Auditory Research publications

The cochlea encodes sound pressures varying over six orders of magnitude by collective operation of functionally diverse spiral ganglion neurons (SGNs). The mechanisms enabling this functional diversity remain elusive. Here, we asked whether the sound intensity information, contained in the receptor potential of the presynaptic inner hair cell (IHC), is fractionated via heterogeneous synapses. We studied the transfer function of individual IHC synapses by combining patch‐clamp recordings with dual‐color Rhod‐FF and iGluSnFR imaging of presynaptic Ca 2+ signals and glutamate release. Synapses differed in the voltage dependence of release: Those residing at the IHC' pillar side activated at more hyperpolarized potentials and typically showed tight control of release by few Ca 2+ channels. We conclude that heterogeneity of voltage dependence and release site coupling of Ca 2+ channels among the synapses varies synaptic transfer within individual IHCs and, thereby, likely contributes to the functional diversity of SGNs. The mechanism reported here might serve sensory cells and neurons more generally to diversify signaling even in close‐by synapses.

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with “no-repetition” controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection.

Little is known about the functions of Group II metabotropic glutamate receptors (mGluRs2/3) in the inferior colliculus (IC), a midbrain structure that is a major integration region of the central auditory system. We investigated how these receptors modulate sound-evoked and spontaneous firing in the mouse IC in vivo We first performed immunostaining and tested hearing thresholds to validate vesicular GABA transporter (VGAT)-ChR2 transgenic mice on a mixed CBA/CaJ x C57BL/6J genetic background. Transgenic animals allowed for optogenetic cell-type identification. Extracellular single neuron recordings were obtained before and after pharmacological mGluR2/3 activation. We observed increased sound-evoked firing, as assessed by the rate-level functions (RLFs), in a subset of both GABAergic and non-GABAergic IC neurons following mGluR2/3 pharmacological activation. These neurons also displayed elevated spontaneous excitability and were distributed throughout the IC area tested, suggesting a widespread mGluR2/3 distribution in the mouse IC.

Purpose The overall goal of the current study was to determine whether noise type plays a role in perceptual quality ratings. We compared quality ratings using various noise types and signal-to-noise ratio (SNR) ranges using hearing aid simulations to consider the effects of hearing aid processing features. Method Ten older adults with bilateral mild to moderately severe sensorineural hearing loss rated the sound quality of sentences processed through a hearing aid simulation and presented in the presence of five different noise types (six-talker babble, three-talker conversation, street traffic, kitchen, and fast-food restaurant) at four SNRs (3, 8, 12, and 20 dB). Results Everyday noise types differentially affected sound quality ratings even when presented at the same SNR: Kitchen and three-talker noises were rated significantly higher than restaurant, traffic, and multitalker babble, which were not different from each other. The effects of noise type were most pronounced at poorer SNRs. Conclusions The findings of this study showed that noise types differentially affected sound quality ratings. The differences we observed were consistent with the acoustic characteristics of the noise types. Noise types having lower envelope fluctuations yielded lower quality ratings than noise types characterized by sporadic high-intensity events at the same SNR.

Purpose Talkers often modify their speech when communicating with individuals who struggle to understand speech, such as listeners with hearing loss. This study evaluated the benefit of clear speech in school-age children and adults with normal hearing for speech-in-noise and speech-in-speech recognition. Method Masked sentence recognition thresholds were estimated for school-age children and adults using an adaptive procedure. In Experiment 1, the target and masker were summed and presented over a loudspeaker located directly in front of the listener. The masker was either speech-shaped noise or two-talker speech, and target sentences were produced using a clear or conversational speaking style. In Experiment 2, stimuli were presented over headphones. The two-talker speech masker was diotic (M 0 ). Clear and conversational target sentences were presented either in-phase (T 0 ) or out-of-phase (T π ) between the two ears. The M 0 T π condition introduces a segregation cue that was expected to improve performance. Results For speech presented over a single loudspeaker (Experiment 1), the clear-speech benefit was independent of age for the noise masker, but it increased with age for the two-talker masker. Similar age effects for the two-talker speech masker were seen under headphones with diotic presentation (M 0 T 0 ), but comparable clear-speech benefit as a function of age was observed with a binaural cue to facilitate segregation (M 0 T π ). Conclusions Consistent with prior research, children showed a robust clear-speech benefit for speech-in-noise recognition. Immaturity in the ability to segregate target from masker speech may limit young children's ability to benefit from clear-speech modifications for speech-in-speech recognition under some conditions. When provided with a cue that facilitates segregation, children as young as 4–7 years of age derived a clear-speech benefit in a two-talker masker that was similar to the benefit experienced by adults.

Age-related hearing loss (AHL) is a progressive sensorineural hearing loss in elderly people. Although no prevention or treatments have been established for AHL, recent studies have demonstrated that oxidative stress is closely related to pathogenesis of AHL, suggesting that suppression of oxidative stress leads to inhibition of AHL progression. NRF2 is a master transcription factor that regulates various antioxidant proteins and cytoprotection factors. To examine whether NRF2 pathway activation prevents AHL, we used Keap1 -knockdown ( Keap1 FA/FA ) mice, in which KEAP1, a negative regulator of NRF2, is decreased, resulting in the elevation of NRF2 activity. We compared 12-month-old Keap1 FA/FA mice with age-matched wild-type (WT) mice in the same breeding colony. In the Keap1 FA/FA mice, the expression levels of multiple NRF2 target genes were verified to be significantly higher than the expression levels of these genes in the WT mice. Histological analysis showed that cochlear degeneration at the apical and middle turns was ameliorated in the Keap1 FA/FA mice. Auditory brainstem response (ABR) thresholds in the Keap1 FA/FA mice were significantly lower than those in the WT mice, in particular at low–mid frequencies. Immunohistochemical detection of oxidative stress markers suggested that oxidative stress accumulation was attenuated in the Keap1 FA/FA cochlea. Thus, we concluded that NRF2 pathway activation protects the cochlea from oxidative damage during aging, in particular at the apical and middle turns. KEAP1-inhibiting drugs and phytochemicals are expected to be effective in the prevention of AHL.

Neurons of the medial olivary complex inhibit cochlear hair cells through the activation of α9α10-containing nicotinic acetylcholine receptors (nAChRs). Efforts to study the localization of these proteins have been hampered by the absence of reliable antibodies. To overcome this obstacle, CRISPR-Cas9 gene editing was used to generate mice in which a hemagglutinin tag (HA) was attached to the C-terminus of either α9 or α10 proteins. Immunodetection of the HA tag on either subunit in the organ of Corti of adult mice revealed immunopuncta clustered at the synaptic pole of outer hair cells. These puncta were juxtaposed to immunolabeled presynaptic efferent terminals. HA immunopuncta also occurred in inner hair cells of pre-hearing (P7) but not in adult mice. These immunolabeling patterns were similar for both homozygous and heterozygous mice. All HA-tagged genotypes had auditory brainstem responses not significantly different from those of wild type littermates. The activation of efferent neurons in heterozygous mice evoked biphasic postsynaptic currents not significantly different from those of wild type hair cells. However, efferent synaptic responses were significantly smaller and less frequent in the homozygous mice. We show that HA-tagged nAChRs introduced in the mouse by a CRISPR knock-in are regulated and expressed like the native protein, and in the heterozygous condition mediate normal synaptic function. The animals thus generated have clear advantages for localization studies.

Spatial selective listening and auditory choice underlie important processes including attending to a speaker at a cocktail party and knowing how (or whether) to respond. To examine task encoding and the relative timing of potential neural substrates underlying these behaviors, we developed a spatial selective detection paradigm for monkeys, and recorded activity in primary auditory cortex (AC), dorsolateral prefrontal cortex (dlPFC), and the basolateral amygdala (BLA). A comparison of neural responses among these three areas showed that, as expected, AC encoded the side of the cue and target characteristics before dlPFC and BLA. Interestingly, AC also encoded the choice of the monkey before dlPFC and around the time of BLA. Generally, BLA showed weak responses to all task features except the choice. Decoding analyses suggested that errors followed from a failure to encode the target stimulus in both AC and dlPFC, but again, these differences arose earlier in AC. The similarities between AC and dlPFC responses were abolished during passive sensory stimulation with identical trial conditions, suggesting that the robust sensory encoding in dlPFC is contextually gated. Thus, counter to a strictly PFC-driven decision process, in this spatial selective listening task AC neural activity represents the sensory and decision information before dlPFC. Unlike in the visual domain, in this auditory task, the BLA does not appear to be robustly involved in selective spatial processing. SIGNIFICANCE STATEMENT We examined neural correlates of an auditory spatial selective listening task by recording single-neuron activity in behaving monkeys from the amygdala, dorsolateral prefrontal cortex, and auditory cortex. We found that auditory cortex coded spatial cues and choice-related activity before dorsolateral prefrontal cortex or the amygdala. Auditory cortex also had robust delay period activity. Therefore, we found that auditory cortex could support the neural computations that underlie the behavioral processes in the task.

Purpose The two primary purposes of this report are (a) to compare the results of three brief cognitive screens in older adults and (b) to examine associations between performance on each of the screens and auditory function measured either concurrently or 9 years earlier. Method This was a prospective longitudinal study of 98 adults (66 women) with baseline ages ranging from 40 to 85 years. The mean interval between T1 baseline and T2 follow-up measurements was 8.8 years with a range from 7 to 11 years. Measures of hearing threshold, gap detection, and auditory temporal-order identification were completed at T1 and T2. The Mini-Mental State Examination was completed at T1 and T2, whereas the Montreal Cognitive Assessment (MoCA) and A Quick Test were completed at T2 only. Results Higher scores and pass rates were obtained for the Mini-Mental State Examination than for the MoCA or the A Quick Test. The measures were moderately correlated among themselves and with the Wechsler Adult Intelligence Scale–Third Edition. Significant associations emerged frequently between auditory and cognitive functions, most often for the auditory measure of temporal-order identification, including dichotic measures of this ability. Conclusions From this evaluation, the MoCA emerged as the preferred test for clinicians desiring a quick assessment of the cognitive function of their older patients. Auditory temporal-order identification is associated with cognitive function and explains about 10%–20% of the variation in cognitive function independent of age and hearing loss. Supplemental Material https://doi.org/10.23641/asha.12986021

Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor Atoh1, but to date this approach has yielded low and variable efficiency of HC production. Gfi1 is a transcription factor important for HC development and survival. We evaluated the combinatorial effects of Atoh1 and Gfi1 over-expression on HC regeneration using gene transfer methods in neonatal cochlear explants, and in vivo in adult mice. Adenoviral over-expression of Atoh1 and Gfi1 in cultured neonatal cochlear explants resulted in numerous ectopic HC-like cells (HCLCs), with significantly more cells in Atoh1 + Gfi1 cultures than Atoh1 alone. In vitro, ectopic HCLCs emerged in regions medial to inner HCs as well as in the stria vascularis. In vivo experiments were performed in mature Pou4f3 DTR mice in which HCs were completely and specifically ablated by administration of diphtheria toxin. Adenoviral expression of Atoh1 or Atoh1 + Gfi1 in cochlear supporting cells induced appearance of HCLCs, with Atoh1 + Gfi1 expression leading to 6.2-fold increase of new HCLCs after 4 weeks compared to Atoh1 alone. New HCLCs were detected throughout the cochlea, exhibited immature stereocilia and survived for at least 8 weeks. Combinatorial Atoh1 and Gfi1 induction is thus a promising strategy to promote HC regeneration in the mature mammalian cochlea.

The primate cerebral cortex is organized into specialized areas representing different functional modalities (e.g., vision, audition, touch) and their associations along a continuous surface. The functional maps of these areas, however, are often investigated in a single modality at a time. Here, we developed and applied to awake primates a polarization-enhanced wide-field optical imaging method for measuring cortical hemodynamics through the intact skull. Adjacent somatosensory, auditory, and visual cortices were noninvasively localized and rapidly parcellated in awake marmosets ( Callithrix jacchus ), a primate model featuring a smooth cortex. Detailed somatotopy, tonotopy, and retinotopy were also mapped out on an individual-subject basis, with a new pure-tone-responsive tonotopic gradient discovered outside the auditory core. Moreover, the motion-sensitive extent surrounding the primate-specific MT/V5 and the location of a face-sensitive patch were both revealed with respect to retinotopy. This approach provides a powerful tool for mapping the functional landscape across modalities in a single non-human primate subject, and thus opens new opportunities for probing how primate cortical system is organized to enable real-world behaviors.

The pathophysiology underlying spiral ganglion cell defect–induced deafness remains elusive. Using the whole exome sequencing approach, in combination with functional assays and a mouse disease model, we identified the potentially novel deafness-causative MAP1B gene encoding a highly conserved microtubule-associated protein. Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families. Here, we show that MAP1B is highly expressed in the spiral ganglion neurons in the mouse cochlea. Using otic sensory neuron–like cells, generated by pluripotent stem cells from patients carrying the MAP1B mutation and control subject, we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics. Strikingly, otic sensory neuron–like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties. Dysfunctions of these derived otic sensory neuron–like cells were rescued by genetically correcting MAP1B mutation using CRISPR/Cas9 technology. Involvement of MAP1B in hearing was confirmed by audiometric evaluation of Map1b heterozygous KO mice. These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies. The spiral ganglion neurons isolated from Map1b mutant mice exhibited the deficient phosphorylation and disturbed dynamics of microtubules. Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice. Therefore, our data demonstrate that dysfunctions of spiral ganglion neurons induced by MAP1B deficiency caused hearing loss.

Many individuals with seemingly normal hearing abilities struggle to understand speech in noisy backgrounds. To understand why this might be the case, we investigated the neural representation of speech in the auditory midbrain of gerbils with "hidden hearing loss" through noise exposure that increased hearing thresholds only temporarily. In noise-exposed animals, we observed significantly increased neural responses to speech stimuli, with a more pronounced increase at moderate than at high sound intensities. Noise exposure reduced discriminability of neural responses to speech in background noise at high sound intensities, with impairment most severe for tokens with relatively greater spectral energy in the noise-exposure frequency range (2-4 kHz). At moderate sound intensities, discriminability was surprisingly improved, which was unrelated to spectral content. A model combining damage to high-threshold auditory nerve fibers with increased response gain of central auditory neurons reproduced these effects, demonstrating that a specific combination of peripheral damage and central compensation could explain listening difficulties despite normal hearing thresholds.

Auditory brain stem response (ABR) is more commonly used to evaluate cochlear lesions than cochlear compound action potential (CAP). In a noise-induced cochlear damage model, we found that the reduced CAP and enhanced ABR caused the threshold difference. In a unilateral cochlear destruction model, a shadow curve of the ABR from the contralateral healthy ear masked the hearing loss in the destroyed ear.

ML neurons synchronized less than A1 neurons, consistent with a hierarchical temporal-to-rate transformation. Both A1 and ML had a class of modulation transfer functions previously unreported in the cortex with a low-modulation-frequency (MF) peak, a middle-MF trough, and responses similar to unmodulated noise responses at high MFs. The results support a hierarchical shift toward a two-pool opponent code, where subtraction of neural activity between two populations of oppositely tuned neurons encodes AM.

Exposure to loud noise causes damage to the inner ear, including but not limited to outer and inner hair cells (OHCs and IHCs) and IHC ribbon synapses. This cochlear damage impairs auditory processing and increases audiometric thresholds (noise-induced hearing loss, NIHL). However, the exact relationship between the perceptual consequences of NIHL and its underlying cochlear pathology are poorly understood. This study used a nonhuman primate model of NIHL to relate changes in frequency selectivity and audiometric thresholds to indices of cochlear histopathology. Three macaques (one Macaca mulatta and two Macaca radiata) were trained to detect tones in quiet and in noises that were spectrally notched around the tone frequency. Audiograms were derived from tone thresholds in quiet; perceptual auditory filters were derived from tone thresholds in notched-noise maskers using the rounded-exponential fit. Data were obtained before and after a four-hour exposure to a 50-Hz noise centered at 2 kHz at 141 or 146 dB SPL. Noise exposure caused permanent audiometric threshold shifts and broadening of auditory filters at and above 2 kHz, with greater changes observed for the 146-dB-exposed monkeys. The normalized bandwidth of the perceptual auditory filters was strongly correlated with audiometric threshold at each tone frequency. While changes in audiometric threshold and perceptual auditory filter widths were primarily determined by the extent of OHC survival, additional variability was explained by including interactions among OHC, IHC, and ribbon synapse survival. This is the first study to provide within-subject comparisons of auditory filter bandwidths in an animal model of NIHL and correlate these NIHL-related perceptual changes with cochlear histopathology. These results expand the foundations for ongoing investigations of the neural correlates of NIHL-related perceptual changes.

Background: The auditory brainstem response (ABR), specifically wave I, is widely used to noninvasively measure auditory nerve (AN) function. Recent work in humans has introduced novel electrocochleographic measures to comprehensively characterize AN function that emphasize suprathreshold processing and estimate neural synchrony. New method: This study establishes new tools for evaluating AN function in vivo in adult mice using tone-evoked ABRs obtained from young-adult CBA/CaJ mice, adapting the approach previously introduced in humans. Six metrics are obtained from ABR wave I at suprathreshold stimulus levels. Results: Change-point analyses show that the metrics' rate of change with stimulus level differs between moderate and high suprathreshold levels, suggesting that this approach can potentially characterize the presence of heterogeneous AN fiber types. Comparison with existing methods: Traditional ABR approaches focus on response thresholds and averaged amplitudes/latencies. In contrast, our multi-metric approach, which uses single-trial data and suprathreshold stimuli, provides novel information and identifies evidence of neural synchrony deficits and changes in the heterogeneity of AN fibers underlying AN behavior. Conclusion: The techniques reported here provide a novel tool to assess changes in AN function in vivo in a commonly used animal model. A benchmark of most current hearing research is the transition from animal to human studies. Here we established a translational objective approach, applying methods that were first developed in humans to animals. This approach enables researchers to identify changes in AN function arising from the animal models with well-characterized pathology, and predict similar pathological changes in human AN dysfunction and hearing loss.

Age-related hearing loss is a very common sensory disability, affecting one in three older adults. Establishing a link between anatomical, physiological, and behavioral markers of presbycusis in a mouse model can improve the understanding of this disorder in humans. We measured age-related hearing loss for a variety of acoustic signals in quiet and noisy environments using an operant conditioning procedure and investigated the status of peripheral structures in CBA/CaJ mice. Mice showed the greatest degree of hearing loss in the last third of their lifespan, with higher thresholds in noisy than in quiet conditions. Changes in auditory brainstem response thresholds and waveform morphology preceded behavioral hearing loss onset. Loss of hair cells, auditory nerve fibers, and signs of stria vascularis degeneration were observed in old mice. The present work underscores the difficulty in ascribing the primary cause of age-related hearing loss to any particular type of cellular degeneration. Revealing these complex structure-function relationships is critical for establishing successful intervention strategies to restore hearing or prevent presbycusis.

Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.

Action and perception are closely linked in many behaviors necessitating a close coordination between sensory and motor neural processes so as to achieve a well-integrated smoothly evolving task performance. To investigate the detailed nature of these sensorimotor interactions, and their role in learning and executing the skilled motor task of speaking, we analyzed ECoG recordings of responses in the high-γ band (70–150 Hz) in human subjects while they listened to, spoke, or silently articulated speech. We found elaborate spectrotemporally modulated neural activity projecting in both “forward” (motor-to-sensory) and “inverse” directions between the higher-auditory and motor cortical regions engaged during speaking. Furthermore, mathematical simulations demonstrate a key role for the forward projection in “learning” to control the vocal tract, beyond its commonly postulated predictive role during execution. These results therefore offer a broader view of the functional role of the ubiquitous forward projection as an important ingredient in learning, rather than just control, of skilled sensorimotor tasks.