Auditory Research publications

The aim of the present study was to investigate the protective effect of T-type calcium channel blockers against presbycusis, using a C57BL/6J mice model. The expression of three T-type calcium channel receptor subunits in the cochlea of 6-8-week-old C57BL/6J mice was evaluated using reverse transcription-quantitative polymerase chain reaction. The results confirmed that the three subunits were expressed in the cochlea. In addition, the capacity of T-type calcium channel blockers to protect the cochlear hair cells of 24-26-week-old C57BL/6J mice was investigated in mice treated with mibefradil, benidipine or saline for 4 weeks. Differences in hearing threshold were detected using auditory brainstem recording (ABR), while differences in amplitudes were measured using a distortion product otoacoustic emission (DPOAE) test. The ABR test results showed that the hearing threshold significantly decreased at 24 kHz in the mibefradil-treated and benidipine-treated groups compared with the saline-treated group. The DPOAE amplitudes in the mibefradil-treated group were increased compared with those in the saline-treated group at the F2 frequencies of 11.3 and 13.4 kHz. Furthermore, the DPOAE amplitudes in the benidipine-treated group were increased compared with those in the saline-treated group at an F2 frequency of 13.4 kHz. The loss of outer hair cells (OHCs) was not evident in the mibefradil-treated group; however, the stereocilia of the inner hair cells (IHCs) were disorganised and sparse. In summary, these results indicate that the administration of a T-type calcium channel blocker for four consecutive weeks may improve the hearing at 24 kHz of 24-26-week-old C57BL/6J mice. The function and morphology of the OHCs of the C57BL/6J mice were significantly altered by the administration of a T-type calcium channel blocker; however, the IHCs were unaffected.

It is generally believed that the remarkable sensitivity and frequency selectivity of mammalian hearing depend on outer hair cell-generated force, which amplifies sound-induced vibrations inside the cochlea. This ‘reverse transduction’ force production has never been demonstrated experimentally, however, in the living ear. Here by directly measuring microstructure vibrations inside the cochlear partition using a custom-built interferometer, we demonstrate that electrical stimulation can evoke both fast broadband and slow sharply tuned responses of the reticular lamina, but only a slow tuned response of the basilar membrane. Our results indicate that outer hair cells can generate sufficient force to drive the reticular lamina over all audible frequencies in living cochleae. Contrary to expectations, the cellular force causes a travelling wave rather than an immediate local vibration of the basilar membrane; this travelling wave vibrates in phase with the reticular lamina at the best frequency, and results in maximal vibration at the apical ends of outer hair cells.

Ongoing spontaneous activity in cortical circuits defines cortical states, but it still remains unclear how cortical states shape sensory processing across cortical laminae and what type of response properties emerge in the cortex. Recording neural activity from the auditory cortex (AC) and medial geniculate body (MGB) simultaneously with electrical stimulations of the basal forebrain (BF) in urethane-anesthetized rats, we investigated state-dependent spontaneous and auditory-evoked activities in the auditory thalamocortical circuit. BF stimulation induced a short-lasting desynchronized state, with sparser firing and increased power at gamma frequency in superficial layers. In this desynchronized state, the reduction in onset response variability in both AC and MGB was accompanied by cell type-specific firing, with decreased responses of cortical broad spiking cells, but increased responses of cortical narrow spiking cells. This onset response was followed by distinct temporal evolution in AC, with quicker rebound firing in infragranular layers. This temporal profile was associated with improved processing of temporally structured stimuli across AC layers to varying degrees, but not in MGB. Thus, the reduction in response variability during the desynchronized state can be seen subcortically whereas the improvement of temporal tuning emerges across AC layers, emphasizing the importance of state-dependent intracortical processing in hearing.

Grip force control involves mechanisms to adjust to unpredictable and predictable changes in loads during manual manipulation. Somatosensory feedback is critical not just to reactive, feedback control but also to updating the internal representations needed for proactive, feedforward control. The role of primary somatosensory cortex (S1) in these control strategies is not well established. Here we investigated grip force control in a rare case of acute central deafferentation following resection of S1. The subject had complete loss of somatosensation in the right arm without any deficit in muscle strength or reflexes. In the first task, the subject was asked to maintain a constant grip force with and without visual feedback. The subject was able to attain the target force with visual feedback but not maintain that force for more than a few seconds after visual feedback was removed. In the second task, the subject was asked to grip and move an instrumented object. The induced acceleration-dependent loads were countered by adjustments in grip force. Both amplitude and timing of the grip force modulation were not affected by deafferentation. The dissociation of these effects demonstrates the differential contribution of S1 to the mechanisms of grip force control.

Hereditary deafness is one of the most common disabilities affecting newborns. Many forms of hereditary deafness are caused by morphological defects of the stereocilia bundles on the apical surfaces of inner ear hair cells, which are responsible for sound detection. We explored the effectiveness of gene therapy in restoring the hair cell stereocilia architecture in the whirlin mouse model of human deafness, which is deaf due to dysmorphic, short stereocilia. Wild-type whirlin cDNA was delivered via adeno-associated virus (AAV8) by injection through the round window of the cochleas in neonatal whirler mice. Subsequently, whirlin expression was detected in infected hair cells (IHCs), and normal stereocilia length and bundle architecture were restored. Whirlin gene therapy also increased inner hair cell survival in the treated ears compared to the contralateral nontreated ears. These results indicate that a form of inherited deafness due to structural defects in cochlear hair cells is amenable to restoration through gene therapy.

Low-level lead exposure is a risk factor for cognitive and learning disabilities in children and has been specifically associated with deficits in auditory temporal processing that impair aural language and reading abilities. Here, we show that rats exposed to low levels of lead in early life display a significant behavioral impairment in an auditory temporal rate discrimination task. Lead exposure also results in a degradation of the neuronal repetition-rate following capacity and response synchronization in primary auditory cortex. A modified go/no-go repetition-rate discrimination task applied in adult animals for ∼50 days nearly restores to normal these lead-induced deficits in cortical temporal fidelity. Cortical expressions of parvalbumin, brain-derived neurotrophic factor, and NMDA receptor subunits NR2a and NR2b, which are down-regulated in lead-exposed animals, are also partially reversed with training. These studies in an animal model identify the primary auditory cortex as a novel target for low-level lead exposure and demonstrate that perceptual training can ameliorate lead-induced deficits in cortical discrimination between sound sequences.

While functional connectivity in the human cortex has been increasingly studied, its relationship to cortical representation of sensory features has not been documented as much. We used functional magnetic resonance imaging to demonstrate that voxel-by-voxel intrinsic functional connectivity (FC) is selective to frequency preference of voxels in the human auditory cortex. Thus, FC was significantly higher for voxels with similar frequency tuning than for voxels with dissimilar tuning functions. Frequency-selective FC, measured via the correlation of residual hemodynamic activity, was not explained by generic FC that is dependent on spatial distance over the cortex. This pattern remained even when FC was computed using residual activity taken from resting epochs. Further analysis showed that voxels in the core fields in the right hemisphere have a higher frequency selectivity in within-area FC than their counterpart in the left hemisphere, or than in the noncore-fields in the same hemisphere. Frequency-selective FC is consistent with previous findings of topographically organized FC in the human visual and motor cortices. The high degree of frequency selectivity in the right core area is in line with findings and theoretical proposals regarding the asymmetry of human auditory cortex for spectral processing.

Most vertebrates have evolved a tympanic middle ear that enables effective hearing of airborne sound on land. Although inner ears develop during the tadpole stages of toads, tympanic middle ear structures are not complete until months after metamorphosis, potentially limiting the sensitivity of post-metamorphic juveniles to sounds in their environment. We tested the hearing of five species of toads to determine how delayed ear development impairs airborne auditory sensitivity. We performed auditory brainstem recordings to test the hearing of the toads and used micro-CT and histology to relate the development of ear structures to hearing ability. We find a large (14-27 dB) increase in hearing sensitivity from 900 to 2500 Hz over the course of ear development. Thickening of the tympanic annulus cartilage and full ossification of the middle ear bone are associated with increased hearing ability in the final stages of ear maturation. Thus, juvenile toads are at a hearing disadvantage, at least in the high-frequency range, throughout much of their development, because late forming ear elements are critical to middle ear function at these frequencies. We discuss the potential fitness consequences of late hearing development, although research directly addressing selective pressures on hearing sensitivity across ontogeny is lacking. Given that most vertebrate sensory systems function very early in life, toad tympanic hearing may be a sensory development anomaly.

Synaptopathy in the cochlea occurs when the connection between inner hair cells and the auditory nerve is disrupted, leading to impaired hearing and nerve degeneration. Experiments using transgenic mice have shown that overexpression of NT3 by supporting cells repairs synaptopathy caused by overstimulation. To accomplish such therapy in the clinical setting, it would be necessary to activate the neurotrophin receptor on auditory neurons by other means. Here we test the outcome of NT3 overexpression using viral-mediated gene transfer into the perilymph versus the endolymph of the normal guinea pig cochlea. We inoculated two different Ntf3 viral vectors, adenovirus (Adv) or adeno-associated virus (AAV) into the perilymph, to facilitate transgene expression in the mesothelial cells and cochlear duct epithelium, respectively. We assessed outcomes by comparing Auditory brainstem response (ABR) thresholds prior to that at baseline to thresholds at 1 and 3 weeks after inoculation, and then performed histologic evaluation of hair cells, nerve endings, and synaptic ribbons. We observed hearing threshold shifts as well as disorganization of peripheral nerve endings and disruption of synaptic connections between inner hair cells and peripheral nerve endings with both vectors. The data suggest that elevation of NT3 levels in the cochlear fluids can disrupt innervation and degrade hearing.

Multiple redundant acoustic cues can contribute to the perception of a single phonemic contrast. This study investigated the effect of spectral degradation on the discriminability and perceptual saliency of acoustic cues for identification of word-final fricative voicing in “loss” versus “laws”, and possible changes that occurred when low-frequency acoustic cues were restored. Three acoustic cues that contribute to the word-final /s/-/z/ contrast (first formant frequency [F1] offset, vowel–consonant duration ratio, and consonant voicing duration) were systematically varied in synthesized words. A discrimination task measured listeners’ ability to discriminate differences among stimuli within a single cue dimension. A categorization task examined the extent to which listeners make use of a given cue to label a syllable as “loss” versus “laws” when multiple cues are available. Normal-hearing listeners were presented with stimuli that were either unprocessed, processed with an eight-channel noise-band vocoder to approximate spectral degradation in cochlear implants, or low-pass filtered. Listeners were tested in four listening conditions: unprocessed, vocoder, low-pass, and a combined vocoder + low-pass condition that simulated bimodal hearing. Results showed a negative impact of spectral degradation on F1 cue discrimination and a trading relation between spectral and temporal cues in which listeners relied more heavily on the temporal cues for “loss-laws” identification when spectral cues were degraded. Furthermore, the addition of low-frequency fine-structure cues in simulated bimodal hearing increased the perceptual saliency of the F1 cue for “loss-laws” identification compared with vocoded speech. Findings suggest an interplay between the quality of sensory input and cue importance.

Dizziness and vertigo frequently occur after cochlear implantation (CI) surgery, particularly during the early stages. It could recover over time but some of the patients suffered from delayed or sustained vestibular symptoms after CI. This study used rat animal models to investigate the effect of unilateral cochleostomy on the vestibular organs over time. Twenty-seven Sprague Dawley rats underwent cochleostomy to evaluate the postoperative changes in hearing threshold, gain and symmetry of the vestibular ocular response, overall balance function, number of hair cells in the crista, and the c-Fos activity in the brainstem vestibular nucleus. Loss of vestibular function was observed during the early stages, but function recovered partially over time. Histopathological findings demonstrated a mild decrease in vestibular hair cells numbers. Increased c-Fos immunoreactivity in the vestibular nucleus, observed in the early stages after cochleostomy, decreased over time. Cochleostomy is a risk factor for peripheral vestibular organ damage that can cause functional impairment in the peripheral vestibular organs. Altered vestibular nucleus activity may be associated with vestibular compensation and plasticity after unilateral cochleostomy.

Background: Delivery of therapeutic agents directly through the round window (RW) offers promise for treating sensorineural hearing loss. However, hearing loss can result from the surgical approach itself, and the reasons for this are poorly understood. We examined the hearing loss following the 3 major steps involved with the RW approach to access the mouse cochlea: bullostomy, RW puncture, and RW injection. Methods: Twenty-one adult CBA/J mice underwent bullostomy alone, 10 underwent RW puncture, and 8 underwent RW injection with PBS with 5% glycerol. Auditory brainstem responses (ABR) and otoscopy were performed preoperatively and up to 6 weeks postoperatively. Hair cells were stained, and survival was assessed using immunofluorescence. Results: One week postoperatively, mice in all groups showed significant threshold shifts. Otoscopy revealed approximately half of all mice had middle ear effusion (MEE), with a higher incidence of effusion in the RW puncture and RW injection groups. Those with MEE had significant ABR threshold shifts, whereas those without MEE had minimal hearing loss. MEE persisted through 6 weeks in a majority of cases, but in those mice with MEE resolution, there was at least partial improvement in hearing. Immunohistochemistry showed minimal loss of hair cells in all animals. Conclusion: MEE is highly correlated with hearing loss in mice undergoing RW surgery. Otoscopy is an important adjunct to consider after ear surgery in mice, as MEE may contribute to postsurgical hearing loss.

Objective: The purpose of this study was to assess age-related changes in temporal resolution in listeners with relatively normal audiograms. The hypothesis was that increased susceptibility to nonsimultaneous masking contributes to the hearing difficulties experienced by older listeners in complex fluctuating backgrounds. Design: Participants included younger (n = 11), middle-age (n = 12), and older (n = 11) listeners with relatively normal audiograms. The first phase of the study measured masking period patterns for speech-shaped noise maskers and signals. From these data, temporal window shapes were derived. The second phase measured forward-masking functions and assessed how well the temporal window fits accounted for these data. Results: The masking period patterns demonstrated increased susceptibility to backward masking in the older listeners, compatible with a more symmetric temporal window in this group. The forward-masking functions exhibited an age-related decline in recovery to baseline thresholds, and there was also an increase in the variability of the temporal window fits to these data. Conclusions: This study demonstrated an age-related increase in susceptibility to nonsimultaneous masking, supporting the hypothesis that exacerbated nonsimultaneous masking contributes to age-related difficulties understanding speech in fluctuating noise. Further support for this hypothesis comes from limited speech-in-noise data, suggesting an association between susceptibility to forward masking and speech understanding in modulated noise.

Hearing-impaired individuals experience difficulties in detecting or understanding speech, especially in background sounds within the same frequency range. However, normally hearing (NH) human listeners experience less difficulty detecting a target tone in background noise when the envelope of that noise is temporally gated (modulated) than when that envelope is flat across time (unmodulated). This perceptual benefit is called modulation masking release (MMR). When flanking masker energy is added well outside the frequency band of the target, and comodulated with the original modulated masker, detection thresholds improve further (MMR+). In contrast, if the flanking masker is antimodulated with the original masker, thresholds worsen (MMR−). These interactions across disparate frequency ranges are thought to require central nervous system (CNS) processing. Therefore, we explored the effect of developmental conductive hearing loss (CHL) in gerbils on MMR characteristics, as a test for putative CNS mechanisms. The detection thresholds of NH gerbils were lower in modulated noise, when compared with unmodulated noise. The addition of a comodulated flanker further improved performance, whereas an antimodulated flanker worsened performance. However, for CHL-reared gerbils, all three forms of masking release were reduced when compared with NH animals. These results suggest that developmental CHL impairs both within- and across-frequency processing and provide behavioral evidence that CNS mechanisms are affected by a peripheral hearing impairment.

We used the rat primary auditory cortex (A1) as a model to probe the effects of cholinergic enhancement on perceptual learning and auditory processing mechanisms in both young and old animals. Rats learned to perform a two-tone frequency discrimination task over the course of two weeks, combined with either the administration of a cholinesterase inhibitor or saline. We found that while both age groups learned the task more quickly through cholinergic enhancement, the young did so by improving target detection, whereas the old did so by inhibiting erroneous responses to nontarget stimuli. We also found that cholinergic enhancement led to marked functional and structural changes within A1 in both young and old rats. Importantly, we found that several functional changes observed in the old rats, particularly those relating to the processing and inhibition of nontargets, produced cortical processing features that resembled those of young untrained rats more so than those of older adult rats. Overall, these findings demonstrate that combining auditory training with neuromodulation of the cholinergic system can restore many of the auditory cortical functional deficits observed as a result of normal aging and add to the growing body of evidence demonstrating that many age-related perceptual and neuroplastic changes are reversible.

The patients with DiGeorge syndrome (DGS), caused by deletion containing dozens of genes in chromosome 22, often carry cardiovascular problem and hearing loss associated with chronic otitis media. Inside the deletion region, a transcription factor TBX1 was highly suspected. Furthermore, similar DGS phenotypes were found in the Tbx1 heterozygous knockout mice. Using ENU-induced mutagenesis and G1 dominant screening strategy, here we identified a nonsynonymous mutation p.W118R in T-box of TBX1, the DNA binding domain for transcription activity. The mutant mice showed deficiency of inner ear functions, including head tossing and circling, plus increased hearing threshold determined by audiometry. Therefore, our result further confirms the pathogenic basis of Tbx1 in DGS, points out the crucial role of DNA binding activity of TBX1 for the ear function, and provides additional animal model for studying the DGS disease mechanisms.

MYH14 is a member of the myosin family, which has been implicated in many motile processes such as ion-channel gating, organelle translocation, and the cytoskeleton rearrangement. Mutations in MYH14 lead to a DFNA4-type hearing impairment. Further evidence also shows that MYH14 is a candidate noise-induced hearing loss (NIHL) susceptible gene. However, the specific roles of MYH14 in auditory function and NIHL are not fully understood. In the present study, we used CRISPR/Cas9 technology to establish a Myh14 knockout mice line in CBA/CaJ background (now referred to as Myh14 −/− mice) and clarify the role of MYH14 in the cochlea and NIHL. We found that Myh14 −/− mice did not exhibit significant hearing loss until five months of age. In addition, Myh14 −/− mice were more vulnerable to high intensity noise compared to control mice. More significant outer hair cell loss was observed in Myh14 −/− mice than in wild type controls after acoustic trauma. Our findings suggest that Myh14 may play a beneficial role in the protection of the cochlea after acoustic overstimulation in CBA/CaJ mice.

Prestin is the motor protein expressed in the cochlear outer hair cells (OHCs) of mammalian inner ear. The electromotility of OHCs driven by prestin is responsible for the cochlear amplification which is required for normal hearing in adult animals. Postnatal expression of prestin and activity of OHCs may contribute to the maturation of hearing in rodents. However, the temporal and spatial expression of prestin in cochlea during the development is not well characterized. In the present study, we examined the expression and function of prestin from the OHCs in apical, middle, and basal turns of the cochleae of postnatal rats. Prestin first appeared at postnatal day 6 (P6) for basal turn, P7 in middle turn, and P9 for apical turn of cochlea. The expression level increased progressively over the next few days and by P14 reached the mature level for all three segments. By comparison with the time course of the development of auditory brainstem response for different frequencies, our data reveal that prestin expression synchronized with the hearing development. The present study suggests that the onset time of hearing may require the expression of prestin and is determined by the mature function of OHCs.