Auditory Research publications

Introduction: Learning-induced cortical reorganization is facilitated by neuromodulator release. However, the precise temporal relationship between neuromodulator release and neural activity required to induce plasticity is not well understood. In single synapses, eligibility traces regulate plasticity such that neuromodulator arrival must occur within seconds of activity. Cortical plasticity can also be induced by pairing neuromodulator release with neural activity, but it is unknown whether plasticity in populations of neurons is regulated by the same temporal constraints. Methods: To determine whether the synaptic eligibility trace regulates cortical plasticity, we used vagus nerve stimulation (VNS) to drive neuromodulator release 3 s before, 1 s before, concurrent with, or 3 s after tone-evoked activity in auditory cortex. After 20 days of pairing, we used in vivo electrophysiology to quantify the proportion of auditory cortex responding to the paired tone frequency. Results: We found that VNS 1 s before or concurrent with tone onset significantly expanded the representation of the paired tone frequency (-1s, p = 0.04; 0s, p = 0.02), whereas 3 s before or after did not (-3s, p = 0.87; +3s, p = 0.53). Confirming the role of neuromodulators in this eligibility trace, we found that depletion of norepinephrine prevented VNS-tone pairing-induced plasticity (0s + DSP4, p = 0.23). Discussion: Our study demonstrates that cortical plasticity is regulated by time constraints similar to the synaptic eligibility trace and highlights the importance of considering the timing of neuromodulator release when employing methods to enhance plasticity.

Introduction: Hearing is critical for communication and clinical evidence suggests that hearing loss can lead to poorer mental well-being including social isolation, anxiety, depression, and cognitive decline. Deaf animal models offer opportunities to investigate the impact of hearing loss on behavioral correlates of mental health while controlling for genetic variability and shared etiological factors such as environmental stressors, aging, and metabolic diseases. We previously showed that conditional deletion of Ebf1 in the inner ear causes deafness. We hypothesize that otic-specific Ebf1 knockout (KO) mice recapitulate neurobehavioral alterations experienced in congenital deafness. Methods: Slc26a9P2A-Cre and Ebf1 floxed mice were crossed previously to generate the otic-specific Ebf1 conditional KO. We measured auditory brainstem response and behavior in groups of otic-specific Ebf1 conditional KO mice and Cre-negative littermate controls (WT). We performed behavioral tests including elevated plus maze, acoustic startle, locomotor activity, forced swim, and Y-maze. Results: We found that the KO mice spend significantly less time than WT mice in the open arms of the elevated plus maze. KO mice also show significantly increased latency to enter the open arms. Acoustic startle response was decreased in KO mice vs. WT controls and pre-pulse inhibition was also reduced in the KO, consistent with elevated hearing thresholds. We found no significant differences in exploratory behavior, forced swim immobility time, or other behavioral measures examined. Conclusions: Our findings demonstrate that deaf otic-specific KO mice are indeed a model for the study of effects of hearing loss on clinically relevant behavioral correlates. Our results provide new empirical evidence that hearing loss contributes to anxiety, which is consistent with clinical evidence that anxiety is associated with hearing loss in older adults.

The Mongolian gerbil is a common model organism for studying the neural and behavioral mechanisms of binaural and spatial hearing, largely because of its ability to hear lower frequencies better than other rodents and thus utilize both interaural time and level difference cues for sound localization. Prior spatial hearing studies in gerbils have relied on operant conditioning paradigms, requiring large amounts of time-consuming training and testing on multiple different tasks needed to make a comprehensive assessment of spatial hearing ability (including temporal processing, spatial acuity and spatial unmasking). This limits the ability of researchers to thoroughly assess behavioral performance in a population of animals. In this study, we used the prepulse inhibition of the acoustic startle reflex (PPI) to extensively assess spatial hearing and temporal processing abilities in a population of gerbils of both sexes. Results show that gerbils inhibit a startle response to a brief loud sound based on prepulse acoustical cues consisting of a 1) temporal gap in ongoing sounds, 2) change in sound source location, and 3) target sound in the presence of a masker. In each test, the magnitude of the suppression of startle increased monotonically as a function of the magnitude of the acoustical prepulse, not unlike a psychometric function, from which threshold performance could be measured. Thresholds in the gerbils in each task measured using PPI matched those acquired using operant conditioning methods.

The mismatch response (MMR) is a critical neural indicator of the discrimination of speech contrasts. Previous research has demonstrated that language experience can affect MMRs: speech contrasts in one’s native language differ from nonnative speech contrasts. This effect is observed as early as 11–12 months, but not at 6–7 months, reflective of early learning of speech sounds. Yet, many challenges remain when using MMRs to study speech learning in infants, including prolonged recording time, inefficient use of data, and a lack of reconciliation of MMR recorded using different technologies (i.e., EEG vs. magnetoencephalography [MEG]). Using an improved recording paradigm and analysis approach, the current study addressed these challenges by examining (1) whether MEG-MMR is linked to the well-established EEG-MMR in the same adults and (2) whether our methods capture the difference in MEG-MMR between native and nonnative speech contrasts in adults and (3) in older infants. Results from 18 adults with simultaneous M/EEG demonstrated a high correlation between the MEG-MMR and the EEG-MMR. Additionally, MEG-MMRs to native speech contrasts were different from ones to nonnative speech contrasts, replicating spatiotemporal patterns documented in the existing literature. Finally, we replicated this effect in the MEG-MMR in 14 infants aged between 9 and 14 months using the same methods. These findings validate our new methodologies with less than 15 mins of recording time for acquiring and analyzing speech-related MMRs across ages, paving the way for studying early language development, and improving early detection of language-related disorders.

In adults with acquired hearing loss, cortical reorganization and cross‐modal plasticity critically influence the timing and outcomes of cochlear implantation. This study examined the effects of 2 weeks of bilateral auditory deprivation—induced by intense broadband noise—on the structure and gene expression in the primary auditory (A1) and visual (V1) cortices of adult rats. The results revealed that the total neuronal counts in both the A1 and V1 remained unchanged compared to controls. Morphological analysis showed no significant change in mature dendritic spine density in either region, but immature spine density was significantly reduced in the V1 cortex. Ultrastructural examination demonstrated notable synaptic alterations in the A1 cortex, including significant reductions in postsynaptic density (PSD) length, thickness, area, and synaptic vesicle number—changes that were not observed in the V1 cortex. Transcriptomic profiling indicated a region‐specific response, with 197 differentially expressed genes (DEGs) in the A1 cortex, compared to a broader alteration of 545 DEGs in the V1 cortex, which were significantly involved in neuronal signaling and synaptic transmission. These findings demonstrate that auditory deprivation induces distinct molecular and synaptic remodeling in the A1 and V1 cortices, identifying neuronal plasticity and synaptic regulation as central mechanisms for cross‐modal reorganization in the adult brain.

Background DFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the STRC gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. Strc −/− mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16. Methods Using Strc − / − mice, we developed a gene therapy strategy based on the use of dual AAV9‐PHP.eB vectors to deliver the full‐length Strc cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No‐Go behavioral testing with psychometric analysis. Results Dual‐AAV–mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated Strc −/− mice regained normal frequency discrimination, indicating a restoration of higher‐order auditory processing, up to 100 days post‐treatment. Conclusion These findings provide the first proof‐of‐principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model. Key points Dual AAV‐mediated gene delivery restored peripheral hearing in a DFNB16 preclinical mouse model. The same treatment also restored central auditory processing. AAV‐mediated gene therapy represents a promising curative strategy for DFNB16. These results reinforce the translational potential for treating human genetic deafness.

Bilateral cochlear implant (BiCI) users do not perform as well as typical hearing listeners when discriminating the direction of sound motion. This is likely due to the lack of synchronization between two independently operating sound processors. The use of bilaterally linked processors can improve the timing of electrical stimulation across the ears. However, these improvements are potentially counteracted by spectral peak-picking in sound coding strategies that may activate different electrodes across the ears, thereby reducing the fidelity of the binaural cues that BiCI users rely on for sound localization. To improve interaural synchrony, a bilateral peak-picking strategy that guarantees coordinated stimulation across the ears was developed and tested using the CCi-MOBILE, a bilaterally linked research processor. The auditory motion tracking abilities of nine BiCI users were measured using the bilateral peak-picking strategy and compared to performance with commercially available, unsynchronized processors. Results showed no effect of bilateral peak-picking. However, a small benefit was observed when tracking the range of motion of a sound when listening with bilateral synchronization which appears to be due to reduced interaural level difference changes with auditory motion. These findings suggest that dynamic auditory perception with BiCI may likely need bilaterally-synchronized hardware.

Identification of speech sounds is influenced by spectral contrast effects (SCEs), the perceptual magnification of spectral differences between successive sounds. SCEs result in the categorization of a target sound being biased away from spectral properties in the preceding acoustic context. Given remarkable consistency in the magnitudes of these contrast effects within the same frequency region [Stilp (2019) J. Acoust. Soc. Am. 146(2), 1503–1517], it was hypothesized that they would also show stable relationships across different frequency regions. In this study, normal-hearing listeners' phoneme categorization and contrast effects were assessed where phonetic contrasts were driven by changes in low-frequency F1 (“big”-“beg” continuum), mid-frequency F3 (“dot”-“got”), or high-frequency frication spectrum regions (“sheet”-“seat”). On each trial, listeners heard a precursor sentence that was filtered to emphasize energy in the lower or higher range within one of these frequency regions, followed by a target word that hinged on the frequency region that was filtered. Results showed that SCEs influenced categorization in each frequency region, as expected. However, effect magnitudes were not correlated with each other across frequency regions within or across two participant samples. This clarifies perception-in-context on a broader scale as the influence of spectral contrast is independent across different frequency regions.

It is widely known that users of cochlear implants (CIs) often show deficits in binaural hearing. In particular, interaural time difference (ITD) discrimination tends to be substantially worse in CI users. However, only very few studies have investigated how CI stimulation affects the “precedence effect” (PE), and how this might be affected by abnormal hearing experience during development. We performed behavioral experiments to measure temporal weighting functions (TWFs) to quantify the PE in three different cohorts of rats: normally hearing (NH) acoustically stimulated, neonatally deafened (ND) CI-stimulated, and adult deafened (AD) CI-stimulated animals. Lateralization responses were recorded to bursts of eight stimulus pulses in which the ITD of each pulse varied independently, and probit analysis revealed the perceptual weight of each pulse. The NH and ND-CI cohorts were tested at 50, 300, and 900 pps; the AD-CI animals were tested only at 300 pps. The NH animals show a pronounced “onset dominance” at higher pulse rates, that is, the weighting of the first pulse was much larger than for subsequent pulses, exactly as one would expect given previous studies on human listeners. In contrast, the TWFs for the ND-CI and AD-CI animals were much flatter, with a reduction of onset dominance by ∼75%, especially for higher pulse rates. Since neither of our CI cohorts had any experience of reverberation in their electric hearing, we interpret these results to indicate that the PE may require domain-specific experience to develop.

Background: Cisplatin is a widely used chemotherapeutic agent, but its clinical application is limited by serious ototoxic side effects, including hearing loss, tinnitus, and vertigo. Inflammation is now recognized as a significant contributor to cisplatin-induced hearing loss, but the upstream regulators remain largely undefined. This study aimed to identify novel regulators of cisplatin-induced ototoxicity through CRISPR-Cas9 screening and to determine the role of growth arrest and DNA damage-inducible alpha (GADD45A) in cochlear inflammation and hearing loss. Methods: To identify upstream regulators of cisplatin-induced ototoxicity, a CRISPR-Cas9-based loss-of-function screen was first performed in OC1 cells. Following the identification of Gadd45a as a candidate gene, its effects on cisplatin-induced cytotoxicity were evaluated using cell viability assays, flow cytometry, and TUNEL staining. Integrated transcriptomic and proteomic analyses were subsequently conducted to elucidate the downstream molecular mechanisms. Finally, the protective role of Gadd45a inhibition was validated in vivo through siRNA delivery into the posterior semicircular canal and in Gadd45a conditional knockout (cKO) mice. Results: Gadd45a knockout significantly inhibited cisplatin-induced cell death in the OC1 cell line while simultaneously enhancing autophagy signaling. Transcriptomic profiling revealed a marked downregulation of the expression of C-X-C motif chemokine ligand (CXCL) family cytokines following Gadd45a loss, which was further supported by proteomic analysis of culture supernatants. Mechanistically, Gadd45a knockout specifically inhibited nuclear factor κB subunit 1 (NF-κB1) but not RELA proto-oncogene, NF-κB subunit (RELA). Immunofluorescence staining demonstrated that Gadd45a knockout inhibited the nuclear translocation of the NF-κB1 protein, and subsequent studies revealed that the NF-κB1 protein was degraded through the lysosomal pathway. In vivo, both si-Gadd45a injection into the semicircular canal and the knockout of Gadd45a effectively attenuated cisplatin-induced ototoxicity. Conclusions: This study identifies GADD45A as a key regulator of cisplatin ototoxicity and links the balance between apoptosis and autophagy with NF-κB1-CXCL-mediated inflammation. Targeted inhibition of GADD45A signaling may represent a promising therapeutic strategy to prevent hearing loss in patients receiving cisplatin chemotherapy.

Background Usher syndrome (USH) is an autosomal recessive disorder characterized by hearing loss, retinitis pigmentosa, and variable vestibular dysfunction. USH2A is one of the causative genes of USH. This study is aimed at exploring the mechanism of hearing loss induced by USH2A gene knockout. Method USH2A knockout (Ush2a −/− ) mice were used, and auditory brainstem response testing was performed on WT, Ush2a −/− , and Ush2a +/− mice. Then, the cochlea tissues were used to carry out immunofluorescence staining, hematoxylin and eosin (H&E) staining, and scanning electron microscopy (SEM). The mRNA expressions were detected by RT‐qPCR. Finally, the differentially expressed genes (DEGs) in cochlear tissues of Ush2a −/− and WT mice were identified by transcriptome sequencing. Results Compared to WT mice, Ush2a −/− and Ush2a +/− mice exhibited moderate‐to‐severe nonprogressive hearing loss, with more pronounced deficits at low (4 kHz) and high (32/24 kHz) frequencies. HE staining and immunofluorescence staining showed that the modiolus, stria vascularis, basilar membrane, and the number of inner hair cells and outer hair cells (OHCs) in USH2A knockout mice have not changed. However, SEM results showed that severe stereociliary collapse was evident in OHCs of the Ush2a −/− group. In addition, through transcriptomic analysis, 3632 upregulated genes and 2921 downregulated genes were obtained in the Ush2a −/− mice. Among these DEGs, the most DEGs associated with hearing loss were Scn2a, Shank2, Bsn, Fcer1g, Prkce, Tgfb1, and Irf7. Conclusion This study demonstrates that USH2A deficiency disrupts auditory function through stereociliary instability and dysregulation of genes critical for synaptic transmission and cytoskeletal dynamics.

Large language models (LLMs) capture long-range contextual structure in natural language and have recently been shown to align with the human brain’s contextualized linguistic encoding. This makes them a promising computational probe for studying how context-dependent linguistic information is represented during natural speech perception. Speech perception often occurs in multi-talker environments, where attention must dynamically select among competing streams, yet how contextual information from attended and unattended speech is neurally encoded remains underexplored. Here, we investigate how auditory attention modulates neural tracking of context-dependent linguistic representations using electrocorticography (ECoG) and stereoelectroencephalography (sEEG) recordings from three epilepsy patients engaged in a two-conversation “cocktail party” paradigm. To model neural responses to attended and unattended speech streams, we used contextual word embeddings generated by large language models. We find that LLM-derived features reliably predict brain activity for the attended stream and that contextual information from the unattended stream also contributes to neural prediction. Importantly, these contributions extend beyond low-level acoustic features and shallow syntactic information, and depend on the surrounding linguistic context. Moreover, neural tracking of the unattended stream reflects shorter-range contextual integration than that of the attended stream. Together, these findings indicate that neural responses to speech reflect context-dependent linguistic representations from multiple concurrent speech streams, with attention modulating the depth and timescale of contextual integration. Our results highlight the utility of LLMs for probing higher-level linguistic representations in complex, naturalistic listening environments.

Objectives: Cisplatin is an effective anticancer drug that can induce cochleotoxicity in up to 50 to 60% of treated patients. However, the vestibulotoxic potential of cisplatin remains unclear. Our lab previously developed a multicycle model of cisplatin administration in mice that results in hearing loss similar to that observed clinically. The purpose of this study was to comprehensively characterize the functional and morphological consequences of cisplatin on the vestibular periphery in this mouse model. Design: Twenty-nine adult CBA/CaJ mice were assigned to control or cisplatin-treated groups. Cisplatin-treated mice received three consecutive cycles of once-daily cisplatin for 4 days followed by a 10-day recovery period. Mice underwent vestibular sensory evoked potential testing before cisplatin administration, after the final cycle of cisplatin, and 6 mo after treatment cessation. Mice also underwent vestibulo-ocular reflex testing and vestibular afferent single-unit recordings 6 mo after treatment cessation. Following testing, utricles, saccules, and horizontal semicircular canals were microdissected, and vestibular morphology was examined. To examine whether our data in mice were consistent with reports of cisplatin-induced vestibulotoxicity in patients, histopathology reports of human temporal bones were examined for evidence of cisplatin-induced vestibulotoxicity. Results: Vestibular sensory evoked potential thresholds were significantly elevated in cisplatin-treated mice immediately after cessation of cisplatin administration and progressively worsened 6 mo later. Rotational and translational vestibulo-ocular reflexes were generally unaffected by cisplatin. Cisplatin did not cause statistically significant changes in the spontaneous firing rates of semicircular canal afferents but did cause significant decreases in their overall regularity. No statistically significant differences in the spontaneous firing rates or regularity of otolith afferents were observed. However, cisplatin-treated mice exhibited statistically significant decreases in the percentage of low-distortion otolith afferents, indicating that responses of these afferents to head translations were more variable and less precise. Cisplatin-treated mice showed significantly decreased hair cell numbers in the saccule but not in the utricle or horizontal semicircular canal. One temporal bone histopathology report from an individual treated with high cumulative cisplatin was consistent with the results of our study, showing only saccular degeneration with normal utricle and semicircular canal morphology. Conclusions: Our study demonstrates cisplatin’s potential to affect the vestibular end organs adversely and differentially. The saccule was uniquely susceptible in our mouse model, suggesting that it may be possible to screen for cisplatin-induced vestibulotoxicity by testing saccular function. While very little is known about the potential for progression of cisplatin-induced vestibulotoxicity, our results suggest vestibular dysfunction may continue to worsen after cessation of cisplatin treatment. We recommend that ongoing and future efforts at evaluating vestibular function in patients treated with cisplatin include monitoring and evaluation of otolith function.

Hearing impairments, as a prevalent and debilitating non-motor symptom of Parkinson's disease (PD), remain unclear in mechanisms. In this work, we established PD mouse and rat models by using 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), respectively, and investigated their hearing functions and potential mechanisms through auditory brainstem response (ABR), distortion product otoacoustic Emissions (DPOAE), noise exposure, immunofluorescence labeling, volumetric measurement, and colocalization analysis. In MPTP-induced PD mice, we observed significant cholinergic fibers decompensation, heterogeneous dopaminergic fibers damage of cochlear efferent fibers, and adrenergic sympathetic fibers marked loss in the osseous spiral lamina (OSL), corresponding to insignificant cochlear hair cells, ribbon synapse alteration, and auditory sensitivity injury. While in 6-OHDA-induced PD rats, asymmetric alterations in cochlear cholinergic, dopaminergic fibers were found, accompanied by inconsistent adrenergic changes in the OSL, which matched unilateral hair cells, ribbon synapse damage, and hearing loss. Overall, findings from this work indicate that pathological alterations in the cochlea of PD mice and rats, particularly in efferent fibers, may be closely relevant to peripheral hearing alterations.

Sensorineural hearing loss (SNHL) is significantly more prevalent in individuals with chronic kidney disease (CKD) than in the general population. Although a strong independent association has been observed between kidney dysfunction and the risk of hearing loss, the underlying mechanisms linking these conditions remain poorly understood. This study investigated the pathophysiology of hearing impairment using adriamycin nephropathy (AN), a well-established animal model of CKD. AN was induced in male BALB/c mice using 10 or 12 mg/kg of adriamycin (ADR), resulting in severe kidney injury and concurrent hearing loss. ADR-treated mice exhibited significant glomerular injury, podocyte damage, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL), along with increased serum creatinine and blood urea nitrogen levels. Hearing impairment was evident after 4-8 weeks of ADR treatment, as assessed by auditory brainstem response and distortion-product otoacoustic emissions, and was accompanied by cochlear hair cell loss and ribbon synapse degeneration. AN affected cochlear function by altering ion channel expression in the stria vascularis and inducing blood-labyrinth barrier (BLB) hyperpermeability, along with changes in endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes. AN significantly increased cochlear NGAL and NLRP3 levels at 4 and 8 weeks following ADR administration. NGAL was highly expressed in the tectorial membrane, cochlear neurons, and organ of Corti, while its receptor, 24p3R, was co-localized with NGAL. These findings demonstrated the role of NGAL and BLB disruption in ADR-induced SNHL, providing novel insights into the mechanistic link between CKD and hearing loss.

The hippocampus is classically linked to memory, yet increasing evidence points to a broader role in perceptual inference and deviance detection. Predictive coding theories propose that perception minimizes mismatches between expected and actual sensory input, expressed in neural signatures such as mismatch negativity (MMN) and P300. Although MMN arises mainly from sensory and prefrontal cortices, the hippocampus is anatomically interconnected with both and may also contribute to prediction error processing. We recorded single- and multi-unit activity and local field potentials (LFPs) from DG and CA1 in urethane-anesthetized rats during an auditory oddball paradigm and a no-repetition control sequence to dissociate prediction error from repetition suppression. Approximately 20% of hippocampal neurons were sound responsive, and a subset showed deviant selectivity. Spiking activity predominantly reflected prediction errors, while LFPs revealed complementary contributions from repetition suppression and prediction error. Early LFP components were enhanced for randomly presented deviants, whereas later components within the P300 latency range were stronger for predictable deviants, indicating temporally distinct phases of error signaling and top-down modulation. These findings identify the hippocampus as an active contributor to auditory deviance detection and support a hierarchical model in which hippocampal circuits participate in predictive sensory processing beyond memory.

The genetic factors and resulting neural circuit physiology driving variation in attention are poorly understood. Here we took an unbiased forward genetics approach to identify genes of large effect on attention. We studied 200 genetically diverse mice and, through genetic mapping, identified a small locus on chromosome 13 (95% CI 92.22-94.09 Mb) that is significantly associated with variation in pre-attentive processing. Within the locus we identified a gene, Homer1, encoding a synaptic protein, whose downregulation during development led to improvements in multiple measures of attention in adulthood. Mechanistically, reduced Homer1 levels resulted in an upscaling of GABA receptors and enhanced inhibitory tone in the prefrontal cortex, leading to improved neural signal to noise and attentional performance. We thus identify a single genetic locus of large effect on attention and propose Homer1-dependent inhibitory tone, sculpted during a developmental sensitive period, as a key regulator and potential therapeutic target for attentional performance.

Although age-related hearing loss (ARHL) is the most common sensory loss in older adults, underlying mechanisms remain unclear. Recent genome-wide association studies (GWAS) linked variation in several genes with ARHL risk, including KLHDC7B , a gene of unknown function not previously linked to hearing. We demonstrate Klhdc7b is expressed exclusively in sensory hair cells in mouse cochlea. Utilizing two independent mouse knockout models ( Klhdc7b IMPC-/- and Klhdc7b Regn Δ/Δ ) we find that absence of Klhdc7b leads to severe early-onset, progressive hearing loss. Hair cells appear to develop normally, but outer hair cells are progressively lost from base-to-apex of the cochlea, a common pathology in ARHL. These results suggest KLHDC7B is required for maintenance rather than development, of auditory function. The validation in mouse of a human ARHL GWAS association suggests other novel candidates should be investigated. Our work provides two mouse models to study KLHDC7B function, and for development of therapeutic tools for ARHL.