Publications using the System 3

Early sensory experience can exert lasting perceptual consequences. For example, a brief period of auditory deprivation early in life can lead to persistent spatial hearing deficits. Some forms of hearing loss (i.e., conductive; CHL) can distort acoustical cues needed for spatial hearing, which depend on inputs from both ears. We hypothesize that asymmetric acoustic input during development disrupts auditory circuits that integrate binaural information. Here, we identify prolonged maturation of the binaural auditory brainstem in the guinea pig by tracking auditory evoked potentials across development. Using this age range, we induce a reversible unilateral CHL and ask whether behavioral and neural maturation are disrupted. We find that developmental CHL is associated with alterations in a brainstem readout of binaural function, an effect that was not observed in a separate cohort with adult-onset CHL. Startle-based behavioral measures suggest that Early CHL animals exhibit reduced spatial resolution for high-frequency sound sources. Finally, single-unit recordings of auditory midbrain neurons reveal significantly poorer neural acuity to a sound location cue that largely depends on high-frequency sounds. Thus, these findings show that unilateral deprivation can disrupt developing auditory circuits that integrate binaural information and may give rise to lingering spatial hearing deficits.

Age-related hearing loss (ARHL) is a major public health concern, driven by the interplay of multiple factors. Here, we reveal spatiotemporal metabolic shifts in murine inner ears mirroring erythrocytes and plasma. Isotope-labeled glucose tracing demonstrates a metabolic rerouting favoring glycolysis over the pentose phosphate pathway, alongside downregulation of the tricarboxylic acid cycle, indicating impaired energy production and redox homeostasis. Accumulation of medium- and long-chain acylcarnitines further exacerbates lipotoxicity. Notably, age-dependent depletion of arginine, lysine, proline, and glycine disrupts the arginine-polyamine-urea cycle. Translationally, UK Biobank plasma metabolomics links omega-6 fatty acids, linoleic acid, glycine, and albumin to ARHL resilience, while branched-chain amino acids, tyrosine, creatinine, glycoprotein acetyls and urea confer risk. Sex differences in ARHL were linked to fatty acid metabolism divergence. These bioenergetic disruptions in the inner ear are mirrored in erythrocytes and plasma, highlighting potential biomarkers for early ARHL diagnosis and treatment.

Niemann-Pick disease type C (NPC) is a life-threatening neurodegenerative disease caused by impaired intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for treating NPC, but its ototoxicity remains problematic. We previously reported that β- and γ-forms of cyclodextrin (CD) derivatives with various substituents capable of accommodating/solubilizing unesterified cholesterol (UC) exerted more pronounced therapeutic and ototoxic effects when administered intracerebroventricularly than subcutaneously for NPC treatment. However, the impact of substituent variations on these effects is unconfirmed for cyclic hexasaccharides, α-CD derivatives. Here, we investigated these effects for α-CD derivatives with various replaced substituents from the perspective of their interaction with UC. Even when administered intracerebroventricularly, a representative α-CD derivative had no impact on survival in NPC model mice. The normalization of intracellular cholesterol trafficking in NPC model cells and the auditory dysfunction in wild-type mice, both caused by HP-β-CD, were not seen for the α-CD derivatives, regardless of their substituent variations. Solubility and molecular simulation analyses showed negligible UC-solubilizing ability of α-CD derivatives because of their insufficient capacity to accommodate the UC molecule, rather than their substituent variations. These results underscore the importance of UC accommodation by CD for both efficacy and ototoxicity in NPC treatment.

Background: Although several evidence demonstrates a "gut-microbiota-brain axis", suggesting a bidirectional communication between gut microbiota and the central nervous system, less is known about a possible link between the gut and the peripheral nervous system, including the inner ear. Methods: Here, we investigated the impact of intestinal inflammation and the modulation of gut microbiota through fecal microbiota transplantation on hearing sensitivity. Female C57BL/6 mice were assigned to four groups: control (Ctrl), DSS-induced colitis (DSS), FMT from patients with active ulcerative colitis (FMT aUC), and FMT from patients with ulcerative colitis in remission (FMT rUC). Auditory function was evaluated by auditory brainstem responses (ABR). Morphological and molecular analyses on cochlear tissues were performed using immunofluorescence, histological staining, and Western blot to assess inflammation, oxidative stress, and blood-labyrinth barrier integrity. Donor microbiota composition was characterized by 16S rRNA sequencing, and systemic inflammation was evaluated by measuring serum lipopolysaccharide (LPS) levels. Results: We found that intestinal dysbiosis is associated with functional, morphological, and molecular alterations in the cochlea, such as increased oxidative stress, inflammation, and altered blood-labyrinth barrier permeability. This leads to macrophage infiltration and immune response activation through the MyD88/NF-κB pathway. Notably, these effects were exacerbated by FMT from subjects with aUC, while FMT from patients with rUC provided a protective effect on cochlear functions. Conclusions: Overall, our findings suggest that gut inflammation, microbiota alteration, or its therapeutic modulation can impact inner ear pathology: worsening gut inflammatory status negatively affects hearing sensitivity, while the restoration of gut microbiota positively impacts auditory function.

The first-spike latency (FSL) is an important temporal characteristic of a neurophysiological response. We study the FSLs of sound-driven responses in individual neurons in the rat’s auditory midbrain. Responses were elicited by a train of stimuli created using multiple presentations of two tone bursts with different frequencies. Presentations of the two sounds were interleaved temporally in a random order. We found that the mean and the temporal variation of FSL of the response elicited by a sound was increased when the sound was presented more frequently or when it was moved from the ear that drove an excitatory response to the ear that drove an inhibitory effect. Furthermore, the FSL of response to one sound was dependent on the spatial location of the other sound. Results suggested that the timing of the first spike could be used by midbrain neurons to encode information related to the probability of occurrence and spatial location of a sound. It could also be used to gauge how the sound was related to the other sound in spatial location. These results enhance our understanding of neural bases of binaural hearing, especially in an environment with temporally separated competing sounds.

Fear retrieval is fundamental for animals to rapidly enter a self-defense state, which enhances their survival rate. Although the cellular mechanisms and neural circuits underlying fear retrieval have been relatively well studied, particularly in classic fear-related nuclei such as the amygdala, the neural circuits and intrinsic microcircuits of some non-classical fear-related nuclei remain poorly understood. A disinhibitory microcircuit in the temporal association cortex (TeA) was identified in this study, demonstrating a critical role in fear retrieval. Additionally, the response of the TeA to fear retrieval is largely driven by acetylcholine (Ach), which then relay information to the tail of striatum (TS) to mediate freezing behavior. Together, these findings demonstrate the essential role of the TeA and its microcircuit in auditory fear retrieval in response to pure tones, providing new insights into the mechanisms of fear retrieval in the cortex.

Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is a leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 knockout (KO) rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 KO rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of stimulus bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiological recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. Together, these findings indicate that cortical hyperexcitability in Fmr1 KO rats may act to preserve signal-to-noise ratios and signal detection threshold at the expense of sound sensitivity and fine feature discrimination, highlighting a potential mechanistic locus for a range of auditory behavioral phenotypes in FXS.

Insects’ sound and vibration detection including proprioception rely on the scolopidium—a mechanosensory unit enclosing the sensory cilium of chordotonal organ neurons. The cilium, enclosed by a scolopale cell, contains mechanosensitive ion channels with the ciliary tip embedded in a cap. Despite knowledge of the scolopidial structure in multiple insects, the mechanism by which mechanical force elicits transduction remains speculative. We examined scolopidia in the auditory Müller’s organ of the desert locust and present a comprehensive three-dimensional (3D) ultrastructure of a scolopidium using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM). Next, we characterised sound-evoked motions of Müller’s organ and the scolopidium using Optical Coherence Tomography (OCT) and high-speed light microscopy. Finally, we measured transduction currents via patch clamp electrophysiology during mechanical stimulation of individual scolopidia. By combining ultrastructure, sound-evoked motions, and transduction current recordings, our finding suggests that the scolopidium is activated best by stretch along the ciliary axis.

Most patients with sensorineural hearing loss (SNHL) may initially experience high‐frequency hearing loss linked to greater vulnerability of outer hair cells (OHCs) in the cochlear basal turn. However, the molecular mechanism underlying this susceptibility in the high‐frequency region remains unclear. Here, NOX2 is first identified as a differentially expressed gene related to oxidative damage in the apical and basal turns through single‐cell RNA sequencing. In mouse cochleae damaged by neomycin and noise, Nox2‐positive OHCs increase progressively from the apex to base, indicating that NOX2 expression clearly differed significantly between the apical and basal OHCs. In NOX2 knockout mice, OHC damage caused by neomycin and noise exposure is significantly reduced. Furthermore, knocking out NOX2 increases the expression of Nrf2 in the cytoplasm and Nrf2 nuclear translocation in OHCs. In addition, Nrf2 inhibitors counteract the protective effect of NOX2 knockout against neomycin. Finally, when Nox2 is used as the target, ginsenoside Rg1 is identified as a compound with protective effects against neomycin‐induced hearing loss. In summary, these results indicate NOX2 is highly correlated with high‐frequency OHCs vulnerability in the cochlea and is a potential intervention target for the clinical treatment of SNHL.

The preservation of synaptic integrity and physiological activity is pivotal for post-traumatic auditory rehabilitation following acoustic overexposure. Neuritin, a neurotrophic factor that facilitates synapse formation, maturation, and enhanced synaptic transmission, is essential for synapse development. In this study, we established a noise-induced cochlear synaptopathy model in CBA/CaJ mice, revealing a temporal association between endogenous Neuritin expression and synaptic density. Furthermore, administration of recombinant Human Neuritin (rhNeuritin) effectively preserves synaptic density in the cochlear basal turn at 7 days and 14 days following noise exposure. Importantly, it preserves the density of functional synapses (represented by overlapping CtBP2 and GluA2 puncta) and synapse function (indicated by ABR I wave amplitudes), thus diminishing the impairment of auditory function. In addition, rhNeuritin reverses the decrease in phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) levels resulting from noise exposure. By primarily preserving both the number and functionality of synapses in the basal turn, potentially via the induction of ERK1/2 phosphorylation, rhNeuritin mitigated hearing loss. These findings underscore the protective efficacy of rhNeuritin against noise-induced synaptic injury.

Aminoglycoside antibiotics remain indispensable despite their ototoxicity. Like other sensorineural forms, aminoglycoside-induced hearing loss (AGIHL) has no effective pharmacotherapy. Oxidative stress, apoptosis, excitotoxicity and inflammation are key pathological factors of the disease. We hypothesised that selegiline, an irreversible monoamine oxidase-B (MAO-B) inhibitor used in Parkinson’s disease, could be repurposed as an otoprotective agent against AGIHL and its effect on dopamine (DA) release from lateral olivocochlear (LOC) fibres, the efferent division of a protective feedback loop plays a major role in the protection against excitotoxicity. Selegiline mitigated AGIHL in BALB/c mice in a dose-dependent manner at different auditory brainstem response frequencies, including 16 kHz, the hearing sensitivity optimum of the animals. It also enhanced the action potential-evoked DA release from LOC efferents in mouse cochlear preparation dose-dependently. Inhibition of DA reuptake contributed to its basic effect of saving DA from metabolism. Among four selegiline analogues tested, the one that increased LOC DA release also provided otoprotection. In contrast, neither safinamide (a reversible MAO-B inhibitor) nor LJP-1207 (a selective semicarbazide-sensitive amine oxidase/vascular-adhesion protein 1 (SSAO/VAP1) inhibitor) prevented AGIHL, despite their antioxidant and anti-inflammatory properties. The reversibility or lack of MAO-B inhibition in safinamide and LJP-1207, respectively, as well as the absence of the propargylamine moiety with known intrinsic neuroprotective activity in both molecules, may explain their ineffectiveness. Selegiline, or certain propargylamine analogues of it, offer a promising therapy against AGIHL by addressing its multifactorial pathology through antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory actions, while enhancing endogenous DAergic protective mechanisms.

Cisplatin‐induced ototoxicity remains a clinical dilemma with limited mechanistic understanding and no food and drug administration (FDA)‐approved therapies. Despite emerging roles of small extracellular vesicles (sEV) in drug ototoxicity, their molecular cargo profiles and causal roles to cisplatin‐induced ototoxicity are unexplored. This study systematically investigates sEV derived from cochlear explants treated with cisplatin (Cis‐sEV) and controls (Ctrl‐sEV) using multi‐omics profiling. Through small RNA sequencing, 83 differentially expressed microRNAs (miRNAs) are identified in Cis‐sEV compared to Ctrl‐sEV. Notably, mmu‐miR‐34a‐5p, mmu‐miR‐140‐5p, mmu‐miR‐15b‐5p, mmu‐miR‐25‐3p, and mmu‐miR‐339‐5p are significantly upregulation in Cis‐sEVs. Predicted target pathways of these differentially expressed miRNAs are enriched in apoptosis, inflammation, and cellular damage, indicating their potential involvement in cisplatin‐induced cochlear damage. LC‐MS/MS analysis reveals 90 upregulated and 150 downregulated proteins in Cis‐sEV, with many involved in damage response. Specifically, CLTC, CCT2, ANXA6, and HSPA8 are uniquely upregulated proteins in Cis‐sEV, and CLTC and ANXA6 are exclusively co‐localized in hair cells (HCs) post‐cisplatin exposure, suggesting that Cis‐sEV originate primarily from damaged HCs. Moreover, CLTC in sEV may serve as a potential biomarker for cisplatin‐induced ototoxicity as verified in both in vitro and in vivo models. This study provides novel insights into the molecular mechanisms of cisplatin‐induced ototoxicity and identifies potential biomarker and therapeutic targets.

Purpose Present-day cochlear-implant (CI) users can achieve high levels of speech reception in quiet surroundings. Nevertheless, sensitivity to the temporal pitch of sounds is limited, which contributes to deficits in speech reception amid multiple talkers and in appreciation of musical melodies. Short-term, invasive neurophysiological studies in animals have demonstrated limitations in neural phase locking in the tonotopic range of the auditory pathway that is activated by CIs. It remains an open question, however, whether those neural limitations can account for perceptual deficits in those animal species, let alone in human CI users. For that reason, we have evaluated non-invasive recordings of phase locking from cats chronically implanted with a CI. Methods Ten deafened cats (eight female) were implanted with an animal version of a clinical CI array. The electrically evoked frequency following response (eFFRs) was recorded from the scalps of sedated animals at ≥ 10 weeks post-implantation. Stimuli consisted of constant-amplitude electrical pulse trains at rates from ~ 40 to 640 pulses per second. Results Recordings of the eFFR demonstrated robust responses synchronized to electrical pulse trains across all stimulus rates. Analyses of eFFR amplitude and phase transfer functions confirmed that the eFFR, as with its normal-hearing counterpart, originates from multiple subcortical and cortical generators. The slopes of segments of eFFR phase transfer functions revealed stimulus-to-response latencies of generators that dominated the eFFR across restricted ranges of pulse rates. Those rate ranges must coincide with the limits of phase locking by putative generators at successive levels of the auditory neuroaxis and could inform our understanding of the limits to perceptual temporal acuity. Conclusion The eFFR demonstrated here in an animal model provides a valuable non-invasive measure of temporal processing in electric cochlear stimulation that can be related to ongoing perceptual measures in the same animals and is well-suited to evaluate novel modes of auditory prosthesis for enhancing temporal acuity.

Background Inflammation is a principal cause of sensorineural hearing loss resulting from cochlear injury. However, current research investigating the mechanisms of sensorineural inflammatory injury remains inadequate. Methods Cochlear inflammation was induced by administering lipopolysaccharide (LPS) into the otic bulla (OB) and posterior semicircular canal (PSCC). Auditory brainstem responses (ABR) were recorded, and cochlear tissue alterations were analyzed using hematoxylin and eosin (HE) staining and immunofluorescence. Levels of cochlear inflammation were quantified using a cytokine array. Additionally, Toll-like receptor 4 (TLR4) knockout mice were employed to evaluate sensorineural neuroprotection. Results LPS injection into the PSCC caused more pronounced and stable cochlear inflammatory damage compared to injection into the OB. LPS exposure led to significant loss of cochlear hair cells, atrophy of the stria vascularis, and spiral ganglion damage. Furthermore, LPS treatment upregulated TLR4 receptor expression, increased the number of Ionized calcium-binding adapter molecule 1 (IBA1) positive cells, and elevated levels of inflammatory cytokines in the cochlea. TLR4 knockout (TLR4-KO) mice demonstrated reduced LPS-induced cochlear sensorineural damage. Conclusion LPS injection into the PSCC induces sensorineural tissue damage in the cochlea and results in sensorineural hearing loss. These findings suggest that TLR4 inhibition can alleviate cochlear inflammation-induced sensorineural hearing loss. TLR4 represents a potential therapeutic target for sensorineural hearing loss.

Hearing loss often arises from impairments in multiple genes, complicating therapeutic development. MicroRNAs, as master regulators, offer promising targets for complex diseases. We explored miR-96's roles in hair cell (HC) function and noise-induced hearing loss (NIHL), finding that miR-96 -/-, not miR-96 +/- , mice exhibited progressive hearing loss due to gene regulatory network dysregulation from miR-96 loss in HCs not spiral ganglion neurons (SGNs). Viral-mediated delivery of miR-96 into the inner ear partially rescued hearing of miR-96 -/- mice. Tamoxifen-induced depletion of miR-96 in adult UBC CreERT2/+ ; miR-96 fl/fl mice led to hearing loss, with Bach2, Gabra2, Gabra4, and Grk1 upregulation and Tnn, Col11a1, Gjb3, and Hnf4a downregulation. Furthermore, noise trauma reduced miR-96, altering Bach2, Bcl2l1, Slc26a9, Gabrb1, Grk1, Nos2, and Cyp1a1 expression, whereas miR-96 overexpression protected hearing against noise by reversing the expression of Bach2, Bcl2l1, and Cyp1a1. Our findings underscore miR-96's essential role in adult hearing maintenance and NIHL prevention, presenting it as a promising therapeutic target.

Age-related hearing loss (ARHL) is a highly prevalent, burdensome sensorineural hearing loss closely associated with impaired autophagic influx. Our previous studies revealed that neuritin, a neurotrophic factor primarily expressed in the central nervous system, could alleviate drug-induced damages in hair cells (HCs) and spiral ganglion neurons. However, its effects on ARHL and whether these effects are closely related to autophagy remain unclear. Using the Nrn1 knock-in mice and cultured cochlear basilar membrane (CBM) of the neonatal mouse, we show that neuritin could restore aging-associated hearing loss and alleviate senescence-associated damage in the cochlea. Overexpression of neuritin in support cells (SCs) alleviates the loss of cochlear HCs and nerve fibers, reducing the damage to spiral ganglion neurons and the shifts in ABR’s high-frequency threshold. Furthermore, conditional overexpression of neuritin in SCs improves autophagic influx by upregulating the expression of microtubule-associated protein 1 light chain 3 type B (LCB3) protein and downregulating the expression of p21 protein. In cultured neonatal mouse CBM, neuritin administration significantly inhibits D-galactose-induced HC loss, cellular apoptosis, and ROS production and promotes autophagic influx. These effects were weakened when the autophagy inhibitor 3-MA was added. In summary, our results confirm the therapeutic potential of neuritin treatment for ARHL.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

Introduction Ibrutinib, widely used in leukemia treatment, has been implicated in sensorineural hearing loss; however, its underlying mechanisms remain unclear. Methods This study investigated the impact of ibrutinib on hearing using HEI-OC1 cells, cochlear explants and C57BL/6 J mice. We used RNA-sequences analysis to investigate the potential mechanisms of ibrutinib-induced ototoxicity. Mice received ibrutinib and auditory thresholds were assessed via auditory brainstem response testing; to assess the potential protective effects, we co-administered the caspase inhibitor Z-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK) and monitored hearing. Results Z-VAD-FMK mitigated ibrutinib-induced hearing loss by inhibiting apoptosis in auditory cells. Ibrutinib exposure resulted in cochlear hair cell (HC) damage and subsequent hearing loss by inhibiting the protein kinase B and G protein-coupled receptor 83 (GPR83) pathways. RNA sequencing suggested that GPR83 protects HCs by modulating autophagy. Z-VAD-FMK application and GPR83 overexpression attenuated ibrutinib-induced cochlear HC apoptosis and auditory decline. Conclusion These findings confirm ibrutinib’s ototoxicity and highlight the protective role of GPR83 in ibrutinib-induced hearing loss, supporting future clinical investigations into Z-VAD-FMK and GPR83 as interventions for ibrutinib or other chemotherapeutic drug-induced ototoxicity.

A failure of organized communication in the PFC is thought to contribute to the emergence of cognitive impairments in psychiatric diseases, with attentional deficits occurring as a fundamental symptom across various conditions. The 22q11.2 microdeletion syndrome is a rare genetic condition that confers a high risk for developing psychiatric and neurodevelopmental disorders, and mouse models have been shown to display attention impairments and PFC pathology that are relevant to clinical populations. Abnormalities in prefrontal parvalbumin-expressing neurons (PVNs) are part of the observed pathophysiology, and studies in rodents have shown that the direct manipulation of these cells can induce behavioral deficits that align with the cognitive symptoms observed in psychiatric diseases. In the present study, we expanded on the role of PVNs in supporting cognition by investigating their involvement in multiple aspects of attentional functions using a translationally relevant task of focused visual attention, in both non-pathological mice and a model of the 22q11.2 microdeletion syndrome. We observed that task-evoked prefrontal PVN activity was reduced in mice that exhibited poorer attention and in 22q11.2 mutant mice. While PVN activity was shaped across learning in non-pathological mice, mutant mice exhibited a lack of signal dynamics that coincided with attentional deficits. Importantly, we observed that task performance in both poor performing wild-types and 22q11.2 mutants could be alleviated by gamma frequency stimulation of PVNs. Thus, PVNs appear to be involved in the acquisition of task rules and execution of attention and continue to be a promising therapeutic target for cognitive dysfunction in disease.

Background Sensorineural hearing loss (SNHL) is among the most common sensory disorders, significantly affecting various aspects of the quality of life of an individual. Oxidative stress and inflammation have been involved in the progression of various forms of SNHL and are potential pathological mechanisms of the disorder. However, the synergistic effects of oxidative stress and inflammation on cochlear function is not completely understood. Methods We explored the effects of oxidative stress and inflammation on cochlear damage and hearing impairment in male C57BL/6 mice aged 6 to 7 weeks. These in the experimental group were administered with oxidant Menadione bisulfite (MD) and the endotoxin lipopolysaccharide (LPS) via intraperitoneal route to induce oxidative stress and inflammation, whereas the control group received saline. The degree of cochlear damage was analyzed based on auditory thresholds, hair cells (HCs) loss, and the expression of protein markers related to oxidative stress, inflammation, necroptosis, and ferroptosis. Results After six days of alternating MD and LPS injections, there was a notable elevation in hearing thresholds, which was associated with a substantial loss of HCs and spiral ganglion cells. Immunofluorescence analysis demonstrated the activation of oxidative stress, inflammation, necroptosis, and ferroptosis signaling pathways after treatment. Notably, the administration of either MD or LPS alone did not result in significant changes. Conclusion These findings indicate that the interaction between oxidative stress and inflammation may exacerbate cochlear damage and contribute to hearing loss, potentially through the activation of necroptosis and ferroptosis pathways. Our results may identify potential therapeutic targets for the management of SNHL.