Publications using TDT

Intratympanic (IT) injection of corticosteroids is a standard clinical treatment for sensorineural hearing loss; however, achieving both biocompatibility and efficient cochlea drug delivery remains a significant challenge. Herein, we engineered a novel drug nanocrystal (NS)-loaded thermo-reversible hydrogel (NS-TG) system of dexamethasone-21-palmitate (DEX-P), a lipophilic prodrug of dexamethasone (DEX), for improved IT delivery. NSs with a mean diameter of 835.0 nm were fabricated using a dual centrifugation process with polyvinyl alcohol as the stabilizer. The NS-TG system, comprising NSs in a 19% (w/v) Poloxamer 407 hydrogel, exhibited rapid gelation (2–3 min) and a 31-fold increase in drug solubility (1.57 ± 0.02 mg/mL) compared to NS alone, through micellar solubilization. In vitro cytotoxicity assays in HEI-OC1 cells revealed that NS-TG is highly biocompatible, maintaining cell viability, whereas the commercial lipid emulsion (Lipothason®) induced significant cytotoxicity. In vivo pharmacokinetic evaluation in mice revealed that IT NS-TG provided superior cochlear drug absorption compared to DEX-SP solutions and DEX-P NS, despite showing lower absorption than the lipid emulsion. These findings suggest that the DEX-P NS-TG system, pending further investigation, could serve as a promising platform for cochlear steroidal delivery, offering an optimal balance between delivery efficiency and local safety for treating inner ear diseases.

The frontopolar cortex (FPC) is thought to coordinate the more posterior lateral prefrontal cortex (LPFC) during complex, nonroutine behaviors through high-level functions such as management of multiple goals, exploration, and self-generated decision-making. However, direct neurophysiological comparisons with other prefrontal regions are lacking, leaving the FPC’s putative dominance untested. Contrary to this view, our comparison of neuronal activity across the full anteroposterior LPFC in macaques during six distinct tasks probing these functions revealed a posterior-to-mid LPFC dominance, with resource-allocation signals, novelty- and reward-related learning signals, and modality-invariant decision-monitoring signals all showing a common posterior bias. In contrast, regardless of the task demands, FPC exhibited inflexible encoding of just-executed actions and consistent task-related deactivation resembling default-mode network activity. We identified a turning point in this graded posterior-to-anterior transition from task-positive to task-negative regions around the border between the anterior and middle thirds of the LPFC. These findings challenge the prevailing notion that the LPFC is anterior dominant across primate species and provide evolutionary constraints on theories of human prefrontal organization.

Like mammals, some reptiles possess sensitive and frequency-selective hearing at mid- to high-kilohertz frequencies. Both groups employ a place-frequency map within the inner ear to encode sound stimuli, but the mechanisms by which they achieve tuned nerve activation along the cochlea are believed to be distinct. To investigate the mechanical origins of auditory sensation in the reptiles, we measured sound-evoked displacement responses in the hearing organ of the tokay gecko ( Gekko gecko ), known as the basilar papilla. Using optical coherence tomography, we were able to resolve sub-nanometer-scale vibrations throughout the organ both in vivo and ex vivo . We saw that tuning was not present in the tissue-scale mechanics at any position within the organ; it instead exhibits an untuned rotational motion. We developed a mathematical model which predicted that this motion induces hair-bundle-stimulating fluid displacement, and is due to an anatomical asymmetry seen in many reptile species. These results are consistent with the theory that hair-bundle-level mechanics are primarily responsible for tuning in the tokay gecko cochlea, and we argue that our proposed mechanisms generalize to many other species across the Reptilia class. SIGNIFICANCE We present the most comprehensive picture of tissue-scale mechanics in a reptile hearing organ to-date: sound-evoked displacement responses within the basilar papilla of the tokay gecko ( Gekko gecko ) both ex vivo and in vivo , across the animal’s auditory frequency range, and along all three spatial dimensions. We observed that place-frequency tuning is not present in the mechanics of the tissue as it is in mammals. Instead, this organ relies on an untuned rocking mechanism to stimulate hair bundles. A mathematical model shows that this may be at play in other reptile species, indicating a unifying mechanism of hearing in the class Reptilia in which hair bundle mechanics play the leading role in frequency tuning.

Brain neuromodulatory systems exert powerful effects on local neuronal circuit function and behavior. In addition to classical actions directly on neurons, growing evidence indicates that neuromodulators also recruit Ca 2+ -dependent astrocyte mechanisms to regulate synaptic plasticity and network function. The dorsal striatum integrates cortical and thalamic inputs under strong dopamine (DA) and acetylcholine (ACh) neuromodulatory control. To what extent the circuit and behavioral effects of striatal ACh and DA depend on astrocyte Ca 2+ activity remains unclear. We show that locomotion elicits robust DA, ACh, and astrocyte Ca 2+ activity in the dorsolateral striatum (DLS). DA and ACh release exhibits a negative correlation on a fast time scale but shows a positive correlation during continuous locomotion as slower astrocyte Ca 2+ activity builds. Higher ACh and DA release is associated with higher astrocyte events, suggesting that both neurotransmitters drive astrocyte activity. In agreement, pharmacological blockade of muscarinic ACh or D1/D2 DA receptors decreases locomotion-evoked astrocyte Ca 2+ . Closed-loop optogenetic inhibition of striatal cholinergic interneurons (CINs) during locomotion reduces astrocyte Ca 2+ activity, demonstrating a causal contribution of ACh release to astrocyte activity. Locomotion related ACh release was severely compromised in a mouse model of Parkinson’s disease (PD), with the dual loss of DA and ACh attenuating astrocyte Ca 2+ activity. Facilitating astrocyte cholinergic signaling via chemogenetics improved both calcium activity and motor deficits in our recent work. Thus, the pathophysiology of PD in part involves attenuated astrocyte Ca 2+ signaling, placing these non-neuronal cells as a prime underexplored therapeutic target for PD.

Auditory decision-making requires transforming sensory inputs into meaningful choices by integrating external stimuli with internal cognitive processes. Classical hierarchical models propose sequential processing, where primary sensory areas relay sensory information to higher-order regions that compute decision-related processes. However, whether this sequential hierarchy fully captures cortical dynamics remains unclear. Here, we analyzed simultaneous neuronal recordings from primary auditory cortex (A1) and dorsolateral prefrontal cortex (PFC) in two male macaque monkeys performing a spatial auditory decision-making task. Our analyses revealed a clear temporal hierarchy: sensory information was unidirectionally transferred from A1 to PFC, while decision-related information exhibited a bidirectional transfer, first from PFC to A1, and crucially back from A1 to PFC. These findings extend classical hierarchical assumptions, demonstrating a recurrent loop between A1 and PFC during decision-making, and offer a dynamic perspective on the integration of sensory and cognitive processes in the cerebral cortex.

Gait impairments remain a major therapeutic challenge in Parkinson's disease (PD). Apomorphine is gaining renewed clinical attention with the expanding use of pump infusion systems. Yet the specific role of apomorphine on the neural regulation of gait has remained poorly characterized, limiting its targeted use for symptom-specific therapy in PD. Here, we examined the neurobehavioral effects of apomorphine on runway locomotion in the unilateral 6-hydroxydopamine (6-OHDA) rat model. Therapeutic drug doses significantly increased total walking distance, related to reduced akinesia and prolonged gait episodes. Conversely, 3D kinematic analysis revealed reduced limb velocities under medication. At the neural level, therapy doses selectively enhanced cortical high-gamma rhythms without substantially altering beta or low-gamma activity. Instead, beta and low-gamma oscillations were consistently suppressed during motor activity in both medication ON and OFF conditions. Neurobehavioral correlations showed that transitions into gait were facilitated by reductions in beta and low-gamma activity, whereas transitions to akinesia were primarily suppressed when high-gamma activity was elevated. Our findings highlight that cortical oscillations can serve as state specific biomarkers for gait impairments in PD. We further propose that the complex therapy effects of apomorphine are best explained by a shift in motor-state equilibrium that is defined by the transitions of akinesia, stationary movements and gait. Together, these insights establish a mechanistic framework to guide the development of targeted gait therapies in PD.

Purpose: In anesthesia research and clinical practice, the level of consciousness is often assessed by stimulating subjects and observing their responses. It is possible that such stimulation alters the very state of consciousness being assessed. Whether this phenomenon is accompanied by specific cortical activities remains unknown. Here, we tested the effects of behavioral assessments on neuronal activity in the rat primary auditory cortex (A1) and perirhinal cortex (PrC). Methods: Neuronal spiking activity was recorded from microwire arrays targeting A1 and/or PrC in rats (n = 9), whilst presenting 40 Hz click-trains and gradually increasing infusion rates of propofol, remifentanil, ketamine or dexmedetomidine. We assessed righting reflex, pain withdrawal, whisking reflex, and corneal reflex every 12 minutes (every 360 auditory trials). We searched for significant changes in baseline firing rate and stimulus-evoked activities (where present) due to the behavioral assessments, by comparing 4 min intervals before and after the behavioral tests. Results: Out of 1004 units in 20 sessions, we found significantly elevated activity (p < 0.01) following behavioral tests in 32% and 20% of A1 auditory-responsive units and 8.6% and 5.3% of auditory-unresponsive units under propofol and dexmedetomidine, respectively, but not under remifentanil or ketamine. A higher proportion of units modulated their firing following behavioral tests in A1 compared to PrC, with median gains ranging from +0.23 to +1.06, depending on the specific response feature. Conclusion: Behavioral testing increases ongoing firing rate and responses to sounds in some cortical neurons. This increase is more prevalent in A1 than in PrC, mirroring clinical observations that patients exhibit basic responses under sedation, while complex processing, such as memory encoding, is impaired. The degree of neuronal modulation due to behavioral testing varies between anesthetic agents, mirroring their clinical phenotypes.

Mafb and c-Maf transcription factors (TFs) are expressed in medial ganglionic eminence (MGE) lineages, beginning in progenitors and continuing into mature GABAergic parvalbumin-positive (PV + ) and somatostatin-positive (SST + ) cortical interneurons (CINs). Deleting Mafb and c-Maf in MGE before SST versus PV fate specification causes developmental anomalies, including altered numbers of CINs and seizure phenotypes, but the specific contributions of these TFs in postmitotic SST + and PV + CINs to epilepsy remain unknown. To address this, we conditionally deleted Mafb or c-Maf in SST + or PV + interneurons after interneuron fate specification in female and male mice. Deletion of c-Maf, but not Mafb, in SST+ cells was associated with reduced synaptic excitation onto these cells and with spontaneous spike-and-wave discharges, consistent with absence-like seizures. In contrast, deletion of Mafb in SST + CINs reduced their density in superficial cortical layers but did not induce epilepsy. Neither c-Maf nor Mafb deletion in PV + CINs produced major electrophysiological or histological abnormalities in the somatosensory cortex. These findings identify a specific requirement for c-Maf in modulating synaptic excitation of SST + interneurons and show that its loss in SST + cells is associated with the development of absence-like epileptiform activity in vivo. Together, our results refine the understanding of how transcriptional programs shape interneuron function in the mature cortex and highlight c-Maf/MAF-dependent pathways as candidates for investigation in epilepsy genetics.

Platinum electrodes are used in many bionic devices; however, they have limited charge injection capacity (CIC) and signal‐to‐noise ratio (SNR), restricting performance. Iridium oxide has substantially larger CIC and reduced impedance compared to platinum. While these types of electrochemical measurements are typically used to infer improved electrophysiological performance, there are no studies demonstrating this correlation. This article compares the electrochemical and acute electrophysiological recording performance of iridium and electrochemically activated IrOx. Increased iridium activation reduced total impedance at low‐intermediate frequencies and steady‐state electroactive area but had no impact on linear diffusion electroactive area. The total impedance had a poor correlation with background noise, SNR and spike count. The results contribute to the previous literature indicating linear diffusion electroactive area determines the number of neurons within recording distance of the electrode, impacting SNR and spike count. Measurements of impedance are mainly of benefit as an indirect measure of linear diffusion electroactive area, in which case the measurement and analysis must be performed appropriately. A wide range of IrOx activation states can be produced with increased CIC, without concern of neural recording performance impacts. However, higher oxidation states resulting in electrode dissolution or increase in electrode resistance may limit IrOx chronic performance.

Pain management strategies have progressed beyond traditional pharmacologic and physical interventions, integrating advanced neuromodulation techniques such as deep brain stimulation, peripheral nerve stimulation, and high‐frequency spinal cord stimulation (hSCS). Despite its clinical efficacy, the supraspinal mechanisms underlying hSCS remain poorly understood. Prior work in sheep demonstrated that hSCS modulates gamma (γ) band (70–150 Hz) activity in the primary somatosensory and association cortices, implicating cortical involvement in pain modulation. Given the interaction between low‐ and high‐oscillations, we hypothesized that hSCS modulates γ activity in a region‐ and time‐dependent manner through specific coupling with theta rhythms (θ, 4–8 Hz). To test this, we quantified θ–γ phase‐amplitude coupling (PAC) during tibial nerve stimulation (TNS) before (TNS 0 ) and after (TNS 1 ) hSCS to assess cortical processing of TNS‐evoked activity, while recording cortical (association and somatosensory cortices) neural activity using 96‐channel subdural electrocorticography (ECoG). We then computed the corresponding modulation index (MI) to quantify PAC strength. While the preferred θ phase of γ activity remained consistent across conditions in both cortical areas, θ‐γ coupling was more robust and stable in the association than the somatosensory cortex. However, MI increased significantly post‐hSCS in both cortices, indicating enhanced θ‐γ coupling during TNS 1 . Temporally, both cortices showed distinct response patterns: the somatosensory cortex exhibited strongest coupling increase early post‐hSCS, followed by a progressive decline, whereas the association cortex showed a more delayed and temporally distributed enhancement. These findings indicate that hSCS modulates cortical cross‐frequency interactions during TNS‐evoked sensory processing, wherein somatosensory and association cortices show distinct temporal coupling dynamics that may contribute to supraspinal mechanisms of pain modulation.

Auditory and vestibular symptoms in vestibular migraine, cochlear migraine, and Ménière's disease overlap, yet mechanisms linking migraine biology to inner ear dysfunction remain unclear. Calcitonin gene–related peptide (CGRP) is a key mediator of trigeminovascular activation and a major therapeutic target in migraine, but its contribution to cochlear dysfunction is not well defined. Using a repeated nitroglycerin (NTG) paradigm in male Wistar rats, we investigated whether a systemic migraine‐like state affects cochlear function and whether these effects are dependent on CGRP. Rats received saline, NTG, or NTG followed by the CGRP receptor antagonist olcegepant (OLC). NTG increased plasma TNF‐ α and elevated trigeminal c‐Fos; olcegepant partially normalized these markers, whereas behavioral changes in the open‐field test were interpreted cautiously because baseline immobility differed across groups before treatment. NTG produced frequency‐dependent changes in distortion‐product otoacoustic emissions and auditory brain stem response thresholds. Electrocochleography showed limited changes, and scala media proportions did not differ significantly among groups, indicating no evidence of overt endolymphatic hydrops at the studied time point. Inner hair‐cell synaptic markers showed no significant group differences for CtBP2, whereas GluR2 puncta differed between NTG and NTG + OLC ( p = 0.012). Olcegepant attenuated NTG‐associated cochlear functional changes and was associated with differences in postsynaptic GluR2 puncta, alongside region‐specific changes in cochlear CGRP immunoreactivity. These findings support a mechanistic link between migraine‐like trigeminovascular activation and early cochlear dysfunction and suggest that CGRP receptor blockade may benefit migraine patients with cochlear or vestibular symptoms. Future studies should assess females, estrous cycle tracking, hormones, and sex‐specific auditory responses.

Introduction: Transcranial focused ultrasound (tFUS) can noninvasively modulate sensory pathways, but the cell-type-specific mechanisms underlying excitatory or inhibitory effects remain unclear. Here, we investigate how tFUS applied to the somatosensory cortex (S1) influences S1 and posterior medial thalamic nucleus (POm) responses to hind paw vibration-tactile stimulation and which neuronal populations mediate these effects. Methods: Vibration-tactile stimulation evoked potentials (TEPs) and multi-unit activity (MUA) in S1 and POm were recorded from male rats. Optogenetic tagging was used to identify S1 CaMKII-positive, PV-positive, and SST-positive neurons, while waveform features were used to classify putative excitatory (i.e., regular-spiking units - RSUs) and inhibitory neurons (i.e., fast-spiking units - FSUs) in POm. Results: We found that only S1 CaMKII-positive neurons and POm RSUs responded robustly to tactile stimulation. When tFUS was applied to S1, high pulse repetition frequency (PRF), high duty cycle, and high-pressure stimulation (etFUS) produced excitatory modulation of the sensory pathway, whereas low PRF, low duty cycle, and low-pressure stimulation (itFUS) induced inhibitory effects. Further analyses suggested that excitatory modulation may involve activation of S1 CaMKII-positive neurons, while the inhibitory effect may be associated with their deactivation. Conclusions: These findings demonstrate that tFUS exerts bidirectional, parameter-dependent modulation of a sensory pathway and highlight the critical role of CaMKII-positive neurons in mediating these effects. This study provides mechanistic insight into cell-type-specific neuromodulation by tFUS, particularly in bidirectional modulation of a sensory pathway, and informs the optimization of stimulation parameters for targeted therapeutic interventions.

Hypercholesterolemia is a recognized risk factor for sensorineural hearing loss. This study investigated the mechanistic link between blood-labyrinth barrier (BLB) disruption and hypercholesterolemia-associated cochlear damage. Low-density lipoprotein receptor knockout (Ldlr -/-) mice fed a high-fat diet for 8 weeks were used as the experimental model. Auditory assessments showed elevated auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs), especially at high frequencies, consistent with hearing loss driven by outer hair cell dysfunction. BLB disruption occurred before hearing impairment, manifest as increased vascular permeability, damaged tight junctions and downregulated junctional protein levels. Cochlear histopathology confirmed outer and inner hair cell loss. These findings demonstrate a sequential and identify BLB as a key therapeutic target for preventing hypercholesterolemia-associated hearing impairment.

Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen in otitis media (OM), including acute otitis media (AOM) and chronic suppurative otitis media (CSOM), presenting considerable therapeutic challenges due to its biofilm formation, host immune evasion, and promotion of persistent inflammation. This study evaluated the therapeutic potential of Schisandrin C (Sch C), a natural lignan derived from Schisandra chinensis , in mitigating MRSA-induced OM. In rat models of MRSA-induced AOM and CSOM, Sch C significantly reduced bacterial load and inflammatory responses by decreasing pro-inflammatory cytokine levels. By upregulating tight junction protein ZO-1 and downregulating mucin MUC5B, it also restored epithelial barrier integrity. In addition, Sch C treatment improved auditory function. Mechanistic studies revealed that Sch C directly inhibited sortase A (SrtA), a key enzyme responsible for anchoring surface virulence factors in MRSA, by binding to its active site and inhibiting its transpeptidase activity (fluorescence resonance energy transfer IC₅₀ = 38.68 µM). Through inhibiting SrtA, Sch C disrupted MRSA adhesion, invasion, and biofilm formation without exerting direct bactericidal effects. Furthermore, Sch C synergized with ofloxacin, enhancing its efficacy against MRSA otitis by reducing bacterial load, inflammation, and tissue damage. Collectively, these findings establish Sch C as a potent S. aureus SrtA inhibitor, highlighting its promise as a therapeutic strategy for MRSA-induced OM.

Neonatal bilirubin encephalopathy is primarily characterized by central auditory dysfunction and cognitive impairments. However, the precise molecular mechanisms underlying bilirubin-induced neurotoxicity remain poorly understood, hindering the development of effective therapeutic strategies. Using kinase activity prediction tools based on quantitative phosphoproteomics, we identified ROCK2 (Rho-associated protein kinase 2) as a critical kinase regulating the phosphorylation of proteins associated with bilirubin exposure. Molecular docking and MicroScale Thermophoresis assays revealed a strong binding affinity between bilirubin and ROCK2. Interestingly, bilirubin increased ROCK2 protein expression without affecting its mRNA levels, and cycloheximide chase assays revealed enhanced ROCK2 stability, implicating post-translational regulation. While bilirubin did not directly activate ROCK2 kinase activity in vitro, it elevated phosphorylation of its substrate LIMK1, suggesting that ROCK2 accumulation amplifies downstream signaling. In primary rat neurons, ROCK2 inhibitors (Belumosudil and Y-27632) ameliorated bilirubin-induced loss of mitochondrial membrane potential and neuronal cell death. Furthermore, using ROCK2 inhibitors and Rock2+/- mice, we demonstrated that modulation of ROCK2 significantly alleviated bilirubin-induced auditory deficits and cognitive impairments. These behavioral improvements were linked to restored excitatory synaptic transmission in the cochlear nucleus and reduced dendritic damage in hippocampal neurons. These findings position ROCK2 as a promising molecular target for therapeutic intervention in bilirubin encephalopathy.

Background/Objectives: Dopamine is well known for its role in reward learning, where phasic activity encodes prediction errors and supports the formation of cue–outcome associations. More recently, dopamine has been implicated in encoding salience, novelty, and aversive events, suggesting a broader function in shaping learning and memory across motivational contexts. However, how accumbal dopamine contributes to the recovery of extinguished fear, a process central to relapse in anxiety and trauma-related disorders, remains unclear. Methods: Here, we examined NAc core dopamine dynamics during shock-induced reinstatement of an extinguished fear memory. Using dLight fiber photometry, we found that a sustained decrease in baseline dopamine marked extinction recall. In contrast, an unexpected reminder footshock prevented this reduction, maintaining dopamine levels near baseline as freezing behavior re-emerged. Results: The reminder shock also evoked a transient dopamine peak, and optogenetic manipulations demonstrated that dopamine signaling during this period bidirectionally modulated reinstatement, with enhancement of dopamine release increasing reinstatement and inhibition of dopamine terminals markedly attenuating it. Together, these results demonstrate that unexpected aversive events reset NAc core dopamine levels and gate the return of extinguished fear. Conclusions: By revealing that accumbal dopamine contributes to fear recovery, this work broadens current models of dopamine function and identifies a neural mechanism through which surprising events may promote relapse of aversive memories in anxiety- and stress-related disorders.

Chronic sleep disruption and cognitive deficits are debilitating long-term consequences of traumatic brain injury (TBI), yet the endogenous mechanisms that drive network-level recovery remain poorly understood. Here, we demonstrate that during the chronic phase post-injury, network oscillations critical for memory, including slow oscillations, delta waves, and sleep spindles, undergo precise adaptive tuning that sustains sleep-dependent memory consolidation. This functional circuit resilience requires Semaphorin-3A (Sema3a); loss of Sema3a function prevents the protective reorganization of non-rapid eye movement (NREM) sleep architecture, impairs sleep-dependent memory consolidation, and exacerbates cortical lesion size. Together, these findings identify Sema3a as an innate protective mechanism that preserves sleep architecture and cognitive function following TBI.

Background Noise-induced hearing loss (NIHL) is the second leading cause of deafness globally. However, effective pharmacological treatments remain unavailable. Excitotoxicity, an early NIHL event, is a central mechanism in degeneration of cochlear synapses established between inner hair cells (IHCs) and spiral ganglion neurons (SGNs). This excitotoxic damage can trigger the degradation of the neurotrophic TrkB receptor, thereby inhibiting brain-derived neurotrophic factor (BDNF) signaling and challenging neurotrophin-based therapies for hearing loss. Methods We employed an ex vivo model of excitotoxicity, where excitotoxicity was induced in cochlear explants by overstimulation of excitatory glutamate receptors, and an in vivo model of noise overexposure. The effects of excitotoxicity on the neurotrophic system and cell architecture were established by immunohistochemistry. Hearing function was evaluated in vivo by the auditory brainstem responses (ABR) test, performed before and after noise overexposure. Results In this study, we evaluated the therapeutic potential in the inner ear of MTFL 457 , a cell-penetrating peptide designed to prevent TrkB-FL degradation in brain excitotoxicity. MTFL 457 showed efficient distribution across cochlear cell types in both ex vivo and in vivo models, supporting its ability to reach the inner ear and suggesting that it can cross the blood-labyrinth barrier after systemic administration. In explants undergoing excitotoxicity, MTFL 457 prevented TrkB-FL dysregulation, partially restored downstream prosurvival signaling, and significantly reduced neuronal damage and features associated with cochlear synaptopathy. In vivo, despite known sex-dependent differences in susceptibility to noise-induced damage, treatment with MTFL 457 preserved auditory function and synaptic integrity in both males and females, although the magnitude of protection varied between sexes. Together, these findings support a protective effect of MTFL 457 in models of excitotoxic cochlear injury. Conclusions These results support the therapeutic potential of peptide MTFL 457 for treatment of NIHL and possibly other types of sensorineural hearing loss likewise associated with excitotoxicity.

Age‐related vestibular dysfunction (ARVD) is a prevalent and debilitating condition among the elderly, yet its etiology and underlying molecular mechanisms remain poorly understood. We focused on mechanosensitive hair cells (HCs), which are widely recognized as susceptible to aging. Using single‐cell RNA‐seq transcriptomic analysis of young and old mice, we show that old vestibular HCs exhibit conserved transcriptomic hallmarks of cellular aging, including cellular senescence, mitochondrial dysfunction, and impaired proteostasis, along with prominent cell type‐specific changes linked to hair bundle architecture and the mechanotransduction machinery. Consistent with these transcriptomic findings, imaging and electrophysiological recordings from old vestibular sensory epithelia reveal hair bundle degeneration and reduced mechanotransduction activity. Importantly, this structural and functional deterioration precedes HC loss, underscoring impaired hair bundle function as a key driver of ARVD. Furthermore, our comparative analysis identifies both shared and distinct aging signatures in vestibular and cochlear HCs, providing broader insight into the mechanisms that may underlie their different rates of age‐related degeneration.