Auditory Research publications

Cell types are the basic units of the cerebral cortex. Broad and narrow spike waveforms (BW and NW) are the primary criteria for classifying putative excitatory and inhibitory cortical neurons, particularly in non-human primates where genetic accessibility is limited. We have classified cell types in the auditory cortex of marmosets using spike waveforms and firing patterns and identified a new type of neuron: the NW-burst neuron. NW-burst neurons are excitatory, as they drive but do not suppress the firing of connected neurons. Furthermore, NW-burst neurons displayed shorter response latencies, lower response variability, smaller receptive fields, stronger correlations between spatial and non-spatial selectivity, and higher decoding accuracy than other neurons. Together, these findings suggest that cortical NW-burst neurons in non-human primates represent a distinct excitatory cell type. Significance Statement Classifying cell types in non-human primates is challenging due to limited genetic tools. Traditionally, neurons with narrow spikes are assumed to be inhibitory. Challenging this view, we analyzed 1,816 high-quality single units in the marmoset auditory cortex and discovered that narrow-spike burst-firing neurons were excitatory. These neurons exhibited shorter response latencies, smaller receptive fields, and higher decoding accuracy. Crucially, they showed a positive correlation between "where" and "what" selectivity, defying the standard trade-off between spatial and non-spatial response properties. These findings reveal a specific excitatory cell type in the auditory cortex of a non-human primate species that integrates sound information with high temporal fidelity and feature selectivity.

Objectives The aim of this study was to investigate the changes in Epac1 and ferroptosis‐related proteins in aged mice and the House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells, with the goal of elucidating their potential role in age‐related hearing loss. Methods The expression of Epac1 in the cochlea of C57BL/6J mice was examined by using immunofluorescence staining and Western blot analysis. To further verify the role of Epac1 in age‐related hearing loss, small interfering RNA (siRNA) was transfected into HEI‐OC1 cells, resulting in the downregulation of Epac1. Results The results revealed a decrease in Epac1 expression in the cochlea of aged mice. After downregulating the level of Epac1 in vitro, a greater level of ferroptosis was observed, and the aging process was accelerated. Conclusions Epac1 plays a crucial role in the aging process of auditory hair cells via ferroptosis.

Objective: Consequences of hearing abnormalities in migraine remain largely unexplored, particularly regarding peripheral outcomes. This study aims to explore how migraine induces peripheral auditory injury and what role calcitonin gene-related peptide (CGRP) plays in the inner ear, which may contribute to the precise subtyping of migraine and inform targeted auditory-protective therapies. Methods: A mouse model of chronic migraine (CM) was established by intermittent injections of nitroglycerin and validated via mechanical and thermal nociceptive assays. CGRP signaling was assessed by Western blotting and immunofluorescence. Auditory function was evaluated using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) in CM and CGRP blockade (Rimegepant-treated) groups. RNA sequencing of cochlear tissue identified dysregulated signaling pathways, which were subsequently validated in vitro using HEI-OC1 auditory cells and in vivo within the inner ear. Results: Repeated nitroglycerin injections induced persistent mechanical and thermal hyperalgesia, confirming successful model establishment. A significant upregulation of CGRP and its receptors, particularly in outer hair cells (OHCs) were confirmed. The CM mouse exhibited elevated ABR, DPOAE thresholds and OHC injury, all of which were mitigated by Rimegepant treatment. CGRP overstimulation triggered mitochondrial stress and mtDNA leakage in HEI-OC1 cells. Cytosolic mtDNA leakage activated the ZBP1-mediated PANoptosis pathway, leading to OHC injury. As proof of concept, ZBP1 knockdown and PANoptosis inhibition mitigated cellular damage and hearing deficits both in vivo and in vitro. Conclusions: We demonstrated OHCs as the key targets in CM-induced, CGRP-mediated peripheral hearing impairment. CGRP exerts its pathogenic role by triggering a cascade of intracellular stress and inflammatory pathways, ultimately leading to cell death. These findings provide a phenotypic basis for a subtype of migraine-induced hearing loss, paving the way for auditory protection strategies.

Astrocytes control neural communications by influencing GABAergic transmission through uptake and synthesis of GABA. Impaired GABAergic signaling is thought to underlie cortical hyperexcitability in autism. Here we show that dysregulation of astrocyte GABA transport in Fragile X syndrome (FXS), a leading genetic cause of autism, contributes to circuit hyperexcitability. Human FXS astrocytes derived from patient-specific induced pluripotent stem cells and mouse Fmr1 knockout (KO) astrocytes display a significant increase in levels of GABA and GABA-synthesizing enzyme GAD65/67. Our astrocyte-specific Fmr1 KO (cKO) mouse model reveals reduced inhibitory connectivity and impaired cortical responses to sound. Abnormal GABA transport in cortical astrocytes contributes to impaired fidelity of temporal processing and abnormal behaviors in cKO mice. Blocking astrocyte GABA transport enables higher PV expression, improves EEG responses to frequency-modulated sound, and corrects aberrant exploratory behavior. Our findings suggest astrocyte GABA transport plays a key role in regulating cortical inhibition, and contributes to autism-associated phenotypes.

Atypical sensory processing is a common feature of autism, yet the neural computations that give rise to these differences, particularly in relation to biological sex and etiological origin, remain unclear. Here we examine predictive auditory processing at the single-neuron level in the inferior colliculus of two adult rat models of autism: a genetic model with a heterozygous Grin2b deletion (Grin2b + /-) and an environmental model based on prenatal valproic acid exposure. We recorded neuronal responses to an auditory oddball paradigm and a cascade control sequence across lemniscal and non-lemniscal IC divisions under high-intensity stimulation, allowing us to derive indices of repetition suppression, prediction error and neuronal mismatch. Using generalized linear mixed-effects models that accounted for animal identity, inferior colliculus division, sex, and rat model, followed by hierarchical group-level comparisons, we identified robust alterations in predictive processing in both autism-like models. These effects varied across inferior colliculus divisions and differed between sexes, revealing distinct phenotype-specific signatures. The results indicate that sex and etiology jointly modulate early auditory computations in autism. More broadly, our findings highlight the translational value of predictive coding frameworks and support the use of complementary animal models to capture neurobiological heterogeneity across the autism spectrum.

The flexibility of human vocal production is well studied, but the direct role of the auditory system in regulating vocalizations in rodents remains largely unexplored. We show that during vocalizations, a fraction of rat auditory cortex neurons shows pre-call activity and different patterns of responses during calls and playback of calls. Additionally, we classified five auditory cortical vocalization responses: pre-call activated, onset activated, onset suppressed, ramping activated and ramping suppressed neurons. Intriguingly, onset suppressed cells can predict vocalization duration and occurrence. Injecting the auditory cortex with muscimol (GABA_A receptor agonist) prolonged vocalizations, while injecting the auditory cortex with gabazine (GABA_A receptor antagonist) shortened them. Similar reductions in call duration were observed during external white-noise stimulation of the auditory cortex and/or other auditory brain structures, resembling the effects of gabazine. Together, neuronal recordings, pharmacological interference and noise induced vocal modifications indicate direct modulation of vocal productions by the rat auditory cortex.

NF2 (neurofibromatosis type 2)–related schwannomatosis (NF2-SWN) is a cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas. While benign, these tumors can cause substantial morbidity, and effective pharmacological treatments remain limited. Here, we demonstrate that genetic ablation of focal adhesion kinase ( Fak/Ptk2 ) impairs tumor formation and preserves hearing in a murine model of NF2. Mechanistically, we show that Fak deletion decreases macrophage infiltration, attenuates nucleotide-binding oligomerization domain–containing protein 2–, leucine rich repeats (LRR)- and pyrin domain–containing protein 3 inflammasome activation, and suppresses the hepatocyte growth factor–MET axis. Pharmacological inhibition of FAK with single agent VS-4718 did not significantly reduce macroscopic tumor volume; however, its use in combination with the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib resulted in both a significant reduction in tumor volume and the preservation of dorsal root ganglion architecture. Our findings establish a critical role for FAK in schwannoma development and provide rationale for evaluation of combination FAK plus MEK inhibition in future clinical trials for NF2-associated SWN.

Optical coherence tomography (OCT) has allowed in vivo recording of sound-induced vibrations of different regions within the organ of Corti complex (OCC), including the basilar membrane (BM), outer hair cell/Deiters cell (OHC/DC) region, and reticular lamina (RL). In the hook region of the gerbil cochlea, where measurements can be made with a substantially transverse optical axis, the three regions have different and characteristic motion responses: The OHC/DC region has greater motions than the other two regions at frequencies below the best frequency (sub-BF); the RL region typically has the greatest BF peak and smallest sub-BF motion. The phase of the OHC/DC-region motion increasingly lags BM motion phase as frequency increases; the RL-region motion phase leads BM, but with a relatively small value. All three regions are compressively nonlinear in the BF peak, but only the OHC/DC region shows sub-BF compressive nonlinearity. In this paper, we describe the strain that exists within the RL and OHC-body regions. These strains are large where the motion varies over short distances, and a region of large strain can be as short as a single 2.7 µm measurement pixel, or extend over several pixels, with the extensive strains appearing more often at 70 than at 50 dB SPL. Beyond the region of large strain, over a distance that can exceed 20 μm, the OHC/DC region displays nearly unvarying motion spatially -- this region appears to vibrate as a body. Statement of Significance The sensory tissue of the cochlea responds actively to a sound stimulus: cell-based forces amplify and enhance the vibration of the sensory tissue. Measurements employing optical coherence tomography have identified major vibration patterns along a sensory-tissue-spanning line that includes the active outer hair cells. In this article, we describe the transitional motion between these major vibration regions and the motion strains that exist as vibration morphs from one region to the next. The findings are presented in frequency response curves to convey the frequency tuning and its stimulus-level dependence, and in one-dimensional heat maps to convey the extent of regional motions and strains. These findings fuel and constrain conceptual and physics-based models of cochlear amplification.

SignificanceAlthough the transmission of auditory information in the brain has been extensively studied, the mechanism underlying fine auditory discrimination remains incompletely understood. The basal region of the ventromedial nucleus of the thalamus (bVM) has recently been found to convey frequency-specific auditory information to the primary auditory cortex (A1). Inhibition of the bVM significantly impairs fine auditory discrimination in mice. These findings indicate that the bVM plays an important role in frequency information processing. However, direct functional evidence for tonotopic organization within the bVM is still lacking.AimWe aimed to investigate whether bVM neurons exhibit a spatially ordered frequency preference, using a simple yet efficient in vivo functional mapping strategy.ApproachTo characterize the response properties of bVM neurons projecting to A1, we combined Cre-dependent retrograde viral labeling with fiber photometry in awake mice. Using a “one recording site per animal” strategy, we systematically recorded from 26 distinct locations and successfully reconstructed the tonotopic map of the bVM.ResultsWe identified a mediolateral tonotopic gradient within the bVM, with best frequencies progressing from low in medial regions to high in lateral regions.ConclusionsOur findings provide direct functional evidence of tonotopic organization within the bVM, supporting its role as an auditory relay and its contribution to fine auditory discrimination.

Coordinated neuronal activity plays an important role in information processing and transmission in the brain. While ensembles’ activity provides a more specific and less noisy version of sensory stimulus information than single neurons, their role in information transmission in the auditory pathway remains unclear. We investigated the effects of ensemble activity in the medial geniculate body (MGB) on the activation of neurons in the primary auditory cortex (A1) in female rats. MGB ensembles synchronized within narrow time windows more effectively induced A1 responses than single neurons or ensembles defined in broader time windows. This was facilitated by the convergence of ensemble inputs onto target neurons. Transmission efficacy was higher for narrow-spiking (NS) A1 neurons compared with broad-spiking (BS) neurons. Cortical UP states in isolation had no discernable effect on the transmission efficacy of thalamic cNEs. These findings highlight neuronal ensembles as focal functional units that enhance information transmission in the brain.

Melanocytes are important components of the inner-ear cellular architecture. However, limited morphological research hinders our understanding of inner-ear function. Here, we characterize the morphology of inner-ear melanocytes and cells often misidentified as melanocytes. Immunofluorescence, smart-seq, transmission/field emission scanning electron microscopy, and immunoelectron microscopy are used. Cells previously referred to as "perivascular macrophage-like melanocytes" are not observed in the stria vascularis and are actually macrophages; along with melanocytes, they constitute intermediate cells. Cells with a "black ball" appearance in the vestibule are identified as macrophages. We examine variation in melanocytes or macrophages with age, strain, and cisplatin injury. Kir4.1 expression and the greater noise resistance observed in pigmented mice suggest melanocyte functions. Based on melanin distribution in Pou3f4y/- mice, we hypothesize that melanocytes migrate from the modiolus along Reissner's membrane area to the stria vascularis, following a base-to-apex gradient. These findings provide novel ultrastructural and immunological insights into inner-ear function.

Noise‐induced hearing loss (NIHL) is a common cause of acquired sensorineural hearing loss. Excessive endoplasmic reticulum (ER) stress‐induced apoptosis of cochlear hair cells contributes to NIHL. ER autophagy (ER‐phagy) is a critical pathway for maintaining ER homeostasis and cell survival. DDRGK1 (DDRGK domain containing 1) is a crucial receptor in ER‐phagy, essential for the removal of injured ER components. This work investigates the involvement of DDRGK1‐mediated ER‐phagy in NIHL, which has remained unclear. ER‐phagy flux is inhibited in HEI‐OC1 cells treated with hydrogen peroxide. Noise exposure reduces XIAP (X‐linked inhibitor of apoptosis protein) and DDRGK1 protein levels in these cells. Moreover, XIAP binds to DDRGK1, increasing the stability of DDRGK1 and activating ER‐phagy. Notably, in noise‐exposed CBA/CaJ mice, gastrodin, a traditional Chinese medicine ingredient, reduces noise‐induced loss of cochlear hair cells, ribbon synaptic damage, and hearing loss by promoting XIAP expression, thereby increasing DDRGK1 protein levels and activating ER‐phagy. These findings highlight XIAP‐DDRGK1‐mediated ER‐phagy as a novel therapeutic target for NIHL treatment.

Noise-induced hearing loss (NIHL) can be either temporary or permanent, depending on the intensity and duration of noise exposure. Excessive noise exposure activates various cellular mechanisms in the cochlea, including oxidative stress, immune responses, and apoptosis. Still, the mechanisms underlying hearing recovery after transient threshold shift (TTS) and lack of recovery after permanent threshold shift (PTS), as well as their therapeutic implications for NIHL, remain unknown. In this study, we performed a comparative analysis of longitudinal changes in the cochlear transcriptome of TTS and PTS mouse models. Our analysis revealed that noise-induced ER stress activates the unfolded protein response (UPR). Notably, the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the UPR returned to baseline levels following TTS but showed sustained activation following PTS. In addition, the proapoptotic factor C/EBP homologous protein (CHOP) was selectively induced in hair cells following PTS. Administering a PERK inhibitor prior to and following noise exposure hindered hearing restoration after TTS, indicating a requirement for PERK activation in hearing recovery. Inhibition of sustained PERK activation via a PERK inhibitor or reduction of CHOP expression via pharmacological chaperones facilitated partial hearing recovery following PTS. Together, these findings provide insight into the mechanisms underlying NIHL and its prevention, highlighting UPR modulation as a promising therapeutic strategy.

Purpose Sound pressure recordings at different positions at the head such as ear canal, nasal cavity, or on the skin are effective tools to verify, fit, or follow up the output of bone conduction devices (BCDs) intra- and post-operatively. Here, we investigated the possibility of using a surface microphone (SM) as a non-invasive alternative to laser Doppler vibrometry (LDV) measuring cochlear promontory (CP) vibrations in human heads. Methods A percutaneous BCD (Ponto system) was implanted at the standard position in five human (four males/one female) cadaver heads (ten ears). CP vibration was measured using LDV in response to the BCD stimulation. Simultaneously, the sound pressure level (SPL) emitted by the skin was measured by the SM attached to the forehead of the specimens. A linear regression model estimated the vibration amplitudes based on the measured SPL. Results A frequency-independent linear regression between recorded SM SPL and CP velocity showed a significant correlation (slope = 1.012; r 2 = 0.535, p < 0.001). An enforced fixed slope (constant = 166.7 dB) of one resulted in a mean absolute error of MAE = 7.7 ± 2.7 dB across frequencies. Although the initial linear model with a fixed slope of one showed frequency-dependent deviations, applying a frequency-specific correction significantly improved the prediction accuracy ( r 2 = 0.557, MAE = 6.5 ± 1.5 dB). Conclusion Microphone-based recording of acoustic surface emissions offers a non-invasive alternative to LDV to assess BCD output.

Background: Otitis media (OM) is an inflammatory disease of the middle ear characterized by mucosal remodeling, effusion, and conductive hearing loss. Although antibiotics and surgical procedures remain standard treatments, their efficacy is often limited by recurrence, antibiotic resistance, and chronic progression. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulatory technique that activates the cholinergic anti-inflammatory pathway through α7 nicotinic acetylcholine receptor (α7nAChR) signaling. This study aimed to evaluate the anti-inflammatory effects of taVNS in a lipopolysaccharide (LPS)-induced mouse model of acute otitis media (AOM) and to assess whether these effects may involve α7nAChR-dependent mechanisms. Methods: AOM was induced by transtympanic injection of LPS in BALB/c mice, followed by taVNS applied to the auricular concha using biphasic square pulses (0.3 mA, 20 Hz, 200 μs). Methyllycaconitine, a selective α7nAChR antagonist, was administered to assess receptor involvement. Auditory function, tympanic membrane morphology, and mucosal changes were assessed through auditory brainstem response testing, otoscopic imaging, and histological analysis. Cytokine levels in middle ear effusion and serum were quantified by ELISA, while inflammatory gene and protein expression were analyzed using qPCR and Western blotting. Statistical analyses were performed using one-way ANOVA or Kruskal-Wallis tests with post hoc comparisons. Results: taVNS significantly improved hearing thresholds and reduced mucosal thickening and goblet cell hyperplasia in AOM mice. It markedly decreased tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels in middle ear effusion, and mechanistically, this anti-inflammatory effect was associated with suppression of NF-κB activation without altering TLR4 or MYD88 expression. These effects were abolished by methyllycaconitine pretreatment. taVNS also reduced spleen enlargement and systemic cytokine concentrations, indicating modulation of both local and systemic inflammation. Conclusions: taVNS was associated with attenuation of LPS-induced acute otitis media and reduced NF-κB activation and downstream cytokine expression in a manner consistent with the involvement of α7nAChR-related signaling. By attenuating excessive inflammatory responses, taVNS was associated with improved auditory function and reduced middle ear injury, suggesting its potential as a non-invasive therapeutic strategy for LPS-induced acute otitis media.

Many people have trouble understanding speech in noisy environments despite normal audiometric thresholds, a condition referred to as “hidden hearing loss.” A leading hypothesis attributes this deficit to inner hair cell synaptic pathology (cochlear synaptopathy), which can persist after recovery from noise-induced temporary elevation of audiometric thresholds. This pathology impairs the temporally precise sound encoding necessary for spatial hearing, but direct evidence in primates, human or nonhuman, is lacking. Here, we show that a single noise exposure, producing only a temporary threshold elevation, induced long-lasting alterations in synaptic morphology, without synapse loss, resulting in persistent spatial hearing deficits for up to 11 months post-exposure in nonhuman primates of both sexes. These perceptual deficits were accompanied by a reduction in a neurophysiological measure of binaural processing - the binaural interaction component (BIC) of the auditory brainstem response (ABR). Both behavioral and neural deficits persisted despite full recovery of audiometric thresholds. Together, these findings provide the first evidence in primates that noise exposure disrupts spatial hearing and binaural neural circuit function without loss of hair cells or synapses. Because spatial hearing tests and the ABR/BIC are clinically accessible, this work also establishes translational biomarkers for early neural dysfunction underlying hidden hearing loss.

Proper orientation of the apical cytoskeleton in auditory and vestibular hair cells is essential for their sensory function. A recently identified regulator of hair cell orientation is the G protein-coupled receptor GPR156, which signals through inhibitory heterotrimeric G proteins. In hair cells expressing the transcription factor EMX2, GPR156 is apically enriched and polarized at cell junctions. There, GPR156 signaling reverses the interpretation of tissue-level core planar cell polarity cues, effectively reversing the orientation of Emx2 -positive compared to Emx2 -negative hair cells. This mechanism establishes key anatomical features, such as the correct alignment of auditory outer hair cells and the line of polarity reversal in the otolith organs of the vestibular system. Null mice with constitutive Gpr156 inactivation exhibit severe hearing loss, mirroring congenital hearing impairment in human patients with homozygous GPR156 variants. These null mutants also display impaired swimming and vestibulo-ocular reflexes, although the nature of these vestibular deficits differs from those reported in Emx2 mutants. Here, to determine the extent to which functional deficits arise from hair cell misorientation, we conditionally inactivated Gpr156 in postmitotic hair cells in the inner ear. This targeted deletion approach recapitulated the misorientation phenotype observed in null mutants. Notably, 30–40% of cochlear and utricular hair cells affected in the null background retained normal orientation in conditional mutants, likely due to the later timing of Gpr156 inactivation. Despite reduced efficiency, conditional mutants exhibited similar, albeit predictably milder, auditory and vestibular dysfunction. As hair cells can carry out mechano-electrical transduction without GPR156, we conclude that sensory deficits mainly result from its essential role in hair cell orientation.

Music listening is one of the most compelling and rewarding activities humans engage in spontaneously. But what exactly catches people”s attention when listening to music remains unclear. Musicologists have argued that tension - release dynamics in music constitute crucial features of the listening experience. They arise from the intertwining of different low-level and high-level features and sit at the core of music enjoyment by engaging listeners dynamically. This study aims to characterize the relationship between tension dynamics and engagement during naturalistic music listening. Using canonical correlation analysis, we decoded the music envelope from EEG and ECoG responses and found that musical tension patterns, as reported by listeners, were predictive of fluctuations in the coupling between the music and the neural response. Importantly, tension dynamics were significantly correlated with neural measures of envelope tracking even after controlling for loudness and musical expectations, confirming the specific and crucial role of musical tension in engaging listeners. These results shed new light on how musical structure gives rise to internal response modulations that, in turn, dynamically reflect musical engagement. This interplay may underlie the pervasive and emotionally rewarding nature of music. Significance Statement This work addresses a fundamental question in cognition: how engagement dynamically modulates complex auditory input processing. We investigate this issue within the well-controlled yet ecologically valid context of music perception. At the core of the musical experience lies the perception of tension – the shifting sense of expectancy, instability, and resolution that guides listening across time. We show that fluctuations in musical tension, shaped by musical structure, reliably predict modulations of auditory engagement, thereby illuminating an understudied phenomenon: what makes music engaging.

Hypothesis: In our study, we investigated the ototoxic interaction of Janus kinase (JAK) inhibition in combination with aminoglycosides. Background: The therapeutic landscape of JAK inhibitors has undergone a significant transformation since 2018, characterized by a rapid increase in FDA approvals for this class of drugs. Initially approved for conditions like myelofibrosis and polycythemia vera, the indications have expanded to include several inflammatory conditions, such as psoriatic arthritis, ulcerative colitis, and rheumatoid arthritis, leading to a substantial increase in patients exposed to these therapies. The potential interactions of this drug class with ototoxins are unknown. Methods: C57Bl/6N mice corrected for Cadherin23 (Cdh23 tm2.1/kjn ) were treated with kanamycin (KM), (500 mg/kg, subcutaneously, twice daily for 14 d) either alone or with lipopolysaccharide (LPS) (1 mg/kg, intraperitoneally, 3 times during the treatment) to mimic inflammation from gram-negative infections. A separate group also received momelotinib (MMB), a dual JAK1/JAK2 inhibitor, at 50 mg/kg or 20 mg/kg by oral gavage twice daily for 14 days alongside KM and LPS. Hearing function was assessed through auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE), while cochlear damage and hair cell loss were evaluated using whole mount staining for phalloidin and myosin 7a. Results: Inhibition of JAK1 and JAK2 by MMB caused a substantial increase in the hearing loss and cochlear damage in animals exposed KM and LPS as measured by ABR, DPOAE, and outer hair cell (OHC) counts. Conclusion: JAK1 and JAK2 inhibition worsens cochlear damage in mice exposed to aminoglycosides.

Background With age, even mild acoustic injuries can accumulate - ultimately leading to a characteristic clinical picture of age-related hearing loss with the risk of cognitive decline. Age-related hearing loss is currently attributed to the loss of a most vulnerable auditory fiber type contributing to hearing in background noise. Here, we investigated the potential of a new drug, a more stable chemical variant of Dendrogenin B (DX243) that is predicted to display a protective function on neurite outgrowth, rather than on cell survival. Methodology In the rat animal model, DX243 was tested on hearing thresholds, cortical local field potentials (LFP), auditory steady-state responses (ASSR), auditory brainstem responses (ABR), growth function of notched-noise stimuli, inner hair cell (IHC) ribbon numbers, and multi-click pulse responses (MCP) before and after auditory trauma (AT). Results No auditory evoked LFP response changes were seen in the prefrontal cortex, visual cortex, or hippocampus. In contrast, a permanent decline of auditory evoked LFP amplitudes in the auditory cortex (AC) was measured 2 weeks after AT. Daily injection of DX243 for 2 weeks prevented the AT-induced decline in LFP activity, a protective effect that continued for 6 weeks following the final injection. Through a protective effect of DX243 on a trauma-induced decline of LFP in response to amplitude-modulated tones >80 Hz, a subcortical origin of the drug-effect was suggested. DX243 showed no effect on hearing sensitivity and did not affect subcortical processing of sound features that depend on phase-locking at the stimulus onset (e.g., near-threshold ASSR responses, close-to-threshold ABR growth functions, or spontaneous cortical LFP responses). However, with the same dose-response dependency as shown for cortical LFP effects, DX243 significantly protected from AT-induced decreases in ABR growth functions for loud sound stimuli and in background noise, protected from AT-induced loss of IHC ribbons and AT-induced decline of fast ABRs with decreasing time intervals. Conclusion These findings suggest DX243 as a novel neuroprotective drug, that specifically protects auditory fibers contributing to the coding of the temporal envelope and detection of tones in masking noise, tasks of our auditory senses, both of which, if they fail, lead to age-related speech-in-noise comprehension deficits.