ABR/DPOAE publications

Neural representation of pitch is influenced by lifelong experiences with music and language at both cortical and subcortical levels of processing. The aim of this article is to determine whether neural plasticity for pitch representation at the level of the brainstem is dependent upon specific dimensions of pitch contours that commonly occur as part of a native listener's language experience. Brainstem frequency following responses (FFRs) were recorded from Chinese and English participants in response to four Mandarin tonal contours presented in a nonspeech context in the form of iterated rippled noise. Pitch strength (whole contour, 250 msec; 40-msec segments) and pitch-tracking accuracy (whole contour) were extracted from the FFRs using autocorrelation algorithms. Narrow band spectrograms were used to extract spectral information. Results showed that the Chinese group exhibits smoother pitch tracking than the English group in three out of the four tones. Moreover, cross-language comparisons of pitch strength of 40-msec segments revealed that the Chinese group exhibits more robust pitch representation of those segments containing rapidly changing pitch movements across all four tones. FFR spectral data were complementary showing that the Chinese group exhibits stronger representation of multiple pitch-relevant harmonics relative to the English group across all four tones. These findings support the view that at early preattentive stages of subcortical processing, neural mechanisms underlying pitch representation are shaped by particular dimensions of the auditory stream rather than speech per se. Adopting a temporal correlation analysis scheme for pitch encoding, we propose that long-term experience sharpens the tuning characteristics of neurons along the pitch axis with enhanced sensitivity to linguistically relevant variations in pitch.

Usher syndrome 3A (USH3A) is an autosomal recessive disorder characterized by progressive loss of hearing and vision due to mutation in the clarin-1 (CLRN1) gene. Lack of an animal model has hindered our ability to understand the function of CLRN1 and the pathophysiology associated with USH3A. Here we report for the first time a mouse model for ear disease in USH3A. Detailed evaluation of inner ear phenotype in the Clrn1 knockout mouse (Clrn1(-/-)) coupled with expression pattern of Clrn1 in the inner ear are presented here. Clrn1 was expressed as early as embryonic day 16.5 in the auditory and vestibular hair cells and associated ganglionic neurons, with its expression being higher in outer hair cells (OHCs) than inner hair cells. Clrn1(-/-) mice showed early onset hearing loss that rapidly progressed to severe levels. Two to three weeks after birth (P14-P21), Clrn1(-/-) mice showed elevated auditory-evoked brainstem response (ABR) thresholds and prolonged peak and interpeak latencies. By P21, approximately 70% of Clrn1(-/-) mice had no detectable ABR and by P30 these mice were deaf. Distortion product otoacoustic emissions were not recordable from Clrn1(-/-) mice. Vestibular function in Clrn1(-/-) mice mirrored the cochlear phenotype, although it deteriorated more gradually than cochlear function. Disorganization of OHC stereocilia was seen as early as P2 and by P21 OHC loss was observed. In sum, hair cell dysfunction and prolonged peak latencies in vestibular and cochlear evoked potentials in Clrn1(-/-) mice strongly indicate that Clrn1 is necessary for hair cell function and associated neural activation.

Exogenous delivery of neurotrophic factors into the cochlea of deafened animals rescues spiral ganglion cells (SGCs) from degeneration. To be clinically relevant for human cochlear implant candidates, the protective effect of neurotrophins should persist after cessation of treatment and the treated SGCs should remain functional. In this study, the survival and functionality of SGCs were investigated after temporary treatment with brain-derived neurotrophic factor (BDNF). Guinea pigs in the experimental group were deafened, and 2 weeks later, the right cochleae were implanted with an electrode array and drug delivery cannula. BDNF was administered to the implanted cochleae during a 4-week period via a mini-osmotic pump. After completion of the treatment, the osmotic pumps were removed. Two weeks later, the animals were killed and the survival of SGCs was analyzed. To monitor the functionality of the auditory nerve, electrically evoked auditory brainstem responses (eABRs) were recorded in awake animals throughout the experiment. BDNF treatment resulted in enhanced survival of SGCs 2 weeks after cessation of the treatment and prevented the decreases in size and circularity that are seen in the untreated contralateral cochleae. The amplitude of the suprathreshold eABR response in BDNF-treated animals was significantly larger than in deafened control animals and comparable to that in normal-hearing control animals. The amplitude in the BDNF-treated group did not decrease significantly after cessation of treatment. The eABR latency in BDNF-treated animals was longer than normal and comparable to that in deafened control animals. These morphological and functional findings demonstrate that neurotrophic intervention had a lasting effect, which is promising for future clinical application of neurotrophic factors in implanted human cochleae.

Background Developmental exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg) can result in a variety of neurotoxic effects, including long-term auditory deficits. However, little is known about the effects of combined exposure to PCBs and MeHg on auditory function. Objective We developmentally exposed rats to PCBs and/or MeHg and assessed auditory function in adulthood to determine the effects of exposure to these contaminants individually and in combination. Methods We exposed female Long-Evans rats to 1 or 3 mg/kg PCB in corn oil, 1.5 or 4.5 ppm MeHg in drinking water, or combined exposure to 1 mg/kg PCB + 1.5 ppm MeHg or 3 mg/kg PCB + 4.5 ppm MeHg. Controls received corn oil vehicle and unadulterated water. Dosing began 28 days before breeding and continued until weaning at postnatal day (PND) 21. Auditory function of the offspring was assessed at approximately PND 200 by measuring distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs). Results Groups exposed to PCBs alone had attenuated DPOAE amplitudes, elevated DPOAE thresholds, and elevated ABR thresholds compared with controls. Groups exposed to MeHg alone did not differ from controls. Unexpectedly, the effects of PCB exposure appeared to be attenuated by coexposure to MeHg. Conclusion Developmental exposure to PCBs can result in permanent hearing deficits, and the changes in DPOAE amplitudes and thresholds suggest a cochlear site of action. Coexposure to MeHg appeared to attenuate the PCB-related deficits, but the mechanism for this unexpected interaction remains to be determined.

Integration of multimodal information is essential for understanding complex environments. In the auditory system, multisensory integration first occurs in the cochlear nucleus (CN), where auditory nerve and somatosensory pathways converge (Shore, 2005). A unique feature of multisensory neurons is their propensity to receive cross-modal compensation after deafening. Based on our findings that the vesicular glutamate transporters, VGLUT1 and VGLUT2, are differentially associated with auditory nerve and somatosensory inputs to the CN, respectively (Zhou et al., 2007), we examined their relative distributions after unilateral deafening. After unilateral intracochlear injections of kanamycin (1 and 2 weeks), VGLUT1 immunoreactivity (ir) in the magnocellular CN ipsilateral to the cochlear damage was significantly decreased, whereas VGLUT2-ir in regions that receive nonauditory input was significantly increased 2 weeks after deafening. The pathway-specific amplification of VGLUT2 expression in the CN suggests that, in compensatory response to deafening, the nonauditory influence on CN is significantly enhanced. One undesirable consequence of enhanced glutamatergic inputs could be the increased spontaneous rates in CN neurons that occur after hearing loss and that have been proposed as correlates of the phantom auditory sensations commonly called tinnitus.

Recently, we characterized the more severe nature of hearing loss in aged Type 2 diabetic human subjects [Frisina, S.T., Mapes, F., Kim, S., Frisina, D.R., Frisina, R.D., 2006. Characterization of hearing loss in aged type II diabetics. Hear. Res. 211, 103-113]. The current study prospectively assessed hearing abilities in middle age CBA/CaJ mice with Type 1 diabetes mellitus (T1DM) (STZ injection) or Type 2 diabetes mellitus (T2DM) (high fat diet), for a period of 6 months. Blood glucose, body weight and auditory tests (Auditory Brainstem Response-ABR, Distortion Product Otoacoustic Emissions-DPOAE) were evaluated at baseline and every 2 months. Tone and broad-band noise-burst responses in the inferior colliculus were obtained at 6 months. Body weights of controls did not change over 6 months (approximately 32 g), but there was a significant (approximately 5 g) decline in the T1DM, while T2DM exhibited approximately 10 g weight gain. Blood glucose levels significantly increased: 3-fold for T1DM, 1.3-fold for T2DM; with no significant changes in controls. ABR threshold elevations were found for both types of diabetes, but were most pronounced in the T2DM, starting as early as 2 months after induction of diabetes. A decline of mean DPOAE amplitudes was observed in both diabetic groups at high frequencies, and for the T2DM at low frequencies. In contrast to ABR thresholds, tone and noise thresholds in the inferior colliculus were lower for both diabetic groups. Induction of diabetes in middle-aged CBA/CaJ mice promotes amplification of age-related peripheral hearing loss which makes it a suitable model for studying the interaction of age-related hearing loss and diabetes. On the other hand, initial results of effects from very high blood glucose level (T1DM) on the auditory midbrain showed disruption of central inhibition, increased response synchrony or enhanced excitation in the inferior colliculus.

Previous studies have indicated the importance of the spiral ligament (SL) in the pathogenesis of sensorineural hearing loss. The aim of this study was to establish a mouse model for SL degeneration as the basis for the development of new strategies for SL regeneration. We injected 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, at various concentrations into the posterior semicircular canal of adult C57BL/6 mice. Saline-injected animals were used as controls. Auditory function was monitored by measurements of auditory brain stem responses (ABRs). On postoperative day 14, cochlear specimens were obtained after the measurement of the endocochlear potential (EP). Animals that were injected with 5 or 10 mM 3-NP showed a massive elevation of ABR thresholds along with extensive degeneration of the cochleae. Cochleae injected with 1 mM 3-NP exhibited selective degeneration of the SL fibrocytes but alterations in EP levels and ABR thresholds were not of sufficient magnitude to allow for testing functional recovery after therapeutic interventions. Animals injected with 3 mM 3-NP showed a reduction of around 50% in the EP along with a significant loss of SL fibrocytes, although degeneration of spiral ganglion neurons and hair cells was still present in certain regions. These findings indicate that cochleae injected with 3 mM 3-NP may be useful in investigations designed to test the feasibility of new therapeutic manipulations for functional SL regeneration.

Presbycusis -- age-related hearing loss, is the number one communication disorder, and one of the top three chronic medical conditions of our aged population. Aquaporins, particularly aquaporin 4 (Aqp4), are membrane proteins with important roles in water and ion flux across cell membranes, including cells of the inner ear and pathways of the brain used for hearing. To more fully understand the biological bases of presbycusis, 39 CBA mice, a well-studied animal model of presbycusis, underwent non-invasive hearing testing as a function of sound frequency (auditory brainstem response -- ABR thresholds, and distortion-product otoacoustic emission -- DPOAE magnitudes), and were clustered into four groups based on age and hearing ability. Aqp4 gene expression, as determined by genechip microarray analysis and quantitative real-time PCR, was compared to the young adult control group in the three older groups: middle aged with good hearing, old age with mild presbycusis, and old age with severe presbycusis. Linear regression and ANOVA showed statistically significant changes in Aqp4 gene expression and ABR and DPOAE hearing status in the cochlea and auditory midbrain -- inferior colliculus. Down-regulation in the cochlea was seen, and an initial down-, then up-regulation was discovered for the inferior colliculus Aqp4 expression. It is theorized that these changes in Aqp4 gene expression represent an age-related disruption of ion flux in the fluids of the cochlea that are responsible for ionic gradients underlying sound transduction in cochlear hair cells necessary for hearing. In regard to central auditory processing at the level of the auditory midbrain, aquaporin gene expression changes may affect neurotransmitter cycling involving supporting cells, thus impairing complex sound neural processing with age.

The transduction of sound in the auditory periphery, the cochlea, is inhibited by efferent cholinergic neurons projecting from the brainstem and synapsing directly on mechanosensory hair cells. One fundamental question in auditory neuroscience is what role(s) this feedback plays in our ability to hear. In the present study, we have engineered a genetically modified mouse model in which the magnitude and duration of efferent cholinergic effects are increased, and we assess the consequences of this manipulation on cochlear function. We generated the Chrna9L9'T line of knockin mice with a threonine for leucine change (L9'T) at position 9' of the second transmembrane domain of the alpha9 nicotinic cholinergic subunit, rendering alpha9-containing receptors that were hypersensitive to acetylcholine and had slower desensitization kinetics. The Chrna9L9'T allele produced a 3-fold prolongation of efferent synaptic currents in vitro. In vivo, Chrna9L9'T mice had baseline elevation of cochlear thresholds and efferent-mediated inhibition of cochlear responses was dramatically enhanced and lengthened: both effects were reversed by strychnine blockade of the alpha9alpha10 hair cell nicotinic receptor. Importantly, relative to their wild-type littermates, Chrna9(L9'T/L9'T) mice showed less permanent hearing loss following exposure to intense noise. Thus, a point mutation designed to alter alpha9alpha10 receptor gating has provided an animal model in which not only is efferent inhibition more powerful, but also one in which sound-induced hearing loss can be restrained, indicating the ability of efferent feedback to ameliorate sound trauma.

OBJECTIVE: In chinchillas, moderate doses of carboplatin administered systemically selectively destroy inner hair cells and type I vestibular hair cells; however, it is unclear whether this unique damage pattern persists if carboplatin is applied directly to the cochlea, how quickly the damage develops and what cell death pathways are involved. STUDY DESIGN: To address these questions, carboplatin (5 mg/ml, 50 µl) was applied to the round window. RESULTS: Carboplatin caused a rapid decline in distortion product otoacoustic emissions, significantly increased compound action potential thresholds and caused massive inner hair cell loss and less severe outer hair cell loss. Hair cell loss was initially more severe in the base than the apex of the cochlea, but by 28 days post-treatment most cochlear hair cells were missing and hair cell density in the utricle, saccule and lateral crista was greatly reduced. At one day post-treatment, many hair cell nuclei were condensed or fragmented indicative of apoptosis, and expressed initiator caspase-8 and executioner caspase-3, but not initiator caspase-9. Carboplatin-treated animals circled towards the treated ear and during the swim test rolled towards the treated ear. CONCLUSION: These results indicate that local application of carboplatin causes loss of hair cells that begins near the base of the cochlea and spreads towards the apex with increasing survival time. Hair cell loss is initiated by caspase-8 followed by executioner caspase-3.

Induction of peripheral tolerance by oral administration of low-dose β-tubulin antigen may be an effective, antigen-specific method to suppress experimental autoimmune hearing loss. Five groups of mice were fed with phosphate-buffered saline (PBS), ovalbumin (OVA), 20, 30 or 200 μg of β-tubulin, respectively. All mice were then immunized by β-tubulin. Hearing thresholds were measured before and after immunization. Inner ear histology and cytokine profile were examined. Mice fed with 20 or 30 μg of β-tubulin showed less hearing loss and less inner ear damage compared to the groups treated with PBS, OVA or 200 μg of β-tubulin. Interferon-gamma (IFN-γ) was decreased while interleukin-4 (IL-4), IL-5, IL-13 and TGF-β were increased in both sera and in cell culture supernatants of the mice fed with 20 or 30 μg of β-tubulin. However, no cytokine profile change was found in the group treated with 200 μg of tubulin. These results suggest that a low dose of β-tubulin is active orally in an antigen-specific fashion and capable of inhibiting the autoimmune reactions in the inner ear by suppressingTh1 (IFN-γ) and increasing Th2 and Th3 (IL-4, IL-5, IL-13 and TGF-β) cytokines. Oral antigen tolerance may be used to treat autoimmune inner ear disease.

Increasing evidence suggests the involvement of oxidative stress in noise-induced hearing loss. The present study analysed, in an animal experimental model, the time course of the pathogenic mechanisms of noise-induced cochlear damage and the efficacy of the antioxidant drug N-acetylcysteine in reducing noise ototoxicity. Animals were divided into two groups, exposed to noise one treated with N-acetylcysteine for 3 days and one (the control group) with saline. Acoustic trauma was induced by a continuous pure tone of 6 kHz, at 120 dB SPL for 30 minutes. Electrocochleographic recordings were made from an implanted round window electrode and the compound action potentials were measured daily at 2-16 kHz for 7 days. Morphological changes were analysed by scanning electron microscopy. The acoustic threshold measured 1 hour after acoustic trauma was elevated in the control group to 70-90 dB in the higher frequencies of the compound action potential audiogram, with a maximum threshold elevation ranging between 12 and 16 kHz. During the first 24 h, following acoustic trauma, there was a partial recovery of compound action potential thresholds of about 20 dB to reach a final threshold elevation of about 50-70 dB; there was no further improvement over the remaining experimental week. Animals treated with N-acetylcysteine showed a similar temporary threshold shift but a clear improvement in the recovery of compound action potential thresholds, with significantly reduced permanent threshold shift and hair cell loss. These data suggest that N-acetylcysteine is able to attenuate the toxic effect of acoustic trauma and could represent an interesting molecule for preventing inner ear injuries.

Background: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained. Methods: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided. Results: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics. Conclusion: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

Immediate effects of sequential and progressively enlarged spiral ganglion (SG) lesions were recorded from cochleas and inferior colliculi. Small SG-lesions produced modest elevations in cochlear tone-evoked compound action potential (CAP) thresholds across narrow frequency ranges; progressively enlarged lesions produced progressively higher CAP-threshold elevations across progressively wider frequency ranges. No comparable changes in distortion product otoacoustic emissions (DPOAEs) amplitudes were observed consistent with silencing of auditory nerve sectors without affecting organ of Corti function. Frequency response areas (FRAs) of inferior colliculus (IC) neurons were recorded before and immediately after SG-lesions using multi-site silicon arrays fixed in place with recording sites arrayed along IC frequency gradient. Individual post-lesion FRAs exhibited progressively elevated response thresholds and diminished response amplitudes at lesion frequencies, whereas responses at non-lesion frequencies were either unchanged or enhanced. Characteristic frequencies were shifted and silent areas were introduced within these FRAs. Sequentially larger lesions produced sequentially larger shifts in CF and/or enlarged silent areas within affected FRAs, producing immediate changes in IC frequency organization. These results contrast with those from the auditory nerve, extend previous reports of experience-induced plasticity in the auditory CNS, and support results indicating afferent convergence onto ICC neurons across broad frequency bands.

The Kv1.1 potassium channel subunit, encoded by the Kcna1 gene, is heavily expressed in the auditory brainstem and is thought to have a critical role in producing the high temporal precision of action potentials characteristic of the auditory system. Our intent was to determine whether temporal acuity was reduced in Kcna1 null-mutant (-/-) mice, compared to wild-type (+/+) and heterozygotic mice (+/-), as measured by the encoding of gaps in the inferior colliculus by near-field auditory evoked potentials (NFAEP) or behavioral gap detection (BGD) using a prepulse inhibition paradigm. NFAEPs were collected at 40, 60 and 80 dB SPL with gap durations from 0.5 to 64 ms. BGD data were collected using silent gaps in 70 dB noise from 1 to 15 ms in duration. There were no systematic effects of Kcna1 genotype on NFAEP recovery functions, NFAEP latencies, or the time constant for BGD, but there was a small reduction in asymptotic prepulse inhibition for the longest gap stimuli in -/- mice. Gap thresholds were approximately 1-2 ms across genotypes, stimulus conditions, and paradigms. These data suggest that the neural pathways encoding behaviorally relevant, rapid auditory temporal fluctuations are not limited by the absence of Kv1.1 expression.

Auditory neurons in the superior colliculus (SC) respond preferentially to sounds from restricted directions to form a map of auditory space. The development of this representation is shaped by sensory experience, but little is known about the relative contribution of peripheral and central factors to the emergence of adult responses. By recording from the SC of anesthetized ferrets at different age points, we show that the map matures gradually after birth; the spatial receptive fields (SRFs) become more sharply tuned and topographic order emerges by the end of the second postnatal month. Principal components analysis of the head-related transfer function revealed that the time course of map development is mirrored by the maturation of the spatial cues generated by the growing head and external ears. However, using virtual acoustic space stimuli, we show that these acoustical changes are not by themselves responsible for the emergence of SC map topography. Presenting stimuli to infant ferrets through virtual adult ears did not improve the order in the representation of sound azimuth in the SC. But by using linear discriminant analysis to compare different response properties across age, we found that the SRFs of infant neurons nevertheless became more adult-like when stimuli were delivered through virtual adult ears. Hence, although the emergence of auditory topography is likely to depend on refinements in neural circuitry, maturation of the structure of the SRFs (particularly their spatial extent) can be largely accounted for by changes in the acoustics associated with growth of the head and ears.

Rodents have proven to be a useful model system to screen genes, ototoxic compounds and sound exposure protocols that may play a role in hearing loss. High-throughput screening depends upon a rapid and reliable functional assay for hearing loss. This study describes the use of a frequency modulated (FM) chirp stimulus as an alternative to the click to derive a rapid assessment of auditory brainstem response (ABR) threshold in the rodent. We designed a rising frequency A-chirp based upon the spatial mapping of preferred frequency along the rat basilar membrane to provide a more synchronous and equipotent input across the length of the cochlea. We observed that the ABR wave I and wave IV amplitudes evoked by the A-chirp were significantly greater than the click and that A-chirp minimum response thresholds were lower than the click. Subsequent analyses compared the efficacy of the A-chirp to linear, time-reversed and amplitude-reversed chirps and confirmed that the A-chirp was most effective chirp configuration. These data suggest that the A-chirp may be optimally suited as a single screening broad-frequency stimulus for rapid ABR threshold estimations in the rodent and could serve to complement more detailed frequency-specific physiologic and behavioral estimates of hearing threshold.

Accurate temporal processing of sound is essential for detecting word structures in speech. Maternal smoking affects speech processing in newborns and may influence child language development; however, it is unclear how neonatal exposure to nicotine, present in cigarettes, affects the normal development of temporal processing. The present study used the gap-induced prepulse inhibition (gap-PPI) of the acoustic startle response to investigate the effects of neonatal nicotine exposure on the normal development of gap detection, a behavioral testing procedure of auditory temporal resolution. Neonatal rats were injected twice per day with saline (control), 1mg/kg nicotine (N-1 mg) or 5 mg/kg nicotine (N-5 mg) from postnatal day 8-12 (P8-P12). During the first month after birth, rats showed poor gap-PPI in all three groups. At P45 and P60, gap-PPI in control rats improved significantly, whereas rats exposed to nicotine exhibited less improvement. At P60, the gap-detection threshold in the N-5 mg group was significantly higher than in the control group, suggesting that neonatal nicotine exposure affects the normal development of gap-detection acuity. Additionally, 1h after receiving an acute nicotine injection (1 mg/kg), gap-PPI recorded in adult rats from the N-5 mg group showed a temporary significant improvement. These results suggest that neonatal nicotine exposure reduces gap-PPI implying an impairment of the normal development of auditory temporal processing by inducing changes in cholinergic systems.

The survival of the auditory nerve in cases of sensorineural hearing loss is believed to be a major factor in effective cochlear implant function. The current study assesses two measures of cochlear implant thresholds following a post-deafening treatment intended to halt auditory nerve degeneration. We used an adenoviral construct containing a gene insert for brain-derived neurotrophic factor (BDNF), a construct that has previously been shown to promote neuronal survival in a number of biological systems. We implanted ototoxically deafened guinea pigs with a multichannel cochlear implant and delivered a single inoculation of an adenovirus suspension coding for BDNF (Ad.BDNF) into the scala tympani at the time of implantation. Thresholds to electrical stimulation were assessed both psychophysically and electrophysiologically over a period of 80 days. Spiral ganglion cell survival was analyzed at the 80 days time point. Compared to the control group, the Ad.BDNF treated group had lower psychophysical and electrophysiological thresholds as well as higher survival of spiral ganglion cells. Electrophysiological, but not psychophysical, thresholds correlated well with the density of spiral ganglion cells. These results indicate that the changes in the anatomy of the auditory nerve induced by the combination of Ad.BDNF inoculation and the electrical stimulation used for testing improved functional measures of CI performance.

Mutations in COCH (coagulation factor C homology) are etiologic for the late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. We introduced the G88E mutation by gene targeting into the mouse and have created a Coch(G88E/G88E) mouse model for the study of DFNA9 pathogenesis and cochlin function. Vestibular-evoked potential (VsEP) thresholds of Coch(G88E/G88E) mice were elevated at all ages tested compared with wild-type littermates. At the oldest ages, two out of eight Coch(G88E/G88E) mice had no measurable VsEP. Auditory brainstem response (ABR) thresholds of Coch(G88E/G88E) mice were substantially elevated at 21 months but not at younger ages tested. At 21 months, four of eight Coch(G88E/G88E) mice had absent ABRs at all frequencies tested and two of three Coch(G88E)(/+) mice had absent ABRs at three of four frequencies tested. Distortion product otoacoustic emission amplitudes of Coch(G88E/G88E) mice were substantially lower than Coch(+/+) mice and absent in the same Coch(G88E/G88E) mice with absent ABRs. These results suggest that vestibular function is affected beginning as early as 11 months when cochlear function appears to be normal, and dysfunction increases with age. Hearing loss declines substantially at 21 months of age and progresses to profound hearing loss at some to all frequencies tested. This is the only mouse model developed to date where hearing loss begins at such an advanced age, providing an opportunity to study both progressive age-related hearing loss and possible interventional therapies.