL. Functional changes to the cochlear neural sensitivity were assessed using the N1 audiogram. principal findings were: (1) The order of damage to receptor cells with increasing sound intensity was OHC1, then IHC, then OHC2 and OHC3. (2) The spatial distribution of damage to OHC1 and IHC differed with IHC tending to show damage mainly in the vicinity of the exposure frequently location and OHC1 damage spreading basal-ward of this point. (3) N1 threshold losses spread progressively to lower frequencies as exposure intensity increased. This was accompanied by an apical spread of damage to the receptor cells.

The dynamic properties of single olivocochlear efferent neurones in the guinea pig cochlea were examined using sinusoidally amplitude modulated (AM) pure tones. The neural discharge, when displayed as a cyclic histogram, clearly followed the rapid fluctuations in the continuous input sound. Modulation transfer functions (MTFs) were constructed and in most cases showed a peak in the modulation response (MR) at a modulation frequency (MF) of 100 Hz. At this frequency a gain of as much as 12 dB was evident relative to the 30% modulated input signal. In 24% of neurones however, a large MR was present even at low MFs. This plurality of MTFs may be the result of recorded neurones emanating from a variety of cell bodies of origin. Efferent group delays (mean of 8.2 +/- 1.0 ms) were shorter and more tightly distributed than the minimum onset latency measurements (mean of 24.2 +/- 12.5) made on the same neurones. It seems evident that a post-synaptic potential build is required from the onset of a stimulus to the first spike discharge. This may occur within a single afferent-interneurone(s)-efferent reflex arc. Among a variety of alternative explanations, the observation is consistent with the notion that the olivocochlear neurones receive facilitatory input from higher centres, which is suppressed under barbiturate anaesthesia. Continuous AM signals may allow post-synaptic build up and eliminate the dependence on this higher input and hence yield a short group delay.

Monaural losses in hearing sensitivity induced by an intense pure tone could be reduced if an acoustic stimulus of the same frequency was simultaneously delivered to the other ear. The reduction was eliminated when the contralateral stimulus was set at a frequency other than the ipsilateral trauma frequency and also after the administration of strychnine, a known blocker of auditory efferent activity. This suggests that acoustic activation of auditory efferents is responsible for the reduced ipsilateral sensitivity loss.

Acoustic overstimulation of the guinea pig cochlea with a 16 kHz pure tone induces a loss in threshold sensitivity that can be either temporary or permanent depending on the duration of the trauma. When a second tone of lower frequency (10, 5 or 2 kHz) is presented to the same cochlea simultaneously with the first tone, then the resultant threshold loss produced by the 16 kHz tone is significantly less. This applies to both temporary and permanent threshold losses. The reduced threshold loss disappears as the intensity of the second tone decreases. This type of nonlinear cochlea behaviour is similar to other acoustically evoked nonlinearities generally grouped under the term, two-tone suppression or inhibition. The results disagree with the "equal energy hypothesis' as a method to establish damage risk criteria in noise-induced hearing loss.

The neural activity of single cells within the spiral ganglion of the first turn of the guinea pig cochlea has been recorded. Period histograms of the spike activity have been collected. The histograms were synchronised with a loud low frequency tone (40 Hz) presented at a constant intensity below the threshold of the cells to phase locking. The activity evoked by a continuous high frequency tone within the tip of the frequency threshold curve was modulated by the presence of a subthreshold low frequency tone. Suppression of this evoked activity was observed for low frequency displacements of the cochlear partition towards scala tympani, and potentiation was observed for moderate displacements towards scala vestibuli. At higher intensities of the low frequency tone suppression is also observed for peak displacements of the partition towards scala vestibuli. The changes to these histograms with increases in the intensity of the high frequency tone are described. Hysteresis, flattening of the histograms at high intensities and nonmonotonic growth of firing rate at certain phases of the low frequency tone were observed. These changes are believed to be due to fast adaptation of the neural response rather than similar changes to the d.c. receptor potential within the inner hair cells that the neurons innervate.

A capacitance probe is used to measure the vibrational displacement of the basilar membrane in the basal turn of the guinea pig. Nonlinear behaviour is exhibited in the region of the mechanical cut-off frequency similar to that previously described only for the squirrel monkey. The degree of nonlinearity appears to be directly correlated with the single unit threshold as reflected in the N1 action potential. Loss of neural sensitivity indicates loss of nonlinear behaviour in the mechanics which is undetectable shortly after death.

Temporary threshold shifts (TTS) of the cochlear action potential in one (ipsilateral) ear, caused by a brief intense pure tone, were reduced either by (1) contralateral acoustic stimulation at the same frequency, or (2) destruction of the contralateral cochlea. The effect of contralateral cochlear destruction persisted, though slightly reduced in effect, after a delay of one hour between the destruction and the ipsilateral exposure. Contralateral acoustic stimulation had no effect after a delay of 10 min. The effect of contralateral cochlear destruction could be blocked by strychnine, a known antagonist of auditory efferent activity. However, contralateral cochlear destruction resulted in none of the effects upon normal ipsilateral thresholds or input-output curves for the action potential classically seen when the efferent pathways are stimulated. The results suggest that the crossed effects reported here are due to a complex interaction between the activity in both cochleas, possibly resulting in a reduction in a central inhibitory influence on an efferent feedback pathway that is then expressed during the ipsilateral exposure.

Electrical stimulation at the round window with pulsed short trains has been shown to elicit classical efferent effects on N1 amplitudes at the cochlea. This report demonstrates that round window stimulation as a continuous burst can reduce temporary threshold shifts (TTS) caused by a simultaneous monaural loud sound exposure. This result is similar to recent reports that stimulation of the crossed olivocochlear bundle (COCB) at the floor of the fourth ventricle can reduce TTS. Like COCB stimulation at the brainstem, the effect of round window stimulation could be abolished by strychnine, with a time course paralleling the blocking action of strychnine on the traditional COCB effects of pulsed short trains on N1 amplitudes. This report also established parameters for optimal effects of the round window stimulus and found them to be similar to the optimal parameters for the effects of brainstem stimulation on TTS. Tonic effects on TTS were also observed, with reductions in TTS being obtained as much as 7 min after a 1 min-long round window stimulus. Such tonic effects did not appear to be due to persistent effects at the cochlea but were suggested to be due to a long term resetting of some central site activated by antidromic stimulation from the round window.

From the original measurements of G. von Békésy (1942) until a few years ago, the basilar membrane was considered to undergo simple passive linear vibration. Recent measurements have completely altered this notion. It is now known that the BM is highly non linear and very sharply tuned. Indeed, BM can now account for most of the properties of the eighth nerve response to sound. The non linearity can be approximated by a hyperbolic function and appears to be part of an active process in the outer hair cell. At the characteristic frequency, CAP threshold (10 dB SPL) corresponds to 0.3 nm motion and the non linearity shows half saturation at 10 nm. The sigmoid shape of the full range BM input-output curve is due to the combination of a less sensitive linear passive component with the added sensitivity of the active non linear function. A hyperbolic input-output function is also present in the cochlear microphonics, and at low frequencies the half saturation value again corresponds to 10 nm BM displacement. With induced threshold loss (e.g. noise trauma) the nonlinearity disappears from the BM, but is still present in the CM. This suggests that the pathology is in the active mechanical feedback process, rather than in the receptor system. It appears that BM mechanics at low amplitudes near the resonant frequency is controlled by a nonlinear mechano-electrical transducer followed by a vulnerable, linear, active mechanism (electro-mechanical?) feeding back in positive phase onto BM vibration.

Measurements were made of inner hair cell receptor potentials and basilar membrane motion in the 17-21 kHz region of the guinea pig cochlea. The latter were made using the Mossbauer technique. Isoamplitude curves at 0.9 mV d.c. receptor potential were compared with isovelocity curves at 0.04 mm/s and the corresponding basilar membrane displacement at CF. The Mossbauer source (20 X 60 or 60 X 85 microns) was placed either in the middle of the basilar membrane or on the extreme modiolar edge. These two source positions yielded broad and narrow mechanical tuning curves, respectively. The latter approximated the receptor potential curves most closely but deviated by 10-15 dB on the low frequency side of the tuning curve tip.

Period histograms were generated from single unit data obtained from the spiral ganglion of the first turn of the guinea pig cochlea in response to continuous tones between 40 and 500 Hz. With the lowest intensities used, spontaneous activity was suppressed during basilar membrane displacement (inferred from cochlear microphonic phase) towards scala vestibula and activity was enhanced during displacement towards scala tympani. At higher intensities the response changed to excitation during maximal basilar membrane velocity towards scala vestibuli. These patterns were delayed by about 0.5 ms producing large phase delays at the higher frequencies. We postulate that the displacement response is produced by cochlear microphonic originating from the outer hair cells acting on the inner hair cell membrane. In contrast, the velocity response is produced by the inner hair cell receptor potential. The effect of a 40 Hz tone on activity evoked by tones above, at, and below the characteristic frequency was investigated by generating period histograms synchronous with the 40 Hz tone. We found that activity evoked by tones around the characteristic frequency of the cell was suppressed during displacement of the basilar membrane towards scala tympani and enhanced in the opposite direction at 40 Hz intensities that had no effect on spontaneous activity. Further increase in the 40 Hz intensity produced suppression during scala vestibuli displacement with activity remaining only during the zero crossings. Still further increase produces the 40 Hz tone alone response. Activity evoked by tones in the low frequency 'tails' of the frequency threshold curve was not similarly modulated. This phenomenon is though to be related to basilar membrane nonlinearity for frequencies close to the cut-off. Investigation of the effect of a 40 Hz tone on the threshold of the compound action potential confirmed data obtained from single units.

By deforming and making incisions in the basilar membrane (BM), von Békésy showed that the BM seems to behave as a thin elastic plate, rather than as a membrane. However, it has never been shown whether a traveling wave could be sustained by a prestretched material in which the tension is insufficient to cause a visible retraction of the cut edges of an incision when viewed with a light microscope. We have shown that the necessary radial tension would decrease exponentially along the cochlea, from a value of 39 +/- 9 N/m at the base, with a space constant of 4.3 +/- 1.1 mm, for the guinea pig. This variable tension would be produced by a constant prestretching surface force of 2.4 +/- 0.1 X 10(6) N/m2, acting on the BM edges. Using values of Young's modulus in the radial direction, ranging from that of elastin to collagen, it is shown that this force would most likely cause a visible retraction of the cut edges of an incision. Therefore one must either conclude, once again, that the BM is effectively an unstretched material or question the original interpretation of the incision experiments.

Temporary threshold shifts (TTS), of the cochlear action potential in the guinea pig, caused by a high frequency exposure tone could be reduced by a prior exposure at the same frequency but lower intensity. The TTS caused by the initial, low intensity exposure tone was allowed to recover to levels where the thresholds were not significantly different from normal thresholds. Re-exposure at the high intensity now resulted in less TTS being recorded, both at the half-octave point and across the range of frequencies affected by the pure tone, when compared to exposure to the high intensity tone without such priming. This protective effect of prior exposure was not affected by intraperitoneal injections of strychnine, distinguishing it from recent reports of protective mechanisms operative during TTS.

Low-frequency microphonic potentials (100 Hz to 2000 Hz) have been measured in the first turn of the guinea pig cochlea before and after a variety of manipulations of the cochlea. These included ablation of the apical turns, iontophoresis of streptomycin, dc current injection into the first turn, acoustic trauma and two-tone interference with pure tones. These manipulations indicate that the low-frequency microphonic measured in the first turn and at the round window is generated predominantly by the hair cells of this region. It is a convenient and relatively uncomplicated indicator of the integrity of the mechano-electrical transduction process of these cells.

Guinea pig auditory ganglion cell responses to 100-ms duration tone bursts were recorded over a range of stimulus intensities. The responses, recorded in the form of peristimulus/poststimulus time histograms, were analysed by reduction into two phases. The first phase was a rapid exponential adaptation from an initial onset response; the second was a more gradual reduction in the firing rate which, over the 100 ms duration of the stimulus, appeared to be a linear function of time. The first, rapid, phase was nonlinear in its response to changes in stimulus intensity, exhibiting a change in amplitude and having a time constant which decreased with increasing intensity. Individual units were consistent in the magnitude and time course of this phase. The second phase was also nonlinear with intensity, and was far more variable from unit to unit. With the recording parameters employed it was not possible to determine whether the effect of intensity on the second phase was an effect on the magnitude or time course, or both. Stimulus termination responses were also analysed, and typically were of one of two forms. If, at any particular stimulus intensity, the unit under study showed little sign of the slower adaptation then the termination response was a simple depression of activity (perhaps to zero) which recovered with an exponential time constant of about 25 ms, independent of intensity. If, however, the peristimulus responses showed a significant amount of the slow adaptation then the termination responses also exhibited a second, slower, phase of recovery. This was modelled over the recording epoch as a linear function of time. The magnitude of the slow offset response also increased with intensity faster than did the average firing rate.

Exposure of guinea pig cochleas to short (25, 250 and 1000 ms), intense (90 or 100 dB SPL) 10 kHz pure tones reduced cochlear sensitivity to 14 kHz test tones presented at intervals varying from 5 ms to 70 s after the exposure tone. The recovery of cochlear sensitivity, determined as the SPL required to evoke a 20 microV compound action potential (CAP), depended on both the intensity and the duration of the exposure tone and appeared to take place in two or more phases. After a 25 ms, 100 dB SPL exposure, CAP threshold increased by up to 13.5 dB and generally recovered very rapidly (25 ms), although some loss persisted for as long as 400 ms. A similar, but greater and longer, elevation of threshold was seen after long exposure tones. Lower exposure tone intensities (90 dB SPL) produced threshold elevations which generally lasted for only short durations (25-35 ms). The rapid recovery is consistent with the time course of recovery from rapid adaptation, while the slow recovery component is similar to that seen in the cochlea after much longer exposures and may be related to the phenomenon of temporary threshold shift. Long and/or loud exposures also frequently resulted in a third form of threshold elevation, identified in only a few animals, which recovered with a time constant in excess of 25 s. A fourth component occasionally persisted for the duration of the experiment.

The low-frequency (200 Hz) microphonic potentials at the round window and in the organ of Corti of the first turn of the guinea pig cochlea have been measured before and after acoustic overstimulation. Reductions in the amplitude of this microphonic after loud sound are highly correlated with neural threshold elevation in this region. The fall in the microphonic amplitude appears due to an inactivation of mechano-electrical transduction channels at the apex of the outer hair cells into a closed state. These results are consistent with the idea that the current through the outer hair cells controls the mechanical sensitivity of the organ of Corti, and that the temporary loss of mechanical and neural sensitivity following loud sound is due to a simple inactivation of the mechano-electrical transduction channels.

Venom from the spider Argiope trifasciata, a highly specific blocker of the ionic channels associated with invertebrate glutamatergic receptors, was perfused through scala tympani of the basal turn of the pig cochlea. Its effect on spontaneous and driven activity of single afferent neurons was studied. 0.1 U/ml spider venom altered the maximum driven activity without an effect on spontaneous activity. 1 U/ml spider venom suppressed both spontaneous and driven activity. These findings are consistent with the hypothesis that L-glutamate is the neurotransmitter of the synapse between inner hair cells and primary auditory afferent neurons. The results also suggest that the differences in spontaneous activity between neurons may originate in variations in neurotransmitter release.

Destruction of the cochlea contralateral to one subsequently exposed to a high intensity acoustic exposure has been shown to reduce the threshold losses caused by the exposure (Rajan and Johnstone, 1983a). The present study tested this manipulation on a wide variety of exposures of varying intensity and duration and found that the amount by which ipsilateral threshold losses were reduced was related to the amount of threshold losses that would have occurred in the absence of the contralateral manipulation. This loss-related protection is also found when the COCB is electrically stimulated during loud sound exposures (Rajan, 1988b; Rajan and Johnstone, 1988b). When the COCB was lesioned at the floor of the fourth ventricle contralateral cochlea destruction no longer protected the test cochlea, confirming that the crossed cochlear protection was exercised through the COCB. The contralateral manipulation did not appear to directly activate the COCB but may have acted in a facilitatory manner on the COCB, allowing activation only when a sufficiently high level exposure was subsequently presented ipsilaterally: a variety of responses at the ipsilateral cochlea and at the brainstem, remeasured after contralateral cochlear destruction and prior to an ipsilateral loud sound exposure, were found to be unaltered, although the TTS to the subsequent exposure was significantly reduced.

This report demonstrates that electrical stimulation of the efferents at the round window reduces temporary threshold shifts in a protective manner. For a standard set of stimulating parameters greatest reductions in TTS were found to exposures that caused the greatest amounts of TTS to occur. Low level exposures that caused low levels of TTS from which the cochlea could recover relatively quickly were not affected by the standard electrical stimulus. Intermediate reductions were obtained to intermediate levels of exposure, resulting in intermediate levels of TTS. Increasing current levels or duration of stimulation did not produce reductions in the low level TTS; a higher rate of stimulation was, however, able to reduce the low level TTS. Even with the higher rate of stimulation, greatest reductions in TTS occurred at the higher levels of exposure. These results are identical to the effects of COCB stimulation at the level of the brainstem and argue for viewing the COCB as a protective pathway.

It is argued in this paper that many nonlinear phenomena in audition and many types of sensorineural hearing loss can be explained by a disruption of the mechano-electrical transduction process at the apex of the outer hair cells. This is done using experimental data and a simple model of the active role of outer hair cells in cochlear mechanics based on our previous experiments with acoustic trauma. The causes of sensorineural loss addressed include acoustic trauma, aminoglycoside ototoxicity, intoxication with loop diuretics, hypoxia and Meniere's disease. The nonlinear phenomena discussed include loudness compression, two-tone suppression and modulation of cochlear sensitivity by very low-frequency tones. In every case considered the reduction in neural sensitivity was related to the reduction in outer hair cell receptor current in a quantitatively similar way. We conclude that the link is causal.