Auditory Research publications

Among the different autism spectrum disorders, Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Sensory and especially auditory hypersensitivity is a key symptom in patients, which is well mimicked in the Fmr1 -/- mouse model. However, the physiological mechanisms underlying FXS’s acoustic hypersensitivity in particular remain poorly understood. Here, we categorized spike response patterns to pure tones of different frequencies and intensities from neurons in the inferior colliculus (IC), a central integrator in the ascending auditory pathway. Based on this categorization we analyzed differences in response patterns between IC neurons of wild-type (WT) and Fmr1 -/- mice. Our results report broadening of frequency tuning, an increased firing in response to monaural as well as binaural stimuli, an altered balance of excitation-inhibition, and reduced response latencies, all expected features of acoustic hypersensitivity. Furthermore, we noticed that all neuronal response types in Fmr1 -/- mice displayed enhanced offset-rebound activity outside their excitatory frequency response area. These results provide evidence that the loss of Fmr1 not only increases spike responses in IC neurons similar to auditory brainstem neurons, but also changes response patterns such as offset spiking. One can speculate this to be an underlying aspect of the receptive language problems associated with Fragile X syndrome.

While most anuran species are highly vocal, few of them seem to be endowed with a complex call repertoire. Odorrana tormota , combines a remarkable vocalization complexity with auditory sensitivity over an extended spectral range spanning from audible to ultrasonic frequencies. This species is also exceptional for its ability to modify its middle ear tuning by closing the Eustachian tubes (ET). Using scanning laser Doppler vibrometry, the tympanal vibrations were measured to investigate if the tuning shift caused by the ET closure contributes to intraspecific acoustic communication. To gain insight into the inner ear frequency selectivity and sensitivity of this species, distortion product otoacoustic emissions were recorded at multiple frequency-level combinations. Our measurements of inner ear responses indicated that in O. tormota each sex is more sensitive to the frequencies of the other sex's vocalizations, female ears are more sensitive to 2–7 kHz, while male ears are more sensitive to 3–15 kHz. We also found that in both sexes the ET closure impacts the sensitivity of the middle and inner ear at frequencies used for communication with conspecifics. This study broadens our understanding of peripheral auditory mechanisms contributing to intraspecific acoustic communication in anurans.

Vertigo is a debilitating disease affecting 15–20% of adults worldwide. Vestibular peripheral vertigo is the most common cause of vertigo, often due to Meniere's disease and benign paroxysmal positional vertigo. Although some vertigo symptoms can be controlled by conservative treatment and/or vestibular rehabilitation therapy, these treatments do not work for some patients. Semicircular canal occlusion surgery has proven to be very effective for these patients with intractable vertigo. However, its application is limited due to concern that the procedure will disrupt normal hearing. In this study, we investigated if occlusion of two semicircular canals would jeopardize auditory function by comparing auditory function and hair cell morphology between the surgical and contralateral ears before and after the surgery in a mouse model. By measuring the auditory brainstem response and distortion product otoacoustic emission 4 weeks post-surgery, we show that auditory function does not significantly change between the surgical and contralateral ears. In addition, confocal imaging has shown no hair cell loss in the cochlear and vestibular sensory epithelia, and scanning electron microscopy also indicates normal stereocilia morphology in the surgical ear. More importantly, the endocochlear potential measured from the surgical ear is not significantly different than that seen in the contralateral ear. Our study suggests that occlusion of two semicircular canals does not disrupt normal hearing in the mouse model, providing a basis to extend the procedure to patients, even those with normal hearing, benefitting more patients with intractable vertigo attacks.

Anthropogenic noise of variable temporal patterns is increasing in aquatic environments, causing physiological stress and sensory impairment. However, scarce information exists on exposure effects to continuous versus intermittent disturbances, which is critical for noise sustainable management. We tested the effects of different noise regimes on the auditory system and behaviour in the zebrafish ( Danio rerio ). Adult zebrafish were exposed for 24 h to either white noise (150 ± 10 dB re 1 μPa) or silent control. Acoustic playbacks varied in temporal patterns—continuous, fast and slow regular intermittent, and irregular intermittent. Auditory sensitivity was assessed with Auditory Evoked Potential recordings, revealing hearing loss and increased response latency in all noise-treated groups. The highest mean threshold shifts (c. 13 dB) were registered in continuous and fast intermittent treatments, and no differences were found between regular and irregular regimes. Inner ear saccule did not reveal significant hair cell loss but showed a decrease in presynaptic Ribeye b protein especially after continuous exposure. Behavioural assessment using the standardized Novel Tank Diving assay showed that all noise-treated fish spent > 98% time in the bottom within the first minute compared to 82% in control, indicating noise-induced anxiety/stress. We provide first data on how different noise time regimes impact a reference fish model, suggesting that overall acoustic energy is more important than regularity when predicting noise effects.

The purpose of this study is to take preliminary steps to unify psychoacoustic techniques with reaction-time methodologies to address the perceptual mechanisms responsible for the detection of one vs. multiple sounds. We measured auditory redundancy gains for auditory detection of pure tones widely spaced in frequency using the tools of Systems Factorial Technology to evince the system architecture and workload capacity in two different scenarios (SOFT and LOUD). We adopted an experimental design in which the presence or absence of a target at each of two frequencies was combined factorially with two stimulus levels. Replicating previous work, results did not allow an assessment of system architecture due to a failure to observe factor influence at the level of distribution ordering for dual-target stimuli for both SOFT and LOUD scenarios. All subjects demonstrated very modest redundancy gains for the dual-target compared to the single-target stimuli, and results were similar for both LOUD and SOFT. We propose that these results can be predicted by a mental architecture that falls into the class of integrated subadditive parallel systems, using a well-supported assumption that reaction time is driven by loudness. We demonstrate that modeled loudness of the experimental sounds (which ranged between about 0.2 and 14 sones) is highly correlated with mean reaction time ( r = −0.87), and we provide a proof-of-concept model based on Steven’s Power law that predicts both a failure of distributional ordering for dual-target stimuli and very modest redundancy gains.

Objective . Although neural-enabled prostheses have been used to restore some lost functionality in clinical trials, they have faced difficulty in achieving high degree of freedom, natural use compared to healthy limbs. This study investigated the in vivo functionality of a flexible and scalable regenerative peripheral-nerve interface suspended within a microchannel-embedded, tissue-engineered hydrogel (the magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI)) as a potential approach to improving current issues in peripheral nerve interfaces. Approach . Assembled MARTEENI devices were implanted in the gaps of severed sciatic nerves in Lewis rats. Both acute and chronic electrophysiology were recorded, and channel-isolated activity was examined. In terminal experiments, evoked activity during paw compression and stimulus response curves generated from proximal nerve stimulation were examined. Electrochemical impedance spectroscopy was performed to assess the complex impedance of recording sites during chronic data collection. Features of the foreign-body response (FBR) in non-functional implants were examined using immunohistological methods. Main results . Channel-isolated activity was observed in acute, chronic, and terminal experiments and showed a typically biphasic morphology with peak-to-peak amplitudes varying between 50 and 500 µ V. For chronic experiments, electrophysiology was observed for 77 days post-implant. Within the templated hydrogel, regenerating axons formed minifascicles that varied in both size and axon count and were also found to surround device threads. No axons were found to penetrate the FBR. Together these results suggest the MARTEENI is a promising approach for interfacing with peripheral nerves. Significance . Findings demonstrate a high likelihood that observed electrophysiological activity recorded from implanted MARTEENIs originated from neural tissue. The variation in minifascicle size seen histologically suggests that amplitude distributions observed in functional MARTEENIs may be due to a combination of individual axon and mini-compound action potentials. This study provided an assessment of a functional MARTEENI in an in vivo animal model for the first time.

Kanamycin and cisplatin are ototoxic drugs. The mechanisms are incompletely known. With subcutaneous kanamycin (400 mg/kg, 15 days), auditory threshold shifts were detected at days 12–13 at 16 and 32 kHz, extending to 8 and 4 kHz at days 14–15. The outer hair cell (OHC) loss was concentrated past day 12. The maximum cochlear length showing apoptotic cells, tested with TUNEL, was at day 13. At day 15, 1/5 of the apical cochlea contained preserved OHCs. 3-nitrotyrosine (3-NT) immunolabeling, showing oxidative stress, was found in surviving OHCs and in basal and middle portions of the stria vascularis (SV). The antioxidant Gpx1 gene expression was decreased. The immunocytochemistry showed diminished Gpx1 in OHCs. With intraperitoneal cisplatin (16 mg/kg, single injection), no evoked auditory activity was recorded at the end of treatment, at 72 h. The basal third of the cochlea lacked OHCs. Apoptosis occupied the adjacent 1/3, and the apical third contained preserved OHCs. 3-NT immunolabeling was extensive in OHCs and the SV. Gpx1 and Sod1 gene expression was downregulated. Gpx1 immunostaining diminished in middle and basal SV. More OHCs survived cisplatin than kanamycin towards the apex, despite undetectable evoked activity. Differential regulation of antioxidant enzyme levels suggests differences in the antioxidant response for both drugs.

Voluntary stream segregation was investigated in cochlear implant (CI) users and normal-hearing (NH) listeners using a segregation-promoting objective approach which evaluated the role of spectral and amplitude-modulation (AM) rate separations on stream segregation and its build-up. Sequences of 9 or 3 pairs of A and B narrowband noise (NBN) bursts were presented which differed in either center frequency of the noise band, the AM-rate, or both. In some sequences (delayed sequences), the last B burst was delayed by 35 ms from their otherwise-steady temporal position. In the other sequences (no-delay sequences), the last B bursts were temporally advanced from 0 to 10 ms. A single interval yes/no procedure was utilized to measure participants’ sensitivity ( d ′ ) in identifying delayed vs. no-delay sequences. A higher d ′ value showed the higher ability to segregate the A and B subsequences. For NH listeners, performance improved with each spectral separation. However, for CI users, performance was only significantly better for the condition with the largest spectral separation. Additionally, performance was significantly poorer for the largest AM-rate separation than for the condition with no AM-rate separation for both groups. The significant effect of sequence duration in both groups indicated that listeners made more improvement with lengthening the duration of stimulus sequences, supporting the build-up effect. The results of this study suggest that CI users are less able than NH listeners to segregate NBN bursts into different auditory streams when they are moderately separated in the spectral domain. Contrary to our hypothesis, our results indicate that AM-rate separation may interfere with the segregation of streams of NBN. Additionally, our results add evidence to the literature that CI users build up stream segregation at a rate comparable to NH listeners, when the inter-stream spectral separations are adequately large.

Intra organ of Corti (OC) vibrations differ from those measured at the basilar membrane (BM), with higher amplitudes and a wide-band nonlinearity extending well below a region's best frequency. The vibrations are boosted by the cochlear amplifier, the active processes within the mammalian hearing organ, and are thus sensitive to metabolic or pharmacological manipulation. We introduced salicylate, a known blocker of outer hair cell (OHC) based electromotility, into the perilymphatic space by applying sodium salicylate onto the round window membrane. Vibration patterns of an area of the OC were mapped with phase sensitive optical coherence tomography before and after treatment; distortion product otoacoustic emissions (DPOAEs) were measured at similar times to assess the cochlear condition. Following treatment, all regions showed a loss of vibration amplitude and tuning while OHC-region vibrations retained their wide-band nonlinearity. OC vibrations, which had been relatively confined in a region including OHCs and extending to the BM at the outer pillar foot, became less confined with structures lateral to the OHCs sometimes exhibiting the highest amplitudes. Vibrations and DPOAEs could recover to baseline levels over approximately three hours post treatment. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.

Given its inputs from auditory structures and neuromodulatory systems, the posterior tail of the striatum is ideally positioned to influence behavioral responses to acoustic stimuli according to context and previous rewards. Results from previous studies indicate that neurons in this striatal region display selective responses to sounds. However, it is not clear whether different striatal cell classes code for distinct features of sounds or how different striatal output pathways may use acoustic information to guide behavior. Here we compared the sound-evoked responses of posterior striatal neurons that form the striatal direct pathway (and express the dopamine receptor D 1 ) to the responses of neighboring neurons in naive mice. We achieved this via optogenetic photo-identification of D 1 -expressing neurons during extracellular electrophysiological recordings in awake head-fixed mice of both sexes. We found that the frequency tuning of sound-responsive direct-pathway striatal neurons is comparable with that of their sound-responsive neighbors. Moreover, we found that both populations encode amplitude-modulated sounds in a similar fashion. These results suggest that different classes of neurons in the posterior striatum of naive animals have similar access to acoustic features conveyed by the auditory system even outside the context of an auditory task.

Foraging on nocturnally migrating birds is one of the most challenging foraging tasks in the animal kingdom. Only three bat species (e.g., Ia io) known to date can prey on migratory birds. However, how these bats have exploited this challenging dietary niche remains unknown. Here, we demonstrate that I. io hunts at the altitude of migrating birds during the bird migration season. The foraging I. io exhibited high flight altitudes (up to 4945 m above sea level) and high flight speeds (up to 143.7 km h-1). I. io in flight can actively prey on birds in the night sky via echolocation cues. Genes associated with DNA damage repair, hypoxia adaptation, biting and mastication, and digestion and metabolism have evolved to adapt to this species' avivorous habits. Our results suggest that the evolution of behavioral innovation and genomic novelty are associated with the exploitation of challenging dietary opportunities.

The transduction of acoustic information by hair cells depends upon mechanosensitive stereociliary bundles that project from their apical surface. Mutations or absence of the stereociliary protein EPS8 cause deafness in humans and mice, respectively. Eps8 knockout mice (Eps8 -/- ) have hair cells with immature stereocilia and fail to become sensory receptors. Here, we show that exogenous delivery of Eps8 using Anc80L65 in P1-P2 Eps8 -/- mice in vivo rescued the hair bundle structure of apical-coil hair cells. Rescued hair bundles correctly localize EPS8, WHIRLIN, MYO15, and BAIAP2L2, and generate normal mechanoelectrical transducer currents. Inner hair cells with normal-looking stereocilia re-expressed adult-like basolateral ion channels (BK and KCNQ4) and have normal exocytosis. The number of hair cells undergoing full recovery was not sufficient to rescue hearing in Eps8 -/- mice. Adeno-associated virus (AAV)-transduction of P3 apical-coil and P1-P2 basal-coil hair cells does not rescue hair cells, nor does Anc80L65-Eps8 delivery in adult Eps8 -/- mice. We propose that AAV-induced gene-base therapy is an efficient strategy to recover the complex hair-cell defects in Eps8 -/- mice. However, this therapeutic approach may need to be performed in utero since, at postnatal ages, Eps8 -/- hair cells appear to have matured or accumulated damage beyond the point of repair.

Inner ear gene therapy using adeno-associated viruses (AAVs) has been successfully applied to several mouse models of hereditary hearing loss to improve their auditory function. While most inner ear gene therapy studies have focused on the mechanosensory hair cells and supporting cells in the organ of Corti, the cochlear lateral wall and the endolymphatic sac have not garnered much attention. The cochlear lateral wall and the endolymphatic sac play critical roles in inner ear ionic and fluid homeostasis. Mutations in genes expressed in the cochlear lateral wall and the endolymphatic sac are present in a large percentage of patients with hereditary hearing loss. In this study, we examine the transduction patterns and efficiencies of conventional (AAV2 and AAV8) and synthetic (AAV2.7m8, AAV8BP2, and Anc80L65) AAVs in the mouse inner ear. We found that AAV8BP2 and AAV8 are capable of transducing the marginal cells and intermediate cells in the stria vascularis. These two AAVs can also transduce the epithelial cells of the endolymphatic sac. Our data suggest that AAV8BP2 and AAV8 are highly useful viral vectors for gene therapy studies targeting the cochlear lateral wall and the endolymphatic sac.

Hearing loss is not unique to humans and is experienced by all animals in the face of wild and eclectic differences in ear morphology. Here, we exploited the high throughput and accessible tympanal ear of the desert locust, Schistocerca gregaria to rigorously quantify changes in the auditory system due to noise exposure and age. In this exploratory study, we analyzed tympanal displacements, morphology of the auditory Müller's organ and measured activity of the auditory nerve, the transduction current, and electrophysiological properties of individual auditory receptors. This work shows that hearing loss manifests as a complex disorder due to differential effects of age and noise on several processes and cell types within the ear. The "middle-aged deafness" pattern of hearing loss found in locusts mirrors that found for humans exposed to noise early in their life suggesting a fundamental interaction of the use of an auditory system (noise) and its aging.

Gene therapy would benefit from the effective editing of targeted cells with CRISPR-Cas9 tools. However, it is difficult to precisely assess the editing performance in vivo because the tissues contain many non-targeted cells, which is one of the major barriers to clinical translation. Here, in the Atoh1-GFP;Kcnq4 +/G229D mice, recapitulating a novel mutation we identified in a hereditary hearing loss pedigree, the high-efficiency editing of CRISPR-Cas9 in hair cells (34.10% on average) was precisely detected by sorting out labeled cells compared with only 1.45% efficiency in the whole cochlear tissue. After injection of the developed AAV_SaCas9-KKH_sgRNA agents, the Kcnq4 +/G229D mice showed significantly lower auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) thresholds, shorter ABR wave I latencies, higher ABR wave I amplitudes, increased number of surviving outer hair cells (OHCs), and more hyperpolarized resting membrane potentials of OHCs. These findings provide an innovative approach to accurately assess the underestimated editing efficiency of CRISPR-Cas9 in vivo and offer a promising strategy for the treatment of KCNQ4-related deafness.

Opsin-3 ( Opn3 , encephalopsin) was the first nonvisual opsin gene discovered in mammals. Since then, several Opn3 functions have been described, and in two cases (adipose tissue, smooth muscle) light sensing activity is implicated. In addition to peripheral tissues, Opn3 is robustly expressed within the central nervous system, for which it derives its name. Despite this expression, no studies have investigated developmental or adult CNS consequences of Opn3 loss-of-function. Here, the behavioral consequences of mice deficient in Opn3 were investigated. Opn3 -deficient mice perform comparably to wild-type mice in measures of motor coordination, socialization, anxiety-like behavior, and various aspects of learning and memory. However, Opn3 -deficient mice have an attenuated acoustic startle reflex (ASR) relative to littermates. This deficit is not because of changes in hearing sensitivity, although Opn3 was shown to be expressed in auditory and vestibular structures, including cochlear outer hair cells. Interestingly, the ASR was not acutely light-dependent and did not vary between daytime and nighttime trials, despite known functions of Opn3 in photoreception and circadian gene amplitude. Together, these results demonstrate the first role of Opn3 on behavior, although the role of this opsin in the CNS remains largely elusive.

Background Deafness-dystonia-optic neuronopathy (DDON) syndrome, a condition that predominantly affects males, is caused by mutations in translocase of mitochondrial inner membrane 8A ( TIMM8A ) /deafness dystonia protein 1 ( DDP1 ) gene and characterized by progressive deafness coupled with other neurological abnormalities. In a previous study, we demonstrated the phenotype of male mice carrying the hemizygous mutation of Timm8a1-I23fs49X . In a follow-up to that study, this study aimed to observe the behavioral changes in the female mutant (MUT) mice with homologous mutation of Timm8a1 and to elucidate the underlying mechanism for the behavioral changes. Materials and methods Histological analysis, transmission electron microscopy (EM), Western blotting, hearing measurement by auditory brainstem response (ABR), and behavioral observation were compared between the MUT mice and wild-type (WT) littermates. Results The weight of the female MUT mice was less than that of the WT mice. Among MUT mice, both male and female mice showed hearing impairment, anxiety-like behavior by the elevated plus maze test, and cognitive deficit by the Morris water maze test. Furthermore, the female MUT mice exhibited coordination problems in the balance beam test. Although the general neuronal loss was not found in the hippocampus of the MUT genotype, EM assessment indicated that the mitochondrial size showing as aspect ratio and form factor in the hippocampus of the MUT strain was significantly reduced compared to that in the WT genotype. More importantly, this phenomenon was correlated with the upregulation of translation of mitochondrial fission process protein 1(Mtfp1)/mitochondrial 18 kDa protein (Mtp18), a key fission factor that is a positive regulator of mitochondrial fission and mitochondrial size. Interestingly, significant reductions in the size of the uterus and ovaries were noted in the female MUT mice, which contributed to significantly lower fertility in the MUT mice. Conclusion Together, a homologous mutation in the Timm8a1 gene caused the hearing impairment and psychiatric behavioral changes in the MUT mice; the latter phenotype might be related to a reduction in mitochondrial size regulated by MTP18.

The cochlea decomposes sounds into separate frequency channels, from which the auditory brain must reconstruct the auditory scene. To do this the auditory system must make decisions about which frequency information should be grouped together, and which should remain distinct. Two key cues for grouping are temporal coherence, resulting from coherent changes in power across frequency, and temporal predictability, resulting from regular or predictable changes over time. To test how these cues contribute to the construction of a sound scene we present listeners with a range of precursor sounds, which act to prime the auditory system by providing information about each sounds structure, followed by a fixed masker in which participants were required to detect the presence of an embedded tone. By manipulating temporal coherence and/or temporal predictability in the precursor we assess how prior sound exposure influences subsequent auditory grouping. In Experiment 1, we measure the contribution of temporal predictability by presenting temporally regular or jittered precursors, and temporal coherence by using either narrow or broadband sounds, demonstrating that both independently contribute to masking/unmasking. In Experiment 2, we measure the relative impact of temporal coherence and temporal predictability and ask whether the influence of each in the precursor signifies an enhancement or interference of unmasking. We observed that interfering precursors produced the largest changes to thresholds.

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K + currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

Sensory information, including auditory feedback, is used by talkers to maintain fluent speech articulation. Current models of speech motor control posit that speakers continually adjust their motor commands based on discrepancies between the sensory predictions made by a forward model and the sensory consequences of their speech movements. Here, in two within-subject design experiments, we used a real-time formant manipulation system to explore how reliant speech articulation is on the accuracy or predictability of auditory feedback information. This involved introducing random formant perturbations during vowel production that varied systematically in their spatial location in formant space (Experiment 1) and temporal consistency (Experiment 2). Our results indicate that, on average, speakers’ responses to auditory feedback manipulations varied based on the relevance and degree of the error that was introduced in the various feedback conditions. In Experiment 1, speakers’ average production was not reliably influenced by random perturbations that were introduced every utterance to the first (F1) and second (F2) formants in various locations of formant space that had an overall average of 0 Hz. However, when perturbations were applied that had a mean of +100 Hz in F1 and −125 Hz in F2, speakers demonstrated reliable compensatory responses that reflected the average magnitude of the applied perturbations. In Experiment 2, speakers did not significantly compensate for perturbations of varying magnitudes that were held constant for one and three trials at a time. Speakers’ average productions did, however, significantly deviate from a control condition when perturbations were held constant for six trials. Within the context of these conditions, our findings provide evidence that the control of speech movements is, at least in part, dependent upon the reliability and stability of the sensory information that it receives over time.