ABR/DPOAE publications

BACKGROUND: Noise-induced hearing loss (NIHL) has been traditionally attributed to outer hair cell (OHC) damage, but synaptic injury at inner hair cell (IHC)–spiral ganglion neuron (SGN) junctions may better explain persistent functional deficits. OBJECTIVE: To test whether IHC ribbon loss and functional synapse loss scale with pathological noise intensity and to define their longitudinal relationship to hearing function. METHODS: A rodent NIHL model was exposed to 100 dB SPL for 2 h or 110 dB SPL for 4 h. Cochleae were immunolabeled for CtBP2 (presynaptic ribbons) and GluA2 (postsynaptic AMPA receptor puncta). Putative functional synapses were quantified as closely apposed CtBP2/GluA2 pairs. Hearing function was assessed longitudinally and correlated with synaptic measures. RESULTS: Both exposure conditions produced graded reductions in IHC ribbon counts and CtBP2/GluA2 pairs, with greater losses after 110 dB/4 h. The number of CtBP2/GluA2 apposed pairs closely tracked preserved hearing function, providing a stronger association with functional outcome than ribbon counts alone. Ribbon loss remained largely stable across post-exposure intervals, whereas functional synapse loss was disproportionately larger at early time points, consistent with transient pre–post misalignment. Over time, CtBP2/GluA2 pairing partially recovered toward levels predicted by surviving ribbons, suggesting re-alignment or reconnection of a subset of remaining synaptic elements. CONCLUSION: Pathological noise intensity drives exposure-dependent IHC synaptopathy in addition to OHC injury. Functional synapse counts (CtBP2/GluA2 pairs) sensitively reflect stored hearing function and indicate a potential post-exposure window for synaptic re-establishment.

It is widely accepted that tinnitus arises from maladaptive neuroplasticity in the central auditory system, which compensates for reduced peripheral input; notably, the loss of inner hair cell (IHC) synapses is considered a key underlying factor. IHC synapses can immediately and permanently degenerate after noise exposure, independent of hair cell loss, whereas the cell bodies and central projections of cochlear neurons can survive for months to years, providing an extended therapeutic window for improving afferent input through synapse regeneration. Using NHPN-1010 (a combination of 2,4-disulfophenyl-N-tert-butylnitrone and N-acetylcysteine), we propose a delayed treatment strategy (≥ 4 weeks after trauma) for noise-induced tinnitus (NIT) in rats. NHPN-1010 enhanced gap-prepulse inhibition of acoustic startle responses-indicative of diminished tinnitus-like deficits-coupled with a concomitant upregulation of GABAergic inhibition in the dorsal cochlear nucleus, relative to vehicle alone (saline). Furthermore, NHPN-1010, compared to saline, led to increased wave-I amplitudes of auditory brainstem responses, the effect accompanied by a corresponding rise in the number of presynaptic ribbons in IHCs. Our findings suggest that NHPN-1010 plays a therapeutic role in NIT by promoting cochlear synaptogenesis and normalizing central auditory signaling.

Age-related hearing loss (ARHL) is a prevalent sensory deficit characterized by cochlear hair cell apoptosis, yet the underlying epigenetic mechanisms remain unclear. This study investigated the role of E2F1-mediated 53BP2 lactylation in ARHL pathogenesis using naturally aging C57BL/6J mice and HEI-OC1 cochlear hair cell-like cells. We found that E2F1 was significantly upregulated in aged cochleae, correlating with elevated ABR thresholds, hair cell loss, and apoptotic marker expression. In vitro, E2F1 overexpression promoted HEI-OC1 cell apoptosis by stabilizing p53, while E2F1 knockdown attenuated p53 accumulation and cell death under oxidative stress. Mechanistically, mass spectrometry identified 53BP2 lactylation at lysine 476 (K476), which was enhanced by E2F1. The K476R mutation abolished 53BP2-p53 binding, reduced p53 stability, and inhibited apoptosis. Further, E2F1 transcriptionally upregulated p300, a lactyltransferase that directly mediates 53BP2 K476 lactylation. p300 knockdown reversed E2F1-induced 53BP2 lactylation and p53-dependent apoptosis. These findings reveal a novel E2F1-p300-53BP2 lactylation-p53 signaling axis driving cochlear hair cell apoptosis in ARHL, highlighting potential therapeutic targets for age-related hearing loss.

Electromotility in mammalian outer hair cells (OHC) is the mechanism underlying cochlear amplification. It is brought about by the piezoelectric-like property of the membrane protein prestin (Slc26a5) that lies in the OHCs lateral plasma membrane. Prestin connects to an underlying cytoskeletal network of circumferential actin filaments that bridge longitudinal spectrin filaments. This network, in turn, lies between the plasma membrane and a closely apposed ER-like tubular array of subsurface cisternae (SSC). Two previous papers examining spectrin knockouts in embryonic hair cells were confined to analyzing the effects on the apical cuticular plate and overlying stereocilia. In this paper, we examine the effects of conditional knockouts of alpha2 spectrin in postnatal OHCs. We find a significant auditory phenotype likely due to the novel disassociation of prestin's gating charge movement from OHC electromotility. In addition, OHCs show enlargement in their SSC and plasma membrane-SSC space with preserved cuticular plates and overlying stereocilia, the latter contrasts with the findings in embryonic knockouts.

Alzheimer's disease (AD) is a brain condition with heterogeneity in disease progression due to genetic and environmental variables. There is a critical need to better understand the relationship of AD pathologies and potential modifiable factors like hearing loss. Auditory processing measurements in AD mouse models have been reported, but the results are mixed. Most were conducted using evoked potential recordings measured under anesthesia, unlike typical hearing assessments on aging adult humans. Here, we used operant conditioning and signal detection theory to measure daily pure tone behavioral detection throughout the lifespan of trained mutant and wild-type (WT) control APP/PS1 (on a C57BL/6J background) and 5xFAD (on a C57/SJL background) mice. At the conclusion of operant testing, auditory brainstem response (ABR) measures were taken on the same subjects to determine if evoked potentials provided accurate estimates of perceptual abilities. Behavioral detection worsened significantly across the lifespan in APP/PS1 mice, but there were no differences between mutant and WT mice. For 5xFAD mice, behavioral thresholds generally worsened over the lifespan but with substantial variability, which may be explained by genetic heterogeneity among the background strain. There were no differences between 5xFAD mutant and WT mice. ABR hearing threshold estimates generally matched behavioral findings, with APP/PS1 having significantly worse thresholds than 5xFAD mice but no within-model differences between mutants and WTs. The within-subject differences between behavioral and ABR thresholds ranged from <1 dB to over 40 dB across subjects, suggesting physiological measurements of auditory function are not necessarily reflective of an animal's acoustic perception.

Background/Objectives: Blast-induced hearing loss (BIHL) is a major concern, particularly for military personnel, and is linked to impaired auditory neuron survival and synaptic plasticity. This study investigates the potential of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) to reduce the severity of BIHL and promote recovery in a mouse model. Methods: Eight-week-old male C57BL/6J mice were used. A custom-built, compressed air-driven system utilizing a modified paintball apparatus was employed to deliver controlled unilateral double blasts (~22 psi exposure pressure) to the left ear. The blasts were administered 30 min apart. Immediately following the second blast, mice received either 7,8-DHF (10 mg/kg) or vehicle (10% DMSO) via intraperitoneal injection. Auditory brainstem responses (ABRs) were measured in both ears at baseline (pre-blast) and at several post-exposure time points. Results: The consecutive blast exposure induced a significant elevation in ABR thresholds, indicative of hearing loss, in both the ipsilateral (exposed) and contralateral (unexposed) ears of vehicle-treated mice. Notably, mice treated with 7,8-DHF demonstrated a marked improvement in hearing recovery compared to the vehicle group. Significant reductions in ABR thresholds were observed in the ipsilateral ear at 4 weeks post-blast (p < 0.0001) and in the contralateral ear as early as 1-week post-blast (p = 0.0236). However, the recovery was partial, with ABR thresholds plateauing after 4 weeks. Conclusions: A controlled blast model demonstrates that systemic administration of the TrkB agonist 7,8-DHF exerts a protective effect, partially restoring auditory function after blast injury. This supports the therapeutic potential of targeting the BDNF-TrkB signaling pathway for managing BIHL.

Prairie voles ( Microtus ochrogaster ) are a semi-fossorial rodent that are an emerging model in social neuroscience. Comparing laboratory-reared and wild-caught individuals is essential for understanding how environmental history shapes neural and sensory traits and for assessing the ecological validity of laboratory findings. Despite this, relatively few studies have taken this approach. We used auditory brainstem responses (ABRs) to compare ABR thresholds and ABR wave characteristics between laboratory-reared and wild-caught prairie voles. ABR recordings show that, similar to other semi-fossorial rodents, M. ochrogaster exhibit a hearing range of 1–46 kHz with peak sensitivity between 8–24 kHz in wild-caught and 8–32 kHz in laboratory-reared voles. However, wild-caught prairie voles displayed significantly lower ABR thresholds at 1, 4, 8, 16, and 24 kHz compared to laboratory-reared prairie voles. There were significant differences in interpeak latency between both tested groups, with laboratory-reared prairie voles showing faster interpeak latency responses than wild-caught voles. However, there were no differences in amplitude ratios between groups. Laboratory-reared prairie voles showed faster normalized latencies and higher relative amplitude of the binaural interaction component (BIC) of the ABR than wild-caught voles. There were no significant differences in ABR thresholds, interpeak latency, amplitude ratio, normalized latency, and relative amplitude between the sexes. These differences in auditory processing support the importance of integrating both wild and captive populations to advance comparative auditory research.

Introduction Cisplatin-induced ototoxicity remains a major clinical challenge in chemotherapy, with limited pharmacological strategies available to prevent auditory damage. In this study, we explored the protective potential of baicalin, a flavonoid compound, against cisplatin-triggered cochlear injury. Methods In vivo, baicalin was administered to C57BL/6 mice prior to cisplatin treatment. Auditory function was assessed using auditory brainstem response (ABR) and distortion product otoacoustic emission measurements, and cochlear hair cell integrity was examined. In vitro, both House Ear Institute-Organ of Corti 1 (HEI-OC1) auditory cells and cochlear explants were used. Cell viability, apoptosis, mitochondrial reactive oxygen species (ROS) accumulation, and mitochondrial membrane potential (ΔΨm) were evaluated using MitoSOX Red, TMRM, and JC-1 fluorescence probes. The involvement of the p38 MAPK pathway was investigated using anisomycin (an activator) and SB203580 (an inhibitor) at the protein level. Results In vivo, baicalin administration significantly mitigated cisplatin-induced hearing loss, as evidenced by improved ABR and distortion product otoacoustic emission thresholds and preserved cochlear outer hair cell structural and functional integrity. In vitro, baicalin pretreatment significantly improved cell viability and attenuated cisplatin-induced apoptosis. Mechanistically, baicalin markedly reduced mitochondrial ROS accumulation and maintained ΔΨm. Furthermore, baicalin pretreatment effectively inhibited p38 MAPK activation; this protective effect was reversed by anisomycin and mimicked by SB203580. Discussion Collectively, these findings demonstrate that baicalin provides robust otoprotection against cisplatin-induced hearing loss. In vitro studies further indicate that this protective effect is associated with the attenuation of oxidative stress, maintenance of mitochondrial integrity, and inhibition of p38 MAPK–mediated apoptosis. Together, the results highlight baicalin as a promising candidate for therapeutic intervention against cisplatin-induced hearing loss.

Introduction Spectral information of speech sounds is spatially arranged from low to high frequencies in the auditory cortex, known as tonotopic maps. Recently, we identified an envelope steepness map encoding the rise-ramp steepness of sounds, which is located orthogonally to the tonotopic map. Temporal components, particularly the sound envelope defined by the rise-ramp steepness, play a crucial role in speech perception. We hypothesized that the ability to sense temporal components of sounds, such as envelope steepness, would be diminished in aged mice. Methods Responses to variations in rise-ramp time were investigated using transcranial macroscale calcium imaging of the auditory cortices of GCaMP6f-expressing mice. Normalized distance relative to the rise-ramp time of 0.01 ms was plotted for each rise-ramp time (0.1, 1, 10, and 100 ms) in the logarithmic scale graph: the steeper the slope of the fitted regression lines, the greater the distance between the peaks of the rise-ramp time of 0.01 ms and 100 ms. The slope of this regression line was compared between the different age groups: 1/3 months and 6/9/12 months after birth. Results The slope of the fitted regression line for 5 kHz in the bilateral anterior auditory field and 20 kHz in the bilateral primary auditory field was significantly less steep in mice at 6/9/12 months after birth than at 1/3 months after birth. Conclusion The shorter distance from the peak of 0.01 ms to 100 ms in animals 6/9/12 months after birth suggests difficulty in the separation of the rise-ramp time in aged animals. These findings may support the cortical mechanisms underlying age-related decline in speech perception.

Hearing loss is a pervasive global health challenge with profound impacts on communication, cognitive function, and quality of life. Recent studies have established age-related hearing loss as a significant risk factor for dementia, highlighting the importance of hearing loss research. Auditory brainstem responses (ABRs), which are electrophysiological recordings of acoustically evoked synchronized neural activity from the auditory nerve and brainstem, serve as in vivo correlates for sensory hair cell and synaptic function, hearing sensitivity, and other critical readouts of auditory pathway physiology, making them highly valuable for both basic neuroscience and clinical research. Despite the utility of the ABR, traditional ABR analyses rely heavily on subjective manual interpretation, which may introduce variability and pose challenges for reproducibility across studies. Here, we introduce Auditory Brainstem Response Analyzer (ABRA), a novel suite of open-source ABR analysis tools powered by deep learning, which automates and standardizes ABR waveform analysis. ABRA employs convolutional neural networks trained on diverse datasets collected from multiple experimental settings, achieving rapid and unbiased extraction of key ABR metrics, including peak amplitude, latency, and auditory threshold estimates. We demonstrate that ABRA’s deep learning models provide performance comparable to expert human annotators while dramatically reducing analysis time and enhancing reproducibility across datasets from different laboratories. By bridging hearing research, sensory neuroscience, and advanced computational techniques, ABRA facilitates broader interdisciplinary insights into auditory function. An online version of the tool is available for use at no cost at https://abra.ucsd.edu .

In the mammalian cochlea upon acoustic stimulation, outer hair cells (OHCs) push and pull the basilar membrane, amplifying its vibration and therefore expanding the dynamic range of hearing. As a result, spiking patterns in auditory nerve fibers (ANFs) are believed to be significantly different, but how the central nervous system adapts to this substantial change is poorly understood. In this study, we took advantage of Prestin −/− mice of either sex where prestin, the motor protein in OHCs, was genetically knocked out, therefore removing cochlear amplification completely without changing the cellular structure of the cochlea significantly. While exocytosis from inner hair cells in the cochlea was largely intact, transmission at the endbulb of Held synapse between ANFs and bushy cells in the cochlear nucleus was significantly changed in Prestin −/− mice. Specifically, excitability of bushy cells was significantly increased, due to combination of slightly more depolarized resting membrane potential, increased membrane input resistance, and smaller and briefer afterhyperpolarization. Furthermore, synaptic strength was greatly reduced, caused by substantial decrease in the readily releasable pool (RRP) of synaptic vesicles. Significantly, paired-pulse plasticity at this synapse was reversed from depression in WT mice to facilitation in Prestin −/− mice, likely caused by quicker refilling of RRP observed in Prestin −/− mice. In conclusion, we found that transmission at the endbulb of Held synapse is significantly altered in absence of cochlear amplification, revealing interplay between the peripheral and central processing of auditory signals that contributes to expanded dynamic range of hearing seen in mammals and humans.

Mutations in SLC26A4 are the second most common cause of hereditary hearing loss (HL) in many Asian countries, leading to DFNB4, a condition characterized by progressive HL and inner ear malformations. While gene therapy holds great potential, its postnatal application has remained unexplored because of the lack of suitable animal models and the challenges of prenatal intervention. To our knowledge, this study represents the first preclinical investigation of postnatal gene therapy for DFNB4 using a clinically relevant Slc26a4 -mutant mouse model that closely replicates human auditory phenotypes. Utilizing the synthetic AAV.Anc80L65 vector, we achieved robust SLC26A4 delivery to critical cochlear regions, including the endolymphatic sac and cochlear lateral wall. Comprehensive phenotypic analyses revealed a critical therapeutic window spanning the neonatal and juvenile stages, within which AAV.Anc80L65-mediated SLC26A4 delivery significantly improved hearing, as evidenced by lower auditory brainstem response thresholds. Moreover, the therapy preserved hair cells, reduced endolymphatic sac enlargement, partially restored the endocochlear potential, and mitigated inner ear structural degeneration. These therapeutic effects persisted into adulthood, highlighting the long-term efficacy of postnatal gene therapy. Together, these findings establish a critical therapeutic window for DFNB4 and demonstrate the feasibility of targeting the endolymphatic sac and cochlear lateral wall for effective intervention.

Cisplatin‐induced ototoxicity is a detrimental side effect of chemotherapy leading to hearing loss, for which no treatments are currently available. Despite the growing recognition of the endocannabinoid (eCB) system (ECS) as a significant contributor to different physiological and pathological processes, its role in hearing remains poorly investigated. To fill this knowledge gap, we performed a molecular profiling of the ECS in auditory hair cell (HC)‐like UB/OC1 cells derived from the mouse organ of Corti (OC), demonstrating the presence of the main eCBs‐binding receptors and metabolic enzymes along with the major eCBs ( N ‐arachidonoylethanolamine, AEA, and 2‐arachidonoylglycerol, 2‐AG) and additional eCB‐like compounds. Subsequently, we established an in vitro model of cisplatin‐induced ototoxicity, which was characterized by the downregulation of the HC marker myosin 7a (Myo 7a), and activation of nuclear factor kappa‐light‐chain‐enhancer of activated B‐cells (NF‐κB) associated with caspase‐3‐mediated cell death. In this model, we observed a downregulation of cannabinoid receptor 2 (CB 2 R), diacylglycerol lipase β (DAGLβ), and α/β hydrolase domain‐containing protein 6 (ABHD6), indicating a perturbation of the 2‐AG metabolic pathway. Furthermore, we validated the observed in vitro alterations in the OC of an in vivo model of cisplatin‐induced ototoxicity, thereby strengthening the physiological relevance of our findings. Finally, we demonstrated that pharmacological blockade of CB 2 R through SR144528 mitigates cisplatin‐induced HC damage via inhibition of caspase‐3 cleavage in UB/OC1 HC‐like cells, thereby providing novel mechanistic insights into the role of CB 2 R in ototoxicity. Overall, our study demonstrates the involvement of selective elements of the ECS in cisplatin‐induced ototoxicity, hence identifying novel potential biomolecular targets for chemotherapy‐related side effects.

Shaker‐1 mice carry a spontaneous missense mutation in Myo7a ( Myo7a Sh1 ) that interferes with the motor function of MYO7A. Mutation in the orthologous gene in humans causes syndromic (Usher 1B) or non‐syndromic forms of deafness. In hair cells, MYO7A is expressed throughout the stereocilia, where it has been implicated in tip‐link tensioning required for gating the mechanoelectrical transducer (MET) channel and setting its resting open probability ( P o ). The Myo7a Sh1 mutation progressively dysregulated the height of shorter stereocilia rows from the end of the first postnatal week onwards, associated with reduced MET current amplitude and hearing loss. Noise exposure exacerbated stereocilia dysfunction in Myo7a Sh1/Sh1 mice. Following the onset of maturation, hair cells from Myo7a Sh1/Sh1 mice showed normal resting P o and calcium sensitivity of the MET channel. In immature Myo7a Sh1/Sh1 hair cells, the resting P o was very small or absent in comparison to control cells, but it was restored by changing the membrane lipid bilayer fluidity or thickness by depleting cholesterol or PIP 2 . Bundle stiffness in immature IHCs was not affected by the absence of functional MYO7A but decreased after their onset of maturation in both genotypes. Expression of a subset of genes was affected similarly in immature Myo7a Sh1/Sh1 mice and in adult Myo7a conditional knockout mice, indicating a common response pathway in Myo7a ‐deficient mice. This study reveals that MET channel gating might differ depending on hair cell developmental stage, and MYO7A is likely to influence, albeit indirectly, force transmission via the lipid bilayer to the MET channel and maintenance of the shorter rows of transducing stereocilia. image Key points Shaker‐1 mice carry a spontaneous missense mutation in the shaker‐1 gene ( Myo7a Sh1 ) that interferes with the motor function of MYO7A, a protein expressed in hair‐cell stereocilia. The absence of functional MYO7A ( Myo7a Sh1/Sh1 mice) caused a progressive dysregulation in the height of the shortest two rows of stereocilia and the consequent loss of mechanoelectrical transduction (MET) current. Although immature hair cells from Myo7a Sh1/Sh1 mice exhibited a markedly reduced resting open probability of their MET channels, this was restored upon maturation or following depletion of cholesterol or PIP 2 from the lipid bilayer. Hair‐bundle stiffness was affected in immature inner hair cells from Myo7a Sh1/Sh1 mice, suggesting that MYO7A is not required for establishing the resting tension of the tip links gating the MET channels. We conclude that MYO7A is crucial for the structural integrity of the MET complex and transport of key proteins required to transfer forces efficiently from the lipid bilayer to the MET channel.

Binaural cues are crucial for sound localization, and understanding the neural mechanisms of binaural sound processing gives important insights into how receivers localize signalers, which in anurans is a key component of mate selection. We characterized the binaural interaction component (BIC) by collecting monaural and binaural auditory brainstem responses (ABR) using click stimuli with varying interaural time difference (ITD) and interaural level difference (ILD) in male and female Cope’s gray treefrogs ( Hyla chrysoscelis ). We hypothesized that the latency of the BIC peaks would increase with larger ITDs and ILDs. We also hypothesized that females would show a stronger relationship between binaural cues and BIC characteristics than males because of the greater importance of directional hearing for females. We characterized two prominent BIC peaks, DN1 and DN2. Both BIC peak latencies had a positive relationship with ITD, but there was no effect of ITD on peak amplitudes. The amplitude and latency of the BIC peaks were not affected by variation in ILD. There were no sex or body size effects on ABR characteristics including BIC characteristics or the effects of ITD or ILD on the BIC. Our findings demonstrate that the BIC is driven primarily by ITD in H. chrysoscelis . This is the first study to characterize the BIC in an amphibian, which expands the comparative understanding of the neural mechanisms of binaural hearing in vertebrates.

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.

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.

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.

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.