No abstract

High doses of salicylate, the anti-inflammatory component of aspirin, induce transient tinnitus and hearing loss. Systemic injection of 250 mg/kg of salicylate, a dose that reliably induces tinnitus in rats, significantly reduced the sound evoked output of the rat cochlea. Paradoxically, salicylate significantly increased the amplitude of the sound-evoked field potential from the auditory cortex (AC) of conscious rats, but not the inferior colliculus (IC). When rats were anesthetized with isoflurane, which increases GABA-mediated inhibition, the salicylate-induced AC amplitude enhancement was abolished, whereas ketamine, which blocks N-methyl-D-aspartate receptors, further increased the salicylate-induced AC amplitude enhancement. Direct application of salicylate to the cochlea, however, reduced the response amplitude of the cochlea, IC and AC, suggesting the AC amplitude enhancement induced by systemic injection of salicylate does not originate from the cochlea. To identify a behavioral correlate of the salicylate-induced AC enhancement, the acoustic startle response was measured before and after salicylate treatment. Salicylate significantly increased the amplitude of the startle response. Collectively, these results suggest that high doses of salicylate increase the gain of the central auditory system, presumably by down-regulating GABA-mediated inhibition, leading to an exaggerated acoustic startle response. The enhanced startle response may be the behavioral correlate of hyperacusis that often accompanies tinnitus and hearing loss. Published by Elsevier Ltd on behalf of IBRO. Keywordssalicylate; tinnitus; hyperacusis; auditory cortex; inferior colliculus; GABA A challenging question for tinnitus research is to identify the neural generator(s) in the cochlea and/or central auditory system (CAS) of tinnitus. Although the phantom sound of tinnitus is commonly induced by noise exposure or ototoxic drugs, increasing evidence suggests that noise and drug-induced cochlear damage that reduces the output of the cochlea induces a plethora of functional changes in the CAS. In many cases of cochlear damage, the CAS appears to increase its gain to compensate for the reduced sensorineural input from the cochlea. An excessive increase in central gain may give rise to the phantom sound of tinnitus under quiet conditions, as well as an intolerance to loud sounds (hyperacusis) (Gerken, 1996;Salvi et al., 2000;Eggermont and Roberts, 2004 which has been linked to chronic tinnitus in humans (Goldstein and Shulman, 1996;Nelson and Chen, 2004). Chronic tinnitus and hyperacusis in humans are most often associated with cochlear damage induced by aging, noise or ototoxic drugs. The salicylate-induced pathology provides a reversible and highly reliable method to investigate how the CAS adjusts due to insult as well as the possible neural correlates of tinnitus and hyperacusis.Previous studies have shown that acoustic trauma which damages hair cells in the cochlea causes an enhancement in sound-evoked activity in the cochlear ...

Tone detection and temporal gap detection thresholds were determined in CBA/CaJ mice using a Go/No-go procedure and the psychophysical Method of Constant Stimuli. In the first experiment, audiograms were constructed for five CBA/CaJ mice. Thresholds were obtained for eight pure tones ranging in frequency from 1 to 42 kHz. Audiograms showed peak sensitivity between 8 and 24 kHz, with higher thresholds at lower and higher frequencies. In the second experiment, thresholds for gap detection in broadband and narrowband noise bursts were measured at several sensation levels. For broadband noise, gap thresholds were between 1 and 2 ms, except at very low sensation levels, where thresholds increased significantly. Gap thresholds also increased significantly for lowpass-filtered noise bursts with a cutoff frequency below 18 kHz. Our experiments revised absolute auditory thresholds in the CBA/CaJ mouse strain and demonstrated excellent gap detection ability in the mouse. These results add to the baseline behavioral data from normal-hearing mice which have become increasingly important for assessing auditory abilities in genetically altered mice.

The neuronal mechanism underlying the phantom auditory perception of tinnitus remains at present elusive. For over 25 years, temporary tinnitus following acute salicylate intoxication in rats has been used as a model to understand how a phantom sound can be generated. Behavioral studies have indicated the pitch of salicylate-induced tinnitus in the rat is approximately 16 kHz. In order to better understand the origin of the tinnitus pitch, in the present study, measurements were made at the levels of auditory input and output; both cochlear and cortical physiological recordings were performed in ketamine/xylazine anesthetized rats. Both compound action potentials and distortion product otoacoustic emission measurements revealed a salicylate-induced band-pass-like cochlear deficit in which the reduction of cochlear input was least at 16 kHz and significantly greater at high and low frequencies. In a separate group of rats, frequency receptive fields of primary auditory cortex neurons were tracked using multichannel microelectrodes before and after systemic salicylate treatment. Tracking frequency receptive fields following salicylate revealed a population of neurons that shifted their frequency of maximum sensitivity (i.e., characteristic frequency) towards the tinnitus frequency region of the tonotopic axis (~16 kHz). The data presented here supports the hypothesis that salicylateinduced tinnitus results from an expanded cortical representation of the tinnitus pitch determined by an altered profile of input from the cochlea. Moreover, the pliability of cortical frequency receptive fields during salicylateinduced tinnitus is likely due to salicylate's direct action on intracortical inhibitory networks. Such a disproportionate representation of middle frequencies in the auditory cortex following salicylate may result in a finer analysis of signals within this region which may pathologically enhance the functional importance of spurious neuronal activity concentrated at tinnitus frequencies.

High doses of sodium salicylate (SS) have long been known to induce temporary hearing loss and tinnitus, effects attributed to cochlear dysfunction. However, our recent publications reviewed here show that SS can induce profound, permanent, and unexpected changes in the cochlea and central nervous system. Prolonged treatment with SS permanently decreased the cochlear compound action potential (CAP) amplitude in vivo. In vitro, high dose SS resulted in a permanent loss of spiral ganglion neurons and nerve fibers, but did not damage hair cells. Acute treatment with high-dose SS produced a frequency-dependent decrease in the amplitude of distortion product otoacoustic emissions and CAP. Losses were greatest at low and high frequencies, but least at the mid-frequencies (10-20 kHz), the mid-frequency band that corresponds to the tinnitus pitch measured behaviorally. In the auditory cortex, medial geniculate body and amygdala, high-dose SS enhanced sound-evoked neural responses at high stimulus levels, but it suppressed activity at low intensities and elevated response threshold. When SS was applied directly to the auditory cortex or amygdala, it only enhanced sound evoked activity, but did not elevate response threshold. Current source density analysis revealed enhanced current flow into the supragranular layer of auditory cortex following systemic SS treatment. Systemic SS treatment also altered tuning in auditory cortex and amygdala; low frequency and high frequency multiunit clusters up-shifted or down-shifted their characteristic frequency into the 10-20 kHz range thereby altering auditory cortex tonotopy and enhancing neural activity at mid-frequencies corresponding to the tinnitus pitch. These results suggest that SS-induced hyperactivity in auditory cortex originates in the central nervous system, that the amygdala potentiates these effects and that the SS-induced tonotopic shifts in auditory cortex, the putative neural correlate of tinnitus, arises from the interaction between the frequency-dependent losses in the cochlea and hyperactivity in the central nervous system.