EFFECTS OF MODERATE NOISE EXPOSURE ON HEARING FUNCTION IN C57BL/6J MICE

Objective To study characteristics of hearing loss after exposure to moderate noise exposure in C57BL/6J mice. Methods Male C57BL/6J mice with normal hearing at age of 5-6 weeks were chosen for this study. The mice were randomly sclccted to be studied immediately after exposure （Group P0）, or 1 day （Group P1）, 3 days （Group P3）, 7 day （Group P7） or 14 days （P14） after exposure. Their before exposure condition served as the normal control. All mice were exposed to a broad-band white noise at 100 dB SPL for 2 hours, ABR thresholds were used to estimate hearing status at each time point. Results ABR threshold elevation was seen at every tested frequency at P0 （P〈0.01）. Elevation at high-frequencies （16 kHz and 32 kHz） was greater than at lower frequencies （4 kHz and 8 kHz, P〈0.05）. From P1 to P14, ABR thresholds continuously improved, and there was no significant difference between P14 and before exposure （P〉0.05）. Conclusion There is a frequency specific re- sponse to 100 dB SPL broad-band white noise in C57BL/6J mice, with the high-frequency being more susceptible. Hearing loss induced by moderate noise exposure appears reversible in C57BL/6J mice.     

Frequency difference limens of C57BL/6 and DBA/2 mice: relationship to auditory neuronal response properties and hearing impairment

Frequency difference limens (DLs) were measured in DBA/2 and C57BL/6 mice using an avoidance conditioning procedure and were viewed in relation to previously obtained neurophysiological data. DRA mice had significantly smaller DLs at 12 and 16 kHz, despite progressive sensorineural hearing loss and disrupted tonotopic organization characteristic of this strain. C57 mice had smaller DLs at 8 kHz. Several inferior colliculus (IC) neuronal response properties, that may be related to DL performance, differ between strains. Compared to C57s, a large proportion of DBA neurons respond to 12 and 16 kHz, many more best frequencies (BF, the frequency for which a neuron is most sensitive) fall between 10 and 20 kHz, response ranges are narrow, and neural intensity functions are steep. For C57 mice, a large proportion of neurons respond to 8 kHz, and more neurons have BFs between 5 and 10 kHz.     

Influence of genotype and age on acute acoustic trauma and recovery in CBA/Ca and C57BL/6J mice.

Two inbred strains of mice, CBA/Ca (with a moderate auditory impairment starting late in life) and C57BL/6J (with a progressive auditory degeneration starting during young adulthood), were exposed to a 120 dB SPL broadband noise (2-7 kHz) for 5 min at the age of 1, 3, or 6 months. Compound and permanent threshold shifts (CTS and PTS) were determined by auditory brainstem response during the first day (CTS) and 1 month (PTS) after exposure. With increasing age, susceptibility to CTS at middle frequencies (8 and 12.5 kHz) decreased in CBA mice, yet was retained in C57 mice. C57 mice were more severely affected by CTS than age-matched CBA mice. Noise-induced CTS was positively correlated to pre-exposure thresholds in C57 mice and to PTS over all ages and strains. The amount of recovery from CTS to PTS was, however, independent of age and strain. There was only a 2% risk of classifying CBA mice as C57 mice by pre-exposure thresholds at high frequency, while there was about 40% risk by CTS. The results indicate that genetic predisposition can affect susceptibility to auditory degeneration and noise impairment in a systematic manner, allowing the identification of susceptible individuals by pre-exposure audiometric examination, especially at high frequencies.     

Low-Frequency Tone Pips Elicit Exaggerated Startle Reflexes in C57BL/6J Mice with Hearing Loss

The strength of the acoustic startle reflex (ASR) as a function of age was studied in adult C57BL/6J and CBA/CaJ mice, because altered ASR levels are a potential behavioral consequence of the neural reorganization that accompanies the early-onset hearing loss of the C57BL, in contrast to the normal-hearing CBA. For C57BL mice at 14–36 weeks of age, compared with 7-week-old mice, high-frequency thresholds measured with the auditory brainstem response (ABR) were less sensitive by about 25–30 dB while the hearing loss at low frequencies was 10–15 dB, but by 60 weeks losses of 45–50 dB were present across the entire spectrum. Their ASR amplitudes for 16 kHz tone pips were highest at 7 weeks and then declined with age, but, for 4 kHz tones the ASR increased in strength at 18 weeks and beyond to levels above that of the younger mice. This hyperreactivity persisted even in 60-week-old mice. The ASR for 16 kHz stimuli was positively correlated with hearing sensitivity, but the ASR for 4 kHz stimuli was positively correlated with hearing loss for mice that were 18–36 weeks of age. Furthermore, ASR amplitudes for 4 kHz stimuli were positively correlated with the 16 kHz ASR in young C57BL mice but negatively correlated in older mice. There were no similar ASR or ABR changes in adult CBA mice through 19 weeks of age. Correlations between ASR and ABR scores were always weakly positive, and correlations between 4 kHz and 16 kHz ASR amplitudes were always strongly positive. The ASR data in older C57BL mice with hearing loss are consistent with reports describing their increased neural representation of low-frequency sounds and reinforce the value of this strain for studying the functional consequences that accompany age-related cochlear degeneration.     

不同剂量白喉毒素对野生型听力成熟小鼠耳蜗结构及听功能的影响

目的 观察不同剂量白喉毒素对野生型听力成熟小鼠的耳蜗结构及听功能的影响,为建立白喉毒素受体介导的细胞敲除系统动物模型提供参考.方法 4周龄C57BL/6J小鼠30只随机分为50 ng/g组、100 ng/g组和对照组,每组10只;其中50 ng/g组和100 ng/g组小鼠分别单次腹腔注射白喉毒素50 ng/g、100 ng/g,对照组小鼠单次腹腔注射等量生理盐水,注射后7天观察两组动物的一般情况,并记录小鼠ABR反应阈,观察小鼠内外毛细胞、螺旋神经节神经元.结果 在白喉毒素注射后第7天,各组动物情况良好,无明显体重下降,中耳腔无积液.50 ng/g组小鼠2、8、32 kHz ABR反应阈分别为57.5±2.74、20.83±2.04、45.83±2.04 dB SPL,与对照组比较(分别为56.25±2.31、20.0±3.78、49.38±6.78 dB SPL)差异无统计学意义;内、外毛细胞损失率分别为0.8%±0.5%、1%±0.6%;对照组分别为0.3%±0.5%、0.4%±0.3%;螺旋神经节神经元SGN密度为39.45±3.65个/105 μm2、对照组为41.03±3.73个/105 μm2,均未见明显细胞缺失.100 ng/g组小鼠2、8、32 kHz ABR反应阈分别为85±3.54、63±4.47、90±0 dB SPL,较前两组显著升高(t=19.62,P<0.001),内、外毛细胞损失率分别为0.5%±0.1%、10.7%±0.3%,损伤严重,底、中、顶回缺失达10%(t=42.219, P<0.001);SGN密度为25.55±3.66个/105 μm2,平均减少38%,与对照组相比差异有显著统计学意义(t=10.985,P<0.001).结论 100 ng/g白喉毒素注射能引起听力成熟野生型C57BL/6J小鼠外毛细胞及螺旋神经元的损伤.     

Comparison of the auditory sensitivity of neurons in the cochlear nucleus and inferior colliculus of young and aging C57BL/6J and CBA/J mice

Thresholds of neurons to sounds were compared as a function of central auditory structure [ventral cochlear nucleus (VCN), dorsal cochlear nucleus (DCN), and inferior colliculus (IC)] in young and middle-aged C57BL/6J mice (multiple- and single-unit recordings) and in young and old CBA/J mice (single-unit recordings). Middle-aged C57 mice show progressive loss of sensitivity to high frequencies and noise due to cochlear pathology; CBA mice show little loss of sensitivity through most of their lifespan. Multiple-unit threshold curves (MTCs) for tones indicated that neurons in the C57 VCN suffered a greater degree of age-related loss of sensitivity than neurons in the IC (from an earlier study). Furthermore, whereas the low frequency portions of MTCs in IC neurons in high frequency tonotopic regions typically become 'sensitized' in middle-aged C57 mice (i.e., lower thresholds than young mice), such was not the case for VCN neurons. In contrast to VCN neurons, MTCs of the population of DCN neurons studied were statistically indistinguishable from those of the IC. Measurements of single-unit response areas in C57 mice corroborated the MTCs. In CBA mice, little effect of age was found in comparing single-unit response areas of young and old mice. The findings indicate that sensorineural impairment in middle-aged C57 mice is accompanied by threshold changes that are more severe in the VCN than in the IC or DCN. Because the VCN and DCN are believed to play different roles in hearing, the functions they support should, likewise, be affected to different extents by age-related hearing loss.     

Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice

Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of age-related hearing loss (AHL) in mice. In linkage backcrosses, the recessive Cdh23 allele (ahl) of the C57BL/6J strain, when homozygous, confers increased susceptibility to AHL, while the dominant allele (Ahl+) of the CBA/CaJ strain confers resistance. To determine the isolated effects of these alleles on different strain backgrounds, we produced the reciprocal congenic strains B6.CBACa-Cdh23^Ahl+ and CBACa.B6-Cdh23^ahl and tested 15-30 mice from each for hearing loss progression. ABR thresholds for 8 kHz, 16 kHz, and 32 kHz pure-tone stimuli were measured at 3, 6, 9, 12, 15 and 18 months of age and compared with age-matched mice of the C57BL/6J and CBA/CaJ parental strains. Mice of the C57BL/6N strain, which is the source of embryonic stem cells for the large International Knockout Mouse Consortium, were also tested for comparisons with C57BL/6J mice. Mice of the C57BL/6J and C57BL/6N strains exhibited identical hearing loss profiles: their 32 kHz ABR thresholds were significantly higher than those of CBA/CaJ and congenic strain mice by 6 months of age, and their 16 kHz thresholds were significantly higher by 12 months. Thresholds of the CBA/CaJ, the B6.CBACa-Cdh23^Ahl+, and the CBACa.B6-Cdh23^ahl strain mice differed little from one another and only slightly increased throughout the 18-month test period. Hearing loss, which corresponded well with cochlear hair cell loss, was most profound in the C57BL/6J and C57BL/6NJ strains. These results indicate that the CBA/CaJ-derived Cdh23^Ahl+ allele dramatically lessens hearing loss and hair cell death in an otherwise C57BL/6J genetic background, but that the C57BL/6J-derived Cdh23^ahl allele has little effect on hearing loss in an otherwise CBA/CaJ background. We conclude that although Cdh23^ahl homozygosity is necessary, it is not by itself sufficient to account for the accelerated hearing loss of C57BL/6J mice.     

Endocochlear potentials and compound action potential recovery: functions in the C57BL/6J mouse

The C57BL/6J mouse suffers from cochlear degeneration beginning at an early age and has been used as a model of age-related hearing loss (presbyacusis). Here, the endocochlear potential (EP) and compound action potential (CAP) responses were determined in one-, four-, 12- and 24-month-old C57BL/6J mice. CAP measures included thresholds to tone pips, input/output (I/O) functions, and recovery functions to conditioning tones. EP values among the four age groups did not differ significantly (P>0.05) in either the basal or apical turns. CAP thresholds were increased significantly by 10 to 30 dB in the four-month group compared to the one-month controls at 11.3, 16, 20, and 22.6 kHz. CAP I/O functions were shallower in the four-month group compared to controls at all frequencies. In the 12- and 24-month-old mice, CAP responses were absent, despite normal EP values in these animals. Recovery functions after conditioning tones were obtained at 8, 16, 20 and 22.6 kHz; the functions had fast and slow components at all frequencies tested in both the one- and four-month-old groups. The corresponding recovery curves were identical for both age groups, even with significant threshold shifts in the older group. The two component recovery curves provide the first physiological evidence that different spontaneous rate (SR) classes of auditory neurons exist in the C57BL/6J mouse. Moreover, the unchanged recovery functions in the older group suggest that there was no loss of activity of the low-SR fiber population with age under conditions where the EP remains stable, in contrast to the gerbil model of presbyacusis where there is a loss of low-SR fiber activity and EP does decline with age.     

Distortion Product Otoacoustic Emissions and Auditory Evoked Potentials in the Hedgehog Tenrec, <Emphasis Type="Italic">Echinops telfairi</Emphasis>

The hedgehog tenrec, Echinops telfairi, has certain basal mammalian features, like a cloaca and a sparsely differentiated brain with smooth cerebral hemispheres. The peripheral auditory capabilities of this species were investigated by means of distortion product otoacoustic emissions (DPOAE). For comparison, we determined auditory evoked potentials (AEP) in the inferior colliculus and the auditory cortex. Both methods show that the auditory range of E. telfairi extends well into ultrasonic frequencies, with a region of highest sensitivity at around 16 kHz. The total auditory range spans about 4 octaves at 40 dB SPL. The low-frequency limit of auditory processing is found at frequencies of about 2–3 kHz. The DPOAE and the AEP thresholds of E. telfairi do not run fully parallel in the high-frequency range. For a threshold value of 40 dB SPL, cochlear mechanical thresholds as measured with DPOAE extend up to 50 kHz, whereas neuronal thresholds reach the high-frequency limit at about 30 kHz. Frequency tuning, as assessed from DPOAE suppression tuning curves, was low to moderate with Q _10dB values ranging from 1.7 to 8. The lack of discontinuity in the group delay (derived from DPOAE measurements) reveals that cochlear frequency representation is tonotopic without any region of specialized mechanical tuning. Markus Drexl, Michael Faulstich, and Boris von Stebut contributed equally to the data presented in this study.     

High frequency distortion products from the ears of two bat species, Megaderma lyra and Carollia perspicillata.

In two echolocating bat species, Megaderma lyra and Carollia perspicillata 2f₁−f₂ distortion products were measured acoustically in the outer ear canal for f₁ frequencies between 5 and 95 kHz in an attempt to study nonlinear cochlear processes at high frequencies. Similar to other mammals, the input/output (I/O) functions of 2f₁−f₂ show non-monotonicities and notches at f₁ levels between 40–70 dB SPL. The slope of the initial rise of the 2f₁−f₂ I/O functions increased with f_t frequency from 0.73 (5 kHz) to 1.41 (95 kHz) in Megaderma and from 0.66 (7.5 kHz) to 1.47 (95 kHz) in Carollia. With increasing f₁ frequency the optimum frequency ratio f₂/f₁ in order to evoke maximum distortion level decreases from 1.18 (5 kHz) to 1.09 (95 kHz) in Megaderma and from 1.21 (75 kHz) to 1.11 (95 kHz) in Carollia. This is taken as indication of a general increase of the quality of tuning of the distortion generating mechanism with frequency. The f₁ levels that were sufficient to elicit distortion levels of − 10 dB SPL were used to construct iso-distortion threshold curves which lay on average 37.2 dB (Megaderma) and 33.9 dB (Carollia) above the neuronal threshold curves [Rübsamen et al., J. Comp. Physiol. A 163 (1988); Sterbing et al., Proc. 18th Göttingen Neurobiol. Conf. Thieme Verlag, Stuttgart (1990)] and roughly parallel these. Highest distortion levels (40–50 dB SPL with f₁ levels of 80 dB SPL) and lowest distortion thresholds were measured in the f₁ frequency range of 10–30 kHz (Megaderma) and 15–30 kHz (Carollia). For both bat species these respective frequency ranges correlate with broad minima in the neuronal audiogram. Thus in these animals distortion measurement can be used as noninvasive means to assess relative hearing threshold. Systemic application of salicylate (100–400 mg/kg) which is known to block outer hair cell (OHC) motility (Shehata et al., 1991) reduced the level of distortion by up to 25 dB (f_t frequency: 20 kHz) and up to 36 dB (f₁ frequency: 70 kHz).     

Neural plasticity in the mouse inferior colliculus: relationship to hearing loss, augmented acoustic stimulation, and prepulse inhibition

C57BL/6J (C57) and DBA/2J (DBA) mice exhibit progressive high-frequency hearing loss. Extracellular recordings of responses of neurons in the inferior colliculus (IC) evoked by 70-dB SPL tones indicated that normal tonotopic organization was greatly disrupted in both strains: still-audible lower frequencies (4-12 kHz) evoked responses in a large percentage of recording sites in ventral tonotopic regions that normally respond strongly to high frequencies only. To relate the IC responses to an auditory behavior, prepulse inhibition (PPI) was measured using 70-dB tones as prepulses. As high-frequency hearing loss progressed in C57 mice, prepulses of 4-12 kHz elicited stronger PPI, and this was significantly correlated with changes in the percentage of IC recording sites responding to 70-dB tones (the neural pathway for PPI includes the IC). The analysis was extended to DBA mice that had been exposed to an augmented acoustic environment (AAE) - a procedure that improves PPI. In these mice, a higher percentage of IC recording sites responded to 70-dB tones, and this was correlated with improved PPI. The data suggest that responses of IC neurons reflect both hearing loss-induced plasticity and changes induced by exposure to an AAE, and these neural changes are correlated with the magnitude of PPI.     

The functional age of hearing loss in a mouse model of presbycusis. I. Behavioral assessments

Presbycusis is a common form of hearing loss that progresses from high to low frequencies with advancing age. C57BL/6J mice experience a rapid progression of presbycusis-like hearing deficits and thus provide a convenient animal model for evaluating behavioral, physiological and anatomical correlates of the disorder. Previous studies of C57BL/6J mice have relied on short-term observations of age-matched subject groups to reconstruct a time course for auditory pathologies. Such statistical approaches are weakened by the variability of hearing thresholds in young mice and the inconsistent timing of degenerative effects in older mice. The present study was designed to resolve these ambiguities by tracking the hearing abilities of individual C57BL/6J mice from age 16 weeks until the onset of hearing loss in specific listening conditions. Testing at frequencies of 8 and 16 kHz in quiet confirmed the high-to-low frequency progression that is characteristic of presbycusis. Often the hearing loss developed in two phases, one gradual and the other abrupt. Testing in noise revealed deficits that were first manifested as threshold instability and then an increased susceptibility to masking. These changes occurred before hearing loss in quiet. CBA/CaJ mice did not show significant loss during a similar period of observation. Our findings provide a well-ordered chronology for isolating the functional consequences of multiple cochlear pathologies that arise during the time course of presbycusis. This neurobehavioral assessment is termed the functional age of hearing loss. Neuroanatomical assessments of behaviorally characterized C57BL/6J mice are presented in the companion paper [Hear. Res. 183 (2003) 29-36].     

Cochlear developmental defect and background-dependent hearing thresholds in the Jackson circler (jc) mutant mouse

Jackson circler (jc) is a spontaneous, recessive mouse mutation that results in circling behavior and an impaired acoustic startle response. In this study, we refined the phenotypic and genetic parameters of the original jc mutation and characterized a new mutant allele, jc(2J). In open-field behavior tests, homozygous jc mutants exhibited abnormal circling and ambulatory behavior that was indistinguishable from that of phenotypically similar mutants with defects in the vestibule of the inner ear. The jc/jc and jc(2J)/jc(2J) mice had stable elevated auditory-evoked brainstem response (ABR) thresholds at the 16kHz stimulus of 88+/-9dB sound pressure levels (SPL) and 43+/-11dB SPL, respectively. Peak latencies and peak time intervals were normal in jc mutants. The jc mice showed no measurable distortion-product otoacoustic emissions (DPOAEs) above the system noise floor. In the mutant cochlea, the apical turn failed to form due to the developmental growth arrest of the cochlear duct at the level of the first turn at gestational day 13.5. In a large intrasubspecific intercross, jc localized to a 0.2cM interval at position 25cM on chromosome 10, which is homologous to the human 6q21 region. On CZECHII/Ei and CAST/Ei backgrounds jc/jc mutant hearing thresholds at the 16kHz stimulus were significantly lower than those observed on the C57BL/6J background, with means of 62+/-22dB SPL and 55+/-18dB SPL, respectively. Genome-wide linkage scans of backcross, intercross, and congenic progeny revealed a complex pattern of genetic and stochastic effects.     

Comparison between local field potentials and unit cluster activity in primary auditory cortex and anterior auditory field in the cat

Multi-unit (MU) activity and local field potentials (LFP) were simultaneously recorded from 161 sites in the middle cortical layers of the primary auditory cortex (AI) and the anterior auditory field (AAF) in 51 cats. Responses were obtained for frequencies between 625 Hz and 40 kHz, at intensities from 75 dB SPL to threshold. We compared the response properties of MU activity and LFP triggers, in terms of characteristic frequency (CF), threshold at CF, minimum latency and frequency tuning-curve bandwidth 20 dB above threshold. On average, thresholds at CF were significantly lower for LFP events than those for MU spikes (4.6 dB for AI, and 3 dB for AAF). Minimum latencies were significantly shorter for LFP events than for MU spikes (1.5 ms in AI, and 1.7 ms in AAF). Frequency tuning curves were significantly broader for LFP events than those for MU spikes (1.0 octave in AI, and 1.3 octaves in AAF). In contrast, the CF was not significantly different between LFP events and MU spikes. The LFP results indicate that cortical neurons receive convergent sub-cortical inputs from a broad frequency range. The sharper tuning curves for MU activity compared to those of LFP events are likely the result of intracortical inhibitory processes.     

Age-Related Hearing Loss in C57BL/6J Mice has both Frequency-Specific and Non-Frequency-Specific Components that Produce a Hyperacusis-Like Exaggeration of the Acoustic Startle Reflex

Auditory brainstem-evoked response (ABR) thresholds were obtained in a longitudinal study of C57BL/6J mice between 10 and 53 weeks old, with repeated testing every 2 weeks. On alternate weeks, acoustic startle reflex (ASR) amplitudes were measured, elicited by tone pips with stimulus frequencies of 3, 6, 12, and 24 kHz, and intensities from subthreshold up to 110 dB sound pressure level. The increase in ABR thresholds for 3 and 6 kHz test stimuli followed a linear time course with increasing age from 10 to 53 weeks, with a slope of about 0.7 dB/week, and for 48 kHz a second linear time course, but beginning at 10 weeks with a slope of about 2.3 dB/week. ABR thresholds for 12, 24, and 32 kHz increased after one linear segment with a 0.7 dB slope, then after a variable delay related to the test frequency, shifted to a second segment having slopes of 3–5 dB/week. Hearing loss initially reduced the ASR for all eliciting stimuli, but at about 6 months of age, the response elicited by intense 3 and 6 kHz stimuli began to increase to reach values about three times above normal, and previously subthreshold stimuli came to elicit vigorous responses seen at first only for the intense stimuli. This hyperacusis-like effect appeared in all mice but was especially pronounced in mice with more serious hearing loss. These ABR data, together with a review of histopathological data in the C57BL/6 literature, suggest that the non-frequency-specific slow time course of hearing loss results from pathology in the lateral wall of the cochlea, whereas the stimulus-specific hearing loss with a rapid time course results from hair cell loss. Delayed exaggeration of the ASR with hearing loss reveals a deficit in centrifugal inhibitory control over the afferent reflex pathways after central neural reorganization, suggesting that this mouse may provide a useful model of age-related tinnitus and associated hyperacusis.     

Inner ear morphology in CBA/Ca and C57BL/6J mice in relationship to noise,age and phenotype

Summary CBA/Ca mice showing moderate hearing losses with onset late in life and C57BL/6J mice with progressive hearing losses starting when animals were young adults were exposed to a 2–7 kHz, 120 dB SPL noise band for 5 min in order to investigate morphological consequences to noise as a function of age and genotype. Permanent threshold shifts were determined by auditory brainstem responses 1 month after noise exposure at 1, 3 and 6 months of age. CBA mice had a decreasing susceptibility to noise with increasing age, while C57 mice remained equally susceptible throughout all ages tested. The threshold shifts were then analyzed in relation to morphological changes of the organ of Corti as visualized by light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). CBA mice exposed at 1 month and sacrificed at 2 months had seemingly normal cochlear morphologies under LM. In these animals SEM findings demonstrated mild stereocilia damage to noise trauma, but not when mice were exposed at 3 and 6 months. There was no visible morphological aging of hair cells found during the period tested. In contrast; the C57 mice had early hair cell changes including bent and fused stereocilia, bulging of the cuticular plates, hair cell loss and swelling of afferent dendrites. These changes became more pronounced throughout the test periods with the variability of damage in this strain more evident over time. This pattern was also aggravated in all C57 age groups tested after noise exposure. Quantification with cytocochleograms demonstrated a statistically different reaction pattern to noise trauma between the two different genotypes of mice.     

Aberrant frequency tuning and early stereociliary derangement in genetic inner ear disease

We have developed an auditory brainstem response (ABR) based method for frequency selective forward masking tuning curve technique. Normative data from CBA/CBA mice are compared with tuning curves (TCs) from heterozygote dancer mice which in most cases initially had a normal ABR threshold. The sharpest tuning in normal mice was obtained at 10 kHz (Q10 = 7.6) and 12 kHz (Q10 = 10.9). With increasing age the mutants showed a broadening of the TC tip before ABR threshold impairment occurred. Morphological analysis of the cochleae from dancer mutants revealed an early disarray of hair cell stereocilia which became increasingly more severely affected with advancing age. We conclude that the broadening of the TC tip is an early finding in the genetically induced cochlear susceptibility which can be correlated to stereociliary dysfunction.     

Aminoglycoside ototoxicity in adult CBA, C57BL and BALB mice and the Sprague-Dawley rat

The availability of genetic information, transgenic and knock-out animals make the mouse a primary model in biomedical research. Aminoglycoside ototoxicity, however, has rarely been studied in mature mice because they are considered highly resistant to the drugs. This study presents models for kanamycin ototoxicity in adult CBA/J, C57BL/6 and BALB/c mouse strains and a comparison to Sprague-Dawley rats. Five-week-old mice were injected subcutaneously twice daily with 400-900 mg kanamycin base/kg body weight for 15 days. Kanamycin induced dose-dependent auditory threshold shifts of up to 70 dB at 24 kHz as measured by auditory brain stem-evoked responses. Vestibular function was also affected in all strains. The functional deficits were accompanied by hair cell loss in both cochlear and vestibular neurosensory epithelia. Concomitant administration of the antioxidant 2,3-dihydroxybenzoate significantly attenuated the kanamycin-induced threshold shifts. In adult male Sprague-Dawley rats, doses of 1 x 500 mg or 2 x 300 mg kanamycin base/kg body weight/day x 14 days induced threshold shifts of approximately 50 dB at 20 kHz. These were accompanied by loss of outer hair cells. The order of susceptibility, BALB>CBA>C57, was not due to differences in the pharmacokinetics of kanamycin. It also did not correlate with the presence of Ahl/Ahl2 genes which predispose C57 and BALB strains, respectively, to accelerated age-related hearing loss. Pigmentation, however, paralleled this rank order suggesting an influence of melanin on cochlear antioxidant status.     

Age-related changes in sensitivity of the postpubertal ear to acoustic trauma

Although the age of the postpubertal mammal is typically ignored in evaluating the damaging effects of noise on the ear, it was shown to account for over 65% of the variability in the mouse. 44 inbred CBA/J mice, ranging in age from 60 (early postpuberty) to 360 days (late middle age), were tested for cochlear AP thresholds at frequencies from 2 to 64 kHz. They were then subjected to 5 min of a 124 dB octave band (12–24 kHz) noise. Although all the mice had similar pre-exposure thresholds, the extent of noise-induced AP threshold elevation and the frequencies most severely affected depended upon the ages of the mice. The youngest subjects had the greatest threshold elevations, being most pronounced at, and 1 octave above, the center frequency of the noise exposure. With increasing age there was a progressively less severe effect. The oldest subjects had cochlear AP threshold elevations which were restricted to a frequency 2 octaves above the exposure frequency.