Auditory Neurophysiology publications

Rat ultrasonic vocalizations (USVs) are ethologically-essential social signals. Under natural conditions, 22kHz USVs and 50kHz USVs are emitted in association with negative and positive emotional states, respectively. Our first experiment examined freezing behavior elicited in naïve Sprague-Dawley rats by a 22kHz USV, a 50kHz USV, and frequency-matched tones. None of the stimuli elicited freezing, which is the most commonly-used index of fear. The second experiment examined single-unit responses to these stimuli in the amygdala (AM), which is well-known for its role in innate and acquired fear responses. Among 127 well-discriminated single units, 82% were auditory-responsive. Elicited firing patterns were classified using a multi-dimensional scheme that included transient (phasic) responses to the stimulus onsets and/or offsets as well as sustained (tonic) responses during the stimulus. Tonic responses, which are not ordinarily evaluated in AM, were 4.4-times more common than phasic responses. The 22kHz stimuli tended to elicit tonic increases in the firing rates, whereas the 50kHz stimuli more often elicited tonic decreases in firing rates. These opposing tonic responses correspond with the ethological valence of USVs in the two frequency bands. Thus, a relatively-small sample of single-unit responses in AM furnished a more sensitive index of emotional valence than freezing behavior. Latency analysis suggested that stimuli in the two frequency bands are processed through different pathways to AM. One possible interpretation is that phasic responses in AM reflect the detection of a stimulus change, whereas tonic responses indicate the valence of the detected stimulus.

Animal models of ototoxicity represent an elementary tool in otolaryngologic research. Such models are usually created via the consecutive injection of ototoxic drugs or the co-administration of ethacrynic acid and low-dose ototoxic drugs. Injection via the round window membrane (RWM) is one approach that allows for local drug delivery into the inner ear. In this study, 47 guinea pigs received an injection of varying doses of cisplatin via the RWM, and data concerning the animals' auditory brainstem responses, hair cells, and spiral ganglion neurons were analyzed. Our results indicate the high efficiency and generally small reaction of the subjects, suggesting that the application of cisplatin via the RWM is an effective animal model for ototoxicity research.

Sensory training therapies for tinnitus are based on the assumption that, notwithstanding neural changes related to tinnitus, auditory training can alter the response properties of neurons in auditory pathways. To assess this assumption, we investigated whether brain changes induced by sensory training in tinnitus sufferers and measured by electroencephalography (EEG) are similar to those induced in age and hearing loss matched individuals without tinnitus trained on the same auditory task. Auditory training was given using a 5 kHz 40-Hz amplitude-modulated (AM) sound that was in the tinnitus frequency region of the tinnitus subjects and enabled extraction of the 40-Hz auditory steady-state response (ASSR) and P2 transient response known to localize to primary and non-primary auditory cortex, respectively. P2 amplitude increased over training sessions equally in participants with tinnitus and in control subjects, suggesting normal remodeling of non-primary auditory regions in tinnitus. However, training-induced changes in the ASSR differed between the tinnitus and control groups. In controls the phase delay between the 40-Hz response and stimulus waveforms reduced by about 10° over training, in agreement with previous results obtained in young normal hearing individuals. However, ASSR phase did not change significantly with training in the tinnitus group, although some participants showed phase shifts resembling controls. On the other hand, ASSR amplitude increased with training in the tinnitus group, whereas in controls this response (which is difficult to remodel in young normal hearing subjects) did not change with training. These results suggest that neural changes related to tinnitus altered how neural plasticity was expressed in the region of primary but not non-primary auditory cortex. Auditory training did not reduce tinnitus loudness although a small effect on the tinnitus spectrum was detected.

Studies on the maturation of auditory motion processing in children have yielded inconsistent reports. The present study combines subjective and objective measurements to investigate how the auditory perceptual abilities of children change during development and whether these changes are paralleled by changes in the event-related brain potential (ERP). We employed the mismatch negativity (MMN) to determine maturational changes in the discrimination of interaural time differences (ITDs) that generate lateralized moving auditory percepts. MMNs were elicited in children, teenagers, and adults, using a small and a large ITD at stimulus offset with respect to each subject's discrimination threshold. In adults and teenagers large deviants elicited prominent MMNs, whereas small deviants at the behavioral threshold elicited only a marginal or no MMN. In contrast, pronounced MMNs for both deviant sizes were found in children. Behaviorally, however, most of the children showed higher discrimination thresholds than teens and adults. Although automatic ITD detection is functional, active discrimination is still limited in children. The lack of MMN deviance dependency in children suggests that unlike in teenagers and adults, neural signatures of automatic auditory motion processing do not mirror discrimination abilities. The study critically accounts for advanced understanding of children's central auditory development.

Future implementation of regenerative treatments for sensorineural hearing loss may be hindered by the lack of diagnostic tools that specify the target(s) within the cochlea and auditory nerve for delivery of therapeutic agents. Recent research has indicated that the amplitude of high-level compound action potentials (CAPs) is a good predictor of overall auditory nerve survival, but does not pinpoint the location of neural damage. A location-specific estimate of nerve pathology may be possible by using a masking paradigm and high-level CAPs to map auditory nerve firing density throughout the cochlea. This initial study in gerbil utilized a high-pass masking paradigm to determine normative ranges for CAP-derived neural firing density functions using broadband chirp stimuli and low-frequency tonebursts, and to determine if cochlear outer hair cell (OHC) pathology alters the distribution of neural firing in the cochlea. Neural firing distributions for moderate-intensity (60 dB pSPL) chirps were affected by OHC pathology whereas those derived with high-level (90 dB pSPL) chirps were not. These results suggest that CAP-derived neural firing distributions for high-level chirps may provide an estimate of auditory nerve survival that is independent of OHC pathology.

The superior paraolivary nucleus (SPON; alternative abbreviation: SPN for the same nucleus in certain species) is a prominent brainstem structure that provides strong inhibitory input to the auditory midbrain. Previous studies established that SPON neurons encode temporal sound features with high precision. These earlier characterizations of SPON responses were recorded under the influence of ketamine, a dissociative anesthetic agent and known antagonist of N-methyl-d-aspartate glutamate (NMDA) receptors. Because NMDA alters neural responses from the auditory brainstem, single unit extracellular recordings of SPON neurons were performed in the presence and absence of ketamine. In doing so, this study represents the first in vivo examination of the SPON of the mouse. Herein, independent data sets of SPON neurons are characterized that did or did not receive ketamine, as well as neurons that were recorded both prior to and following ketamine administration. In all conditions, SPON neurons exhibited contralaterally driven spikes triggered by the offset of pure tone stimuli. Ketamine lowered both evoked and spontaneous spiking, decreased the sharpness of frequency tuning, and increased auditory thresholds and first-spike latencies. In addition, ketamine limited the range of modulation frequencies to which neurons phase-locked to sinusoidally amplitude-modulated tones.

Acoustic over-exposure (AOE) triggers deafness in animals and humans and provokes auditory nerve degeneration. Weeks after exposure there is an increase in the cellular excitability within the dorsal cochlear nucleus (DCN) and this is considered as a possible neural correlate of tinnitus. The origin of this DCN hyperactivity phenomenon is still unknown but it is associated with neurons lying within the fusiform cell layer. Here we investigated changes of excitability within identified fusiform cells following AOE. Wistar rats were exposed to a loud (110 dB SPL) single tone (14.8 kHz) for 4 h. Auditory brainstem response recordings performed 3-4 days after AOE showed that the hearing thresholds were significantly elevated by about 20-30 dB SPL for frequencies above 15 kHz. Control fusiform cells fired with a regular firing pattern as assessed by the coefficient of variation of the inter-spike interval distribution of 0.19 ± 0.11 (n = 5). Three to four days after AOE, 40% of fusiform cells exhibited irregular bursting discharge patterns (coefficient of variation of the inter-spike interval distribution of 1.8 ± 0.6, n = 5; p < 0.05). Additionally the maximal firing following step current injections was reduced in these cells (from 83 ± 11 Hz, n = 5 in unexposed condition to 43 ± 6 Hz, n = 5 after AOE) and this was accompanied by an increased firing gain (from 0.09 ± 0.01 Hz/pA, n = 5 in unexposed condition to 0.56 ± 0.25 Hz/pA, n = 5 after AOE). Current and voltage clamp recordings suggest that the presence of bursts in fusiform cells is related to a down regulation of high voltage activated potassium currents. In conclusion we showed that AOE triggers deafness at early stages and this is correlated with profound changes in the firing pattern and frequency of the DCN major output fusiform cells. The changes here described could represent the initial network imbalance prior to the emergence of tinnitus.

The inferior colliculus (IC) is a major center for integration of auditory information as it receives ascending projections from a variety of brainstem nuclei as well as descending projections from the thalamus and auditory cortex. The ascending projections are both excitatory and inhibitory and their convergence at the IC results in a microcircuitry that is important for shaping responses to simple, binaural, and modulated sounds in the IC. Here, we examined the role inhibition plays in shaping selectivity to vocalizations in the IC of awake, normal-hearing adult mice (CBA/CaJ strain). Neurons in the IC of mice show selectivity in their responses to vocalizations, and we hypothesized that this selectivity is created by inhibitory microcircuitry in the IC. We compared single unit responses in the IC to pure tones and a variety of ultrasonic mouse vocalizations before and after iontophoretic application of GABA(A) receptor (GABA(A)R) and glycine receptor (GlyR) antagonists. The most pronounced effects of blocking GABA(A)R and GlyR on IC neurons were to increase spike rates and broaden excitatory frequency tuning curves in response to pure tone stimuli, and to decrease selectivity to vocalizations. Thus, inhibition plays an important role in creating selectivity to vocalizations in the IC.

Behavioral adaption to a changing environment is critical for an animal's survival. How well the brain can modify its functional properties based on experience essentially defines the limits of behavioral adaptation. In adult animals the extent to which experience shapes brain function has not been fully explored. Moreover, the perceptual consequences of experience-induced changes in the brains of adults remain unknown. Here we show that the tonotopic map in the primary auditory cortex of adult rats living with low-level ambient noise underwent a dramatic reorganization. Behaviorally, chronic noise-exposure impaired fine, but not coarse pitch discrimination. When tested in a noisy environment, the noise-exposed rats performed as well as in a quiet environment whereas the control rats performed poorly. This suggests that noise-exposed animals had adapted to living in a noisy environment. Behavioral pattern analyses revealed that stress or distraction engendered by the noisy background could not account for the poor performance of the control rats in a noisy environment. A reorganized auditory map may therefore have served as the neural substrate for the consistent performance of the noise-exposed rats in a noisy environment.

Objectives: From our previous study about the weak expressions of potassium-chloride (KCC2) and sodium-potassium-2 chloride (NKCC1) co-transporters in the lateral superior olive (LSO) in circling mice, we hypothesized that partially damaged cochlea of circling mice might be a cause of the weak expressions of KCC2 or NKCC1. To test this possibility, we reproduced the altered expressions of KCC2 and NKCC1 in the LSO of rats, whose cochleae were partially destroyed with kanamycin. Methods: Rat pups were treated with kanamycin from postnatal (P)3 to P8 (700 mg/kg, subcutaneous injection, twice a day) and sacrificed for immunohistochemical analysis, scanning electron microscope (SEM) and auditory brain stem response. Results: The SEM study revealed partially missing hair cells in P9 rats treated with kanamycin, and the hearing threshold was elevated to 63.8±2.5 dB SPL (4 ears) at P16. Both KCC2 and NKCC1 immunoreactivities were more prominent in control rats on P16. On 9 paired slices, the mean densities of NKCC1 immunoreactivities were 118.0±1.0 (control) and 112.2±1.2 (kanamycin treated), whereas those of KCC2 were 115.7±1.5 (control) and 112.0±0.8 (kanamycin treated). Conclusion: We concluded that weak expressions of KCC2 and NKCC1 in circling mice were due to partial destruction of cochleae.

The central nucleus of the inferior colliculus (IC) is organized into a series of fibro-dendritic laminae, orthogonal to the tonotopic progression. Many neurons have their dendrites confined to one lamina while others have dendrites that cross over a number of laminae. Here, we have used juxtacellular labeling in urethane anesthetized guinea pigs to visualize the cells with biocytin and have analyzed their response properties, in order to try and link their structure and function. Out of a sample of 38 filled cells, 15 had dendrites confined within the fibro-dendritic laminae and in 13 we were also able to reconstruct their local axonal tree. Based on dendritic morphology they were subdivided into flat or less flat; small, medium, or large; elongated or disk-shaped cells. Two of the elongated cells had many dendritic spines while the other cells had few or none. Twelve of the cells had their local axonal tree restricted to the same lamina as their dendrites while one cell had its dendrites in a separate lamina from the axon. The axonal plexus was more extensive (width 0.7-1.4 mm) within the lamina than the dendrites (width generally 0.07-0.53 mm). The intrinsic axons were largely confined to a single lamina within the central nucleus, but at least half the cells also had output axons with two heading for the commissure and five heading into the brachium. We were able to identify similarities in the physiological response profiles of small groups of our filled cells but none appeared to represent a homogeneous morphological cell type. The only common feature of our sample was one of exclusion in that the onset response, a response commonly recorded from IC cells, was never seen in laminar cells, but was in cells with a stellate morphology. Thus cells with laminar dendrites have a wide variety of physiological responses and morphological subtypes, but over 90% have an extensive local axonal tree within their local lamina.

Neural responses in the mammalian auditory midbrain (inferior colliculus; IC) arise from complex interactions of synaptic excitation, inhibition, and intrinsic properties of the cell. Temporally selective duration-tuned neurons (DTNs) in the IC are hypothesized to arise through the convergence of excitatory and inhibitory synaptic inputs offset in time. Synaptic inhibition can be inferred from extracellular recordings by presenting pairs of pulses (paired tone stimulation) and comparing the evoked responses of the cell to each pulse. We obtained single unit recordings from the IC of the awake big brown bat (Eptesicus fuscus) and used paired tone stimulation to measure the recovery cycle times of DTNs and non-temporally selective auditory neurons. By systematically varying the interpulse interval (IPI) of the paired tone stimulus, we determined the minimum IPI required for a neuron's spike count or its spike latency (first- or last-spike latency) in response to the second tone to recover to within ≥50% of the cell's baseline count or to within 1 SD of it's baseline latency in response to the first tone. Recovery times of shortpass DTNs were significantly shorter than those of bandpass DTNs, and recovery times of bandpass DTNs were longer than allpass neurons not selective for stimulus duration. Recovery times measured with spike counts were positively correlated with those measured with spike latencies. Recovery times were also correlated with first-spike latency (FSL). These findings, combined with previous studies on duration tuning in the IC, suggest that persistent inhibition is a defining characteristic of DTNs. Herein, we discuss measuring recovery times of neurons with spike counts and latencies. We also highlight how persistent inhibition could determine neural recovery times and serve as a potential mechanism underlying the precedence effect in humans. Finally, we explore implications of recovery times for DTNs in the context of bat hearing and echolocation.

Auditory neurons in the inferior colliculus (IC) of the pallid bat have highly rate selective responses to downward frequency modulated (FM) sweeps attributable to the spectrotemporal pattern of their echolocation call (a brief FM pulse). Several mechanisms are known to shape FM rate selectivity within the pallid bat IC. Here we explore how two mechanisms, stimulus duration and high-frequency inhibition (HFI), can interact to shape FM rate selectivity within the same neuron. Results from extracellular recordings indicated that a derived duration-rate function (based on tonal response) was highly predictive of the shape of the FM rate response. Longpass duration selectivity for tones was predictive of slowpass rate selectivity for FM sweeps, both of which required long stimulus durations and remained intact following iontophoretic blockade of inhibitory input. Bandpass duration selectivity for tones, sensitive to only a narrow range of tone durations, was predictive of bandpass rate selectivity for FM sweeps. Conversion of the tone duration response from bandpass to longpass after blocking inhibition was coincident with a change in FM rate selectivity from bandpass to slowpass indicating an active inhibitory component to the formation of bandpass selectivity. Independent of the effect of duration tuning on FM rate selectivity, the presence of HFI acted as a fastpass FM rate filter by suppressing slow FM sweep rates. In cases where both mechanisms were present, both had to be eliminated, by removing inhibition, before bandpass FM rate selectivity was affected. It is unknown why the auditory system utilizes multiple mechanisms capable of shaping identical forms of FM rate selectivity though it may represent distinct but convergent modes of neural signaling directed at shaping response selectivity for important biologically relevant sounds.

The brain is a densely interconnected network that relies on populations of neurons within and across multiple nuclei to code for features leading to perception and action. However, the neurophysiology field is still dominated by the characterization of individual neurons, rather than simultaneous recordings across multiple regions, without consistent spatial reconstruction of their locations for comparisons across studies. There are sophisticated histological and imaging techniques for performing brain reconstructions. However, what is needed is a method that is relatively easy and inexpensive to implement in a typical neurophysiology lab and provides consistent identification of electrode locations to make it widely used for pooling data across studies and research groups. This paper presents our initial development of such an approach for reconstructing electrode tracks and site locations within the guinea pig inferior colliculus (IC) to identify its functional organization for frequency coding relevant for a new auditory midbrain implant (AMI). Encouragingly, the spatial error associated with different individuals reconstructing electrode tracks for the same midbrain was less than 65 μm, corresponding to an error of ~1.5% relative to the entire IC structure (~4-5 mm diameter sphere). Furthermore, the reconstructed frequency laminae of the IC were consistently aligned across three sampled midbrains, demonstrating the ability to use our method to combine location data across animals. Hopefully, through further improvements in our reconstruction method, it can be used as a standard protocol across neurophysiology labs to characterize neural data not only within the IC but also within other brain regions to help bridge the gap between cellular activity and network function. Clinically, correlating function with location within and across multiple brain regions can guide optimal placement of electrodes for the growing field of neural prosthetics.

Stimulus-specific adaptation (SSA) is the ability of some neurons to respond better to rare than to frequent, repetitive stimuli. In the auditory system, SSA has been found at the level of the midbrain, thalamus, and cortex. While previous studies have used the whole overall neuronal response to characterize SSA, here we present a detailed analysis on the variations within the time course of the evoked responses. The extracellular activity of well isolated single neurons from the inferior colliculus (IC) was recorded during stimulation using an oddball paradigm, which is able to elicit SSA. At the same time, these responses were evaluated before, during, and after the microiontophoretic application of gabazine, a specific antagonist of GABA(A) receptors, to study the contribution of inhibition to the responses of these neurons. We then analyzed the difference signal (DS), which is the difference in the PSTH in response to rare and frequent stimuli. We found that, even in a sample of neurons showing strong SSA (i.e., showing larger preference for rare stimuli), the DS was variable and one third of the neurons contained portions that responded significantly better to the frequent stimuli than to the rare. This variability is not observed when averaging the responses of multiple cells. Furthermore, the blockade of GABA(A) receptors increased the number of neurons showing portions that responded better to the frequent stimuli, indicating that inhibition in the IC refines and sharpens SSA in the neural responses.

The auditory pathways coursing through the brainstem are organized bilaterally in mirror image about the midline and at several levels the two sides are interconnected. One of the most prominent points of interconnection is the commissure of the inferior colliculus (CoIC). Anatomical studies have revealed that these fibers make reciprocal connections which follow the tonotopic organization of the inferior colliculus (IC), and that the commissure contains both excitatory and, albeit fewer, inhibitory fibers. The role of these connections in sound processing is largely unknown. Here we describe a method to address this question in the anaesthetized guinea pig. We used a cryoloop placed on one IC to produce reversible deactivation while recording electrophysiological responses to sounds in both ICs. We recorded single units, multi-unit clusters and local field potentials (LFPs) before, during and after cooling. The degree and spread of cooling was measured with a thermocouple placed in the IC and other auditory structures. Cooling sufficient to eliminate firing was restricted to the IC contacted by the cryoloop. The temperature of other auditory brainstem structures, including the contralateral IC and the cochlea were minimally affected. Cooling below 20°C reduced or eliminated the firing of action potentials in frequency laminae at depths corresponding to characteristic frequencies up to ~8 kHz. Modulation of neural activity also occurred in the un-cooled IC with changes in single unit firing and LFPs. Components of LFPs signaling lemniscal afferent input to the IC showed little change in amplitude or latency with cooling, whereas the later components, which likely reflect inter- and intra-collicular processing, showed marked changes in form and amplitude. We conclude that the cryoloop is an effective method of selectively deactivating one IC in guinea pig, and demonstrate that auditory processing in the IC is strongly influenced by the other.

The inferior colliculus (IC) receives ascending excitatory and inhibitory inputs from multiple sources, but how these auditory inputs converge to generate IC spike patterns is poorly understood. Simulating patterns of in vivo spike train data from cellular and synaptic models creates a powerful framework to identify factors that contribute to changes in IC responses, such as those resulting in age-related loss of temporal processing. A conductance-based single neuron IC model was constructed, and its responses were compared to those observed during in vivo IC recordings in rats. IC spike patterns were evoked using amplitude-modulated tone or noise carriers at 20-40 dB above threshold and were classified as low-pass, band-pass, band-reject, all-pass, or complex based on their rate modulation transfer function tuning shape. Their temporal modulation transfer functions were also measured. These spike patterns provided experimental measures of rate, vector strength, and firing pattern for comparison with model outputs. Patterns of excitatory and inhibitory synaptic convergence to IC neurons were based on anatomical studies and generalized input tuning for modulation frequency. Responses of modeled ascending inputs were derived from experimental data from previous studies. Adapting and sustained IC intrinsic models were created, with adaptation created via calcium-activated potassium currents. Short-term synaptic plasticity was incorporated into the model in the form of synaptic depression, which was shown to have a substantial effect on the magnitude and time course of the IC response. The most commonly observed IC response sub-types were recreated and enabled dissociation of inherited response properties from those that were generated in IC. Furthermore, the model was used to make predictions about the consequences of reduction in inhibition for age-related loss of temporal processing due to a reduction in GABA seen anatomically with age.

In their shallow-water habitats, bullfrog (Rana catesbeiana) tadpoles are exposed to both underwater and airborne sources of acoustic stimulation. We probed the representation of underwater particle motion throughout the tadpole's dorsal medulla to determine its spatial extent over larval life. Using neurobiotin-filled micropipettes, we recorded neural activity to z-axis particle motion (frequencies of 40-200 Hz) in the medial vestibular nucleus, lateral vestibular nucleus, dorsal medullary nucleus (DMN), and along the dorsal arcuate pathway. Sensitivity was comparable in the medial and lateral vestibular nuclei, with estimated thresholds between 0.016 and 12.5 μm displacement. Neither best responding frequency nor estimated threshold varied significantly over larval stage. Transport of neurobiotin from active recording sites was also stable over development. The DMN responded poorly to z-axis particle motion, but did respond to low-frequency pressure stimulation. These data suggest that particle motion is represented widely and stably in the tadpole's vestibular medulla. This is in marked contrast to the representation of pressure stimulation in the auditory midbrain, where a transient "deaf period" of non-responsiveness and decreased connectivity occurs immediately prior to metamorphic climax. We suggest that, in bullfrogs, sensitivity to particle motion and to pressure follows different developmental trajectories.

Habituation is the most basic form of learning, yet many gaps remain in our understanding of its underlying neural mechanisms. We demonstrate that in the owl's optic tectum (OT), a single, low-level, relatively short auditory stimulus is sufficient to induce a significant reduction in the neural response to a stimulus presented up to 60 s later. This type of neural adaptation was absent in neurons from the central nucleus of the inferior colliculus and from the auditory thalamus; however, it was apparent in the OT and the forebrain entopallium. By presenting sequences that alternate between two different auditory stimuli, we show that this long-lasting adaptation is stimulus specific. The response to an odd stimulus in the sequence was not smaller than the response to the same stimulus when it was first in the sequence. Finally, we measured the habituation of reflexive eye movements and show that the behavioral habituation is correlated with the neural adaptation. The finding of a long-lasting specific adaptation in areas related to the gaze control system and not elsewhere suggests its involvement in habituation processes and opens new directions for research on mechanisms of habituation.

Hypothesis: Impairments of the medial olivocochlear system (MOCS) increase the risk of environmentally induced auditory neuropathy spectrum disorder (ANSD). Background: ANSD is a problem in the neural transmission of auditory information that accounts for 10% to 15% of the cases of pediatric hearing loss. The underlying mechanisms of the disorder remain poorly understood, but noise exposure is an important risk factor. The goal of this study was to identify environmental conditions and genetic predispositions that lead to ANSD. Our approach was based on the assumption that noise induces ANSD by impeding the functional maturation of the brain's sound coding pathways. Because the MOCS adjusts the sensitivity of the inner ear to noise, impairments of this feedback are predicted to increase the disruptive effects of environmental exposures. Methods: An animal model of ANSD was created by rearing mice in noise. MOCS protection was assessed by comparing the incidence of noise-induced ANSD among knockout mice lacking feedback and wild-type (WT) controls. The mice were screened for ANSD with distortion product otoacoustic emissions, auditory brainstem responses, and behavioral measures of gap detection. Single-unit recording procedures were used to link these deficits to impaired synaptic transmission in the ventral cochlear nucleus. Results: ANSD manifested in noise-reared mice as intact distortion product otoacoustic emissions, abnormal auditory brainstem responses, and impaired gap detection. The phenotype was not observed among quiet-reared WT mice but was occasionally noted among noise-reared WT mice. The incidence of ANSD significantly increased among knockout mice, especially when they were reared in noise. Conclusion: Noise promotes ANSD by altering the functional maturation of the brain's temporal pathways. Noise-induced impairments are reduced by the sound-attenuating effects of the MOCS. Noise levels do not need to be unnaturally loud to constitute significant risk in MOCS-compromised individuals.