The time course of apoptosis and the corresponding neuronal loss was previously shown in central auditory pathway of mice after a single noise exposure. However, repeated acoustic exposure is a major risk factor for noise-induced hearing loss. The present study investigated apoptosis by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay after a second noise trauma in the ventral and dorsal cochlear nucleus and central nucleus of the inferior colliculus. Mice [Naval Medical Research Institute (NMRI) strain] were noise exposed [115 dB sound pressure level, 5–20 kHz, 3 h) at day 0. A double group received the identical noise exposure a second time at day 7 post-exposure and apoptosis was either analyzed immediately (7-day group-double) or 1 week later (14-day group-double). Corresponding single exposure groups were chosen as controls. No differences in TUNEL were seen between 7-day or 14-day single and double-trauma groups. Interestingly, independent of the second noise exposure, apoptosis increased significantly in the 14-day groups compared to the 7-day groups in all investigated areas. It seems that the first noise trauma has a long-lasting effect on apoptotic mechanisms in the central auditory pathway that were not largely influenced by a second trauma. Homeostatic mechanisms induced by the first trauma might protect the central auditory pathway from further damage during a specific time slot. These results might help to understand the underlying mechanisms of different psychoacoustic phenomena in noise-induced hearing loss.
Keywords: Noise-induced apoptosis, noise-induced hearing loss, repeated noise exposure, TUNEL-staining
|How to cite this article:|
Frohlich F, Gröschel M, Strübing I, Ernst A, Basta D. Apoptosis in the cochlear nucleus and inferior colliculus upon repeated noise exposure. Noise Health 2018;20:223-31
|How to cite this URL:|
Frohlich F, Gröschel M, Strübing I, Ernst A, Basta D. Apoptosis in the cochlear nucleus and inferior colliculus upon repeated noise exposure. Noise Health [serial online] 2018 [cited 2021 Oct 26];20:223-31. Available from: https://www.noiseandhealth.org/text.asp?2018/20/97/223/272479
| Introduction|| |
Noise is well known as an important environmental factor for hearing disorders. Repeated noise exposure is a major risk factor for noise-induced hearing loss (NIHL), the most common consequence of noise overexposure.
Previous studies have shown the influence of acoustic overexposure on the middle (e.g., deluxation of ossicles) and inner ear (e.g., hair cell loss).,,,, This has been investigated for decades and is still the subject of research. Change in the central auditory pathway because of acoustic overstimulation is another important topic that has been addressed during the last few years. Deafferentation because of acoustic overexposure as well as after cochlea ablation was shown in the cochlear nucleus (CN).,, NIHL leads to axon degeneration in the CN and superior olivary complex., Besides the effect of deafferentation, acoustic overstimulation has a direct impact on central mechanisms and leads to an intense metabolic activity that can result in the formation of free radicals and reactive oxygen species or lipid peroxidation.,,, Reactive oxygen species and mitochondrial dysfunction are major causes of cell pathologies that accelerate cell death mechanisms such as apoptosis. As a consequence, apoptosis is supposed to be directly stimulated by noise and hypothesized as one underlying pathophysiological mechanism for noise-induced neuronal loss in the central auditory pathway.,,,, Noise-induced apoptosis was recently described in the auditory pathway.,, In humans, for example, factory workers, nightclub visitors, and musicians, repeated acoustic exposure to traumatizing noise is the most common situation. Little is known about central changes after multiple noise exposure. Besides NIHL, a phenomenon called “toughening” and an upregulation of activity-dependent calcium-binding protein in the spiral ganglion and CN were found after repeated noise exposure. Also, an increase in Ca2+-dependent activity in key structures of the central auditory pathway after a second noise trauma was described. The effects on hearing thresholds depend on the noise exposure paradigm and threshold shift amplitudes differ between single and repeated noise trauma in most of the studies.,,
Our working group recently described the time course of apoptosis in the ventral CN (VCN), dorsal CN (DCN), central nucleus of the inferior colliculus (ICC), medial geniculate body, and primary auditory cortex (AI) after a single noise exposure., Apoptosis after repeated noise trauma was already seen in the medial geniculate body and auditory cortex., The present study aimed at investigating the incidence of cell death after a second noise exposure in the VCN, DCN, and ICC. This might help to understand hearing pathologies in NIHL such as tinnitus or changed speech intelligibility.,,
| Material and Methods|| |
Eighteen young adult (30–40 days of age) female normal hearing mice [Naval Medical Research Institute (NMRI) strain] with fully developed auditory systems were used in the present study. Recent studies showed sex-specific results in mice after NIHL., To keep variance of the data low, only female mice were used in the present experiments. The experimental protocol was approved by the government commission for animal studies (LaGeSo, Berlin, Germany; PI: Dr. Dietmar Basta, approval number: G0416/10). Experiments were carried out in accordance with the European Union (EU) Directive 2010/63/EU on the protection of animals used for scientific purposes. All efforts were made to minimize pain and discomfort in the animals.
The noise exposure paradigm has been described in recent publications of our group.,, Briefly, animals were exposed to a broadband flat spectrum noise (5–20 kHz) for 3 hours at 115 dB sound pressure level under anesthesia (6 mg/kg xylazine and 60 mg/kg ketamine) in a soundproof chamber (80 cm × 80 cm × 80 cm, minimal attenuation 60 dB). An amplifier (Tangent AMP-50; Eltax, Aulum, Denmark) and a DVD player were connected to loudspeakers (HTC 11.19; Visaton, Haan, Germany) placed above the animals’ heads. A sound level meter (Voltcraft 329; Conrad Electronic, Wernberg-Köblitz, Germany) was placed next to the animal’s ear to calibrate sound pressure level. A heating pad (Thermolux CM 15W; Acculux, Murrhardt, Germany) was placed under the animals to keep the body temperature constant at 37°C during video camera-controlled anesthesia.
Schedule of treatment
Different groups of animals were investigated at various point of time after single or double noise exposure [Figure 1] analogous to earlier investigations., Eighteen animals of the experimental groups were noise exposed at day 0 and randomly assigned to the experimental groups. The single exposure group was exposed to the initial trauma only and either investigated at day 7 post-exposure (“7-day group-single”; n = 4 animals) or at day 14 post-exposure (“14-day group-single”; n = 5 animals). The remaining nine animals were exposed to noise for a second time 1 week after the first noise trauma (“double trauma group”). Five of these mice were investigated immediately after the second exposure (“7-day group-double”), and the other four animals were left in their cages for 1 week and analyzed on day 14 after the first exposure (“14-day group-double”).
|Figure 1: Schematic illustration of the experimental groups. All mice were noise exposed at day 0 and either analyzed on day 7 (7-day groups) or on day 14 (14-day groups) post-exposure. Double groups were noise exposed for second time at day 7 and either investigated immediately after this trauma (7-day group-double) or 1 week later (14-day group-double) and compared to the corresponding single group (7-day group-single, 14-day group-single).|
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Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) was performed according to earlier investigations., Briefly, on the day of investigation, animals were perfused via the left heart chamber with a fixative solution (4% paraformaldehyde). The skull was carefully opened to remove the brain. After embedding in paraffin, 10-μm-thick slices in the frontal plane were cut using a rotation microtome (Euromex Präzisions Minot Rotations Mikrotom MT.5505; Euromex, Arnhem, The Netherlands). The frontal plane and the sagittal axis were defined according to the mouse brain atlas of Paxinos and Franklin. Comparable sections of the respective investigated structure from each animal were used for the analysis. The slices were stained by using the TUNEL method (In Situ Cell Death Detection Kit POD; Roche, Mannheim, Germany) to visualize cell death mechanisms. After removing the paraffin (2× Rotihistol [Carl Roth, Karlsruhe, Germany] for 10 min) and rehydrating in a descending ethanol series (90% and 70% each for 5 min) and distilled water (5 min), a pretreatment with 5% proteinase K (20.5 µg/mL in 10 mM trishydroxymethylaminomethane, pH 7.5, Roche; 100 µL per slice for 10 min) was performed. DNA strand breaks were provoked via deoxyribonuclease I recombinant (100 U/mL; Roche) used as a positive control as proposed by the manufacturer (Roche). A 3% H2O2 solution (dissolved in methanol) was applied for 5 minutes to block endogenous nucleases and avoid false-positive results. Each slice was incubated for 60 minutes with 50 μL TUNEL reaction mixture [diluted 1:2 with phosphate buffered saline (PBS)] at 37°C in a humidified chamber. To obtain a light microscopic analysis, each slice was incubated for 30 minutes with 50-μL converter POD, with diaminobenzidine as substrate (50 μL per slice for 10 min). After washing in PBS and distilled water, dehydration in an ascending alcohol series (70% ethanol, 90% ethanol, and 100% isopropanol, each for 1 min) was performed. Slices were stored in Rotihistol until mounting with Roti Histokitt (Carl Roth).
TUNEL cell counting and statistical analysis
The stained slices were microscopically magnified (250×, Axiovert 25C; Carl Zeiss, Göttingen, Germany) and colored photomicrographs were taken using a digital camera (Canon Eos 1000D, Tochigi, Japan). Pictures were standardized (“autocontrast” function, Adobe Photoshop CS3 Extended, Version 10.0, 2007, USA) and the number of TUNEL-positive cells was counted in particular grids within VCN (0.22 mm × 0.17 mm), the fusiform layer of DCN (0.16 mm × 0.1 mm), and the ICC (0.45 mm × 0.33 mm) [Figure 2]. The brain areas were defined in accordance with the mouse brain atlas of Paxinos and Franklin. The grid was manually placed in the center of the structure after randomization of the experimental groups. Equivalent regions of interest were investigated in earlier studies for determination of noise-induced neuronal cell loss as well as noise-induced apoptosis after a single noise trauma in VCN, DCN, and ICC., To avoid double counting the same cell in different layers, every second slice was added to the histological analyses. The cell counting was performed manually. To reduce technical and methodical errors to a minimum, the slides were counted after randomization and the counter was “blind” to the structure and the group.
|Figure 2: TUNEL-positive cells in a VCN grid. A VCN grid (0.22 mm × 0.17 mm) captured at 250× magnification. A single TUNEL-positive cell is seen in the grid (7-day group-single). TUNEL = terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling; VCN = ventral and dorsal cochlear nucleus.|
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The statistical procedure was chosen accordingly to earlier investigations about TUNEL in CN and ICC after a single noise exposure. The mean of TUNEL-positive cells (sum of TUNEL-positive cells divided by the number of grids) and standard error (SE) were calculated for all groups and structures. Data from the double noise exposure groups was tested for significant differences against the corresponding single noise exposure groups. Data from the 14-day groups was tested for significant differences against the corresponding 7-day groups.
The data distribution was statistically tested by Kolmogoroff–Smirnoff test. Normally distributed data was tested for significant differences by using the t test, otherwise the Mann–Whitney U test (u-test) was applied. The significance levels were set to P < 0.05 for all tests. The Tukey honestly significant difference (HSD) post hoc test was used to counteract the problem of multiple statistical comparisons and minimize the false discovery rate. SPSS software (SPSS Statistics, Version 20; IBM, Chicago, IL, USA) was used for all statistical calculations. Results with statistical significance at the level of P < 0.05 were marked with an asterisk. Results without statistical significance were marked with “n.s.” (not significant).
| Results|| |
Ventral cochlear nucleus
In VCN, 54 TUNEL-positive cells were counted in 34 slices analyzed in 7-day group-single (45 TUNEL-positive cells in 40 slices in 7-day group-double) and 93 TUNEL-positive cells were found in 29 slices in 14-day group-single (102 TUNEL-positive cells in 28 slices in 14-day group-double). No statistically significant differences in the mean of TUNEL-positive cells per grid were found within the 7-day groups (VCN: 7-day single = 1.59 ± 0.30 SE; 7-day double = 1.13 ± 0.23; PVCN-7-day = 0.156 [u-test]) nor within the 14-day groups (VCN: 14-day single = 3.21 ± 0.61 SE; 14-day double = 3.64 ± 0.48; P14-day = 0.579 [t-test]). The mean of TUNEL-positive cells was statistically significant elevated in the 14-day group compared to 7-day group (Psingle = 0.021 [u-test] and Pdouble = 0.000 [u-test], respectively) [Figure 3].
|Figure 3: Ventral cochlear nucleus. The mean of TUNEL-positive cells and standard error in the ventral cochlear nucleus 1 (7-day groups) or 2 weeks (14-day groups) after the initial noise exposure in the single (light gray) and double exposure groups (dark gray). No differences in the incidence of TUNEL-positive cells were found between single and double-trauma group neither in the 7-day nor 14-day group (n.s.). TUNEL was increased in the 14-day groups compared to 7-day groups (asterisk). n.s. = not significant; TUNEL = terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling.|
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Dorsal cochlear nucleus
In DCN, 20 slices (15 TUNEL-positive cells in total) of 7-day group-single (21 slices [14 TUNEL-positive cells] of 7-day group-double) and 34 slices (80 TUNEL-positive cells) of 14-day group-single (32 slices [75 TUNEL-positive cells] of 14-day group-double) were included in the statistical analysis. No statistically significant differences in the mean of TUNEL-positive cells per grid were found within the 7-day group (DCN: 7-day single = 0.75 ± 0.28 SE; 7-day double = 0.67 ± 0.20; PDCN-7-day = 0.883 [u-test]) nor within the 14-day group (DCN: 14-day single = 2.35 ± 0.35 SE; 14-day double = 2.34 ± 0.35; PDCN-14-day = 0.953 [u-test]). The mean of TUNEL-positive cells was statistically significant elevated in the 14-day group compared to the 7-day group (Psingle = 0.001 [u-test] and Pdouble = 0.000 [u-test], respectively) [Figure 4].
|Figure 4: Dorsal cochlear nucleus. The mean of TUNEL-positive cells and standard error in the dorsal cochlear nucleus 1 (7-day groups) or 2 weeks (14-day groups) after the initial noise exposure in the single (light gray) and double exposure groups (dark gray). Compared to 7-day groups, TUNEL was increased in the 14-day groups (asterisk). No differences in the incidence of TUNEL-positive cells were found between single and double-trauma group neither in the 7-day nor 14-day group (n.s.). n.s. = not significant; TUNEL = terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling.|
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Central nucleus of the inferior colliculus
In ICC, 29 slices were analyzed in 7-day group-single (63 TUNEL-positive cells) (30 slices in 7-day group-double [57 TUNEL-positive cells]) and 38 slices in 14-day group-single (197 TUNEL-positive cells) (28 slices in 14-day group-double [146 TUNEL-positive cells]). No statistically significant differences in TUNEL-positive cells per grid were found within the 7-day group (ICC: 7-day single = 2.17 ± 0.42 SE; 7-day double = 1.90 ± 0.27; PICC-7-day = 0.883 [u-test]) nor within the 14-day group (ICC: 14-day single = 5.18 ± 0.66 SE; 14-day double = 5.21 ± 0.88; PICC-14-day = 0.978 [t-test]). The increase in TUNEL in the 14-day group was statistically significant compared to the 7-day group within the single exposure group (Psingle = 0.000 [t-test]) and double exposure group (Pdouble = 0.005 [u-test]) [Figure 5].
|Figure 5: Inferior colliculus. Mean of TUNEL-positive cells and standard error in the central nucleus of the inferior colliculus 1 (7-day groups) or 2 weeks (14-day groups) after the initial noise exposure in the single (light gray) and double exposure groups (dark gray). Compared to 7-day groups, TUNEL was increased in the 14-day groups (asterisk). No differences in the incidence of TUNEL-positive cells were found between single and double-trauma group neither in the 7-day nor 14-day group (n.s.). n.s. = not significant; TUNEL = terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling.|
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| Discussion|| |
The present study investigated the incidence of cell death mechanisms in the VCN, DCN, and ICC immediately and 1 week after a second noise exposure at traumatizing level. Compared to a corresponding single noise exposure, the influence of the second noise trauma on cell death mechanisms was very limited in the investigated basal structures of the central auditory pathway. Surprisingly, an increase in TUNEL-positive cells was seen in the 14-day groups independent of the number of sound exposures in all investigated areas. This might be a long-term effect upon the first noise exposure rather than a consequence of the second noise trauma.
Influence of a second noise trauma on the incidence of apoptosis in VCN, DCN, and ICC
Our group showed a direct impact of a single noise exposure on apoptosis in the VCN, DCN, and ICC and described the time course of cell death over 1 week post-exposure. In the present study, a second noise trauma was performed 1 week after the first trauma [Figure 1], when the peak of cell death after the first noise exposure had already been exceeded in VCN, DCN, and ICC. It was shown that the incidence of apoptosis immediately increased after the first noise exposure in VCN and ICC. The present second noise exposure could not alter cell death mechanisms in VCN, DCN, and ICC in the same intensity. No increase in TUNEL was seen immediately after the second noise exposure (7-day group-double) compared to the corresponding single group (7-day group-single) [Figure 3],[Figure 4],[Figure 5]. It was shown that the incidence of apoptosis on day 7 after a single noise exposure was either decreased to pretraumatic level (VCN) or slightly upregulated (ICC and DCN) compared to unexposed controls. Therefore, the small number of TUNEL-positive cells in the present 7-day groups is less surprising, especially in the small analyzed area of the DCN. In the present investigation, on day 7 after repeated noise exposure (14-day group-double) [Figure 1], the incidence of TUNEL was increased compared to 7-day group-double. This increase seems to be mainly triggered by factors other than the second noise exposure as it was also seen in the corresponding single groups [Figure 3],[Figure 4],[Figure 5].
With regard to the present results, it should be considered for different reasons that a second traumatizing noise exposure might not be processed in the basal structures of the central auditory pathway in the same manner as the first noise trauma. First of all, the previous studies have shown that the present noise paradigm leads to a permanent threshold shift in NMRI mice with a loss of hair cells in the cochlear frequency range of noise stimulation that extends over time.,,,,, Due to the identical noise trauma characteristic of the first and second noise exposure, it seems plausible that the frequency range of the second noise application has its largest impact on the tonotopic region in the organ of corti that shows destroyed hair cells due to the first noise exposure. Concerning hair cell function as mechanoreceptor and afferent neuron of the VIII cranial nerve, the second noise trauma might not be transduced to the central auditory pathway in the same intensity. Second, a massive reduction in cell densities had been shown 1 week after a single noise exposure in an earlier study (neuronal loss of 39% in DCN, 30% in VCN, and 31% in ICC, respectively), exactly the moment in time when the second noise exposure was performed in the present study. Besides deafferentation due to a noise-damaged cochlea, neuronal loss is hypothesized as a direct consequence of noise. Third, noise mainly affects acoustic-sensitive neurons but the CN integrates also the nonauditory inputs. As a consequence after noise damage, the CN might change in responsiveness to nonauditory stimuli. The compensatory stronger nonauditory input to the CN and the ICC could lead to a weaker sensitivity to a second auditory stimulation. The interaction of several of these effects might protect the central auditory pathway from further damage and contribute to explain the present findings in TUNEL in the double group compared to the single group. Auditory brainstem recordings from earlier investigations performed in the present 14-day groups are shown in [Figure 6]. The additional shift in hearing thresholds was dramatically smaller after a second noise exposure (compared to the first one) and supports the hypothesis of a weaker responsiveness to a second noise exposure. Furthermore, calcium was statistically significantly elevated upon a second noise trauma in VCN, DCN, and ICC. Its role as a mediator in the generation of necrosis and apoptosis was recently described but calcium is also dose dependent highly involved in neuroprotective mechanisms and might have a protective function in the present study.,,,,,, Calcium might also modulate neuronal nitric oxide synthase and calcium-binding protein calretinin, which increased after single and multiple noise trauma in the CN. Nitric oxide is discussed to play a role in cytotoxicity, cell death, and hearing disorders but can be cell protective depending on its dose., The changes on a molecular level might have a protective role during the second noise exposure in the present study. It might hold true that homeostatic mechanisms induced by the first trauma help to protect the CN and ICC from further damage, at least during a specific timeslot. These long-term effects might contribute to the present increase in TUNEL in the 14-day group independent of the number of exposures.
|Figure 6: ABR measurements. ABR threshold shifts at different frequencies of the present 14-day groups (dark gray) and the present single groups (light gray). A threshold shift was seen in the 14-day group-double compared to the corresponding single group in all measured frequencies (dark gray) and statistically significant at 8 kHz (P = 0.045), 12 kHz (P = 0.013), and 20 kHz (P = 0.04). No big changes in ABR thresholds were seen in the 14-day group-single compared to the 7-day group-single (light gray). Either the recovery at 4 kHz (P = 0.923), 8 kHz (P = 0.665), and 12 kHz (P = 0.235) or the worsening at 16 kHz (P = 0.855) and 20 kHz (P = 0.904) had statistical significance. Data from earlier investigations of our group. ABR = auditory brainstem recording.|
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Long-term effects of the initial noise exposure on apoptosis in VCN, DCN, and ICC
It was earlier hypothesized that noise-induced apoptosis and cell loss seem to terminate 1 week after a single noise trauma in the VCN, whereas it was still observed in DCN and ICC., However, the incidence of TUNEL was increased in the present study in VCN, DCN, and ICC in the 14-day group, apparently independently of the second noise exposure (no differences between the single and double groups). There are different reasons for the present increase in TUNEL in the VCN, DCN, and ICC 2 weeks post-exposure. Neuronal degeneration in the CN varies with the age of the animals as well as trauma etiology., Therefore, the time course of cell death after cochlea removal might not totally match with the noise-induced deafferentation. Nevertheless, cochlea removal or destruction led to increased TUNEL and a continuing or reflating process of cell death beyond 1-week post-exposure in the basal structures of the auditory system., Consequently, the present increase in TUNEL in the 14-day group might rather represent long-term effects of the first noise trauma than a consequence of noise itself. This might also explain the findings of earlier auditory brainstem recording measurements that did not show big differences in hearing thresholds in the present single groups [Figure 6]. These long-term effects might include deafferentation and neuroplasticity due to a noise-damaged organ of corti with cochlea damage and changed mechanotransduction after hair call loss.,, Deafferentation, reorganization, and neuroplasticity take place around 2 weeks post-lesion and go along with apoptosis., This is provided by lacking plasticity markers within 1 week post-exposure in the VCN but their upregulation between 15 and 30 days post-exposure. Statistically significant degeneration was found 1-week post-exposure and progressed for weeks post-exposure in the CN.,,, The sustained increase of choline acetyltransferase activity in the CN granular region after trauma could be consistent with the formation of new cholinergic synapses or upregulation of existing cholinergic synapses upon granule cells and could have got caught by the present 14-day group.,, Furthermore, excitatory neurotoxicity in the mammalian central nervous system is largely mediated by excessive release of glutamate that might also contribute to a raising cell death in VCN, DCN, and ICC post-exposure., Axonal sprouting like reactive axonal growth was described to occur from weeks up to months after trauma in the DCN and contributes to the process of reorganization., It was shown that the present noise paradigm led to an increase of spontaneous activity in CN and ICC that reflects a more slowly developing phenomenon and occurs secondarily after induction.,,,, The neuronal hyperactivity as compensatory mechanism for lost excitatory network inputs might push apoptosis as seen in the present 14-day group., However, the ICC might profit from inhibitory interneurons that project from the CN to higher structures and possibly have protecting function. This theory is provided by earlier investigations about TUNEL and neuronal activity that was much lower in the ICC than in the CN., Apoptosis in the ICC may be derived, prolonged, and stimulated from its external inputs. The most powerful of these inputs would be the (hyperactive) inputs from the DCN, as these project directly to the contralateral ICC.,,,,
| Conclusion|| |
The present investigation showed an increase in TUNEL 2 weeks after the initial noise trauma independent of the number of noise exposures. It seems that the first noise trauma has a long-lasting effect on apoptotic mechanisms in the CN and ICC. These results might help to understand the underlying mechanisms of different psychoacoustic phenomena in NIHL such as tinnitus, hyperacusis, or reduced speech perception.
Financial support and sponsorship
The present work was supported by the Deutsche Forschungsgemeinschaft (grant number GR 3519/3-1). The experimental protocol was approved by the governmental commission for animal studies (LaGeSo; approval number: G0416/10). All experiments were made in accordance to ethical standards and performed at the Department of Otolaryngology, Unfallkrankenhaus, Berlin, Germany.
Conflicts of interest
There are no conflicts of interest.
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Research Scientist, Zentrum für klinische Technologieforschung, Warener Straße 7, Haus 49, 12683 Berlin
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]