Auditory Research publications

There is a weak relationship between clinical and self-reported speech perception outcomes in cochlear implant (CI) listeners. Such poor correspondence may be due to differences in clinical and “real-world” listening environments and stimuli. Speech in the real world is often accompanied by visual cues, background environmental noise, and is generally in a conversational context, all factors that could affect listening demand. Thus, our objectives were to determine if brain responses to naturalistic speech could index speech perception and listening demand in CI users. Accordingly, we recorded high-density electroencephalogram (EEG) while CI users listened/watched a naturalistic stimulus (i.e., the television show, “The Office”). We used continuous EEG to quantify “speech neural tracking” (i.e., TRFs, temporal response functions) to the show’s soundtrack and 8–12 Hz (alpha) brain rhythms commonly related to listening effort. Background noise at three different signal-to-noise ratios (SNRs), +5, +10, and +15 dB were presented to vary the difficulty of following the television show, mimicking a natural noisy environment. The task also included an audio-only (no video) condition. After each condition, participants subjectively rated listening demand and the degree of words and conversations they felt they understood. Fifteen CI users reported progressively higher degrees of listening demand and less words and conversation with increasing background noise. Listening demand and conversation understanding in the audio-only condition was comparable to that of the highest noise condition (+5 dB). Increasing background noise affected speech neural tracking at a group level, in addition to eliciting strong individual differences. Mixed effect modeling showed that listening demand and conversation understanding were correlated to early cortical speech tracking, such that high demand and low conversation understanding occurred with lower amplitude TRFs. In the high noise condition, greater listening demand was negatively correlated to parietal alpha power, where higher demand was related to lower alpha power. No significant correlations were observed between TRF/alpha and clinical speech perception scores. These results are similar to previous findings showing little relationship between clinical speech perception and quality-of-life in CI users. However, physiological responses to complex natural speech may provide an objective measure of aspects of quality-of-life measures like self-perceived listening demand.

BACKGROUND: The measurement of low-frequency cubic distortion product otoacoustic emission, for example, 0.5-kHz cubic distortion product otoacoustic emission, is often severely affected by background noise, and currently 0.5-kHz cubic distortion product otoacoustic emission is not commonly applicable in clinical setting. METHODS: The fundamental part of current study was the optimization of recording technology to reduce noise interference with the measurement of 0.5-kHz cubic distortion product otoacoustic emission and to establish the response patterns of cubic distortion product otoacoustic emission across speech frequencies from 0.5 to 8kHz in the presence of normal hearing and noise-induced hearing loss. RESULTS: After a series of optimization, a clinically applicable technology of measuring 0.5-kHz cubic distortion product otoacoustic emission was successfully completed via animal model. Cubic distortion product otoacoustic emission was recorded in 6 guinea pigs across speech frequencies from 0.5 to 8kHz before and after exposure to white bandnoise between 0.5 and 2 kHz. After noise exposure, significant reduction in the signal-to-noise ratio of cubic distortion product otoacoustic emission was found at 0.5 and 2 kHz, indicating our recording technology was sensitive and accurate. Other interesting finding was the reduction in cubic distortion product otoacoustic emiss ion-s ignal -to-n oise ratio at 4 and 6 kHz although the reduction was not statistically significant probably because of short exposure time. The result implied that the damaging effect induced by low-frequency noise exposure might spread upward to high-frequency region. CONCLUSIONS: Our recording technology was stable and reliable and had the great potentiality to be used in clinical setting. Cite this article as: Yu Y, Liu J, Antisdel J, et al. Optimizing the measurement of 0.5-kHz cubic distortion product otoacoustic emission. J Int Adv Otol. 2022;18(6):471-477.

Specialized sound localization circuit development requires synapse strengthening, refinement, and pruning. Many of these functions are carried out by microglia, immune cells that aid in regulating neurogenesis, synaptogenesis, apoptosis, and synaptic removal. We previously showed that postnatal treatment with BLZ945 (BLZ), an inhibitor of colony stimulating factor 1 receptor (CSF1R), eliminates microglia in the brainstem and disables calyceal pruning and maturation of astrocytes in the medial nucleus of the trapezoid body (MNTB). BLZ treatment results in elevated hearing thresholds and delayed signal propagation as measured by auditory brainstem responses (ABR). However, when microglia repopulate the brain following the cessation of BLZ, most of the deficits are repaired. It is unknown whether this recovery is achievable without the return of microglia. Here, we induced sustained microglial elimination with a two-drug approach using BLZ and PLX5622 (PLX). We found that BLZ/PLX treated mice had impaired calyceal pruning, diminished astrocytic GFAP in the lateral, low frequency, region of MNTB, and elevated glycine transporter 2 (GLYT2) levels. BLZ/PLX treated mice had elevated hearing thresholds, diminished peak amplitudes, and altered latencies and inter-peak latencies. These findings suggest that microglia are required to repopulate the brain in order to rectify deficits from their ablation.

Introduction: Noise-induced hearing loss is one of the most common forms of sensorineural hearing loss. Nevertheless, the mechanisms of noise-induced hearing loss are still not fully understood. Objective: To investigate the dynamics of inflammatory responses in the mammalian cochlea following noise trauma at two different times, once during the light cycle and once during the dark. Methods: We challenged C57BL/6J mice with moderate, continuous noise trauma at either 9 a.m. or 9 p.m. Auditory function, histological changes in hair cells, and modifications in gene expression levels of inflammatory mediators were assessed at specific time points. Shifts in auditory brainstem response thresholds were measured at 1, 3, 7 and 14 days after noise exposure to measure potential noise-induced hearing loss. Cochlear basilar-membrane immunofluorescent staining was performed at 3 and 14 days after noise exposure. The mRNA levels of several inflammatory mediators were measured via quantitative real-time polymerase chain reaction before (pre) and after (0, 3, 12, 24 and 72 h) noise exposure. Results: We found that all noise-exposed mice developed a temporary threshold shift and that there were no significant differences between daytime and nighttime noise exposures in terms of inducing hearing-threshold shifts. Similarly, we did not detect significant histological changes in hair cells between these two groups. However, we discovered an interesting phenomenon in that the peak mRNA levels of IL-1β, IL-6, CCL2 and TNF-α were higher in day noise-exposed mice compared to those in night noise-exposed mice, and these mRNA levels subsided more slowly in day noise-exposed mice. Conclusion: Overall, these observations suggest that the circadian timing of noise exposure has a significant effect on noise-induced inflammatory responses in the mouse cochlea and that a greater inflammatory response might occur after daytime exposure.

Intrinsically generated neural activity propagates through the developing auditory system to promote maturation and refinement of sound processing circuits prior to hearing onset. This early patterned activity is induced by non-sensory supporting cells in the organ of Corti, which are highly interconnected through gap junctions containing connexin 26 ( Gjb2 ). Although loss of function mutations in Gjb2 impair cochlear development and are the most common cause of congenital deafness, it is not known if these mutations disrupt spontaneous activity and the developmental trajectory of sound processing circuits in the brain. Here, we show in a new mouse model of Gjb2- mediated congenital deafness that cochlear supporting cells unexpectedly retained intercellular coupling and the capacity to generate spontaneous activity, exhibiting only modest deficits prior to hearing onset. This coordinated activation of IHCs led to coincident bursts of activity in central auditory neurons that will later process similar frequencies of sound. Despite alterations in the structure of the sensory epithelium, hair cells within the cochlea of Gjb2 deficient mice were intact and central auditory neurons could be activated within appropriate tonotopic domains by loud sounds at hearing onset, indicating that early maturation and refinement of auditory circuits was preserved. Only after cessation of spontaneous activity following hearing onset did progressive hair cell degeneration and enhanced auditory neuron excitability manifest. This preservation of cochlear spontaneous activity in the absence of connexin 26 may increase the effectiveness of early therapeutic interventions to restore hearing.

In most anuran amphibians, acoustic communication is of prime importance for mate localization and selection. The tympanic middle ear increases auditory sensitivity and directionality and is therefore expected to be favoured by natural selection. However, especially within the family of true toads (Bufonidae) there is a tendency for species to lose parts of the middle ear apparatus and consequently have a reduced sensitivity to high-frequency sounds (above 1 kHz). Part of the explanation for this may be that development of the middle ear is especially slow in bufonids, and thus the middle ear would be more likely to be lost or non-functional in paedomorphic species. However, a timeline of development of the middle ear has not been established previously. The goal of the present study was to investigate middle ear development in a toad species that has a well-known natural history and acoustic communication behaviour. We made a detailed study of anatomy and biophysics of the middle ear with measurements of auditory sensitivity across age in post-metamorphic natterjack toads (Epidalea calamita). The tadpoles and toadlets were raised in the laboratory, so their exact age was known, their auditory sensitivity was measured using auditory brainstem responses, and middle ear development and function were assessed by anatomical studies and laser vibrometry. We found that the developmental stage of the middle ear depends on the size of the toad rather than its age. The middle ear was functional at the earliest at a snout–vent length of 40 mm, which for these toads was around 500 days post-metamorphosis, close to the time of first reproduction. The functional, adult-like middle ear was shown to have 30 dB increased sensitivity to the dominant frequency of the mating call compared with sensitivities measured in newly metamorphosed individuals.

Neurons that process sensory information exhibit bursts of electrical activity during development, providing early training to circuits that will later encode similar features of the external world. In the mammalian auditory system, this intrinsically generated activity emerges from the cochlea prior to hearing onset, but its role in maturation of auditory circuitry remains poorly understood. We show that selective suppression of cochlear supporting cell spontaneous activity disrupts patterned burst firing of central auditory neurons without affecting cell survival or acoustic thresholds. However, neurons in the inferior colliculus of these mice exhibit enhanced acoustic sensitivity and broader frequency tuning, resulting in wider isofrequency laminae. Despite this enhanced neural responsiveness, total tone-responsive regions in the auditory cortex are substantially smaller. Thus, disruption of pre-hearing cochlear activity causes profound changes in neural encoding of sound, with important implications for restoration of hearing in individuals who experience reduced activity during this critical developmental period.

Many of the sensations experienced by an organism are caused by their own actions, and accurately anticipating both the sensory features and timing of self-generated stimuli is crucial to a variety of behaviors. In the auditory cortex, neural responses to self-generated sounds exhibit frequency-specific suppression, suggesting that movement-based predictions may be implemented early in sensory processing. However, it remains unknown whether this modulation results from a behaviorally specific and temporally precise prediction, nor is it known whether corresponding expectation signals are present locally in the auditory cortex. To address these questions, we trained mice to expect the precise acoustic outcome of a forelimb movement using a closed-loop sound-generating lever. Dense neuronal recordings in the auditory cortex revealed suppression of responses to self-generated sounds that was specific to the expected acoustic features, to a precise position within the movement, and to the movement that was coupled to sound during training. Prediction-based suppression was concentrated in L2/3 and L5, where deviations from expectation also recruited a population of prediction-error neurons that was otherwise unresponsive. Recording in the absence of sound revealed abundant movement signals in deep layers that were biased toward neurons tuned to the expected sound, as well as expectation signals that were present throughout the cortex and peaked at the time of expected auditory feedback. Together, these findings identify distinct populations of auditory cortical neurons with movement, expectation, and error signals consistent with a learned internal model linking an action to its specific acoustic outcome.

Experimental evidence in animals demonstrates cortical neurons innervate subcortex bilaterally to tune brainstem auditory coding. Yet, the role of the descending (corticofugal) auditory system in modulating earlier sound processing in humans during speech perception remains unclear. Here, we measured EEG activity as listeners performed speech identification tasks in different noise backgrounds designed to tax perceptual and attentional processing. We hypothesized brainstem speech coding might be tied to attention and arousal states (indexed by cortical α power) that actively modulate the interplay of brainstem-cortical signal processing. When speech-evoked brainstem frequency-following responses (FFRs) were categorized according to cortical α states, we found low α FFRs in noise were weaker, correlated positively with behavioral response times, and were more "decodable" via neural classifiers. Our data provide new evidence for online corticofugal interplay in humans and establish that brainstem sensory representations are continuously yoked to (i.e., modulated by) the ebb and flow of cortical states to dynamically update perceptual processing.

Neurexins are presynaptic transmembrane proteins crucial for synapse development and organization. Deletion and missense mutations in all three Neurexin genes have been identified in psychiatric disorders, with mutations in the NRXN1 gene most strongly linked to schizophrenia (SZ) and autism spectrum disorder (ASD). While the consequences of NRXN1 deletion have been extensively studied on the synaptic and behavioral levels, circuit endophenotypes that translate to the human condition have not been characterized yet. Therefore, we investigated the electrophysiology of cortico-striatal-thalamic circuits in Nrxn1α −/− rats and wildtype littermates focusing on a set of translational readouts, including spontaneous oscillatory activity, auditory-evoked oscillations and potentials, as well as mismatch negativity-like (MMN) responses and responses to social stimuli. On the behavioral level Nrxn1α −/− rats showed locomotor hyperactivity. In vivo freely moving electrophysiology revealed pronounced increases of spontaneous oscillatory power within the gamma band in all studied brain areas and elevation of gamma coherence in cortico-striatal and thalamocortical circuits of Nrxn1α −/− rats. In contrast, auditory-evoked oscillations driven by chirp-modulated tones showed reduced power in cortical areas confined to slower oscillations. Finally, Nrxn1α −/− rats exhibited altered auditory evoked-potentials and profound deficits in MMN-like responses, explained by reduced prediction error. Despite deficits for auditory stimuli, responses to social stimuli appeared intact. A central hypothesis for psychiatric and neurodevelopmental disorders is that a disbalance of excitation-to-inhibition is underlying oscillatory and sensory deficits. In a first attempt to explore the impact of inhibitory circuit modulation, we assessed the effects of enhancing tonic inhibition via δ-containing GABA A receptors (using Gaboxadol) on endophenotypes possibly associated with network hyperexcitability. Pharmacological experiments applying Gaboxadol showed genotype-specific differences, but failed to normalize oscillatory or sensory processing abnormalities. In conclusion, our study revealed endophenotypes in Nrxn1α −/− rats that could be used as translational biomarkers for drug development in psychiatric disorders.

Age-related hearing loss (presbycusis) affects one-third of the world's population. One hallmark of presbycusis is difficulty hearing in noisy environments. Presbycusis can be separated into two components: the aging ear and the aging brain. To date, the role of the aging brain in presbycusis is not well understood. Activity in the primary auditory cortex (A1) during a behavioral task is because of a combination of responses representing the acoustic stimuli, attentional gain, and behavioral choice. Disruptions in any of these aspects can lead to decreased auditory processing. To investigate how these distinct components are disrupted in aging, we performed in vivo 2-photon Ca 2+ imaging in both male and female mice ( Thy1-GCaMP6s × CBA/CaJ mice) that retain peripheral hearing into old age. We imaged A1 neurons of young adult (2-6 months) and old mice (16-24 months) during a tone detection task in broadband noise. While young mice performed well, old mice performed worse at low signal-to-noise ratios. Calcium imaging showed that old animals have increased prestimulus activity, reduced attentional gain, and increased noise correlations. Increased correlations in old animals exist regardless of cell tuning and behavioral outcome, and these correlated networks exist over a much larger portion of cortical space. Neural decoding techniques suggest that this prestimulus activity is predictive of old animals making early responses. Together, our results suggest a model in which old animals have higher and more correlated prestimulus activity and cannot fully suppress this activity, leading to the decreased representation of targets among distracting stimuli. SIGNIFICANCE STATEMENT Aging inhibits the ability to hear clearly in noisy environments. We show that the aging auditory cortex is unable to fully suppress its responses to background noise. During an auditory behavior, fewer neurons were suppressed in the old relative to young animals, which leads to higher prestimulus activity and more false alarms. We show that this excess activity additionally leads to increased correlations between neurons, reducing the amount of relevant stimulus information in the auditory cortex. Future work identifying the lost circuits that are responsible for proper background suppression could provide new targets for therapeutic strategies to preserve auditory processing ability into old age.

The pattern of ups and downs in a sequence with varying pitch can be heard as a melodic contour. Contrary to single pitch, the neural representation of melodic contour information in the auditory cortex is rarely investigated, and it is not clear whether the processing entails a hemispheric asymmetry. The present magnetoencephalography study assessed the neuromagnetic responses of N = 18 normal-hearing adults to four-note sequences with fixed vs. varying pitch that were presented either monaurally or diotically; data were analyzed using minimum-norm reconstructions. The first note of the sequences elicited prominent transient activity in posterior auditory regions (Planum temporale), especially contralateral to the ear of entry. In contrast, the response to the subsequent notes originated from more anterior areas (Planum polare) and was larger for melodic contours than for fixed pitch sequences, independent from the ear of entry and without hemispheric asymmetry. Together, the results point to a gradient in the early cortical processing of melodic contours, both in spatial and functional terms, where posterior auditory activity reflects the onset of a pitch sequence and anterior activity reflects its subsequent notes, including the difference between sequences with fixed pitch and melodic contours.

Octopus cells are remarkable projection neurons of the mammalian cochlear nucleus, with extremely fast membranes and wide-frequency tuning. They are considered prime examples of coincidence detectors but are poorly characterized in vivo. We discover that octopus cells are selective to frequency sweep direction, a feature that is absent in their auditory nerve inputs. In vivo intracellular recordings reveal that direction selectivity does not derive from across-frequency coincidence detection but hinges on the amplitudes and activation sequence of auditory nerve inputs tuned to clusters of hot spot frequencies. A simple biophysical octopus cell model excited with real nerve spike trains recreates direction selectivity through interaction of intrinsic membrane conductances with the activation sequence of clustered excitatory inputs. We conclude that octopus cells are sequence detectors, sensitive to temporal patterns across cochlear frequency channels. The detection of sequences rather than coincidences is a much simpler but powerful operation to extract temporal information.

Brain asymmetry in the sensitivity to spectrotemporal modulation is an established functional feature that underlies the perception of speech and music. The left auditory cortex (ACx) is believed to specialize in processing fast temporal components of speech sounds, and the right ACx slower components. However, the circuit features and neural computations behind these lateralized spectrotemporal processes are poorly understood. To answer these mechanistic questions we use mice, an animal model that captures some relevant features of human communication systems. In this study, we screened for circuit features that could subserve temporal integration differences between the left and right ACx. We mapped excitatory input to principal neurons in all cortical layers and found significantly stronger recurrent connections in the superficial layers of the right ACx compared to the left. We hypothesized that the underlying recurrent neural dynamics would exhibit differential characteristic timescales corresponding to their hemispheric specialization. To investigate, we recorded spike trains from awake mice and estimated the network time constants using a statistical method to combine evidence from multiple weak signal-to-noise ratio neurons. We found longer temporal integration windows in the superficial layers of the right ACx compared to the left as predicted by stronger recurrent excitation. Our study shows substantial evidence linking stronger recurrent synaptic connections to longer network timescales. These findings support speech processing theories that purport asymmetry in temporal integration is a crucial feature of lateralization in auditory processing.

Inhibitory G proteins (GNAI/Gα i ) bind to the scaffold G protein signaling modulator 2 (GPSM2) to form a conserved polarity complex that regulates cytoskeleton organization. GPSM2 keeps GNAI in a guanosine diphosphate (GDP)-bound state, but how GPSM2-GNAI is generated or relates to heterotrimeric G protein signaling remains unclear. We find that RGS12, a GTPase-activating protein (GAP), is required to polarize GPSM2-GNAI at the hair cell apical membrane and to organize mechanosensory stereocilia in rows of graded heights. Accordingly, RGS12 and the guanine nucleotide exchange factor (GEF) DAPLE are asymmetrically co-enriched at the hair cell apical junction, and Rgs12 mouse mutants are deaf. GPSM2 and RGS12 share GoLoco motifs that stabilize GNAI(GDP), and GPSM2 outcompetes RGS12 to bind GNAI. Our results suggest that polarized GEF/GAP junctional activity might dissociate heterotrimeric G proteins, generating free GNAI(GDP) for GPSM2 at the adjacent apical membrane. GPSM2-GNAI(GDP), in turn, imparts asymmetry to the forming stereocilia to enable sensory function in hair cells.

Inner ear macrophages play a vital role in cochlear homeostasis. Recent studies have demonstrated the existence of macrophages at different sites of the cochlea, with increased cochlear infiltration as an inflammatory response mechanism to injury. However, current methods, such as conventional immunohistochemistry and flow cytometry, provide limited information about the diversity of cochlear macrophages. Recently, multiplex immunohistochemistry (mIHC) successfully identified the heterogeneity of immune cells in cancer tissue and thereby improved our understanding of the disease prognosis. In this study, we modified the mIHC technique for cochlear tissue and utilized it to investigate cochlear macrophage behavior and heterogeneity before and after exposure to ototoxic drugs such as cisplatin. Four-week-old C57BL/6N female mice were intraperitoneally injected with cisplatin at 5 mg/kg/day consecutively for 6 days. Their hearing levels were assessed before and after the injection. Their cochleae were harvested before (day 0) and on days 8 and 15 after the cisplatin injection. Paraffin-embedded sections were sequentially immunostained using macrophage surface markers to identify the different categories of macrophages. Each immunostaining cycle included incubation with primary antibody, incubation with secondary antibody, chromogenic staining, and image scanning. Thereafter, all antibodies were stripped out, and antigen retrieval was performed to prepare the tissue for the next cycle. The results revealed that activated cochlear macrophages were not entirely differentiated into M1 or M2 categories but into multi-marker M1/M2 mixed macrophages. Furthermore, the ratio of these mixed (M1/M2) macrophages to Iba1 + macrophages increased in the auditory nerve after cisplatin exposure, suggesting local auditory nerve inflammation. The increase in the population of activated macrophages in the auditory nerve region was concomitant with the temporary shift of hearing threshold on day 8 post-cisplatin injection. The findings of this study indicate the effectiveness of mIHC in identifying cochlear macrophage heterogeneity both in the resting state and after cisplatin exposure. Therefore, mIHC could be a powerful tool in cochlear immunology research. Our findings may provide new insights into the co-relation between the cochlear macrophage and cisplatin exposure.

Background Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-related hearing loss (ARHL). However, the role of UCP2 in sensory hair cells in ARHL remains unclear. Methods Male C57BL/6 J mice were randomly assigned to an 8-week-old group (Group 1), a 16-week-old group (Group 2), a 16-week-old + adeno-associated virus-inner ear (AAV-ie) group (Group 3), and a 16-week-old + AAV-ie-UCP2 group (Group 4). Mice aged 8 weeks were administrated with AAV-ie-GFP or AAV-ie-UCP2 via posterior semicircular canal injection. Eight weeks after this viral intervention, hearing thresholds and wave-I amplitudes were tested by auditory brainstem response (ABR). Subsequently, the cochlear basilar membrane was dissected for investigation. The number of hair cells and inner hair cell (IHC) synapses, the level of ROS, and the expression of AMP-activated protein kinase α (AMPKα), were assessed by immunofluorescence staining. In addition, mitochondrial function was determined, and the expression of AMPKα and UCP2 proteins was further evaluated using western blotting. Results Mice with early-onset ARHL exhibited enhanced oxidative stress and loss of outer hair cells and IHC synapses, while UCP2 overexpression aggravated hearing loss and cochlear pathophysiological changes in mice. UCP2 overexpression resulted in a notable decrease in the number of IHCs and IHC synapses, caused ATP depletion and excessive ROS generation, increased AMPKα protein levels, and promoted IHC apoptosis, especially in the apical and middle turns of the cochlea. Conclusion Collectively, our data suggest that UCP2 overexpression may cause mitochondrial dysfunction via energy metabolism, which activates mitochondrion-dependent cellular apoptosis and leads to IHC loss, ultimately exacerbating ARHL.

The lateral superior olive (LSO) is a key structure in the central auditory system of mammals that exerts efferent control on cochlear sensitivity and is involved in the processing of binaural level differences for sound localization. Understanding how the LSO contributes to these processes requires knowledge about the resident cells and their connections with other auditory structures. We used standard histological stains and retrograde tracer injections into the inferior colliculus (IC) and cochlea in order to characterize two basic groups of neurons: (1) Principal and periolivary (PO) neurons have projections to the IC as part of the ascending auditory pathway; and (2) lateral olivocochlear (LOC) intrinsic and shell efferents have descending projections to the cochlea. Principal and intrinsic neurons are intermixed within the LSO, exhibit fusiform somata, and have disk-shaped dendritic arborizations. The principal neurons have bilateral, symmetric, and tonotopic projections to the IC. The intrinsic efferents have strictly ipsilateral projections, known to be tonotopic from previous publications. PO and shell neurons represent much smaller populations (<10% of principal and intrinsic neurons, respectively), have multipolar somata, reside outside the LSO, and have non-topographic, bilateral projections. PO and shell neurons appear to have widespread projections to their targets that imply a more diffuse modulatory function. The somata and dendrites of principal and intrinsic neurons form a laminar matrix within the LSO and share quantifiably similar alignment to the tonotopic axis. Their restricted projections emphasize the importance of frequency in binaural processing and efferent control for auditory perception. This study addressed and expanded on previous findings of cell types, circuit laterality, and projection tonotopy in the LSO of the mouse.

Adeno-associated virus (AAV)-mediated gene transfer is an efficient method of gene over-expression in the vestibular end organs. However, AAV has limited usefulness for delivering a large gene, or multiple genes, due to its small packaging capacity (< 5 kb). Co-transduction of dual-AAV vectors can be used to increase the packaging capacity for gene delivery to various organs and tissues. However, its usefulness has not been well validated in the vestibular sensory epithelium. In the present study, we characterized the co-transduction of dual-AAV vectors in mouse utricles following inoculation of two AAV-serotype inner ear (AAV-ie) vectors via canalostomy. Firstly, co-transduction efficiencies were compared between dual-AAV-ie vectors using two different promoters: cytomegalovirus (CMV) and CMV early enhancer/chicken β-actin (CAG). In the group of dual AAV-ie-CAG vectors, the co-transduction rates for striolar hair cells (HCs), extrastriolar HCs, striolar supporting cells (SCs), and extrastriolar SCs were 23.14 ± 2.25%, 27.05 ± 2.10%, 57.65 ± 7.21%, and 60.33 ± 5.69%, respectively. The co-transduction rates in the group of dual AAV-ie-CMV vectors were comparable to those in the dual AAV-ie-CAG group. Next, we examined the co-transduction of dual-AAV-ie-CAG vectors in the utricles of neonatal mice and damaged adult mice. In the neonatal mice, co-transduction rates were 52.88 ± 3.11% and 44.93 ± 2.06% in the striolar and extrastriolar HCs, respectively, which were significantly higher than those in adult mice. In the Pou4f3 +/DTR mice, following diphtheria toxin administration, which eliminated most HCs and spared the SCs, the co-transduction rate of SCs was not significantly different to that of normal utricles. Transgene expression persisted for up to 3 months in the adult mice. Furthermore, sequential administration of two AAV-ie-CAG vectors at an interval of 1 week resulted in a higher co-transduction rate in HCs than concurrent delivery. The auditory brainstem responses and swim tests did not reveal any disruption of auditory or vestibular function after co-transduction with dual-AAV-ie vectors. In conclusion, dual-AAV-ie vectors allow efficient co-transduction in the vestibular sensory epithelium and facilitate the delivery of large or multiple genes for vestibular gene therapy.

Purpose: Vowels and consonants play different roles in language acquisition and speech recognition, yet standard clinical tests do not assess vowel and consonant perception separately. As a result, opportunities for targeted intervention may be lost. This study evaluated closed-set word recognition tests designed to rely predominantly on either vowel or consonant perception and compared results with sentence recognition scores. Method: Participants were children (5–17 years of age) and adults (18–38 years of age) with normal hearing and children with sensorineural hearing loss (7–17 years of age). Speech reception thresholds (SRTs) were measured in speech-shaped noise. Children with hearing loss were tested with their hearing aids. Word recognition was evaluated using a three-alternative forced-choice procedure, with a picture-pointing response; monosyllabic target words varied with respect to either consonant or vowel content. Sentence recognition was evaluated for low- and high-probability sentences. In a subset of conditions, stimuli were low-pass filtered to simulate a steeply sloping hearing loss in participants with normal hearing. Results: Children's SRTs improved with increasing age for words and sentences. Low-pass filtering had a larger effect for consonant-variable words than vowel-variable words for both children and adults with normal hearing, consistent with the greater high-frequency content of consonants. Children with hearing loss tested with hearing aids tended to perform more poorly than age-matched children with normal hearing, particularly for sentence recognition, but consonant- and vowel-variable word recognition did not appear to be differentially affected by the amount of high- and low-frequency hearing loss. Conclusions: Closed-set recognition of consonant- and vowel-variable words appeared to differentially evaluate vowel and consonant perception but did not vary by configuration of hearing loss in this group of pediatric hearing aid users. Word scores obtained in this manner do not fully characterize the auditory abilities necessary for open-set sentence recognition, but they do provide a general estimate.