Consequences of noise- or styrene-induced cochlear damages on glutamate decarboxylase levels in the rat inferior colliculus

Both noise and styrene can injure the cochlea, resulting in a reduction of incoming inputs from the cochlea to the central nervous system. In addition, styrene is known to have neurotoxic properties at high doses. The loss of inputs caused by noise has been shown to be compensated by a new equilibrium between excitatory and inhibitory influences within the inferior colliculus (IC). The main goal of this study was to determine whether styrene-induced hearing loss could also be counterbalanced by a GABAergic adjustment in the IC. For this purpose, rats were exposed to noise (97 dB SPL octave band noise centered at 8 kHz), or to a non-neurotoxic dose of styrene for 4 weeks (700 ppm, 6 h/day, 5 days/week). Auditory sensitivity was tested by evoked potentials, and cochlear damage was assessed by hair cell counts. Glutamate decarboxylase (GAD) was dosed in the IC by indirect competitive enzyme-linked immunosorbent assay. Both noise and styrene caused PTSs that reached 27.0 and 14.6 dB respectively. Outer hair cell (OHC) loss caused by noise did not exceed 9% in the first row, on the other hand OHC loss induced by styrene reached 63% in the third row. Only the noise caused a decrease of GAD of 37% compared to that measured in the controls. No significant modification of GAD concentration has been shown after styrene exposure. Thus, central compensation for cochlear damage may depend on the nature of the ototoxic agent. Unless styrene directly affects IC function, it is reasonable to assume that noise causes a modification of inhibitory neurotransmission within the structure because of impairment of afferent supply to the auditory brainstem. The present findings suggest that central compensation for cochlear damage can preferably occur when afferent fibers are altered.     

Acoustic trauma-induced auditory cortex enhancement and tinnitus

There is growing evidence suggests that noise-induced cochlear damage may lead to hyperexcitability in the central auditory system (CAS) which may give rise to tinnitus. However, the correlation between the onset of the neurophysiological changes in the CAS and the onset of tinnitus has not been well studied. To investigate this relationship, chronic electrodes were implanted into the auditory cortex (AC) and sound evoked activities were measured from awake rats before and after noise exposure. The auditory brainstem response (ABR) was used to assess the degree of noise-induced hearing loss. Tinnitus was evaluated by measuring gap-induced prepulse inhibition (gap-PPI). Rats were exposed monaurally to a high-intensity narrowband noise centered at 12 kHz at a level of 120 dB SPL for 1 h. After the noise exposure, all the rats developed either permanent (>2 weeks) or temporary (<3 days) hearing loss in the exposed ear(s). The AC amplitudes increased significantly 4 h after the noise exposure. Most of the exposed rats also showed decreased gap-PPI. The post-exposure AC enhancement showed a positive correlation with the amount of hearing loss. The onset of tinnitus-like behavior was happened after the onset of AC enhancement.     

Auditory plasticity and hyperactivity following cochlear damage

This paper will review some of the functional changes that occur in the central auditory pathway after the cochlea is damaged by acoustic overstimulation or by carboplatin, an ototoxic drug that selectively destroys inner hair cells (IHCs) in the chinchilla. Acoustic trauma typically impairs the sensitivity and tuning of auditory nerve fibers and reduces the neural output of the cochlea. Surprisingly, our results show that restricted cochlear damage enhances neural activity in the central auditory pathway. Despite a reduction in the auditory-nerve compound action potential (CAP), the local field potential from the inferior colliculus (IC) increases at a faster than normal rate and its maximum amplitude is enhanced at frequencies below the region of hearing loss. To determine if this enhancement was due to loss of sideband inhibition, we recorded from single neurons in the IC and dorsal cochlear nucleus before and after presenting a traumatizing above the unit's characteristic frequency (CF). Following the exposure, some neurons showed substantial broadening of tuning below CF, less inhibition, and a significant increase in discharge rate, consistent with a model involving loss of sideband inhibition. The central auditory system of the chinchilla can be deprived of some of its cochlear inputs by selectively destroying IHCs with carboplatin. Selective IHC loss reduces the amplitude of the CAP without affecting the threshold and tuning of the remaining auditory nerve fibers. Although the output of the cochlea is reduced in proportion to the amount of IHC loss, the IC response shows only a modest amplitude reduction, and remarkably, the response of the auditory cortex is enhanced. These results suggest that the gain of the central auditory pathway can be up- or down regulated to compensate for the amount of neural activity from the cochlea.     

Organic solvents and hearing loss: The challenge for audiology

Organic solvents have been reported to adversely affect human health, including hearing health. Animal models have demonstrated that solvents may induce auditory damage, especially to the outer hair cells. Research on workers exposed to solvents has suggested that these chemicals may also induce auditory damage through effects on the central auditory pathways. Studies conducted with both animals and humans demonstrate that the hearing frequencies affected by solvent exposure are different to those affected by noise, and that solvents may interact synergistically with noise. The present article aims to review the contemporary literature of solvent-induced hearing loss, and consider the implications of solvent-induced auditory damage for clinical audiologists. Possible audiological tests that may be used when auditory damage due to solvent exposure is suspected are discussed.     

Effects of repeated "benign" noise exposures in young CBA mice: shedding light on age-related hearing loss

Temporary hearing threshold shift (TTS) resulting from a "benign" noise exposure can cause irreversible auditory nerve afferent terminal damage and retraction. While hearing thresholds and acute tissue injury recover within 1-2 weeks after a noise overexposure, it is not clear if multiple TTS noise exposures would result in cumulative damage even though sufficient TTS recovery time is provided. Here, we tested whether repeated TTS noise exposures affected permanent hearing thresholds and examined how that related to inner ear histopathology. Despite a peak 35-40 dB TTS 24 hours after each noise exposure, a double dose (2 weeks apart) of 100 dB noise (8-16 kHz) exposures to young (4-week-old) CBA mice resulted in no permanent threshold shifts (PTS) and abnormal distortion product otoacoustic emissions (DPOAE). However, although auditory brainstem response (ABR) thresholds recovered fully in once- and twice-exposed animals, the growth function of ABR wave 1( p-p ) amplitude (synchronized spiral ganglion cell activity) was significantly reduced to a similar extent, suggesting that damage resulting from a second dose of the exposure was not proportional to that observed after the initial exposure. Estimate of surviving inner hair cell afferent terminals using immunostaining of presynaptic ribbons revealed ribbon loss of ～ 40 % at the ～ 23 kHz region after the first round of noise exposure, but no additional loss of ribbons after the second exposure. In contrast, a third dose of the same noise exposure resulted in not only TTS, but also PTS even in regions where DPOAEs were not affected. The pattern of PTS seen was not entirely tonotopically related to the noise band used. Instead, it resembled more to that of age-related hearing loss, i.e., high frequency hearing impairment towards the base of the cochlea. Interestingly, after a 3rd dose of the noise exposure, additional loss of ribbons (another ≈ 25 %) was observed, suggesting a cumulative detrimental effect from individual "benign" noise exposures, which should result in a significant deficit in central temporal processing.     

Long-term effects of carboplatin brainstem infusions on hearing thresholds in monkeys

OBJECTIVE: To isolate the central auditory neurotoxicity of carboplatin from its well-established ototoxic effects. DESIGN: The "best-case scenario" of targeted drug delivery to brain cancer was simulated by infusing carboplatin directly into the brainstem of cynomolgus monkeys with chronically implanted catheters. Because this manner of drug administration produced low levels of carboplatin in spinal fluid and blood, it was assumed that resulting deficits were dictated by the central auditory neurotoxicity of platinum compounds and not peripheral ototoxic effects. The magnitude of this hearing loss was estimated by comparing the auditory brainstem response thresholds of treated monkeys with results from normal controls. SUBJECTS: Six adult male cynomolgus monkeys (Macaca fascicularis) weighing 4 to 6 kg (3 received carboplatin treatment and 3 served as normal controls). INTERVENTION: Brainstem infusions of carboplatin. RESULTS: The average threshold of carboplatin-treated monkeys was elevated 8.8 dB (SD = 7.3 dB) relative to normal controls 6 months after the termination of drug delivery and increased to 10.7 dB with less variation between subjects (SD = 5.6 dB) 1 year after drug treatment. Although small in magnitude, the hearing loss was statistically significant (P<.05). CONCLUSIONS: Brainstem infusions of carboplatin induced some degree of hearing impairment in all treated monkeys. These threshold elevations were modest compared with the ototoxic effects that have been reported after systemic doses of carboplatin. Our findings suggest that the neurotoxic sensitivity of cochlear hair cells is not shared by neurons in the central auditory pathways. As a result, methods for reducing the ototoxic effects of chemotherapy remain a viable strategy for preserving auditory function in patients with brain cancer.     

Hidden cochlear impairments

Pure tone audiometry is a routine clinical examination used to identify hearing loss. A normal pure tone audiogram is usually taken as evidence of normal hearing. Auditory deficits detected in subjects with normal audiograms, such as poor sound discrimination and auditory perceptual disorders, are generally attributed to central problems. Does the pure tone audiogram truly reflect cochlear status? Recent evidence suggests that individuals with normal audiogram may still have reduced peripheral auditory responses but normal central responses, indicating that the pure tone audiometry may not detect some types of cochlear injuries. In the cochlea, the outer hair cells (OHCs), inner hair cells (IHCs), and the spiral ganglion neurons that synapse with IHCs are the 3 key cochlear components in transducing acoustical vibrations into the neural signals. This report reviews three types of cochlear damage identified in laboratory animals that may not lead to overt hearing loss. The first type of cochlear impairment, such as missing a certain proportion of IHCs without damage to OHCs, may reduce the cochlear output and elevate response threshold; however, the reduced peripheral auditory sensitivity may be restored along the auditory pathway via central gain enhancement. The second type of cochlear impairment, such as selective damage to the synapses of the high-threshold thin auditory nerve fibers (ANFs), reduces cochlear output at high stimulation levels with no effect on response threshold. In this case the reduced cochlear output may be compensated along the auditory pathway as well. The third type of cochlear impairment, such as missing a certain number of OHCs without damage to others, may not even affect cochlear function at all. These “hidden” cochlear impairments do not result in overt hearing loss, but they may increase the vulnerability of the cochlea to traumatic exposure and lead to disrupted central auditory processing.     

The cochlea as an independent neuroendocrine organ: expression and possible roles of a local hypothalamic-pituitary-adrenal axis-equivalent signaling system

A key property possessed by the mammalian cochlea is its ability to dynamically alter its own sensitivity. Because hair cells and ganglion cells are prone to damage following exposure to loud sound, extant mechanisms limiting cochlear damage include modulation involving both the mechanical (via outer hair cell motility) and neural signaling (via inner hair cell-ganglion cell synapses) steps of peripheral auditory processing. Feedback systems such as that embodied by the olivocochlear system can alter sensitivity, but respond only after stimulus encoding, allowing potentially damaging sounds to impact the inner ear before sensitivity is adjusted. Less well characterized are potential cellular signaling systems involved in protection against metabolic stress and resultant damage. Although pharmacological manipulation of the olivocochlear system may hold some promise for attenuating cochlear damage, targeting this system may still allow damage to occur that does not depend on a fully functional feedback loop for its mitigation. Thus, understanding endogenous cell signaling systems involved in cochlear protection may lead to new strategies and therapies for prevention of cochlear damage and consequent hearing loss. We have recently discovered a novel cochlear signaling system that is molecularly equivalent to the classic hypothalamic-pituitary-adrenal (HPA) axis. This cochlear HPA-equivalent system functions to balance auditory sensitivity and susceptibility to noise-induced hearing loss, and also protects against cellular metabolic insults resulting from exposures to ototoxic drugs. This system may represent a local cellular response system designed to mitigate damage arising from various types of insult.     

The ototoxic interaction of styrene and noise

The interaction between noise and inhaled styrene on the structure and function of the auditory organ of the male Wistar rat was studied. The animals were exposed either to 600 ppm, 300 ppm or 100 ppm styrene (12 h/day, 5 days/week, for 4 weeks) alone or in combination with a simultaneous 100-105 dB industrial noise stimulant. Auditory sensitivity was tested by auditory brainstem audiometry at 1.0, 2.0, 4.0 and 8.0 kHz frequencies. Inner ear changes were studied by light microscopy. Exposure to 600 ppm styrene alone caused a 3 dB hearing loss only at the highest test frequency (8 kHz). Quantitative morphological analysis of cochlear hair cells (cytocochleograms) showed a severe outer hair cell (OHC) loss particularly in the third OHC row of the upper basal and lower middle coil. Exposure to noise alone caused only a mild hearing loss (2-9 dB), and only an occasional loss of OHCs (<1% missing). Exposure to the combination of noise and 600 ppm styrene caused a moderate flat hearing loss of 23-27 dB. The cytocochleograms showed a more severe damage of the OHCs than after exposure to 600 ppm styrene alone. The inner hair cells were found to be destroyed in some animals in the upper basal turn only after the combination exposure. Only in combination with noise exposure, the lower styrene concentrations (100 and 300 ppm) induced a hearing loss which was equivalent to that seen after exposure to noise alone. We conclude that: (1) There is an ototoxic interaction between styrene and noise. (2) Synergism is manifested only if styrene is applied in concentrations above the critical level (between 300 and 600 ppm in this study).     

Reversible long-term changes in auditory processing in mature auditory cortex in the absence of hearing loss induced by passive, moderate-level sound exposure

It has become increasingly clear that even occasional exposure to loud sounds in occupational or recreational settings can cause irreversible damage to the hair cells of the cochlea and the auditory nerve fibers, even if the resulting partial loss of hearing sensitivity, usually accompanied by tinnitus, disappears within hours or days of the exposure. Such exposure may explain at least some cases of poor speech intelligibility in noise in the face of a normal or near-normal audiogram. Recent findings from our laboratory suggest that long-term changes to auditory brain function-potentially leading to problems with speech intelligibility-can be effected by persistent, passive exposure to more moderate levels of noise (in the 70 dB SPL range) in the apparent absence of damage to the auditory periphery (as reflected in normal distortion product otoacoustic emissions and auditory brainstem responses). Specifically, passive exposure of adult cats to moderate levels of band-pass-filtered noise, or to band-limited ensembles of dense, random tone pips, can lead to a profound decrease of neural activity in the auditory cortex roughly in the exposure frequency range, and to an increase of activity outside that range. This can progress to an apparent reorganization of the cortical tonotopic map, which is reminiscent of the reorganization resulting from hearing loss restricted to a part of the hearing frequency range, although again, no hearing loss was apparent after our moderate-level sound exposure. Here, we review this work focusing specifically on the potential hearing problems that may arise despite a normally functioning auditory periphery.     

Threshold shifts and enhancement of cortical evoked responses after noise exposure in rats

The effect of exposure to various types of noise (broadband, high-frequency or low-frequency) was studied in adult pigmented rats. Thresholds and amplitudes of middle latency responses (MLR) recorded from electrodes implanted on the surface of the auditory cortex were analyzed before and after noise exposure. Exposure to noise with intensities ranging from 105 to 120 dB for 1 h produced only temporary threshold shifts (TTS). Exposure to broadband noise produced TTS throughout the whole frequency range of the rat's hearing, mostly expressed at frequencies of maximal hearing sensitivity (16-32 kHz). Hearing loss produced by high- or low-frequency noise exposure was related to the spectral characteristics of the noise. The exposure to high-intensity noise may also result in amplitude enhancement of the MLR. This phenomenon was seen mainly after broadband noise exposure and occurred in response to both low-frequency and high-frequency test stimuli. High-frequency and low-frequency noise produced amplitude enhancement mainly at frequencies which corresponded to the maximum exposure energy. In contrast to the relatively similar values of TTS obtained in different rats under the same conditions of noise exposure, great inter-individual variability was found in the MLR amplitude enhancement. In all rats the dynamics of recovery functions for amplitude enhancement were different from those for MLR thresholds. The data indicate that whereas post-exposure TTS are related to peripheral changes, the post-exposure MLR amplitude enhancement is most probably connected with a change in the processing of auditory information in the central nervous system.     

GAD levels and muscimol binding in rat inferior colliculus following acoustic trauma

Pharmacological studies of the inferior colliculus (IC) suggest that the inhibitory amino acid neurotransmitter gamma-aminobutyric acid (GABA) plays an important role in shaping responses to simple and complex acoustic stimuli. Several models of auditory dysfunction, including age-related hearing loss, tinnitus, and peripheral deafferentation, suggest an alteration of normal GABA neurotransmission in central auditory pathways. The present study attempts to further characterize noise-induced changes in GABA markers in the IC. Four groups (unexposed control, 0 h post-exposure, 42 h post-exposure, and 30 days post-exposure) of 3-month-old male Fischer 344 rats were exposed to a high intensity sound (12 kHz, 106 dB) for 10 h. Observed hair cell damage was primarily confined to the basal half of the cochlea. There was a significant decrease in glutamic acid decarboxylase (GAD(65)) immunoreactivity in the IC membrane fraction compared to controls (P<0.05) at 0 h (-41%) and 42 h (-28%) post-exposure, with complete recovery by 30 days post-exposure (P>0.98). Observed decreases in cytosolic levels of GAD(65) were not significant. Quantitative muscimol receptor binding revealed a significant increase (+20%) in IC 30 days after sound exposure (P<0.05). These data suggest that changes in GABA neurotransmission occur in the IC of animals exposed to intense sound. Additional studies are needed to determine whether these changes are a result of protective/compensatory mechanisms or merely peripheral differentiation, as well as whether these changes preserve or diminish central auditory system function.     

Age related cochlear toxicity from noise and antibiotics--a review

Laboratory experimental evidence indicates that there is an age related susceptibility to cochlear damage from noise exposure and ototoxic antibiotics. In some rodents there is a critical period of auditory development during which there is greater vulnerability to such damage and, in some species, noise induced damage is influenced by genotype. Available data from patients are inconclusive in this regard. Further careful studies are indicated in this area. All available evidence emphasizes that caution should be exercised in the use of ototoxic drugs during pregnancy, in neonates, young children, and older people.     

Functional reorganization in chinchilla inferior colliculus associated with chronic and acute cochlear damage

This paper describes some of the unexpected functional changes that occur in the inferior colliculus (IC) following noise- and drug-induced cochlear pathology. A striking example of this is the compensation that is seen in IC responsiveness after drug-induced selective inner hair cell (IHC) loss. Despite a massive reduction in the compound action potential (CAP) caused by partial IHC loss, the evoked potential amplitude from the IC shows little or no reduction. Acoustic trauma, which impairs cochlear sensitivity and tuning, also reduces the CAP amplitude. Despite this reduced neural input, IC amplitude sometimes increases at a faster than normal rate and the response amplitude is enhanced at frequencies below the hearing loss. Single unit recordings suggest the IC enhancement phenomenon may be due to the loss of lateral inhibition. After an acute traumatizing exposure to a tone located above the characteristic frequency (CF), approximately 50% of IC neurons show a significant increase in their spike rate, a significant expansion of the low frequency tail of the tuning curve and a significant improvement in sensitivity in the tail of the tuning curve. These changes suggest that IC neurons receive inhibition from a high frequency side band and that this inhibition is diminished by acoustic trauma above CF. To determine if side band inhibition was locally mediated, specific antagonist(s) to inhibitory neurotransmitters were applied and found to produce effects similar to acoustic trauma. The results suggest that lesioned-induced central auditory plasticity could contribute to several symptoms associated with sensorineural hearing loss such as loudness recruitment, tinnitus and poor speech discrimination in noise.     

Symposium: new data for noise standards. IV. The physiological effects of priming for audiogenic seizures in mice

Recent investigations have shown that nonsusceptible strains of mice can be made susceptible to audiogenic seizures by exposing them to intense sound during a “sensitive period.” The parameters of seizures behavior that accompany this priming procedure have been studied extensively and more recently the physiological processes that are associated with this phenomenon have received attention. The results indicate that priming causes a severe loss in cochlear microphonic sensitivity and extensive damage to basal turn hair cells. The patterns of evoked response activity in peripheral auditory nuclei show a loss in threshold sensitivity at low stimulus levels and over recruitment of response amplitude at high stimulus levels. Although there is a severe loss of cochlear function in these animals, intense stimuli paradoxically evoke exceptionally large re-responses and precipitate seizure behavior. Several hypotheses concerning this paradox are offered, and the potential significance of the priming phenomenon is considered.     

Ototoxicity of cisplatin in children

BACKGROUND: The ototoxicity of cisplatin has long been well known for its damage to hair cells. However, the results of published studies vary widely with respect to the intensity and frequency of auditory damage. METHODS: We analyzed the data of 13 young children that have been treated with cisplatin for varying tumor diseases in established combination chemotherapy. The study focused on these major questions: How high is the rate of cisplatin-related incidents of hearing loss in relation to age, sex, nature of tumor, and total dosage of the administered cisplatin? How much does the supplementary application of further ototoxic medications affect the ototoxicity itself? RESULTS: Eight of 13 children examined showed regular hearing capacities in conformity with their age-group, 3 showed a bilateral, and one child showed an one-sided loss of auditory capacity. Deterioration of preexisting auditory damage was observed in one child. No relation to age, sex, nature of tumor, or dosage of administered cisplatin was established. Bilateral hearing loss occurred in three of these children, which indicates that possible synergy of aminoglycoside antibiotics and cisplatin should be investigated with respect to ototoxicity. CONCLUSION: The results indicate that cisplatin, especially in combination with other ototoxic drugs, can lead to severe hearing loss in young children. Since factors other than the possible synergy discusses above favorable to the development of auditory damage cannot be specified, every child under cisplatin therapy should undergo auditory checkups at brief intervals.     

Unitary ototoxic gentamicin exposure may not disrupt the function of cochlear outer hair cells in mice

Background: Previous study showed that mild ototoxic exposure could induce a reversible hearing impairment, and the loss and secondary incomplete recovery of cochlear ribbon synapses could be responsible for the hearing loss. However, it remains unclear whether cochlear outer hair cells’ (OHCs) functions are affected.

Objective: To verify whether the function of OHCs are also affected significantly after the ototoxic exposure.

Methods: Mice were injected intraperitoneally with 100?mg/kg concentration of gentamicin daily for 14 days. Distortion Product of Oto-acoustic Emission (DPOAE) was detected at control (pre-treatment), Day 0, day 4, day 7, day 14 and day 28 after the ototoxic exposure, respectively. In addition, the morphology of OHCs was observed by electron microscopy, OHCs has been counted by light microscopy, and the hearing thresholds were detected by auditory brain response (ABR).

Results: No significant changes have been found in OHC and OHC stereocilia among the experimental groups (p?>?.05). Further, no significant changes or loss was found in the morphology of OHCs either. However, we found ABR threshold elevations occurred after ototoxic exposure.

Conclusions: Unitary ototoxic gentamicin exposure may not disrupt the function of cochlear OHCs in mice, regardless of hearing loss identified in this ototoxic exposure.     

Anatomy and physiology of binaural hearing

Binaural hearing improves performance in most auditory tasks and is essential for some. This paper introduces the brain stem pathways and nuclei involved in binaural interaction and outlines some recent approaches to understanding binaural mechanisms. It also provides examples of basic science approaches to the effects of infant hearing loss on those pathways and mechanisms. Binaural interaction occurs primarily and almost simultaneously at three levels of the brain: the superior olivary complex (SOC), the nuclei of the lateral lemniscus (NLL) and the inferior colliculus (IC). The SOC derives its input from the anterior ventral cochlear nucleus (CN) through branching axons that innervate several SOC subdivisions on both sides of the brain. At least some of these anteroventral CN axons project on up to the contralateral NLL and IC. The IC and NLL also receive direct, major projections from the contralateral CN, via the dorsal and intermediate acoustic striae, and from the SOC bilaterally. The IC receives additional input from the NLL bilaterally, and is thus innervated by every nuclear group within the auditory brain stem. There is little evidence for strict, functional segregation in these binaural pathways, although subdivisions of the SOC appear to be predominantly involved in analysing either interaural time or level differences (ITD, ILD). ITD- and ILD-sensitive neurones are also found in abundance in the central IC. There is emerging evidence that binaural information is coupled with spectral cues derived from the outer ear in several auditory mid-brain regions [the NLL, the external IC and the superior colliculus (SC)] to produce topographic representations of auditory space. Throughout the higher auditory system the response of neurones to stimulation of each ear is either excitatory or inhibitory, and there is a spatial segregation of neurones receiving predominantly excitatory or inhibitory input from the ipsilateral ear in both the medial geniculate body of the thalamus and the auditory cortex. Neonatal, unilateral hearing loss leads to a rearrangement of binaural connections in the auditory brain stem, to changes in the physiology of IC neurones in response to stimulation of the normal ear and to compensatory alterations in the auditory space map in the SC. The same hearing losses in adulthood do not produce these changes. The evidence from this and other work suggests that binaural mechanisms are more sensitive to hearing loss, over a longer developmental period, than mechanisms subserving monaural processing.