Publications using TDT

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.

The cochlea converts sound vibration into electrical impulses and amplifies the low-level sound signal. Urethane, a widely used anesthetic in animal research, has been shown to reduce the neural responses to auditory stimuli. However, the effects of urethane on cochlea, especially on the function of outer hair cells, remain largely unknown. In the present study, we compared the cochlear microphonic responses between awake and urethane-anesthetized rats. The results revealed that the amplitude of the cochlear microphonic was decreased by urethane, resulting in an increase in the threshold at all of the sound frequencies examined. To deduce the possible mechanism underlying the urethane-induced decrease in cochlear sensitivity, we examined the electrical response properties of isolated outer hair cells using whole-cell patch-clamp recording. We found that urethane hyperpolarizes the outer hair cell membrane potential in a dose-dependent manner and elicits larger outward current. This urethane-induced outward current was blocked by strychnine, an antagonist of the α 9 subunit of the nicotinic acetylcholine receptor. Meanwhile, the function of the outer hair cell motor protein, prestin, was not affected. These results suggest that urethane anesthesia is expected to decrease the responses of outer hair cells, whereas the frequency selectivity of cochlea remains unchanged.

Little is known about how outer hair cell loss interacts with noise-induced and age-related auditory nerve degradation (i.e., cochlear synaptopathy) to affect auditory brainstem response (ABR) wave characteristics. Given that listeners with impaired audiograms likely suffer from mixtures of these hearing deficits and that ABR amplitudes have successfully been used to isolate synaptopathy in listeners with normal audiograms, an improved understanding of how different hearing pathologies affect the ABR source generators will improve their sensitivity in hearing diagnostics. We employed a functional model for human ABRs in which different combinations of hearing deficits were simulated and show that high-frequency cochlear gain loss steepens the slope of the ABR Wave-V latency versus intensity and amplitude versus intensity curves. We propose that grouping listeners according to a ratio of these slope metrics (i.e., the ABR growth ratio) might offer a way to factor out the outer hair cell loss deficit and maximally relate individual differences for constant ratios to other peripheral hearing deficits such as cochlear synaptopathy. We compared the model predictions to recorded click-ABRs from 30 participants with normal or high-frequency sloping audiograms and confirm the predicted relationship between the ABR latency growth curve and audiogram slope. Experimental ABR amplitude growth showed large individual differences and was compared with the Wave-I amplitude, Wave-V/I ratio, or the interwave I – W latency in the same listeners. The model simulations along with the ABR recordings suggest that a hearing loss profile depicting the ABR growth ratio versus the Wave-I amplitude or Wave-V/I ratio might be able to differentiate outer hair cell deficits from cochlear synaptopathy in listeners with mixed pathologies.

Auditory brain areas undergo reorganization resulting from abnormal sensory input during early postnatal development. This is evident from studies at the cortical level but it remains unclear whether there is reorganization in the auditory midbrain in a species similar to the human, that is, with early hearing onset. We have explored midbrain plasticity in the chinchilla, a precocious species that matches the human in terms of hearing development. Neonatal chinchillas were chronically exposed to a 2 kHz narrowband sound at 70 dB SPL for 4 weeks. Tonotopic maps in inferior colliculus (central nucleus) were defined based on single neuron characteristic frequency. We hypothesized an overrepresentation of the 2 kHz region of the maps. However, we observed a significant decrease in the proportion of neurons dedicated to the 2 kHz octave band and also away from the exposure frequency at 8 kHz. In addition, we report a significant increase in low frequency representation (<1 kHz), again a change to tonotopic mapping distant to the 2 kHz region. Thus in a precocious species, tonotopic maps in auditory midbrain are altered following abnormal stimulation during development. However, these changes are more complex than the overrepresentation of exposure related frequency regions that are often reported.

The purpose of this study was to determine the effects of age on the spectro-temporal integration of speech. The hypothesis was that the integration of speech fragments distributed over frequency, time, and ear of presentation is reduced in older listeners—even for those with good audiometric hearing. Younger, middle-aged, and older listeners (10 per group) with good audiometric hearing participated. They were each tested under seven conditions that encompassed combinations of spectral, temporal, and binaural integration. Sentences were filtered into two bands centered at 500 Hz and 2500 Hz, with criterion bandwidth tailored for each participant. In some conditions, the speech bands were individually square wave interrupted at a rate of 10 Hz. Configurations of uninterrupted, synchronously interrupted, and asynchronously interrupted frequency bands were constructed that constituted speech fragments distributed across frequency, time, and ear of presentation. The over-arching finding was that, for most configurations, performance was not differentially affected by listener age. Although speech intelligibility varied across condition, there was no evidence of performance deficits in older listeners in any condition. This study indicates that age, per se, does not necessarily undermine the ability to integrate fragments of speech dispersed across frequency and time.

In patients with bilateral hearing loss, the use of two hearing aids (HAs) offers the potential to restore the benefits of binaural hearing, including sound source localization and segregation. However, existing evidence suggests that bilateral HA users’ access to binaural information, namely interaural time and level differences (ITDs and ILDs), can be compromised by device processing. Our objective was to characterize the nature and magnitude of binaural distortions caused by modern digital behind-the-ear HAs using a variety of stimuli and HA program settings. Of particular interest was a common frequency-lowering algorithm known as nonlinear frequency compression, which has not previously been assessed for its effects on binaural information. A binaural beamforming algorithm was also assessed. Wide dynamic range compression was enabled in all programs. HAs were placed on a binaural manikin, and stimuli were presented from an arc of loudspeakers inside an anechoic chamber. Stimuli were broadband noise bursts, 10-Hz sinusoidally amplitude-modulated noise bursts, or consonant–vowel–consonant speech tokens. Binaural information was analyzed in terms of ITDs, ILDs, and interaural coherence, both for whole stimuli and in a time-varying sense (i.e., within a running temporal window) across four different frequency bands (1, 2, 4, and 6 kHz). Key findings were: (a) Nonlinear frequency compression caused distortions of high-frequency envelope ITDs and significantly reduced interaural coherence. (b) For modulated stimuli, all programs caused time-varying distortion of ILDs. (c) HAs altered the relationship between ITDs and ILDs, introducing large ITD–ILD conflicts in some cases. Potential perceptual consequences of measured distortions are discussed.

Even though hearing aid (HA) users can respond very differently to noise reduction (NR) processing, knowledge about possible drivers of this variability (and thus ways of addressing it in HA fittings) is sparse. The current study investigated differences in preferred NR strength among HA users. Participants were groups of experienced users with clear preferences (“NR lovers”; N = 14) or dislikes (“NR haters”; N = 13) for strong NR processing, as determined in two earlier studies. Maximally acceptable background noise levels, detection thresholds for speech distortions caused by NR processing, and self-reported “sound personality” traits were considered as candidate measures for explaining group membership. Participants also adjusted the strength of the (binaural coherence-based) NR algorithm to their preferred level. Consistent with previous findings, NR lovers favored stronger processing than NR haters, although there also was some overlap. While maximally acceptable noise levels and detection thresholds for speech distortions tended to be higher for NR lovers than for NR haters, group differences were only marginally significant. No clear group differences were observed in the self-report data. Taken together, these results indicate that preferred NR strength is an individual trait that is fairly stable across time and that is not easily captured by psychoacoustic, audiological, or self-report measures aimed at indexing susceptibility to background noise and processing artifacts. To achieve more personalized NR processing, an effective approach may be to let HA users determine the optimal setting themselves during the fitting process.

Cell-penetrating peptides (CPPs) are short sequences of amino acids that facilitate the penetration of conjugated cargoes across mammalian cell membranes, and as such, they may provide a safe and effective method for drug delivery to the inner ear. Simple polyarginine peptides have been shown to induce significantly higher cell penetration rates among CPPs. Herein, we show that a peptide consisting of nine arginines ("9R") effectively delivered enhanced green fluorescent protein (EGFP) into guinea pig cochleae via the round window niche without causing any deterioration in auditory function. A second application, 24 hours after the first, prolonged the presence of EGFP. To assess the feasibility of protein transduction using 9R-CPPs via the round window, we used "X-linked inhibitor of apoptosis protein" (XIAP) bonded to a 9R peptide (XIAP-9R). XIAP-9R treatment prior to acoustic trauma significantly reduced putative hearing loss and the number of apoptotic hair cells loss in the cochleae. Thus, the topical application of molecules fused to 9R-CPPs may be a simple and promising strategy for treating inner ear diseases.

The standard method to determine the output level of acoustic and mechanical stimulation to the inner ear is measurement of vibration response of the stapes in human cadaveric temporal bones (TBs) by laser Doppler vibrometry. However, this method is reliable only if the intact ossicular chain is stimulated. For other stimulation modes an alternative method is needed. The differential intracochlear sound pressure between scala vestibuli (SV) and scala tympani (ST) is assumed to correlate with excitation. Using a custom-made pressure sensor it has been successfully measured and used to determine the output level of acoustic and mechanical stimulation. To make this method generally accessible, an off-the-shelf pressure sensor (Samba Preclin 420 LP, Samba Sensors) was tested here for intracochlear sound pressure measurements. During acoustic stimulation, intracochlear sound pressures were simultaneously measurable in SV and ST between 0.1 and 8 kHz with sufficient signal-to-noise ratios with this sensor. The pressure differences were comparable to results obtained with custom-made sensors. Our results demonstrated that the pressure sensor Samba Preclin 420 LP is usable for measurements of intracochlear sound pressures in SV and ST and for the determination of differential intracochlear sound pressures.

Some combinations of musical tones sound pleasing to Western listeners, and are termed consonant, while others sound discordant, and are termed dissonant. The perceptual phenomenon of consonance has been traced to the acoustic property of harmonicity. It has been repeatedly shown that neural correlates of consonance can be found as early as the auditory brainstem as reflected in the harmonicity of the scalp-recorded frequency-following response (FFR). "Neural Pitch Salience" (NPS) measured from FFRs-essentially a time-domain equivalent of the classic pattern recognition models of pitch-has been found to correlate with behavioral judgments of consonance for synthetic stimuli. Following the idea that the auditory system has evolved to process behaviorally relevant natural sounds, and in order to test the generalizability of this finding made with synthetic tones, we recorded FFRs for consonant and dissonant intervals composed of synthetic and natural stimuli. We found that NPS correlated with behavioral judgments of consonance and dissonance for synthetic but not for naturalistic sounds. These results suggest that while some form of harmonicity can be computed from the auditory brainstem response, the general percept of consonance and dissonance is not captured by this measure. It might either be represented in the brainstem in a different code (such as place code) or arise at higher levels of the auditory pathway. Our findings further illustrate the importance of using natural sounds, as a complementary tool to fully-controlled synthetic sounds, when probing auditory perception.

The mammalian cerebellum is a highly multimodal structure, receiving inputs from multiple sensory modalities and integrating them during complex sensorimotor coordination tasks. Previously, using cell-type-specific anatomical projection mapping, it was shown that multimodal pathways converge onto individual cerebellar granule cells (Huang et al., 2013). Here we directly measure synaptic currents using in vivo patch-clamp recordings and confirm that a subset of single granule cells receive convergent functional multimodal (somatosensory, auditory, and visual) inputs via separate mossy fibers. Furthermore, we show that the integration of multimodal signals by granule cells can enhance action potential output. These recordings directly demonstrate functional convergence of multimodal signals onto single granule cells.

Significance Complex pitch perception serves a pivotal role in human audition, especially in speech and music perception. It has been suggested that pitch perception mechanisms demonstrated in humans are not shared by nonhuman species. Here we provide evidence that a New World monkey, the common marmoset, shares all primary features of complex pitch perception mechanisms with humans. Combined with previous findings of a specialized pitch processing region in both marmoset and human auditory cortex, this evidence suggests that pitch perception mechanisms likely originated early in primate evolution.

Although resting-state functional connectivity is a commonly used neuroimaging paradigm, the underlying mechanisms remain unknown. Thalamo-cortical and cortico-cortical circuits generate oscillations at different frequencies during spontaneous activity. However, it remains unclear how the various rhythms interact and whether their interactions are lamina-specific. Here we investigated intra- and inter-laminar spontaneous phase-amplitude coupling (PAC). We recorded local-field potentials using laminar probes inserted in the forelimb representation of rat area S1. We then computed time-series of frequency-band- and lamina-specific current source density (CSD), and PACs of CSD for all possible pairs of the classical frequency bands in the range of 1-150 Hz. We observed both intra- and inter-laminar spontaneous PAC. Of 18 possible combinations, 12 showed PAC, with the highest measures of interaction obtained for the pairs of the theta/gamma and delta/gamma bands. Intra- and inter-laminar PACs involving layers 2/3-5a were higher than those involving layer 6. Current sinks (sources) in the delta band were associated with increased (decreased) amplitudes of high-frequency signals in the beta to fast gamma bands throughout layers 2/3-6. Spontaneous sinks (sources) of the theta and alpha bands in layers 2/3-4 were on average linked to dipoles completed by sources (sinks) in layer 6, associated with high (low) amplitudes of the beta to fast-gamma bands in the entire cortical column. Our findings show that during spontaneous activity, delta, theta, and alpha oscillations are associated with periodic excitability, which for the theta and alpha bands is lamina-dependent. They further emphasize the differences between the function of layer 6 and that of the superficial layers, and the role of layer 6 in controlling activity in those layers. Our study links theories on the involvement of PAC in resting-state functional connectivity with previous work that revealed lamina-specific anatomical thalamo-cortico-cortical connections.

Poorer hearing in the presence of background noise is a significant problem for the hearing impaired. Ototoxic drugs, ageing, and noise exposure can damage the sensory hair cells of the inner ear that are essential for normal hearing sensitivity. The relationship between outer hair cell (OHC) loss and progressively poorer hearing sensitivity in quiet or in competing background noise is supported by a number of human and animal studies. In contrast, the effect of moderate inner hair cell (IHC) loss or dysfunction shows almost no impact on behavioral measures of hearing sensitivity in quiet, when OHCs remain intact, but the relationship between selective IHC loss and hearing in noise remains relatively unknown. Here, a moderately high dose of carboplatin (75 mg/kg) that produced IHC loss in chinchillas ranging from 40 to 80 % had little effect on thresholds in quiet. However, when tested in the presence of competing broadband (BBN) or narrowband noise (NBN), thresholds increased significantly. IHC loss >60 % increased signal-to-noise ratios (SNRs) for tones (500-11,300 Hz) in competing BBN by 5-10 dB and broadened the masking function under NBN. These data suggest that IHC loss or dysfunction may play a significant role in listening in noise independent of OHC integrity and that these deficits may be present even when thresholds in quiet are within normal limits.

Sensory perception depends on the context in which a stimulus occurs. Prevailing models emphasize cortical feedback as the source of contextual modulation. However, higher order thalamic nuclei, such as the pulvinar, interconnect with many cortical and subcortical areas, suggesting a role for the thalamus in providing sensory and behavioral context. Yet the nature of the signals conveyed to cortex by higher order thalamus remains poorly understood. Here we use axonal calcium imaging to measure information provided to visual cortex by the pulvinar equivalent in mice, the lateral posterior nucleus (LP), as well as the dorsolateral geniculate nucleus (dLGN). We found that dLGN conveys retinotopically precise visual signals, while LP provides distributed information from the visual scene. Both LP and dLGN projections carry locomotion signals. However, while dLGN inputs often respond to positive combinations of running and visual flow speed, LP signals discrepancies between self-generated and external visual motion. This higher order thalamic nucleus therefore conveys diverse contextual signals that inform visual cortex about visual scene changes not predicted by the animal's own actions.

Background and objectives: Many studies have reported an association between diabetes and hearing loss. However, these reports were mainly abstractive correlations between common hearing loss and the incidence of diabetes. Therefore, we evaluated the impact of diabetes on the occurrence of and recovery from noise-induced hearing loss. Materials and methods: We used 5-week-old C57BLKS/J-m wild type (+/+) and C57BLKS/J-db/db male mice as the control and diabetic groups, respectively. In one set of experiments, the hearing levels of control and diabetic mice were measured weekly for 7 weeks. In a second set of experiments, control and diabetic mice were exposed to broadband white noise of 110 dB SPL for 3 hours; hearing levels were analyzed before and immediately after exposure, 1, 3, and 5 days, and 1, 2, 3, and 4 weeks after the noise exposure. Results: The hearing levels of the control group were better than those of the diabetic group at each weekly revision for 7 weeks at all auditory brainstem response frequencies (4, 8, 16, and 32 kHz). After noise exposure, both groups of mice showed an immediate increase in the hearing level threshold at all frequencies. Subsequent threshold recovery was seen in both groups with no difference in the hearing level recovery rates between the two groups. Conclusions: Hearing level with aging becomes significantly impaired earlier in diabetic mice but hearing recovery after noise exposure is similar between diabetic and control mice.

Tricellulin (also known as MARVELD2) is considered as a central component of tricellular tight junctions and is distributed among various epithelial tissues. Although mutations in the gene encoding tricellulin are known to cause deafness in humans (DFNB49) and mice, the influence of its systemic deletion in vivo remains unknown. When we generated tricellulin -knockout mice ( Tric −/− ), we found an early-onset rapidly progressive hearing loss associated with the degeneration of hair cells (HCs); however, their body size and overall appearance were normal. Tric −/− mice did not show any morphological change pertaining to other organs such as the gastrointestinal tract, liver, kidney, thyroid gland and heart. The endocochlear potential (EP) was normal in Tric −/− mice, suggesting that the tight junction barrier is maintained in the stria vascularis, where EP is generated. The degeneration of HCs, which occurred after the maturation of EP, was prevented in the culture medium with an ion concentration similar to that of the perilymph. These data demonstrate the specific requirement of tricellulin for maintaining ion homeostasis around cochlear HCs to ensure their survival. The Tric −/− mouse provides a new model for understanding the distinct roles of tricellulin in different epithelial systems as well as in the pathogenesis of DFNB49.

Identifying sounds is critical for an animal to make appropriate behavioral responses to environmental stimuli, including vocalizations from conspecifics. Identification of vocalizations may be supported by neuronal selectivity in the auditory pathway. The first place in the ascending auditory pathway where neuronal selectivity to vocalizations has been found is in the inferior colliculus (IC), but very few brainstem nuclei have been evaluated. Here, we tested whether selectivity to vocalizations is present in the dorsal cochlear nucleus (DCN). We recorded extracellular neural responses in the DCN of mice and found that fusiform cells responded in a heterogeneous and selective manner to mouse ultrasonic vocalizations. Most fusiform cells responded to vocalizations that contained spectral energy at much higher frequencies than the characteristic frequencies of the cells. To understand this mismatch of stimulus properties and frequency tuning of the cells, we developed a dynamic, nonlinear model of the cochlea that simulates cochlear distortion products on the basilar membrane. We preprocessed the vocalization stimuli through this model and compared responses to these distorted vocalizations with responses to the original vocalizations. We found that fusiform cells in the DCN respond in a heterogeneous manner to vocalizations, and that these neurons can use distortion products as a mechanism for encoding ultrasonic vocalizations. In addition, the selective neuronal responses were dependent on the presence of inhibitory sidebands that modulated the response depending on the temporal structure of the distortion product. These findings suggest that important processing of complex sounds occurs at a very early stage of central auditory processing and is not strictly a function of the cortex.