Auditory Research publications

The brain combines information from multiple sensory modalities to interpret the environment. These processes, collectively known as multisensory integration, have been modeled as Bayesian causal inference, which proposes that perception involves the combination of information from different sensory modalities based on their reliability and their likelihood of stemming from the same causes in the outside world. Bayesian causal inference has explained a variety of multisensory effects in simple tasks but is largely untested in complex sensory scenes where multisensory integration can provide the most benefit. Recently, we presented data challenging the ideal Bayesian model from a new auditory spatial discrimination task in which spatially aligned visual stimuli improve performance despite providing no information about the correct response. Here, we tested the hypothesis that, despite deviating from the ideal observer, the influence of task-uninformative stimuli was still dependent on the reliabilities of auditory and visual cues. We reasoned shorter stimulus durations should lead to less reliable auditory spatial encoding, and hence stronger effects of more reliable visual cues, which are easily localized even at short durations. While our results replicated the effect from our previous study across a wide range of stimulus durations, we did not find a significant increase in effect size with shorter stimuli, leaving our principal question not fully answered.

The biomedical community is rapidly developing COVID-19 drugs to bring much-need therapies to market, with over 900 drugs and drug combinations currently in clinical trials. While this pace of drug development is necessary, the risk of producing therapies with significant side-effects is also increased. One likely side-effect of some COVID-19 drugs is hearing loss, yet hearing is not assessed during preclinical development or clinical trials. We used the zebrafish lateral line, an established model for drug-induced sensory hair cell damage, to assess the ototoxic potential of seven drugs in clinical trials for treatment of COVID-19. We found that ivermectin, lopinavir, imatinib, and ritonavir were significantly toxic to lateral line hair cells. By contrast, the approved COVID-19 therapies dexamethasone and remdesivir did not cause damage. We also did not observe damage from the antibiotic azithromycin. Neither lopinavir nor ritonavir altered the number of pre-synaptic ribbons per surviving hair cell, while there was an increase in ribbons following imatinib or ivermectin exposure. Damage from lopinavir, imatinib, and ivermectin was specific to hair cells, with no overall cytotoxicity noted following TUNEL labeling. Ritonavir may be generally cytotoxic, as determined by an increase in the number of TUNEL-positive non-hair cells following ritonavir exposure. Pharmacological inhibition of the mechanotransduction (MET) channel attenuated damage caused by lopinavir and ritonavir but did not alter imatinib or ivermectin toxicity. These results suggest that lopinavir and ritonavir may enter hair cells through the MET channel, similar to known ototoxins such as aminoglycoside antibiotics. Finally, we asked if ivermectin was ototoxic to rats in vivo . While ivermectin is not recommended by the FDA for treating COVID-19, many people have chosen to take ivermectin without a doctor’s guidance, often with serious side-effects. Rats received daily subcutaneous injections for 10 days with a clinically relevant ivermectin dose (0.2 mg/kg). In contrast to our zebrafish assays, ivermectin did not cause ototoxicity in rats. Our research suggests that some drugs in clinical trials for COVID-19 may be ototoxic. This work can help identify drugs with the fewest side-effects and determine which therapies warrant audiometric monitoring.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood–brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.

Sensory responses typically vary depending on the recent history of sensory experience. This is essential for processes, including adaptation, efficient coding, and change detection. In the auditory cortex (AC), the short-term history dependence of sound-evoked (onset) responses has been well characterized. Yet many AC neurons also respond to sound terminations, and little is known about the history dependence of these "offset" responses, whether the short-term dynamics of onset and offset responses are correlated, or how these properties are distributed among cell types. Here we presented awake male and female mice with repeating noise burst stimuli while recording single-unit activity from primary AC. We identified parvalbumin and somatostatin interneurons through optotagging, and also separated narrow-spiking from broad-spiking units. We found that offset responses are typically less depressive than onset responses, and this result was robust to a variety of stimulus parameters, controls, measurement types, and selection criteria. Whether a cell's onset response facilitates or depresses does not predict whether its offset response facilitates or depresses. Cell types differed in the dynamics of their onset responses, and in the prevalence, but not the dynamics, of their offset responses. Finally, we clustered cells according to spiking responses and found that response clusters were associated with cell type. Each cluster contained cells of several types, but even within a cluster, cells often showed cell type-specific response dynamics. We conclude that onset and offset responses are differentially influenced by recent sound history, and discuss the implications of this for the encoding of ongoing sound stimuli.SIGNIFICANCE STATEMENT Sensory neuron responses depend on stimulus history. This history dependence is crucial for sensory processing, is precisely controlled at individual synapses and circuits, and is adaptive to the specific requirements of different sensory systems. In the auditory cortex, neurons respond to sound cessation as well as to sound itself, but how history dependence is used along this separate, "offset" information stream is unknown. We show that offset responses are more facilitatory than sound responses, even in neurons where sound responses depress. In contrast to sound onset responses, offset responses are absent in many cells, are relatively homogeneous, and show no cell type-specific differences in history dependence. Offset responses thus show unique response dynamics, suggesting their unique functions.

Deficits in auditory nerve (AN) function for older adults reduce afferent input to the cortex. The extent to which the cortex in older adults adapts to this loss of afferent input and the mechanisms underlying this adaptation are not well understood. We took a neural systems approach measuring AN and cortical evoked responses within 50 older and 27 younger human adults (59 female) to estimate central gain or increased cortical activity despite reduced AN activity. Relative to younger adults, older adults' AN response amplitudes were smaller, but cortical responses were not. We used the relationship between AN and cortical response amplitudes in younger adults to predict cortical response amplitudes for older adults from their AN responses. Central gain in older adults was thus defined as the difference between their observed cortical responses and those predicted from the parameter estimates of younger adults. In older adults, decreased afferent input contributed to lower cortical GABA levels, greater central gain, and poorer speech recognition in noise (SIN). These effects on SIN occur in addition to, and independent from, effects attributed to elevated hearing thresholds. Our results are consistent with animal models of central gain and suggest that reduced AN afferent input in some older adults may result in changes in cortical encoding and inhibitory neurotransmission, which contribute to reduced SIN. An advancement in our understanding of the changes that occur throughout the auditory system in response to the gradual loss of input with increasing age may provide potential therapeutic targets for intervention.SIGNIFICANCE STATEMENT Age-related hearing loss is one of the most common chronic conditions of aging, yet little is known about how the cortex adapts to this loss of sensory input. We measured AN and cortical responses to the same stimulus in younger and older adults. In older adults we found hyperexcitability in cortical activity relative to concomitant declines in afferent input that are consistent with central gain. Lower levels of cortical GABA, an inhibitory neurotransmitter, were associated with greater central gain, which predicted poorer SIN. The results suggest that the cortex in older adults may adapt to attenuated sensory input by reducing inhibition to amplify the cortical response, but this amplification may lead to poorer SIN.

Recent studies on loudness perception of binaural broadband signals in hearing impaired listeners found large individual differences, suggesting the use of such signals in hearing aid fitting. Likewise, clinical cochlear implant (CI) fitting with narrowband/single-electrode signals might cause suboptimal loudness perception in bilateral and bimodal CI listeners. Here spectral and binaural loudness summation in normal hearing (NH) listeners, bilateral CI (biCI) users, and unilateral CI (uCI) users with normal hearing in the unaided ear was investigated to assess the relevance of binaural/bilateral fitting in CI users. To compare the three groups, categorical loudness scaling was performed for an equal categorical loudness noise (ECLN) consisting of the sum of six spectrally separated third-octave noises at equal loudness. The acoustical ECLN procedure was adapted to an equivalent procedure in the electrical domain using direct stimulation. To ensure the same broadband loudness in binaural measurements with simultaneous electrical and acoustical stimulation, a modified binaural ECLN was introduced and cross validated with self-adjusted loudness in a loudness balancing experiment. Results showed a higher (spectral) loudness summation of the six equally loud narrowband signals in the ECLN in CI compared to NH. Binaural loudness summation was found for all three listener groups (NH, uCI, and biCI). No increased binaural loudness summation could be found for the current uCI and biCI listeners compared to the NH group. In uCI loudness balancing between narrowband signals and single electrodes did not automatically result in a balanced loudness perception across ears, emphasizing the importance of binaural/bilateral fitting.

Noise-induced hearing impairment can mediate delayed injury of spiral neurons (SGNs), resulting in degeneration of nerve fibers, synaptic degeneration and even death of SGNs. We believe that delayed injury is related to mitochondrial energy metabolism disorders. Therefore, we investigated ATP and the electron transport chain (ETC) in rat SGNs after noise injury and found that with prolonged injury time, ATP synthesis and the expression of complexes II and IV decreased, indicating the functional decline of the ETC. The maintenance of ETC function is related to subunit import and assembly of the complex. The disulfide relay mechanism controlled by the apoptosis inducing factor/coiled-coil-helix-coiled-coil-helix domain-containing protein 4(AIF/CHCHD4) pathway can regulate mitochondrial protein import. The results showed that AIF expression in SGNs decreased after noise exposure, indicating that noise damage to SGNs can restore intramitochondrial protein input by downregulating the AIF/CHCHD4 pathway, hindering ETC function; insufficient ETC function is a possible reason for the delayed injury of SGNs.

Auditory brainstem responses (ABRs) to broadband clicks are strongly affected by dyssynchrony, or “latency dispersion”, of their frequency-specific cochlear contributions. Optimized chirp stimuli, designed to compensate for cochlear dispersion, can afford substantial increase in broadband ABR amplitudes, particularly for the prominent wave-V deflection. Reports on the smaller wave I, however, which may be useful for measuring cochlear synaptopathy, have been mixed. This study aimed to test previous claims that ABR latency dispersion differs between waves I and V, and between males and females, and thus that using wave- and/or sex-tailored chirps may provide more reliable wave-I benefit. Using the derived-band technique, we measured responses from frequency-restricted (one-octave-wide) cochlear regions to energy-matched click and chirp stimuli. The derived-band responses’ latencies were used to assess any wave- and/or sex-related dispersion differences across bands, and their amplitudes, to evaluate any within-band dispersion differences. Our results suggest that sex-related dispersion difference within the lowest-frequency cochlear regions (< 1 kHz), where dispersion is generally greatest, may be a predominant driver of the often-reported sex difference in broadband ABR amplitude. At the same time, they showed no systematic dispersion difference between waves I and V. Instead, they suggest that reduced chirp benefit on wave I may arise as a result of chirp-induced desynchronization of on- and off-frequency responses generated at the same cochlear places, and resultant reduction in response contributions from higher-frequency cochlear regions, to which wave I is thought to be particularly sensitive.

In everyday behavior, sensory systems are in constant competition for attentional resources, but the cellular and circuit-level mechanisms of modality-selective attention remain largely uninvestigated. We conducted translaminar recordings in mouse auditory cortex (AC) during an audiovisual (AV) attention shifting task. Attending to sound elements in an AV stream reduced both pre-stimulus and stimulus-evoked spiking activity, primarily in deep-layer neurons and neurons without spectrotemporal tuning. Despite reduced spiking, stimulus decoder accuracy was preserved, suggesting improved sound encoding efficiency. Similarly, task-irrelevant mapping stimuli during inter-trial intervals evoked fewer spikes without impairing stimulus encoding, indicating that attentional modulation generalized beyond training stimuli. Importantly, spiking reductions predicted trial-to-trial behavioral accuracy during auditory attention, but not visual attention. Together, these findings suggest auditory attention facilitates sound discrimination by filtering sound-irrelevant background activity in AC, and that the deepest cortical layers serve as a hub for integrating extramodal contextual information.

Purpose: Vocal roughness is often present in many voice disorders but the assessment of roughness mainly depends on the subjective auditory-perceptual evaluation and lacks acoustic correlates. This study aimed to apply the concept of roughness in general sound quality perception to vocal roughness assessment and to characterize the relationship between vocal roughness and temporal envelop fluctuation measures obtained from an auditory model. Method: Ten /ɑ/ recordings with a wide range of roughness were selected from an existing database. Ten listeners rated the roughness of the recordings in a single-variable matching task. Temporal envelope fluctuations of the recordings were analyzed with an auditory processing model of amplitude modulation that utilizes a modulation filterbank of different modulation frequencies. Pitch strength and the smoothed cepstral peak prominence were also obtained for comparison. Results: Individual simple regression models yielded envelope standard deviation from a modulation filter with a low center frequency (64.3 Hz) as a statistically significant predictor of vocal roughness with a strong coefficient of determination ( r 2 = .80). Pitch strength and CPPS were not significant predictors of roughness. Conclusion: This result supports the possible utility of envelope fluctuation measures from an auditory model as objective correlates of vocal roughness.

The common marmoset ( Callithrix jacchus ) is a small arboreal New World primate which has emerged as a promising model in auditory neuroscience. One potentially useful application of this model system is in the study of the neural mechanism underlying spatial hearing in primate species, as the marmoset’s visually occluded natural habitat in the forest would make sound localization an essential behavior for survival. However, interpretation of neurophysiological data on sound localization requires an understanding of perceptual abilities, and the sound localization behavior of marmosets has not been well studied. The present experiment measured sound localization acuity using an operant conditioning procedure in which marmosets were trained to discriminate changes in sound location in the horizontal (azimuth) or vertical (elevation) dimension. Our results showed that the minimum audible angle (MAA) for horizontal discrimination was on average 15° for band-passed Gaussian noise and 13° for Random Spectral Shape (RSS) stimuli, whereas the MAA for vertical locations was at 17° and 22° for band-passed Gaussian noises containing more and less high frequency energy, respectively.

Eardrum perforation and associated hearing loss is a global health problem. Grafting perforated eardrum with autologous tissues in clinic can restore low‐frequency hearing but often leaves poor recovery of high‐frequency hearing. In this study, the potential of incorporating a thin multilayered graphene membrane (MGM) into the eardrum for broadband hearing recovery in rats is examined. The MGM shows good biocompatibility and biostability to promote the growth of eardrum cells in a regulated manner with little sign of tissue rejection and inflammatory response. After three weeks of implantation, the MGM is found to be encapsulated by a thin layer of newly grown tissue on both sides without a significant folded overgrowth that is often seen in natural healing. The perforation is well sealed, and broadband hearing recovery (1–32 kHz) is enabled and maintained for at least 2 months. Mechanical simulations show that the high elastic modulus of MGM and thin thickness of the reconstructed eardrum play a critical role in the recovery of high‐frequency hearing. This work demonstrates the promise of the use of MGM as a functional graft for perforated eardrum to recover hearing in the broadband frequency region and suggests a new acoustics‐related medical application for graphene‐related 2D materials.

The functional organization of sensory cortices is modulated by both extrinsic events and intrinsic states. The present study aimed to assess the mouse auditory cortex (AC) responses under varying conditions of stimulus complexity and brain state. Using wide-field calcium imaging, our results suggest a complete outline of topographic maps of frequency and FM rate as well as highly responsive regions to mouse ultrasonic vocalizations (USVs) in both awake and anesthetized states. Three new regions responsive to high-frequency tones and four new gradients responsive to frequency modulations (FMs) were identified. These maps are highly replicable across weeks and between animals. In awake versus anesthetized states, cortical responsiveness to pure tones was stronger, and regions that preferentially responded to slow rate FMs were smaller. In both states, fast FM regions showed the greatest contribution to the processing of USVs. Finally, our modeling of how best tone frequency or FM rate changes as a function of distance along a topographic gradient resulted in a sigmoid function. Together, our findings provide a better understanding of mouse AC functional organization and how this organization is modulated by changes in stimulus complexity and brain state. The function of newly identified regions in higher-order auditory/vocal processing and animal behavior should be considered in future research.

Objective: Molecular hydrogen (H 2 ) has shown therapeutic potential in several oxidative stress-related conditions in humans, is well-tolerated, and is easily administered via inhalation.The aim of this preclinical in vivo study was to investigate whether impulse noise trauma can be prevented by H 2 when inhaled immediately after impulse noise exposure. Methods: Guinea pigs (n = 26) were subjected to impulse noise (n = 400; 156 dB SPL; 0.33/s; n = 11; the Noise group), to impulse noise immediately followed by H 2 inhalation (2 mol%; 500 ml/min; 1 hour; n = 10; the Noise + H 2 group), or to H 2 inhalation (n = 5; the H 2 group). The acoustically evoked ABR threshold at 3.15, 6.30, 12.5, 20.0, and 30.0 kHz was assessed before and 4 days after impulse noise and/or H 2 exposure. The cochleae were harvested after the final ABR assessment for quantification of hair cells. Results: Noise exposure caused ABR threshold elevations at all frequencies (median 35, 35, 30, 35, and 35 dB SPL, the Noise group; 20, 25, 10, 13, and 20 dB SPL, the Noise + H 2 group; P < .05) but significantly less so in the Noise + H 2 group ( P < .05). Outer hair cell (OHC) loss was in the apical, mid, and basal regions 8.8%, 53%, and 14% in the Noise group and 3.5%, 22%, and 1.2% in the Noise + H 2 group. The corresponding inner hair cell (IHC) loss was 0.1%, 14%, and 3.5% in the Noise group and 0%, 2.8%, and 0% in the Noise + H 2 group. The difference between the groups was significant in the basal region for OHCs ( P = .003) and apical ( P = .033) and basal ( P = .048) regions for IHCs. Conclusions: Acute acoustic trauma can be reduced by H 2 when inhaled immediately after impulse noise exposure.

Neural coding of the slow amplitude fluctuations of sound (i.e., temporal envelope) is thought to be essential for speech understanding; however, such coding by the human auditory nerve is poorly understood. Here, neural coding of the temporal envelope by the human auditory nerve is inferred from measurements of the compound action potential in response to an amplitude modulated carrier (CAPENV) for modulation frequencies ranging from 20 to 1000 Hz. The envelope following response (EFR) was measured simultaneously with CAPENV from active electrodes placed on the high forehead and tympanic membrane, respectively. Results support the hypothesis that phase locking to higher modulation frequencies (> 80 Hz) will be stronger for CAPENV, compared to EFR, consistent with the upper-frequency limits of phase locking for auditory nerve fibers compared to auditory brainstem/cortex neurons. Future work is needed to determine the extent to which (1) CAPENV is a useful tool for studying how temporal processing of the auditory nerve is affected by aging, hearing loss, and noise-induced cochlear synaptopathy and (2) CAPENV reveals the relationship between auditory nerve temporal processing and perception of the temporal envelope.

Life underground often leads to animals having specialized auditory systems to accommodate the constraints of acoustic transmission in tunnels. Despite living underground, naked mole-rats use a highly vocal communication system, implying that they rely on central auditory processing. However, little is known about these animals' central auditory system, and whether it follows a similar developmental time course as other rodents. Naked mole-rats show slowed development in the hippocampus suggesting they have altered brain development compared to other rodents. Here, we measured morphological characteristics and voltage-gated potassium channel K v 3.3 expression and protein levels at different key developmental time points (postnatal days 9, 14, 21 and adulthood) to determine whether the auditory brainstem (lateral superior olive and medial nucleus of the trapezoid body) develops similarly to two common auditory rodent model species: gerbils and mice. Additionally, we measured the hearing onset of naked mole-rats using auditory brainstem response recordings at the same developmental timepoints. In contrast with other work in naked mole-rats showing that they are highly divergent in many aspects of their physiology, we show that naked mole-rats have a similar hearing onset, between postnatal day (P) 9 and P14, to many other rodents. On the other hand, we show some developmental differences, such as a unique morphology and K v 3.3 protein levels in the brainstem.

Pathogenic mutations in the Gjb2 and Gjb6 genes, encoding connexin 26 (Cx26) and connexin 30 (Cx30), respectively, have been linked to the most frequent monogenic hearing impairment, nonsyndromic hearing loss, and deafness DFNB1. It is known that Cx26 plays an important role in auditory development, while the role of Cx30 in hearing remains controversial. Previous studies found that partial deletion of Cx26 can accelerate age-related hearing loss (ARHL), a multifactorial complex disorder, with both environmental and genetic factors contributing to the etiology of the disease. Here, we investigated the role of Cx30 in cochlear-aging processes using a transgenic mouse model with total deletion of Cx30 (Cx30 ΔΔ mice), in which Cx30 was removed without perturbing the surrounding sequences. We show that these mice are affected by exacerbated ARHL, with increased morphological cochlear damage, oxidative stress, inflammation, and vascular dysfunctions. Overall, our data demonstrate that Cx30 deletion can be considered a genetic risk factor for ARHL, making cochlear structures more susceptible to aging processes.

Irreversible sensorineural hearing loss is one of the most common side effects after cisplatin treatment. Prevention and reversal of hearing loss caused by cisplatin are of great importance for cancer patients, especially children. Oxidative stress is an important cause of hearing loss resulted from cisplatin, unfortunately, there is no drug yet available that can completely prevent and reverse the ototoxicity from cisplatin. Polydatin (PD) possesses excellent antioxidant and anti-inflammatory effects, however, its role in the cisplatin-induced hearing loss has not been investigated. Herein, we have explored the preventive and therapeutic effects of PD on cisplatin-induced hearing loss and the possible underlying mechanisms. In the in vivo setting with guinea pigs, we have demonstrated that PD can reduce the threshold shift of auditory brainstem response (ABR) caused by cisplatin, promote the nuclear translocation of Nuclear factor erythroid-2 related factor 2 (Nrf2), increase the expression of Nrf2 and heme oxygenase-1 (HO-1), and thus reduce the loss of outer hair cells (OHCs). PD can ameliorate cisplatin-induced hearing loss through activating the Nrf2/HO-1 signaling pathway. This study provides a potential strategy for preventing and improving hearing loss resulted from cisplatin treatment in clinics.

Hearing impairment is a cardinal feature of Down syndrome (DS), but its clinical manifestations have been attributed to multiple factors. Murine models could provide mechanistic insights on various causes of hearing loss in DS. To investigate mechanisms of hearing loss in DS in the absence of the cadherin 23 mutation, we backcrossed our DS mice, Dp(16)1Yey, onto normal-hearing CBA/J mice and evaluated their auditory function. Body weights of wild type (WT) and DS mice were similar at 3-months of age, but at 9-months, WT weighed 30% more than DS mice. Distortion product otoacoustic emissions (DPOAE), a test of sensory outer hair cell (OHC) function negatively impacted by conductive hearing loss, were reduced in amplitude and sensitivity across all frequencies in DS mice. The middle ear space in DS mice appeared normal with no evidence of infection. MicroCT structural imaging of DS temporal bones revealed a smaller tympanic membrane diameter, oval window, and middle ear space and localized thickening of the bony otic capsule, but no gross abnormalities of the middle ear ossicles. Histological analysis of the cochlear and vestibular sensory epithelium revealed a normal density of cochlear and vestibular hair cells; however, the cochlear basal membrane was approximately 0.6 mm shorter in DS than WT mice so that the total number of hair cells was greater in WT than DS mice. In DS mice, the early and late peaks in the auditory brainstem response (ABR), reflecting neural responses from the cochlear auditory nerve followed by subsequent neural centers in the brainstem, were reduced in amplitude and ABR thresholds were elevated to a similar degree across all frequencies, consistent with a conductive hearing impairment. The latency of the peaks in the ABR waveform were longer in DS than WT mice when compared at the same intensity; however, the latency delays disappeared when the data were compared at the same intensity above thresholds to compensate for the conductive hearing loss. Future studies using wideband tympanometry and absorbance together with detailed histological analysis of the middle ear could illuminate the nature of the conductive hearing impairment in DS mice.

Irreversible injury to inner ear hair cells induced by aminoglycoside antibiotics contributes to the formation of sensorineural hearing loss. Pitavastatin (PTV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to exert neuroprotective effects. However, its role in aminoglycoside-induced hearing loss remains unknown. The objectives of this study were to investigate the beneficial effects, as well as the mechanism of action of PTV against neomycin-induced ototoxicity. We found that PTV remarkably reduced hair cell loss in mouse cochlear explants and promoted auditory HEI-OC1 cells survival after neomycin stimulation. We also observed that the auditory brainstem response threshold that was increased by neomycin was significantly reduced by pretreatment with PTV in mice. Furthermore, neomycin-induced endoplasmic reticulum stress in hair cells was attenuated by PTV treatment through inhibition of PERK/eIF2α/ATF4 signaling. Additionally, we found that PTV suppressed the RhoA/ROCK/JNK signal pathway, which was activated by neomycin stimulation in HEI-OC1 cells. Collectively, our results showed that PTV might serve as a promising therapeutic agent against aminoglycoside-induced ototoxicity.