Dysfunction of specific auditory fibers impacts cortical oscillations, driving an autism phenotype despite near-normal hearing.

Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation-inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of BdnfPax2 KO mice. These mice develop an autism-like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of BdnfPax2 KOs, connected to maturation deficits of high-spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation-inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high-spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior.

Cochlear Ribbon Synapses in Aged Gerbils.

In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea via specialized ribbon synapses. Auditory nerve fibers of different physiological types differ subtly in their synaptic location and morphology. Low-spontaneous-rate auditory nerve fibers typically connect on the modiolar side of the inner hair cell, while high-spontaneous-rate fibers are typically found on the pillar side. In aging and noise-damaged ears, this fine-tuned balance between auditory nerve fiber populations can be disrupted and the functional consequences are currently unclear. Here, using immunofluorescent labeling of presynaptic ribbons and postsynaptic glutamate receptor patches, we investigated changes in synaptic morphology at three different tonotopic locations along the cochlea of aging gerbils compared to those of young adults. Quiet-aged gerbils showed about 20% loss of afferent ribbon synapses. While the loss was random at apical, low-frequency cochlear locations, at the basal, high-frequency location it almost exclusively affected the modiolar-located synapses. The subtle differences in volumes of pre- and postsynaptic elements located on the inner hair cell's modiolar versus pillar side were unaffected by age. This is consistent with known physiology and suggests a predominant, age-related loss in the low-spontaneous-rate auditory nerve population in the cochlear base, but not the apex.

Induction of Activity-Dependent Plasticity at Auditory Nerve Synapses.

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.

Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism.

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (Mef2c-Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c-Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types; and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments.SIGNIFICANCE STATEMENT This is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.

Direct Cochlear Recordings in Humans Show a Theta Rhythmic Modulation of Auditory Nerve Activity by Selective Attention.

The architecture of the efferent auditory system enables prioritization of strongly overlapping spatiotemporal cochlear activation patterns elicited by relevant and irrelevant inputs. So far, attempts at finding such attentional modulations of cochlear activity delivered indirect insights in humans or required direct recordings in animals. The extent to which spiral ganglion cells forming the human auditory nerve are sensitive to selective attention remains largely unknown. We investigated this question by testing the effects of attending to either the auditory or visual modality in human cochlear implant (CI) users (3 female, 13 male). Auditory nerve activity was directly recorded with standard CIs during a silent (anticipatory) cue-target interval. When attending the upcoming auditory input, ongoing auditory nerve activity within the theta range (5-8 Hz) was enhanced. Crucially, using the broadband signal (4-25 Hz), a classifier was even able to decode the attended modality from single-trial data. Follow-up analysis showed that the effect was not driven by a narrow frequency in particular. Using direct cochlear recordings from deaf individuals, our findings suggest that cochlear spiral ganglion cells are sensitive to top-down attentional modulations. Given the putatively broad hair-cell degeneration of these individuals, the effects are likely mediated by alternative efferent pathways compared with previous studies using otoacoustic emissions. Successful classification of single-trial data could additionally have a significant impact on future closed-loop CI developments that incorporate real-time optimization of CI parameters based on the current mental state of the user.SIGNIFICANCE STATEMENT The efferent auditory system in principle allows top-down modulation of auditory nerve activity; however, evidence for this is lacking in humans. Using cochlear recordings in participants performing an audiovisual attention task, we show that ongoing auditory nerve activity in the silent cue-target period is directly modulated by selective attention. Specifically, ongoing auditory nerve activity is enhanced within the theta range when attending upcoming auditory input. Furthermore, over a broader frequency range, the attended modality can be decoded from single-trial data. Demonstrating this direct top-down influence on auditory nerve activity substantially extends previous works that focus on outer hair cell activity. Generally, our work could promote the use of standard cochlear implant electrodes to study cognitive neuroscientific questions.

Time Course of Activity-Dependent Changes in Auditory Nerve Synapses Reveals Multiple Underlying Cellular Mechanisms.

Abnormal levels of acoustic activity can result in hearing problems such as tinnitus and language processing disorders, but the underlying cellular and synaptic changes triggered by abnormal activity are not well understood. To address this issue, we studied the time course of activity-dependent changes that occur at auditory nerve synapses in mice of both sexes after noise exposure and conductive hearing loss. We found that EPSC amplitude and synaptic depression decreased within 2 d of noise exposure through a decrease in the probability of vesicle release (Pr). This was followed by a gradual increase in EPSC amplitude through a larger pool of releasable vesicles (N). Occlusion of the ear canal led to a rapid decrease in EPSC amplitude through a decrease in N, which was followed by an increase in EPSC amplitude and synaptic depression through an increase in Pr After returning to normal sound levels, synaptic depression recovered to control levels within 1-2 d. However, repeated exposure to noise for as little as 8 h/d caused synaptic changes after 7 d, suggesting recovery did not fully offset changes. Thus, there appear to be three activity-dependent mechanisms in auditory nerve synapses-bidirectional changes in Pr in 1-2 d, slower bidirectional changes in N through synaptic growth or retraction, and rapid downregulation of N with low activity. The dynamic changes indicate that multiple mechanisms are present to fine-tune synaptic fidelity across different acoustic conditions in a simple relay.SIGNIFICANCE STATEMENT Hearing impairments can arise from exposure to noise or conductive hearing loss. This appears to result from changes in the brain, but the mechanisms are not well understood. We study this issue by studying the synapses made by auditory nerve fibers called endbulbs of Held. These synapses undergo bidirectional changes in size and release probability of neurotransmitter in response to increased or decreased activity. Here, we made a close examination of how quickly these synaptic characteristics change, which indicates there are at least three cellular mechanisms underlying changes. Furthermore, repeated exposure to brief periods of noise can produce cumulative effects. These changes could significantly affect hearing, especially because they occur at the start of the central auditory pathway.

Distorted Tonotopy Severely Degrades Neural Representations of Connected Speech in Noise following Acoustic Trauma.

Listeners with sensorineural hearing loss (SNHL) struggle to understand speech, especially in noise, despite audibility compensation. These real-world suprathreshold deficits are hypothesized to arise from degraded frequency tuning and reduced temporal-coding precision; however, peripheral neurophysiological studies testing these hypotheses have been largely limited to in-quiet artificial vowels. Here, we measured single auditory-nerve-fiber responses to a connected speech sentence in noise from anesthetized male chinchillas with normal hearing (NH) or noise-induced hearing loss (NIHL). Our results demonstrated that temporal precision was not degraded following acoustic trauma, and furthermore that sharpness of cochlear frequency tuning was not the major factor affecting impaired peripheral coding of connected speech in noise. Rather, the loss of cochlear tonotopy, a hallmark of NH, contributed the most to both consonant-coding and vowel-coding degradations. Because distorted tonotopy varies in degree across etiologies (e.g., noise exposure, age), these results have important implications for understanding and treating individual differences in speech perception for people suffering from SNHL.SIGNIFICANCE STATEMENT Difficulty understanding speech in noise is the primary complaint in audiology clinics and can leave people with sensorineural hearing loss (SNHL) suffering from communication difficulties that affect their professional, social, and family lives, as well as their mental health. We measured single-neuron responses from a preclinical SNHL animal model to characterize salient neural-coding deficits for naturally spoken speech in noise. We found the major mechanism affecting neural coding was not a commonly assumed factor, but rather a disruption of tonotopicity, the systematic mapping of acoustic frequency to cochlear place that is a hallmark of normal hearing. Because the degree of distorted tonotopy varies across hearing-loss etiologies, these results have important implications for precision audiology approaches to diagnosis and treatment of SNHL.

Effect of congenital inner ear malformations (IEMs) on electrically evoked compound action potential (ECAP) responses in cochlear implant children.

PURPOSE: The study was designed to assess the electrically evoked compound action potential (ECAP) responses in children with inner ear malformations compared to children with normal inner ear anatomy. METHODS: The study included 235 prelingual deaf children who were implanted in cochlear implant unit in King Fahad University hospital-Imam Abdulrahman Bin Faisel University. Subjects were using either Cochlear Nucleus or Medel cochlear implant devices. We had 171 (64.5%) subjects with normal inner ear anatomy and 94 (35.5%) subjects with inner ear malformations (IEMs) and they were classified into 6 groups according to inner ear anatomy. Fourteen subjects (14.9%) subjects had enlarged vestibular aqueduct (EVA), 30 (32%) subjects had Mondini deformity, 25 (26.6%) subjects had incomplete partition type two (IPII), 9 (9.6%) subjects had incomplete partition type one (IPI) and 16 (17%) subjects had hypoplastic cochlea type III or IV. Intraoperative electrically evoked compound action potential (ECAP) responses were analyzed and compared in all subjects. RESULTS AND CONCLUSIONS: Measurable ECAP responses can be elicited in patients with IEMs in most of the channels. Severe malformations can affect the prevalence of measuring ECAP and getting identifiable waveform morphology. Additionally, increased thresholds and lower slope of AGF was observed in IEMs specially in more severe malformations (e.g. IPI). IPI patients with better word recognition scores tended to show more identifiable ECAP measurements. This could suggest the presence of some correlation between ECAP responses and patients' performance after cochlear implantation.

Assessment of visual and auditory evoked potentials in young obese males.

Background: Obesity is a chronic condition, affecting central and peripheral nervous system. Studies on cranial nerve conduction in obesity are scarce and unclear; therefore, we planned this study. The aim of this study was to evaluate optic and auditory nerve conductions in obesity. Methods: It was a case-control study, with inclusion of 40 young males (20 obese and 20 controls) in age group of 18-30 years. We recorded pattern reversal visual evoked potential (PRVEP) and brainstem auditory evoked potential (BAEP). The PRVEP P100 latency and BAEP absolute and interpeak latencies were analyzed. Results: In obese individuals, BAEP absolute latencies of wave V were significantly prolonged in both the ears and wave I in left ear. In addition, significant prolongation of interpeak latency III-V was observed in both the ears and I-V latency, in right ear among obese cases. A positive correlation was seen between body mass index and interpeak latency I-V. In PRVEP recordings, P100 latency did not show any significant difference in both the groups. Conclusion: Therefore, we can conclude that obesity does not affect optic nerve conduction, but auditory nerve conduction is affected. BAEP I-V interpeak latency may be an indicator of subclinical auditory conduction defects in young obese males.

[Prospects for cochlear implantation in patients with auditory nerve dysplasia]. / Perspektivy kokhlearnoi implantatsii u patsientov s displaziei slukhovogo nerva.

Auditory nerve dysplasia (AND) can encompass various conditions of the auditory nerve (AN), ranging from true aplasia to hypoplasia. The purpose of this review is to discuss the prospect of cochlear implantation (CI) and subsequent auditory speech rehabilitation for AN abnormality. Studies of different authors when working with this category of children, possible results and methods of diagnostics of the AN condition are presented.

Neural Presbyacusis in Humans Inferred from Age-Related Differences in Auditory Nerve Function and Structure.

A common complaint of older adults is difficulty understanding speech, particularly in challenging listening conditions. Accumulating evidence suggests that these difficulties may reflect a loss and/or dysfunction of auditory nerve (AN) fibers. We used a novel approach to study age-related changes in AN structure and several measures of AN function, including neural synchrony, in 58 older adults and 42 younger adults. AN activity was measured in response to an auditory click (compound action potential; CAP), presented at stimulus levels ranging from 70 to 110 dB pSPL. Poorer AN function was observed for older than younger adults across CAP measures at higher but not lower stimulus levels. Associations across metrics and stimulus levels were consistent with age-related AN disengagement and AN dyssynchrony. High-resolution T2-weighted structural imaging revealed age-related differences in the density of cranial nerve VIII, with lower density in older adults with poorer neural synchrony. Individual differences in neural synchrony were the strongest predictor of speech recognition, such that poorer synchrony predicted poorer recognition of time-compressed speech and poorer speech recognition in noise for both younger and older adults. These results have broad clinical implications and are consistent with an interpretation that age-related atrophy at the level of the AN contributes to poorer neural synchrony and may explain some of the perceptual difficulties of older adults.SIGNIFICANCE STATEMENT Differences in auditory nerve (AN) pathophysiology may contribute to the large variations in hearing and communication abilities of older adults. However, current diagnostics focus largely on the increase in detection thresholds, which is likely because of the absence of indirect measures of AN function in standard clinical test batteries. Using novel metrics of AN function, combined with estimates of AN structure and auditory function, we identified age-related differences across measures that we interpret to represent age-related reductions in AN engagement and poorer neural synchrony. Structure-function associations are consistent with an explanation of AN deficits that arise from age-related atrophy of the AN. Associations between neural synchrony and speech recognition suggest that individual and age-related deficits in neural synchrony contribute to speech recognition deficits.

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea.

The auditory nerve (AN) of the inner ear is the primary conveyor of acoustic information from sensory hair cells to the brainstem. Approximately 95% of peripheral AN fibers are myelinated by glial cells. The integrity of myelin and the glial-associated paranodal structures at the node of Ranvier is critical for normal AN activity and axonal survival and function in the central auditory nervous system. However, little is known about the node of Ranvier's spatiotemporal development in the AN, how the aging process (or injury) affects the activity of myelinating glial cells, and how downstream alterations in myelin and paranodal structure contribute to AN degeneration and sensorineural hearing loss. Here, we characterized two types of Ranvier nodes-the axonal node and the ganglion node-in the mouse peripheral AN, and found that they are distinct in several features of postnatal myelination and age-related degeneration. Cellular, molecular, and structure-function correlations revealed that the two node types are each critical for different aspects of peripheral AN function. Neural processing speed and synchrony is associated with the length of the axonal node, while stimulus level-dependent amplitude growth and action potentials are associated with the ganglion node. Moreover, our data indicate that dysregulation of glial cells (e.g., satellite cells) and degeneration of the ganglion node structure are an important new mechanism of age-related hearing loss.

Noise Masking in Cochlear Synaptopathy: Auditory Brainstem Response vs. Auditory Nerve Response in Mouse.

After acoustic overexposure, many auditory-nerve fiber (ANF) synapses permanently retract from surviving cochlear hair cells. This synaptopathy is hard to diagnose, since it does not elevate audiometric thresholds until almost no synapses remain, nevertheless it may degrade discrimination of complex stimuli especially in noisy environments. Here, we study an assay based on masking the auditory brainstem responses (ABRs) to a moderate-level probe tone with continuous noise of varied sound levels, and we investigate the underlying ANF responses at the single-fiber level. Synaptopathy was induced by overexposure to octave-band noise, resulting in a permanent synaptic loss of ~50%, without permanent threshold elevation except at the highest frequencies. The normal progressive delay of ABR peaks with increasing masker level is diminished in synaptopathic ears; however, the single-fiber analysis suggests that this normal latency shift does not arise because contributing ANFs shift from low-threshold fibers (with high spontaneous rates) to high-threshold fibers (with low spontaneous rates). Rather, it may arise because of a shift in the cochlear region dominating the response. Surprisingly, the dynamic range of masking, i.e. the difference between the lowest masker level that attenuates the ABR to a fixed-level probe and the lowest masker level that eliminates the ABR, is enhanced in the synaptopathic ears. This ABR behavior mirrors the single-fiber data showing a paradoxical enhancement of onset-response synchrony and resistance to masking in responses of ANFs in the synaptopathic regions. An assay based on the dynamic range of masking could be useful in diagnosing synaptic damage in human populations.

Neural processing and perception of Schroeder-phase harmonic tone complexes in the gerbil: Relating single-unit neurophysiology to behavior.

Schroeder-phase harmonic tone complexes have been used in physiological and psychophysical studies in several species to gain insight into cochlear function. Each pitch period of the Schroeder stimulus contains a linear frequency sweep; the duty cycle, sweep velocity, and direction are controlled by parameters of the phase spectrum. Here, responses to a range of Schroeder-phase harmonic tone complexes were studied both behaviorally and in neural recordings from the auditory nerve and inferior colliculus of Mongolian gerbils. Gerbils were able to discriminate Schroeder-phase harmonic tone complexes based on sweep direction, duty cycle, and/or velocity for fundamental frequencies up to 200 Hz. Temporal representation in neural responses based on the van Rossum spike-distance metric, with time constants of either 1 ms or related to the stimulus' period, was compared with average discharge rates. Neural responses and behavioral performance were both expressed in terms of sensitivity, d', to allow direct comparisons. Our results suggest that in the auditory nerve, stimulus fine structure is represented by spike timing, whereas envelope is represented by rate. In the inferior colliculus, both temporal fine structure and envelope appear to be represented best by rate. However, correlations between neural d' values and behavioral sensitivity for sweep direction were strongest for both temporal metrics, for both auditory nerve and inferior colliculus. Furthermore, the high sensitivity observed in the inferior colliculus neural rate-based discrimination suggests that these neurons integrate across multiple inputs arising from the auditory periphery.

Brainstem auditory evoked potential combined with high resolution cranial base CT can optimize the diagnosis of auditory nerve injury.

PURPOSE: Auditory nerve injury is one of the most common nerve injury complications of skull base fractures. However, there is currently a lack of auxiliary examination methods for its direct diagnosis. The purpose of this study was to find a more efficient and accurate means of diagnosis for auditory nerve injury. METHODS: Through retrospectively analyzing the results of brainstem auditory evoked potential (BAEP) and high-resolution CT (HRCT) in 37 patients with hearing impairment following trauma from January 1, 2018 to July 31, 2020, the role of the two inspection methods in the diagnosis of auditory nerve injury was studied. Inclusion criteria were patient had a clear history of trauma and unilateral hearing impairment after trauma; while exclusion criteria were: (1) severe patient with a Glasgow coma scale score ≤5 because these patients were classified as severe head injury and admitted to the intensive care unit, (2) patient in the subacute stage admitted 72 h after trauma, and (3) patient with prior hearing impairment before trauma. According to Goodman's classification of hearing impairment, the patients were divided into low/medium/severe injury groups. In addition, patients were divided into HRCT-positive and negative groups for further investigation with their BAEP results. The positive rates of BEAP for each group were observed, and the results were analyzed by Chi-square test (p < 0.05, regarded as statistical difference). RESULTS: A total of 37 patients were included, including 21 males and 16 females. All of them were hospitalized patients with GCS score of 6-15 at the time of admission. The BAEP positive rate in the medium and severe injury group was 100%, which was significantly higher than that in the low injury group (27.27%) (p < 0.01). The rate of BEAP positivity was significantly higher in the HRCT-positive group (20/30, 66.7%) than in the HRCT-negative group (1/7, 14.3%) (p < 0.05). Twenty patients (54.05%) were both positive for BEAP and HRCT test, and considered to have auditory nerve damage. Six patients (16.22%) were both negative for BEAP and HRCT test, and 10 patients (27.03%) were BAEP-negative but HRCT-positive: all the 16 patients were considered as non-neurological injury. The rest 1 case (2.70%) was BAEP-positive but HRCT-negative, which we speculate may have auditory nerve concussion. CONCLUSION: By way of BAEP combining with skull base HRCT, we may improve the accuracy of the diagnosis of auditory nerve injury. Such a diagnostic strategy may be beneficial to guiding treatment plans and evaluating prognosis.

Phase Locking of Auditory Nerve Fibers: The Role of Lowpass Filtering by Hair Cells.

Phase locking of auditory-nerve-fiber (ANF) responses to the temporal fine structure of acoustic stimuli, a hallmark of the auditory system's temporal precision, is important for many aspects of hearing. Previous work has shown that phase-locked period histograms are often well described by exponential transfer functions relating instantaneous stimulus pressure to instantaneous spike rate, with no observed clipping of the histograms. The operating points and slopes of these functions change with stimulus level. The mechanism underlying this apparent gain control is unclear but is distinct from mechanical compression, is independent of refractoriness and spike-rate adaptation, and is apparently instantaneous. Here we show that these findings can be accounted for by a model consisting of a static Boltzmann transducer function yielding a clipped output, followed by a lowpass filter and a static exponential transfer function. Using responses to tones of ANFs from cats of both sexes, we show that, for a given ANF, the period histograms obtained at all stimulus levels for a given stimulus frequency can be described using one set of level-independent model parameters. The model also accounts for changes in the maximum and minimum instantaneous spike rates with changes in stimulus level. Notably, the estimated cutoff frequency is lower for low- than for high-spontaneous-rate ANFs, implying a synapse-specific contribution to lowpass filtering. These findings advance our understanding of ANF phase locking by highlighting the role of peripheral filtering mechanisms in shaping responses of individual ANFs.SIGNIFICANCE STATEMENT Phase locking of auditory-nerve-fiber responses to the temporal fine structure of acoustic stimuli is important for many aspects of hearing. Period histograms typically retain an approximately sinusoidal shape across stimulus levels, with the peripheral auditory system operating as though its overall transfer function is an exponential function whose slope decreases with increasing stimulus level. This apparent gain control can be accounted for by a static saturating transducer function followed by a lowpass filter. In addition to attenuating the AC component, the filter approximately recovers the sinusoidal waveform of the stimulus. The estimated cutoff frequency varies with spontaneous rate, revealing a synaptic contribution to lowpass filtering. These findings highlight the significant impact of peripheral filtering mechanisms on phase locking.

Mechanisms and Functional Consequences of Presynaptic Homeostatic Plasticity at Auditory Nerve Synapses.

Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca2+ influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca2+ cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca2+ channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca2+ influx is homeostatically regulated in vivo to enhance synaptic fidelity.SIGNIFICANCE STATEMENT Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca2+ influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.

Auditory-nerve responses in mice with noise-induced cochlear synaptopathy.

Cochlear synaptopathy is the noise-induced or age-related loss of ribbon synapses between inner hair cells (IHCs) and auditory-nerve fibers (ANFs), first reported in CBA/CaJ mice. Recordings from single ANFs in anesthetized, noise-exposed guinea pigs suggested that neurons with low spontaneous rates (SRs) and high thresholds are more vulnerable than low-threshold, high-SR fibers. However, there is extensive postexposure regeneration of ANFs in guinea pigs but not in mice. Here, we exposed CBA/CaJ mice to octave-band noise and recorded sound-evoked and spontaneous activity from single ANFs at least 2 wk later. Confocal analysis of cochleae immunostained for pre- and postsynaptic markers confirmed the expected loss of 40%-50% of ANF synapses in the basal half of the cochlea; however, our data were not consistent with a selective loss of low-SR fibers. Rather they suggested a loss of both SR groups in synaptopathic regions. Single-fiber thresholds and frequency tuning recovered to pre-exposure levels; however, response to tone bursts showed increased peak and steady-state firing rates, as well as decreased jitter in first-spike latencies. This apparent gain-of-function increased the robustness of tone-burst responses in the presence of continuous masking noise. This study suggests that the nature of noise-induced synaptic damage varies between different species and that, in mouse, the noise-induced hyperexcitability seen in central auditory circuits is also observed at the level of the auditory nerve.NEW & NOTEWORTHY Noise-induced damage to synapses between inner hair cells and auditory-nerve fibers (ANFs) can occur without permanent hair cell damage, resulting in pathophysiology that "hides" behind normal thresholds. Prior single-fiber neurophysiology in guinea pig suggested that noise selectively targets high-threshold ANFs. Here, we show that the lingering pathophysiology differs in mouse, with both ANF groups affected and a paradoxical gain-of-function in surviving low-threshold fibers, including increased onset rate, decreased onset jitter, and reduced maskability.

The role of the medial olivocochlear reflex in psychophysical masking and intensity resolution in humans: a review.

This review addresses the putative role of the medial olivocochlear (MOC) reflex in psychophysical masking and intensity resolution in humans. A framework for interpreting psychophysical results in terms of the expected influence of the MOC reflex is introduced. This framework is used to review the effects of a precursor or contralateral acoustic stimulation on 1) simultaneous masking of brief tones, 2) behavioral estimates of cochlear gain and frequency resolution in forward masking, 3) the buildup and decay of forward masking, and 4) measures of intensity resolution. Support, or lack thereof, for a role of the MOC reflex in psychophysical perception is discussed in terms of studies on estimates of MOC strength from otoacoustic emissions and the effects of resection of the olivocochlear bundle in patients with vestibular neurectomy. Novel, innovative approaches are needed to resolve the dissatisfying conclusion that current results are unable to definitively confirm or refute the role of the MOC reflex in masking and intensity resolution.

Envelope following responses predict speech-in-noise performance in normal-hearing listeners.

Permanent threshold elevation after noise exposure or aging is caused by loss of sensory cells; however, animal studies show that hair cell loss is often preceded by degeneration of the synapses between sensory cells and auditory nerve fibers. Silencing these neurons is likely to degrade auditory processing and may contribute to difficulties understanding speech in noisy backgrounds. Reduction of suprathreshold ABR amplitudes can be used to quantify synaptopathy in inbred mice. However, ABR amplitudes are highly variable in humans, and thus more challenging to use. Since noise-induced neuropathy preferentially targets fibers with high thresholds and low spontaneous rate and because phase locking to temporal envelopes is particularly strong in these fibers, measuring envelope following responses (EFRs) might be a more robust measure of cochlear synaptopathy. A recent auditory model further suggests that modulation of carrier tones with rectangular envelopes should be less sensitive to cochlear amplifier dysfunction and, therefore, a better metric of cochlear neural damage than sinusoidal amplitude modulation. In this study, we measure performance scores on a variety of difficult word-recognition tasks among listeners with normal audiograms and assess correlations with EFR magnitudes to rectangular versus sinusoidal modulation. Higher harmonics of EFR magnitudes evoked by a rectangular-envelope stimulus were significantly correlated with word scores, whereas those evoked by sinusoidally modulated tones did not. These results support previous reports that individual differences in synaptopathy may be a source of speech recognition variability despite the presence of normal thresholds at standard audiometric frequencies.NEW & NOTEWORTHY Recent studies suggest that millions of people may be at risk of permanent impairment from cochlear synaptopathy, the age-related and noise-induced degeneration of neural connections in the inner ear. This study examines electrophysiological responses to stimuli designed to improve detection of neural damage in subjects with normal hearing sensitivity. The resultant correlations with word recognition performance are consistent with a contribution of cochlear neural damage to deficits in hearing in noise abilities.