Does Intraoperative Extracochlear Electrocochleography Correlate With Postoperative Audiometric Hearing Thresholds in Cochlear Implant Surgery? A Retrospective Analysis of Cochlear Monitoring.

In recent years, tools for early detection of irreversible trauma to the basilar membrane during hearing preservation cochlear implant (CI) surgery were established in several clinics. A link with the degree of postoperative hearing preservation in patients was investigated, but patient populations were usually small. Therefore, this study's aim was to analyze data from intraoperative extracochlear electrocochleography (ECochG) recordings for a larger group.During hearing preservation CI surgery, extracochlear recordings were made before, during, and after CI electrode insertion using a cotton wick electrode placed at the promontory. Before and after insertion, amplitudes and stimulus response thresholds were recorded at 250, 500, and 1000 Hz. During insertion, response amplitudes were recorded at one frequency and one stimulus level. Data from 121 patient ears were analyzed.The key benefit of extracochlear recordings is that they can be performed before, during, and after CI electrode insertion. However, extracochlear ECochG threshold changes before and after CI insertion were relatively small and did not independently correlate well with hearing preservation, although at 250 Hz they added some significant information. Some tendencies-although no significant relationships-were detected between amplitude behavior and hearing preservation. Rising amplitudes seem favorable and falling amplitudes disadvantageous, but constant amplitudes do not appear to allow stringent predictions.Extracochlear ECochG measurements seem to only partially realize expected benefits. The questions now are: do gains justify the effort, and do other procedures or possible combinations lead to greater benefits for patients?

Intracochlear Recording of Electrocochleography During and After Cochlear Implant Insertion Dependent on the Location in the Cochlea.

To preserve residual hearing during cochlear implant (CI) surgery it is desirable to use intraoperative monitoring of inner ear function (cochlear monitoring). A promising method is electrocochleography (ECochG). Within this project the relations between intracochlear ECochG recordings, position of the recording contact in the cochlea with respect to anatomy and frequency and preservation of residual hearing were investigated. The aim was to better understand the changes in ECochG signals and whether these are due to the electrode position in the cochlea or to trauma generated during insertion. During and after insertion of hearing preservation electrodes, intraoperative ECochG recordings were performed using the CI electrode (MED-EL). During insertion, the recordings were performed at discrete insertion steps on electrode contact 1. After insertion as well as postoperatively the recordings were performed at different electrode contacts. The electrode location in the cochlea during insertion was estimated by mathematical models using preoperative clinical imaging, the postoperative location was measured using postoperative clinical imaging. The recordings were analyzed from six adult CI recipients. In the four patients with good residual hearing in the low frequencies the signal amplitude rose with largest amplitudes being recorded closest to the generators of the stimulation frequency, while in both cases with severe pantonal hearing losses the amplitude initially rose and then dropped. This might be due to various reasons as discussed in the following. Our results indicate that this approach can provide valuable information for the interpretation of intracochlearly recorded ECochG signals.

Quantitative profiling of cochlear synaptosomal proteins in cisplatin-induced synaptic dysfunction.

The disruption of ribbon synapses in the cochlea impairs the transmission of auditory signals from the cochlear sensory receptor cells to the auditory cortex. Although cisplatin-induced loss of ribbon synapses is well-documented, and studies have reported nitration of cochlear proteins after cisplatin treatment, yet the underlying mechanism of cochlear synaptopathy is not fully understood. This study tests the hypothesis that cisplatin treatment alters the abundance of cochlear synaptosomal proteins, and selective targeting of nitrative stress prevents the associated synaptic dysfunction. Auditory brainstem responses of mice treated with cisplatin showed a reduction in amplitude and an increase in latency of wave I, indicating cisplatin-induced synaptic dysfunction. The mass spectrometry analysis of cochlear synaptosomal proteins identified 102 proteins that decreased in abundance and 249 that increased in abundance after cisplatin treatment. Pathway analysis suggested that the dysregulated proteins were involved in calcium binding, calcium ion regulation, synapses, and endocytosis pathways. Inhibition of nitrative stress by co-treatment with MnTBAP, a peroxynitrite scavenger, attenuated cisplatin-induced changes in the abundance of 27 proteins. Furthermore, MnTBAP co-treatment prevented the cisplatin-induced decrease in the amplitude and increase in the latency of wave I. Together, these findings suggest a potential role of oxidative/nitrative stress in cisplatin-induced cochlear synaptic dysfunction.

Perceptual Consequences of Cochlear Deafferentation in Humans.

Cochlear synaptopathy, a form of cochlear deafferentation, has been demonstrated in a number of animal species, including non-human primates. Both age and noise exposure contribute to synaptopathy in animal models, indicating that it may be a common type of auditory dysfunction in humans. Temporal bone and auditory physiological data suggest that age and occupational/military noise exposure also lead to synaptopathy in humans. The predicted perceptual consequences of synaptopathy include tinnitus, hyperacusis, and difficulty with speech-in-noise perception. However, confirming the perceptual impacts of this form of cochlear deafferentation presents a particular challenge because synaptopathy can only be confirmed through post-mortem temporal bone analysis and auditory perception is difficult to evaluate in animals. Animal data suggest that deafferentation leads to increased central gain, signs of tinnitus and abnormal loudness perception, and deficits in temporal processing and signal-in-noise detection. If equivalent changes occur in humans following deafferentation, this would be expected to increase the likelihood of developing tinnitus, hyperacusis, and difficulty with speech-in-noise perception. Physiological data from humans is consistent with the hypothesis that deafferentation is associated with increased central gain and a greater likelihood of tinnitus perception, while human data on the relationship between deafferentation and hyperacusis is extremely limited. Many human studies have investigated the relationship between physiological correlates of deafferentation and difficulty with speech-in-noise perception, with mixed findings. A non-linear relationship between deafferentation and speech perception may have contributed to the mixed results. When differences in sample characteristics and study measurements are considered, the findings may be more consistent.

Alpha9alpha10 knockout mice show altered physiological and behavioral responses to signals in masking noise.

Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (α9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (α9α10KOs) may exhibit more severe MOC-related phenotypes. Like α9KOs, α9α10KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in α9α10KO mice. Wild-type (WT) and α9α10KO mice had similar ABR thresholds and acoustic startle response amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. α9α10KO mice had larger ABR Wave I amplitudes than WTs in quiet and noise. Other ABR metrics of hearing-in-noise function yielded conflicting findings regarding α9α10KO susceptibility to masking effects. α9α10KO mice also had larger startle amplitudes in tone backgrounds than WTs. Overall, α9α10KO mice had grossly normal auditory function in quiet and noise, although their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.

Murine cochlear damage models in the context of hair cell regeneration research.

Understanding the complex pathologies associated with hearing loss is a significant motivation for conducting inner ear research. Lifelong exposure to loud noise, ototoxic drugs, genetic diversity, sex, and aging collectively contribute to human hearing loss. Replicating this pathology in research animals is challenging because hearing impairment has varied causes and different manifestations. A central aspect, however, is the loss of sensory hair cells and the inability of the mammalian cochlea to replace them. Researching therapeutic strategies to rekindle regenerative cochlear capacity, therefore, requires the generation of animal models in which cochlear hair cells are eliminated. This review discusses different approaches to ablate cochlear hair cells in adult mice. We inventoried the cochlear cyto- and histo-pathology caused by acoustic overstimulation, systemic and locally applied drugs, and various genetic tools. The focus is not to prescribe a perfect damage model but to highlight the limitations and advantages of existing approaches and identify areas for further refinement of damage models for use in regenerative studies.

Electrocochleographic frequency-following responses as a potential marker of age-related cochlear neural degeneration.

Auditory nerve (AN) fibers that innervate inner hair cells in the cochlea degenerate with advancing age. It has been proposed that age-related reductions in brainstem frequency-following responses (FFR) to the carrier of low-frequency, high-intensity pure tones may partially reflect this neural loss in the cochlea (Märcher-Rørsted et al., 2022). If the loss of AN fibers is the primary factor contributing to age-related changes in the brainstem FFR, then the FFR could serve as an indicator of cochlear neural degeneration. In this study, we employed electrocochleography (ECochG) to investigate the effects of age on frequency-following neurophonic potentials, i.e., neural responses phase-locked to the carrier frequency of the tone stimulus. We compared these findings to the brainstem-generated FFRs obtained simultaneously using the same stimulation. We conducted recordings in young and older individuals with normal hearing. Responses to pure tones (250 ms, 516 and 1086 Hz, 85 dB SPL) and clicks were recorded using both ECochG at the tympanic membrane and traditional scalp electroencephalographic (EEG) recordings of the FFR. Distortion product otoacoustic emissions (DPOAE) were also collected. In the ECochG recordings, sustained AN neurophonic (ANN) responses to tonal stimulation, as well as the click-evoked compound action potential (CAP) of the AN, were significantly reduced in the older listeners compared to young controls, despite normal audiometric thresholds. In the EEG recordings, brainstem FFRs to the same tone stimulation were also diminished in the older participants. Unlike the reduced AN CAP response, the transient-evoked wave-V remained unaffected. These findings could indicate that a decreased number of AN fibers contributes to the response in the older participants. The results suggest that the scalp-recorded FFR, as opposed to the clinical standard wave-V of the auditory brainstem response, may serve as a more reliable indicator of age-related cochlear neural degeneration.

L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice.

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Surface electrical stimulation of the auditory cortex preserves efferent medial olivocochlear neurons and reduces cochlear traits of age-related hearing loss.

The auditory cortex is the source of descending connections providing contextual feedback for auditory signal processing at almost all levels of the lemniscal auditory pathway. Such feedback is essential for cognitive processing. It is likely that corticofugal pathways are degraded with aging, becoming important players in age-related hearing loss and, by extension, in cognitive decline. We are testing the hypothesis that surface, epidural stimulation of the auditory cortex during aging may regulate the activity of corticofugal pathways, resulting in modulation of central and peripheral traits of auditory aging. Increased auditory thresholds during ongoing age-related hearing loss in the rat are attenuated after two weeks of epidural stimulation with direct current applied to the surface of the auditory cortex for two weeks in alternate days (Fernández del Campo et al., 2024). Here we report that the same cortical electrical stimulation protocol induces structural and cytochemical changes in the aging cochlea and auditory brainstem, which may underlie recovery of age-degraded auditory sensitivity. Specifically, we found that in 18 month-old rats after two weeks of cortical electrical stimulation there is, relative to age-matched non-stimulated rats: a) a larger number of choline acetyltransferase immunoreactive neuronal cell body profiles in the ventral nucleus of the trapezoid body, originating the medial olivocochlear system.; b) a reduction of age-related dystrophic changes in the stria vascularis; c) diminished immunoreactivity for the pro-inflammatory cytokine TNFα in the stria vascularis and spiral ligament. d) diminished immunoreactivity for Iba1 and changes in the morphology of Iba1 immunoreactive cells in the lateral wall, suggesting reduced activation of macrophage/microglia; d) Increased immunoreactivity levels for calretinin in spiral ganglion neurons, suggesting excitability modulation by corticofugal stimulation. Altogether, these findings support that non-invasive neuromodulation of the auditory cortex during aging preserves the cochlear efferent system and ameliorates cochlear aging traits, including stria vascularis dystrophy, dysregulated inflammation and altered excitability in primary auditory neurons.

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice.

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17ß-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.

3D printed biomimetic cochleae and machine learning co-modelling provides clinical informatics for cochlear implant patients.

Cochlear implants restore hearing in patients with severe to profound deafness by delivering electrical stimuli inside the cochlea. Understanding stimulus current spread, and how it correlates to patient-dependent factors, is hampered by the poor accessibility of the inner ear and by the lack of clinically-relevant in vitro, in vivo or in silico models. Here, we present 3D printing-neural network co-modelling for interpreting electric field imaging profiles of cochlear implant patients. With tuneable electro-anatomy, the 3D printed cochleae can replicate clinical scenarios of electric field imaging profiles at the off-stimuli positions. The co-modelling framework demonstrated autonomous and robust predictions of patient profiles or cochlear geometry, unfolded the electro-anatomical factors causing current spread, assisted on-demand printing for implant testing, and inferred patients' in vivo cochlear tissue resistivity (estimated mean = 6.6 kΩcm). We anticipate our framework will facilitate physical modelling and digital twin innovations for neuromodulation implants.

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma.

Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL.

Thymoquinone ameliorates age-related hearing loss in C57BL/6J mice by modulating Sirt1 activity and Bak1 expression.

Age-related hearing loss (AHL) is the most common sensory disorder of aged population. Currently, one of the most important sources of experimental medicine for AHL is medicinal plants. This study performed the first investigation of the effect of thymoquinone (TQ), a potent antioxidant, on AHL. Here, we used inbred C57BL/6J mice (B6 mice) as a successful experimental model of the early onset of AHL. The behavioral assessment of hearing revealed that the injection of a high dose of TQ (40 mg/kg; TQ40) significantly improved the auditory sensitivity of B6 mice at all tested frequencies (8, 16 and 22 kHz). Histological sections of cochlea from B6 mice injected with a low dose (20 mg/kg; TQ20) and high dose showed relatively less degenerative signs in the modiolus, hair cells and spiral ligaments, the main constituents of the cochlea. In addition, TQ40 completely restored the normal pattern of hair cells in B6 mice, as shown in scanning electron micrographs. Our data indicated that TQ20 and TQ40 reduced levels of Bak1-mediated apoptosis in the cochlea of B6 mice. Interestingly, the level of Sirt1, a positive regulator of autophagy, was significantly increased in B6 mice administered TQ40. In conclusion, TQ relieves the symptoms of AHL by downregulating Bak1 and activating Sirt1 in the cochlea of B6 mice.

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss.

Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/- mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

Cochlear Synaptopathy: A Primary Factor Affecting Speech Recognition Performance in Presbycusis.

The results of recent animal studies have suggested that cochlear synaptopathy may be an important factor involved in presbycusis. Therefore, here, we aimed to examine whether cochlear synaptopathy frequently exists in patients with presbycusis and to describe the effect of cochlear synaptopathy on speech recognition in noise. Based on the medical history and an audiological examination, 94 elderly patients with bilateral, symmetrical, sensorineural hearing loss were diagnosed as presbycusis. An electrocochleogram, auditory brainstem responses, auditory cortical evoked potentials, and speech audiometry were recorded to access the function of the auditory pathway. First, 65 ears with hearing levels of 41-50 dB HL were grouped based on the summating potential/action potential (SP/AP) ratio, and the amplitudes of AP and SP were compared between the two resulting groups. Second, 188 ears were divided into two groups: the normal SP/AP and abnormal SP/AP groups. The speech recognition abilities in the two groups were compared. Finally, the relationship between abnormal electrocochleogram and poor speech recognition (signal-to-noise ratio loss ≥7 dB) was analyzed in 188 ears. The results of the present study showed: (1) a remarkable reduction in the action potential amplitude was observed in patients with abnormal SP/AP ratios; this suggests that cochlear synaptopathy was involved in presbycusis. (2) There was a large proportion of patients with poor speech recognition in the abnormal SP/AP group. Furthermore, a larger number of cases with abnormal SP/AP ratios were confirmed among patients with presbycusis and poor speech recognition. We concluded that cochlear synaptopathy is not uncommon among elderly individuals who have hearing ability deficits, and it may have a more pronounced effect on ears with declining auditory performance in noisy environments.

Intracochlear distortion products are broadly generated by outer hair cells but their contributions to otoacoustic emissions are spatially restricted.

Detection of low-level sounds by the mammalian cochlea requires electromechanical feedback from outer hair cells (OHCs). This feedback arises due to the electromotile response of OHCs, which is driven by the modulation of their receptor potential caused by the stimulation of mechano-sensitive ion channels. Nonlinearity in these channels distorts impinging sounds, creating distortion-products that are detectable in the ear canal as distortion-product otoacoustic emissions (DPOAEs). Ongoing efforts aim to develop DPOAEs, which reflects the ear's health, into diagnostic tools for sensory hearing loss. These efforts are hampered by limited knowledge on the cochlear extent contributing to DPOAEs. Here, we report on intracochlear distortion products (IDPs) in OHC electrical responses and intracochlear fluid pressures. Experiments and simulations with a physiologically motivated cochlear model show that widely generated electrical IDPs lead to mechanical vibrations in a frequency-dependent manner. The local cochlear impedance restricts the region from which IDPs contribute to DPOAEs at low to moderate intensity, which suggests that DPOAEs may be used clinically to provide location-specific information about cochlear damage.

The role of oxidative stress in the susceptibility of noise-impaired cochleae to synaptic loss induced by intracochlear electrical stimulation.

Intracochlear electrical stimulation (ES) generated by cochlear implants (CIs) is used to activate auditory nerves to restore hearing perception in deaf subjects and those with residual hearing who use electroacoustic stimulation (EAS) technology. Approximately 1/3 of EAS recipients experience loss of residual hearing a few months after ES activation, but the underlying mechanism is unknown. Clinical evidence indicates that the loss is related to the previous history of noise-induced hearing loss (NIHL). In this report, we investigated the impact of intracochlear ES on oxidative stress levels and synaptic counts in inner hair cells (IHCs) of the apical, middle and basal regions of guinea pigs with normal hearing (NH) and NIHL. Our results demonstrated that intracochlear ES with an intensity of 6 dB above the thresholds of electrically evoked compound action potentials (ECAPs) could induce the elevation of oxidative stress levels, resulting in a loss of IHC synapses near the electrodes in the basal and middle regions of the NH cochleae. Furthermore, the apical region of cochleae with NIHL were more susceptible to synaptic loss induced by relatively low-intensity ES than that of NH cochleae, resulting from the additional elevation of oxidative stress levels and the reduced antioxidant capability throughout the whole cochlea.

Distribution and Afferent Effects of Transplanted mESCs on Cochlea in Acute and Chronic Neural Hearing Loss Models.

Hearing loss is a sensory deprivation that can affect the quality of life. Currently, only rehabilitation devices such as hearing aids and cochlear implants are used, without a definitive cure. However, in chronic hearing-deprived patients, in whom secondary auditory neural degeneration is expected, a relatively poor rehabilitation prognosis is projected. Stem cell therapy for cochlear neural structures would be an easier and feasible strategy compared with cochlear sensory cells. Considering the highly developed cochlear implantation technology, improving cochlear neural health has significant medical and social effects. Stem cell delivery to Rosenthal's canal in an acutely damaged mouse model has been performed and showed cell survival and the possibility of differentiation. The results of stem cell transplantation in chronic auditory neural hearing loss should be evaluated because neural stem cell replacement therapy for chronic (long-term) sensorineural hearing loss is a major target in clinics. In the present study, we established a mouse model that mimicked chronic auditory neural hearing loss (secondary degeneration of auditory neurons after loss of sensory input). Then, mouse embryonic stem cells (mESCs) were transplanted into the scala tympani and survival and distribution of transplanted cells were compared between the acute and chronic auditory neural hearing loss models induced by ouabain or kanamycin (KM), respectively. The mESC survival was similar to the acute model, and perilymphatic distribution of cell aggregates was more predominant in the chronic model. Lastly, the effects of mESC transplantation on neural signal transduction observed in the cochlear nucleus (CN) were compared and a statistical increase was observed in the chronic model compared with other models. These results indicated that after transplantation, mESCs survived in the cochlea and increased the neural signaling toward the central auditory pathway, even in the chronic (secondary) hearing loss mouse model.

Effects of Androgen Receptor Inhibition on Kanamycin-Induced Hearing Loss in Rats.

Megalin has been proposed as an endocytic receptor for aminoglycosides as well as estrogen and androgen. We aimed to investigate the otoprotective effects of antiandrogens (flutamide, FM) on kanamycin (KM)-induced hearing loss in rats. Rats were divided into four groups. The KM group was administered KM (20 mg/kg/day) for 5 days, while the FM group received FM (15 mg/kg/day) for 10 days. In the KM + FM group, KM and FM (15 mg/kg/day) were simultaneously injected for 5 days and then FM was injected for 5 days. Auditory brainstem responses were measured. Western blotting and/or quantitative reverse transcriptase-polymerase chain reaction were performed for megalin, cytochrome P450 1A1 (Cyp1a1), Cyp1b1, metallothionein 1A (MT1A), MT2A, tumor necrosis factor (TNF)-α, caspase 3, and cleaved caspase 3. The FM + KM group showed attenuated auditory thresholds when compared with the KM group at 4, 8, 16, and 32 kHz (all p < 0.05). The KM + FM group showed lower megalin and Cyp1b1 levels than the KM group (all p < 0.05). The KM + FM group revealed lower MT1A, TNFα, and caspase 3 protein levels, compared with those in the KM group (all p < 0.05). Androgen receptor inhibition protects against cochlear injuries in KM-induced hearing loss rats by attenuating megalin expression, revealing anti-inflammatory and anti-apoptotic effects.

Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming.

Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte-specific ADORA2B (eAdora2b-/-) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b-/- mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B-BPGM axis is a key component for anti-aging and anti-age-related functional decline.