Auditory Research publications

Background Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual's auditory capabilities. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on alterations in chromatin-accessible regions. Methods We employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq between young and aging cochleae, and conducted integrated analysis as well as motif/TF-gene prediction. Additionally, the essential role of super-enhancers (SEs) in the development of ARHL was identified by comparative analysis to previous research. Meanwhile, an ARHL mouse model and an aging mimic hair cell (HC) model were established with a comprehensive identification of senescence phenotypes to access the role of SEs in ARHL progression. Results The control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL. The potential senescence-associated super-enhancers (SASEs) of ARHL were identified, most of which exhibited decreased chromatin accessibility. The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs and was noticeably altered following treatment with JQ1 (a commonly used SE inhibitor). Conclusion The chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL. Potential SEs involved in ARHL were identified, which might provide a basis for future therapeutics targeting SASEs related to ARHL.

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X chromosome-linked gene Methyl-CpG Binding Protein 2 (MECP2). Restoring MeCP2 expression after disease onset in a mouse model of RTT reverses phenotypes, providing hope for development of treatments for RTT. Translatable biomarkers of improvement and treatment responses have the potential to accelerate both preclinical and clinical evaluation of targeted therapies in RTT. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials, that correlate with disease severity, suggesting that they could be useful as biomarkers of disease improvement or early treatment response. We recently demonstrated that treatment of RTT mice with a positive allosteric modulator (PAM) of muscarinic acetylcholine subtype 1 receptor (M1) improved phenotypes, suggesting that modulation of M1 activity is a potential therapy in RTT. To evaluate whether neurophysiological features could be useful biomarkers to assess the effects of M1 PAM treatment, we acutely administered the M1 PAM VU0486846 (VU846) at doses of 1, 3, 10 and 30 ​mg/kg in wildtype and RTT mice. This resulted in an inverted U-shaped dose response with maximal improvement of AEP features at 3 ​mg/kg but with no marked effect on basal EEG power or epileptiform discharges in RTT mice and no significant changes in wildtype mice. These findings suggest that M1 potentiation can improve neural circuit synchrony to auditory stimuli in RTT mice and that neurophysiological features have potential as pharmacodynamic or treatment-responsive biomarkers for preclinical and clinical evaluation of putative therapies in RTT.

Recent studies have shown promising therapeutic potential for psychedelics in treating neuropsychiatric conditions. Musical experience during psilocybin-assisted therapy is predictive of treatment outcome, yet little is known about how psilocybin affects auditory processing. Here, we conducted two-photon imaging experiments in auditory cortex of awake mice that received a dose of psilocybin. Our results suggest that psilocybin modulates the roles of intrinsic neural activity versus stimulus-driven influences on auditory perception.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which changes in hearing sensitivity precede cognitive decline. Despite a well-known link between dementia and hearing loss, few AD model mouse lines have hearing characterized. We screened for hearing loss using auditory brainstem responses (ABR) in young (3–4 months) and aging (9–10 months) mice with a P301S tauopathy (PS19 mice). Compared to wild types, aging PS19 mice did not show accelerated hearing loss but did show latency differences in centrally generated ABR waveform components. These results suggest that tauopathy causes mild central auditory dysfunction in the absence of overt hearing loss.

Sound is an important navigational cue for mammals. During spatial navigation, hippocampal place cells encode spatial representations of the environment based on visual information, but to what extent audiospatial information can enable reliable place cell mapping is largely unknown. We assessed this by recording from CA1 place cells in the dark, under circumstances where reliable visual, tactile, or olfactory information was unavailable. Male rats were exposed to auditory cues of different frequencies that were delivered from local or distal spatial locations. We observed that distal, but not local cue presentation, enables and supports stable place fields, regardless of the sound frequency used. Our data suggest that a context dependency exists regarding the relevance of auditory information for place field mapping: whereas locally available auditory cues do not serve as a salient spatial basis for the anchoring of place fields, auditory cue localization supports spatial representations by place cells when available in the form of distal information. Furthermore, our results demonstrate that CA1 neurons can effectively use auditory stimuli to generate place fields, and that hippocampal pyramidal neurons are not solely dependent on visual cues for the generation of place field representations based on allocentric reference frames.

Echolocating bats rely on precise auditory temporal processing to detect echoes generated by calls that may be emitted at rates reaching 150–200 Hz. High call rates can introduce forward masking perceptual effects that interfere with echo detection; however, bats may have evolved specializations to prevent repetition suppression of auditory responses and facilitate detection of sounds separated by brief intervals. Recovery of the auditory brainstem response (ABR) was assessed in two species that differ in the temporal characteristics of their echolocation behaviors: Eptesicus fuscus, which uses high call rates to capture prey, and Carollia perspicillata, which uses lower call rates to avoid obstacles and forage for fruit. We observed significant species differences in the effects of forward masking on ABR wave 1, in which E. fuscus maintained comparable ABR wave 1 amplitudes when stimulated at intervals of <3 ms, whereas post-stimulus recovery in C. perspicillata required 12 ms. When the intensity of the second stimulus was reduced by 20–30 dB relative to the first, however, C. perspicillata showed greater recovery of wave 1 amplitudes. The results demonstrate that species differences in temporal resolution are established at early levels of the auditory pathway and that these differences reflect auditory processing requirements of species-specific echolocation behaviors.

The human medial olivocochlear (MOC) reflex was assessed by observing the effects of contralateral acoustic stimulation (CAS) on the cochlear microphonic (CM) across a range of probe frequencies. A frequency-swept probe tone (125-4757 Hz, 90 dB SPL) was presented in two directions (up sweep and down sweep) to normal-hearing young adults. This study assessed MOC effects on the CM in individual participants using a statistical approach that calculated minimum detectable changes in magnitude and phase based on CM signal-to-noise ratio (SNR). Significant increases in CM magnitude, typically 1-2 dB in size, were observed for most participants from 354 to 1414 Hz, where the size and consistency of these effects depended on participant, probe frequency, sweep direction, and SNR. CAS-related phase lags were also observed, consistent with CM-based MOC studies in laboratory animals. Observed effects on CM magnitude and phase were in the opposite directions of reported effects on otoacoustic emissions (OAEs). OAEs are sensitive to changes in the motility of outer hair cells located near the peak region of the traveling wave, while the effects of CAS on the CM likely originate from MOC-related changes in the conductance of outer hair cells located in the basal tail of the traveling wave. Thus, MOC effects on the CM are complementary to those observed for OAEs.

JOURNAL/nrgr/04.03/01300535-202505000-00030/figure1/v/2026-05-07T070001Z/r/image-tiff Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction. However, there are currently no effective pharmacological interventions for patients with noise-induced hearing loss. Here, we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss, and elucidate its underlying regulatory mechanisms. We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 dB for 4 hours. We found that tranylcypromine treatment led to the upregulation of Sestrin2 (SESN2) and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine. The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click, 4, 8, and 16 kHz frequencies compared with the noise exposure group treated with saline. These findings indicate that tranylcypromine treatment resulted in increased SESN2, light chain 3B, and lysosome-associated membrane glycoprotein 1 expression after noise exposure, leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3, thereby reducing noise-induced hair cell loss. Additionally, immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway. Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domain-containing 3 (NLRP3) production. In conclusion, our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2, which induced autophagy, thereby restricting NLRP3-related inflammasome signaling, alleviating cochlear hair cell loss, and protecting hearing function. These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

Typical statistical practices in the biological sciences have been increasingly called into question due to difficulties in the replication of an increasing number of studies, many of which are confounded by the relative difficulty of null significance hypothesis testing designs and interpretation of p -values. Bayesian inference, representing a fundamentally different approach to hypothesis testing, is receiving renewed interest as a potential alternative or complement to traditional null significance hypothesis testing due to its ease of interpretation and explicit declarations of prior assumptions. Bayesian models are more mathematically complex than equivalent frequentist approaches, which have historically limited applications to simplified analysis cases. However, the advent of probability distribution sampling tools with exponential increases in computational power now allows for quick and robust inference under any distribution of data. Here we present a practical tutorial on the use of Bayesian inference in the context of neuroscientific studies in both rat electrophysiological and computational modeling data. We first start with an intuitive discussion of Bayes' rule and inference followed by the formulation of Bayesian-based regression and ANOVA models using data from a variety of neuroscientific studies. We show how Bayesian inference leads to easily interpretable analysis of data while providing an open-source toolbox to facilitate the use of Bayesian tools.

Cisplatin is an election chemotherapeutic agent used for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. Here, we show evidence that a cocktail of vitamins A, C, and E along with Mg++ (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in rats. The addition of 500 mg N-acetylcysteine (NAC), which, administered individually, also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation results in functional degradation of ACEMg otoprotection. Mg++ administered alone, as MgSO4, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection is also greatly degraded. Increasing the dose of NAC to 1000 mg also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet-to-be-defined “antioxidation threshold”, results in unrecoverable redox imbalance with loss of otoprotectant activity.

Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration–approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR’s crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.

Cisplatin is a widely used antineoplastic drug for treating various types of cancers. However, it can cause severe side effects, such as bilateral and irreversible hearing loss, which significantly impacts quality of life. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in the pathogenesis of cisplatin-induced ototoxicity. Here, we investigated the effects of nuciferine, a natural active ingredient isolated from lotus species, on the ferroptosis of cochlear hair cells. Firstly, our results demonstrated that nuciferine can protect hair cells against RSL3-induced and cisplatin-induced damage. Secondly, nuciferine treatment reduced ferrous iron (Fe2+) overload in cochlear hair cells via inhibiting NCOA4-mediated ferritinophagy. Inhibition of ferritinophagy by knocking down Ncoa4 alleviated cisplatin-induced ototoxicity. Importantly, nuciferine treatment mitigated cochlear hair cell loss and damage to ribbon synapse, and improved mouse hearing function in an acute cisplatin-induced hearing loss model. Our findings highlight the role of NCOA4-mediated ferritinophagy in the pathogenesis of cisplatin-induced ototoxicity and provide evidence for nuciferine as a promising protective agent for treating cisplatin-induced hearing loss.

Many animals can extract useful information from the vocalizations of other species. Neuroimaging studies have evidenced areas sensitive to conspecific vocalizations in the cerebral cortex of primates, but how these areas process heterospecific vocalizations remains unclear. Using fMRI-guided electrophysiology, we recorded the spiking activity of individual neurons in the anterior temporal voice patches of two macaques while they listened to complex sounds including vocalizations from several species. In addition to cells selective for conspecific macaque vocalizations, we identified an unsuspected subpopulation of neurons with strong selectivity for human voice, not merely explained by spectral or temporal structure of the sounds. The auditory representational geometry implemented by these neurons was strongly related to that measured in the human voice areas with neuroimaging and only weakly to low-level acoustical structure. These findings provide new insights into the neural mechanisms involved in auditory expertise and the evolution of communication systems in primates.

In individuals with hearing loss, protection of residual hearing is essential following cochlear implantation to facilitate acoustic and electric hearing. Hearing preservation requires slow insertion, atraumatic electrode and delivery of the optimal quantity of a pharmacological agent. Several studies have reported variable hearing outcomes with osmotic pump-mediated steroid delivery. New drugs, such as sialyllactose (SL) which have anti-inflammatory effect in many body parts, can prevent tissue overgrowth. In the present study, the positive effects of the pharmacological agent SL against insults were evaluated in vitro using HEI-OC1 cells. An animal model to simulate the damage due to electrode insertion during cochlear implantation was used. SL was delivered using osmotic pumps to prevent loss of the residual hearing in this animal model. Hearing deterioration, tissue fibrosis and ossification were confirmed in this animal model. Increased gene expressions of inflammatory cytokines were identified in the cochleae following dummy electrode insertion. Following the administration of SL, insertion led to a decrease in hearing threshold shifts, tissue reactions, and inflammatory markers. These results emphasize the possible role of SL in hearing preservation and improve our understanding of the mechanism underlying hearing loss after cochlear implantation.

Aberrant neuronal circuit dynamics are at the core of complex neuropsychiatric disorders, such as schizophrenia (SZ). Clinical assessment of the integrity of neuronal circuits in SZ has consistently described aberrant resting-state gamma oscillatory activity, decreased auditory-evoked gamma responses, and abnormal mismatch responses. We hypothesized that corticothalamic circuit manipulation could recapitulate SZ circuit phenotypes in rodent models. In this study, we optogenetically inhibited the mediodorsal thalamus-to-prefrontal cortex (MDT-to-PFC) or the PFC-to-MDT projection in rats and assessed circuit function through electrophysiological readouts. We found that MDT–PFC perturbation could not recapitulate SZ-linked phenotypes such as broadband gamma disruption, altered evoked oscillatory activity, and diminished mismatch negativity responses. Therefore, the induced functional impairment of the MDT–PFC pathways cannot account for the oscillatory abnormalities described in SZ.

JOURNAL/nrgr/04.03/01300535-202510000-00031/figure1/v/2026-04-25T153616Z/r/image-tiff Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum. However, their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target. In addition, the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure. To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides, we used a C57BL/6J mouse model treated with kanamycin. We found that the mice exhibited auditory deficits following the acute loss of outer hair cells. Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time. Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response, particularly those related to the NLRP3 inflammasome. Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed, accompanied by infiltration of macrophages and the release of proinflammatory cytokines. Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model. These findings suggest that NLRP3 inflammasome–mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration. Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

Amplitude modulation is an important acoustic cue for sound discrimination, and humans and animals are able to detect small modulation depths behaviorally. In the inferior colliculus (IC), both firing rate and phase-locking may be used to detect amplitude modulation. How neural representations that detect modulation change with age are poorly understood, including the extent to which age-related changes may be attributed to the inherited properties of ascending inputs to IC neurons. Here, simultaneous measures of local field potentials (LFPs) and single-unit responses were made from the inferior colliculus of Young and Aged rats using both noise and tone carriers in response to sinusoidally amplitude-modulated sounds of varying depths. We found that Young units had higher firing rates than Aged for noise carriers, whereas Aged units had higher phase-locking (vector strength), especially for tone carriers. Sustained LFPs were larger in Young animals for modulation frequencies 8-16 Hz and comparable at higher modulation frequencies. Onset LFP amplitudes were much larger in Young animals and were correlated with the evoked firing rates, while LFP onset latencies were shorter in Aged animals. Unit neurometric thresholds by synchrony or firing rate measures did not differ significantly across age and were comparable to behavioral thresholds in previous studies whereas LFP thresholds were lower than behavior.

The disruption of ribbon synapses in the cochlea impairs the transmission of auditory signals from the cochlear sensory receptor cells to the auditory cortex. Although cisplatin-induced loss of ribbon synapses is well-documented, and studies have reported nitration of cochlear proteins after cisplatin treatment, yet the underlying mechanism of cochlear synaptopathy is not fully understood. This study tests the hypothesis that cisplatin treatment alters the abundance of cochlear synaptosomal proteins, and selective targeting of nitrative stress prevents the associated synaptic dysfunction. Auditory brainstem responses of mice treated with cisplatin showed a reduction in amplitude and an increase in latency of wave I, indicating cisplatin-induced synaptic dysfunction. The mass spectrometry analysis of cochlear synaptosomal proteins identified 102 proteins that decreased in abundance and 249 that increased in abundance after cisplatin treatment. Pathway analysis suggested that the dysregulated proteins were involved in calcium binding, calcium ion regulation, synapses, and endocytosis pathways. Inhibition of nitrative stress by co-treatment with MnTBAP, a peroxynitrite scavenger, attenuated cisplatin-induced changes in the abundance of 27 proteins. Furthermore, MnTBAP co-treatment prevented the cisplatin-induced decrease in the amplitude and increase in the latency of wave I. Together, these findings suggest a potential role of oxidative/nitrative stress in cisplatin-induced cochlear synaptic dysfunction.

Amplitude modulation (AM) of a masker reduces its masking on a simultaneously presented unmodulated pure-tone target, which likely involves dip listening. This study tested the idea that dip-listening efficiency may depend on stimulus context, i.e., the match in AM peakedness (AMP) between the masker and a precursor or postcursor stimulus, assuming a form of temporal pattern analysis process. Masked thresholds were measured in normal-hearing listeners using Schroeder-phase harmonic complexes as maskers and precursors or postcursors. Experiment 1 showed threshold elevation (i.e., interference) when a flat cursor preceded or followed a peaked masker, suggesting proactive and retroactive temporal pattern analysis. Threshold decline (facilitation) was observed when the masker AMP was matched to the precursor, irrespective of stimulus AMP, suggesting only proactive processing. Subsequent experiments showed that both interference and facilitation (1) remained robust when a temporal gap was inserted between masker and cursor, (2) disappeared when an F0-difference was introduced between masker and precursor, and (3) decreased when the presentation level was reduced. These results suggest an important role of envelope regularity in dip listening, especially when masker and cursor are F0-matched and, therefore, form one perceptual stream. The reported effects seem to represent a time-domain variant of comodulation masking release.