Auditory Research publications

Hearing loss is a common disability affecting the world’s population today. While several studies have shown that inner ear gene therapy can be successfully applied to mouse models of hereditary hearing loss to improve hearing, most of these studies rely on inner ear gene delivery in the neonatal age, when mouse inner ear has not fully developed. However, the human inner ear is fully developed at birth. Therefore, in order for inner ear gene therapy to be successfully applied in patients with hearing loss, one must demonstrate that gene delivery can be safely and reliably performed in the mature mammalian inner ear. The posterior semicircular canal approach has been shown to be an effective gene delivery method in the neonatal mouse inner ear. In this study, we examine the steps involved in posterior semicircular canal gene delivery in the adult mouse inner ear. We observe that the adult mouse inner ear is more susceptible to surgical trauma. We also find that the duration of perilymphatic leakage and injection rate have a significant effect on the post-surgical hearing outcome. Our results show that AAV2.7m8 is capable of transducing the adult mouse inner and outer hair cells with high efficiency.

The transport system in cochlear hair cells (HCs) is important for their function, and the kinesin family of proteins transport numerous cellular cargos via the microtubule network in the cytoplasm. Here, we found that Klc2 (kinesin light chain 2), the light chain of kinesin-1 that mediates cargo binding and regulates kinesin-1 motility, is essential for cochlear function. We generated mice lacking Klc2, and they suffered from low-frequency hearing loss as early as 1 month of age. We demonstrated that deficiency of Klc2 resulted in abnormal transport of mitochondria and the down-regulation of the GABAA receptor family. In addition, Whole genome sequencing(WGS) of patient showed KLC2 was related to low-frequency hearing in human. Hence, to explore therapeutic approaches, we developed adeno-associated virus containing the Klc2 wide-type cDNA sequence, and Klc2-null mice delivered virus showed apparent recovery, including decreased ABR threshold and reduced Out Hair Cell (OHC) loss. In summary, we show that the kinesin transport system plays an indispensable and special role in cochlear HC function in mice and human, and that mitochondrial localization is essential for HC survival.

Objective . Research by Oby (2016 J. Neural. Eng. 13 036009) demonstrated that the optimal threshold for extracting information from visual and motor cortices may differ from the optimal threshold for identifying single neurons via spike sorting methods. The optimal threshold for extracting information from auditory cortex has yet to be identified, nor has the optimal temporal scale for representing auditory cortical activity. Here, we describe a procedure to jointly optimize the extracellular threshold and bin size with respect to the decoding accuracy achieved by a linear classifier for a diverse set of auditory stimuli. Approach . We used linear multichannel arrays to record extracellular neural activity from the auditory cortex of awake squirrel monkeys passively listening to both simple and complex sounds. We executed a grid search of the coordinate space defined by the voltage threshold (in units of standard deviation) and the bin size (in units of milliseconds), and computed decoding accuracy at each point. Main results . The optimal threshold for information extraction was consistently near two standard deviations below the voltage trace mean, which falls significantly below the range of three to five standard deviations typically used as inputs to spike sorting algorithms in basic research and in brain-computer interface (BCI) applications. The optimal binwidth was minimized at the optimal voltage threshold, particularly for acoustic stimuli dominated by temporally dynamic features, indicating that permissive thresholding permits readout of cortical responses with temporal precision on the order of a few milliseconds. Significance . The improvements in decoding accuracy we observed for optimal readout parameters suggest that standard thresholding methods substantially underestimate the information present in auditory cortical spiking patterns. The fact that optimal thresholds were relatively low indicates that local populations of cortical neurons exhibit high temporal coherence that could be leveraged in service of future auditory BCI applications.

Humans are rapidly changing the marine environment through a multitude of effects, including increased greenhouse gas emissions resulting in warmer and acidified oceans. Elevated CO 2 conditions can cause sensory deficits and altered behaviours in marine organisms, either directly by affecting end organ sensitivity or due to likely alterations in brain chemistry. Previous studies show that auditory-associated behaviours of larval and juvenile fishes can be affected by elevated CO 2 (1000 µatm). Here, using auditory evoked potentials (AEP) and micro-computer tomography (microCT) we show that raising juvenile snapper, Chrysophyrs auratus , under predicted future CO 2 conditions resulted in significant changes to their hearing ability. Specifically, snapper raised under elevated CO 2 conditions had a significant decrease in low frequency (less than 200 Hz) hearing sensitivity. MicroCT demonstrated that these elevated CO 2 snapper had sacculus otolith's that were significantly larger and had fluctuating asymmetry, which likely explains the difference in hearing sensitivity. We suggest that elevated CO 2 conditions have a dual effect on hearing, directly effecting the sensitivity of the hearing end organs and altering previously described hearing induced behaviours. This is the first time that predicted future CO 2 conditions have been empirically linked through modification of auditory anatomy to changes in fish hearing ability. Given the widespread and well-documented impact of elevated CO 2 on fish auditory anatomy, predictions of how fish life-history functions dependent on hearing may respond to climate change may need to be reassessed.

Significance The katydid tympanal ears have outer, middle, and inner ear components analogous to mammalian ears. Unlike mammals, each ear has two tympana exposed to sound both externally and internally, with a delayed internal version arriving via the gas-filled ear canal (EC). The two combined inputs in each ear play a significant role in directional hearing. Here, we demonstrate that the major factor causing the internal delay is the EC geometry. The EC bifurcates asymmetrically, producing two additional internal paths that impose different sound velocities for each tympanum. Therefore, various versions of the same signal reach the ears at various times, increasing the chance to pinpoint the sound source. Findings could inspire algorithms for accurate acoustic triangulation in detection sensors.

Significance Our ability to identify sounds and understand communication signals depends upon our brains’ capacity to combine information about diverse sound features, including temporal patterns. The central nucleus of the inferior colliculus (ICC) performs an initial stage of this integration, but a circuit-based understanding of these processes has been hampered by difficulties in separating clearly defined functional cell types. Here we identify and characterize a major excitatory projection neuron of the ICC. These neurons show uniform intrinsic firing patterns and tuning to frequency, but strikingly diverse temporal responses to sound. Our results suggest that diversity in temporal coding is represented even within a single cell class and is likely primarily driven by differences in circuit connectivity.

When spectral components of a complex sound are presented not simultaneously but distributed over time, human listeners can still, to a degree, perceptually recover the spectral profile of the sound. This capability of integrating spectral information over time was investigated using a cued informational masking paradigm. Listeners detected a 1-kHz pure tone in a simultaneous masker composed of six random-frequency tones drawn on every trial. The spectral profile of the masker was cued using a precursor sound that consisted of a sequence of 50-ms bursts, separated by inter-burst intervals of 100 ms. Each burst in the precursor consisted of pure tones at the masker frequencies with tones appearing at each of the masker frequencies at different presentation probabilities. As the presentation probability increased in different conditions, the detectability of the target improved, indicating reliable precursor cuing regarding the spectral content of the masker. For many listeners, performance did not significantly improve as the number of precursor bursts increased from 2 to 16, indicating inefficient integration of information beyond 2 bursts. Additional analyses suggest that when intensity of the bursts is relatively constant, the contribution of the precursor is dominated by information in the initial burst.

Tinnitus has similarities to chronic neuropathic pain where there are changes in the firing rate of different types of afferent neurons. We postulated that one possible cause of tinnitus is a change in the distribution of spontaneous firing rates in at least one type of afferent auditory nerve fibre in anaesthetised guinea pigs. In control animals there was a bimodal distribution of spontaneous rates, but the position of the second mode was different depending upon whether the fibres responded best to high (> 4 kHz) or low (≤4 kHz) frequency tonal stimulation. The simplest and most reliable way of inducing tinnitus in experimental animals is to administer a high dose of sodium salicylate. The distribution of the spontaneous firing rates was different when salicylate (350 mg/kg) was administered, even when the sample was matched for the distribution of characteristic frequencies in the control population. The proportion of medium spontaneous rate fibres (MSR, 1≤ spikes/s ≤20) increased while the proportion of the highest, high spontaneous firing rate fibres (HSR, > 80 spikes/s) decreased following salicylate. The median rate fell from 64.7 spikes/s (control) to 35.4 spikes/s (salicylate); a highly significant change (Kruskal-Wallis test p < 0.001). When the changes were compared with various models of statistical probability, the most accurate model was one where most HSR fibres decreased their firing rate by 32 spikes/s. Thus, we have shown a reduction in the firing rate of HSR fibres that may be related to tinnitus.

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.

We previously reported that dysregulation of histone deacetylase 2 (Hdac2) was associated with the prognosis of sudden sensorineural hearing loss. However, the underlying molecular mechanisms are poorly understood. In the present study, we developed an acute hearing loss animal model in guinea pigs by infusing lipopolysaccharides (LPS) into the cochlea and measured the expression of Hdac2 in the sensory epithelium. We observed that the level of Hdac2 was significantly decreased in the LPS-infused cochleae. The levels of apoptosis-inhibition genes Bcl-2 and Bcl-xl were also decreased in the cochlea and correlated positively with the levels of Hdac2. Caspase3 or TUNEL-positive spiral ganglion neurons, hair cells, and supporting cells were observed in the LPS-infused cochleae. These in vivo observations were recapitulated in cell culture experiments. Based on bioinformatics analysis, we found miR-204-5p was engaged in the regulation of Hdac2 on Bcl-2. Molecular mechanism experiments displayed that miR-204-5p could be regulated by Hdac2 through interacting with transcription factor Sp1. Taken together, these results indicated that the Hdac2/Sp1/miR-204-5p/Bcl-2 regulatory axis mediated apoptosis in the cochlea, providing potential insights into the progression of acute hearing loss. To our knowledge, the study describes a miRNA-related mechanism for Hdac2-mediated regulation in the cochlea for the first time.

The ability to use temporal relationships between cross-modal cues facilitates perception and behavior. Previously we observed that temporally correlated changes in the size of a visual stimulus and the intensity in an auditory stimulus influenced the ability of listeners to perform an auditory selective attention task (Maddox, Atilgan, Bizley, & Lee, 2015). Participants detected timbral changes in a target sound while ignoring those in a simultaneously presented masker. When the visual stimulus was temporally coherent with the target sound, performance was significantly better than when the visual stimulus was temporally coherent with the masker, despite the visual stimulus conveying no task-relevant information. Here, we trained observers to detect audiovisual temporal coherence and asked whether this changed the way in which they were able to exploit visual information in the auditory selective attention task. We observed that after training, participants were able to benefit from temporal coherence between the visual stimulus and both the target and masker streams, relative to the condition in which the visual stimulus was coherent with neither sound. However, we did not observe such changes in a second group that were trained to discriminate modulation rate differences between temporally coherent audiovisual streams, although they did show an improvement in their overall performance. A control group did not change their performance between pretest and post-test and did not change how they exploited visual information. These results provide insights into how crossmodal experience may optimize multisensory integration.

Despite a widespread expression pattern in the central nervous system, the role of the sodium bicarbonate cotransporter NBCn1/Slc4a7 has not been investigated for locomotor activity, emotion and cognition. Here, we addressed the behavioral consequences of NBCn1 knockout and evaluated hearing and vision that are reportedly impaired in an earlier line of NBCn1 knockout mice and may contribute to behavioral changes. In a circular open field, the knockout mice traveled a shorter distance, especially in the periphery of the chamber, than wildtype littermates. The knockout mice also traveled a shorter total distance in a home cage-like open field. Rearing and grooming behaviors were reduced. The knockout and control mice displayed similar time spent and number of open and closed arms in the elevated plus maze test, indicating negligible change in anxiety. In the Morris water maze test, both groups of mice learned the location of an escape platform within comparable time on the training trials and showed similar platform identification on the probe trial. The knockout mice maintained normal visual responses in the optokinetic drum and produced evoked potentials in response to light stimuli. However, these mice failed to produce auditory evoked potentials. qPCR revealed a robust expression of an alternatively transcribed NBCn1 variant in the knockout mouse retina. These results indicate that NBCn1 deletion leads to reduced locomotor activity in mice by affecting their exploratory behaviors or emotionality. The deletion also causes hearing loss, but its effect on vision varies between different lines of knockout mice.

Budgerigars ( Melopsittacus undulatus ) are small Australian parrots with a well-documented, learned vocal repertoire and a high degree of vocal production learning. These birds live in large, social flocks and they vocally interact with each other in a dynamic, reciprocal manner. We assume that budgerigars must process and integrate a wide variety of sensory stimuli when selecting appropriate vocal responses to conspecifics during vocal interactions, but the relative contributions of these different stimuli to that process are next to impossible to tease apart in a natural context. Here we show that budgerigars, under operant control, can learn to respond to specific stimuli with a specific vocal response. Budgerigars were trained to produce contact calls to a combination of auditory and visual cues. Birds learned to produce specific contact calls to stimuli that differed either in location (visual or auditory) or quality (visual). Interestingly, the birds could not learn to associate different vocal responses with different auditory stimuli coming from the same location. Surprisingly, this was so even when the auditory stimuli and the responses were the same (i.e., the bird’s own contact call). These results show that even in a highly controlled operant context, acoustic cues alone were not sufficient to support vocal production learning in budgerigars. From a different perspective, these results highlight the significant role that social interaction likely plays in vocal production learning so elegantly shown by Irene Pepperberg’s work in parrots.

Noise-induced hearing loss (NIHL) is characterized by cellular damage to the inner ear, which is exacerbated by inflammation. High-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP), acts as a mediator of inflammation or an intercellular messenger according to its cellular localization. Blocking or regulating HMGB1 offers an attractive approach in ameliorating NIHL. However, the precise therapeutic intervention must be based on a deeper understanding of its dynamic molecular distribution and function in cochlear pathogenesis after acoustic trauma. Here, we have presented the spatiotemporal dynamics of the expression of HMGB1, exhibiting distribution variability in specific cochlear regions and cells following noise exposure. After gene manipulation, we further investigated the characteristics of cellular HMGB1 in HEI-OC1 cells. The higher cell viability observed in the HMGB1 knocked-down group after stimulation with H 2 O 2 indicated the possible negative effect of HMGB1 on cellular lifespan. In conclusion, this study demonstrated that HMGB1 is involved in NIHL pathogenesis and its molecular biology has essential and subtle influences, preserving a translational potential for pharmacological intervention.

Background: Allylnitrile is a compound found in cruciferous vegetables and has the same lethality and toxic effects as the other nitriles. In 2013, a viable allylnitrile ototoxicity mouse model was established. The toxicity of allylnitrile was limited through inhibition of CYP2E1 with trans-1,2-dichloroethylene (TDCE). The allylnitrile intoxication model has been extensively tested in the 129S1 mouse strain for vestibular function, which showed significant HC loss in the vestibular organ accompanied by severe behavioral abnormalities. However, the effect of allylnitrile on auditory function remains to be evaluated. Commonly used anesthetics to conduct hearing measurements are isoflurane and ketamine/xylazine anesthesia but the effect of these anesthetics on hearing assessment is still unknown. In this study we will evaluate the otovestibular effects of oral allylnitrile administration in mice. In addition, we will compare the influence of isoflurane and ketamine/xylazine anesthesia on hearing thresholds. Methods and Materials: Fourteen Coch+/– CBACa mice were randomly allocated into an allylnitrile ( n = 8) and a control group ( n = 6). Baseline measurements were done with isoflurane and 1 week later under ketamine/xylazine anesthesia. After baseline audiovestibular measurements, mice were co-administered with a single dose of allylnitrile and, to reduce systemic toxicity, three intraperitoneal injections of TDCE were given. Hearing loss was evaluated by recordings of auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). Specific behavioral test batteries for vestibular function were used to assess alterations in vestibular function. Results: Hearing thresholds were significantly elevated when using isoflurane anesthesia compared to ketamine/xylazine anesthesia for all frequencies of the ABR and the mid-to-high frequencies in DPOAE. Allylnitrile-treated mice lacked detectable ABR thresholds at each frequency tested, while DPOAE thresholds were significantly elevated in the low-frequency region of the cochlea and completely lacking in the mid-to high frequency region. Vestibular function was not affected by allylnitrile administration. Conclusion: Isoflurane anesthesia has a negative confounding effect on the measurement of hearing thresholds in mice. A single oral dose of allylnitrile induced hearing loss but did not significantly alter vestibular function in mice. This is the first study to show that administration of allylnitrile can cause a complete loss of hearing function in mice.

Significant scientific and translational questions remain in auditory neuroscience surrounding the neural correlates of perception. Relating perceptual and neural data collected from humans can be useful; however, human-based neural data are typically limited to evoked far-field responses, which lack anatomical and physiological specificity. Laboratory-controlled preclinical animal models offer the advantage of comparing single-unit and evoked responses from the same animals. This ability provides opportunities to develop invaluable insight into proper interpretations of evoked responses, which benefits both basic-science studies of neural mechanisms and translational applications, e.g., diagnostic development. However, these comparisons have been limited by a disconnect between the types of spectrotemporal analyses used with single-unit spike trains and evoked responses, which results because these response types are fundamentally different (point-process versus continuous-valued signals) even though the responses themselves are related. Here, we describe a unifying framework to study temporal coding of complex sounds that allows spike-train and evoked-response data to be analyzed and compared using the same advanced signal-processing techniques. The framework uses a set of peristimulus-time histograms computed from single-unit spike trains in response to polarity-alternating stimuli to allow advanced spectral analyses of both slow (envelope) and rapid (temporal fine structure) response components. Demonstrated benefits include: (1) novel spectrally specific temporal-coding measures that are less confounded by distortions due to hair-cell transduction, synaptic rectification, and neural stochasticity compared to previous metrics, e.g., the correlogram peak-height, (2) spectrally specific analyses of spike-train modulation coding (magnitude and phase), which can be directly compared to modern perceptually based models of speech intelligibility (e.g., that depend on modulation filter banks), and (3) superior spectral resolution in analyzing the neural representation of nonstationary sounds, such as speech and music. This unifying framework significantly expands the potential of preclinical animal models to advance our understanding of the physiological correlates of perceptual deficits in real-world listening following sensorineural hearing loss.

Endolymphatic potential (EP) is the main driving force behind the sensory transduction of hearing, and K + is the main charge carrier. Kir5.1 is a K + transporter that plays a significant role in maintaining EP homeostasis, but the expression pattern and role of Kir5.1 (which is encoded by the Kcnj16 gene) in the mouse auditory system has remained unclear. In this study, we found that Kir5.1 was expressed in the mouse cochlea. We checked the inner ear morphology and measured auditory function in Kcnj16 –/– mice and found that loss of Kcnj16 did not appear to affect the development of hair cells. There was no significant difference in auditory function between Kcnj16 –/– mice and wild-type littermates, although the expression of Kcnma1 , Kcnq4 , and Kcne1 were significantly decreased in the Kcnj16 –/– mice. Additionally, no significant differences were found in the number or distribution of ribbon synapses between the Kcnj16 –/– and wild-type mice. In summary, our results suggest that the Kcnj16 gene is not essential for auditory function in mice.

Recent studies have shown that rats are a useful model for binaural cochlear implant (CI) research, with behavioral sensitivity to interaural time differences (ITDs) of CI stimuli which are better than those of human patients. Here, we characterize ITD tuning in the rat inferior colliculus (IC) and explore whether quality of tuning can predict behavioral performance. We recorded IC responses to stimuli of varying pulse rates and envelope types and quantified both mutual information (MI) and neural d ′ as measures of ITD sensitivity. Neural d ′ values paralleled behavioral ones, declining with increasing click rates or when envelopes changed from rectangular to Hanning windows. While MI values increased with experience, neural d ′ did not. However, neural d ′ values correlated much better with behavioral performance than MI. Thus, neural d ′ appears to be a particularly well suited to predicting how stimulus parameters will impact behavioral performance.

Languages can use a common repertoire of vocal sounds to signify distinct meanings. In tonal languages, such as Mandarin Chinese, pitch contours of syllables distinguish one word from another, whereas in non-tonal languages, such as English, pitch is used to convey intonation. The neural computations underlying language specialization in speech perception are unknown. Here, we use a cross-linguistic approach to address this. Native Mandarin- and English- speaking participants each listened to both Mandarin and English speech, while neural activity was directly recorded from the non-primary auditory cortex. Both groups show language-general coding of speaker-invariant pitch at the single electrode level. At the electrode population level, we find language-specific distribution of cortical tuning parameters in Mandarin speakers only, with enhanced sensitivity to Mandarin tone categories. Our results show that speech perception relies upon a shared cortical auditory feature processing mechanism, which may be tuned to the statistics of a given language.

Systemic nicotine enhances neural processing in primary auditory cortex (A1) as determined using tone-evoked, current-source density (CSD) measurements. For example, nicotine enhances the characteristic frequency (CF)-evoked current sink in layer 4 of A1, increasing amplitude and decreasing latency. However, since presenting auditory stimuli within a stream of stimuli increases the complexity of response dynamics, we sought to determine the effects of nicotine on CSD responses to trains of CF stimuli (one-second trains at 2–40 Hz; each train repeated 25 times). CSD recordings were obtained using a 16-channel multiprobe inserted in A1 of urethane/xylazine-anesthetized mice, and analysis focused on two current sinks in the middle (layer 4) and deep (layers 5/6) layers. CF trains produced adaptation of the layer 4 response that was weak at 2 Hz, stronger at 5–10 Hz and complete at 20–40 Hz. In contrast, the layer 5/6 current sink exhibited less adaptation at 2–10 Hz, and simultaneously recorded auditory brainstem responses (ABRs) showed no adaptation even at 40 Hz. Systemic nicotine (2.1 mg/kg) enhanced layer 4 responses throughout the one-second stimulus train at rates ≤10 Hz. Nicotine enhanced both response amplitude within each train and the consistency of response timing across 25 trials. Nicotine did not alter the degree of adaptation over one-second trials, but its effect to increase amplitudes revealed a novel, slower form of adaptation that developed over multiple trials. Nicotine did not affect responses that were fully adapted (20–40 Hz trains), nor did nicotine affect any aspect of the layer 5/6 current sink or ABRs. The overall effect of nicotine in layer 4 was to enhance all responses within each train, to emphasize earlier trials across multiple trials, and to improve the consistency of timing across all trials. These effects may improve processing of complex acoustic streams, including speech, that contain information in the 2–10 Hz range.