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.

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.

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.

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.

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.

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.

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.

Transplantation of adipose-derived stromal cells protects functional and morphological auditory nerve integrity in a model of cochlear implantation.

Cochlear implants are considered the gold standard therapy for subjects with severe hearing loss and deafness. Cochlear implants bypass the damaged hair cells and directly stimulate spiral ganglion neurons (SGNs) of the auditory nerve. Hence, the presence of functional SGNs is crucial for speech perception in electric hearing with a cochlear implant. In deaf individuals, SGNs progressively degenerate due to the lack of neurotrophic support, normally provided by sensory cells of the inner ear. Adipose-derived stromal cells (ASCs) are known to produce neurotrophic factors. In a guinea pig model of sensory hearing loss and cochlear implantation, ASCs were autologously transplanted into the scala tympani prior to insertion of a cochlear implant on one side. Electrically evoked auditory brain stem responses (eABR) were recorded 8 weeks after cochlear implantation. At conclusion of the experiment, the cochleae were histologically evaluated. Compared to untreated control animals, transplantation of ASCs resulted in an increased number of SGNs and their peripheral neurites. In ASC-transplanted animals, mean eABR thresholds were lower and suprathreshold amplitudes larger, suggesting a larger population of intact auditory nerve fibers. Moreover, when compared to controls, amplitude-level functions of eABRs in ASC transplanted animals demonstrated steeper slopes in response to increasing interphase gaps (IPGs), indicative of better functionality of the auditory nerve. In summary, results suggest that transplantation of autologous ASCs into the deaf inner ear may have protective effects on the survival of SGNs and their peripheral processes and may thus contribute to long-term benefits in speech discrimination performance in cochlear implant subjects.

Altered mapping of sound frequency to cochlear place in ears with endolymphatic hydrops provide insight into the pitch anomaly of diplacusis.

A fundamental property of mammalian hearing is the conversion of sound pressure into a frequency-specific place of maximum vibration along the cochlear length, thereby creating a tonotopic map. The tonotopic map makes possible systematic frequency tuning across auditory-nerve fibers, which enables the brain to use pitch to separate sounds from different environmental sources and process the speech and music that connects us to people and the world. Sometimes a tone has a different pitch in the left and right ears, a perceptual anomaly known as diplacusis. Diplacusis has been attributed to a change in the cochlear frequency-place map, but the hypothesized abnormal cochlear map has never been demonstrated. Here we assess cochlear frequency-place maps in guinea-pig ears with experimentally-induced endolymphatic hydrops, a hallmark of Ménière's disease. Our findings are consistent with the hypothesis that diplacusis is due to an altered cochlear map. Map changes can lead to altered pitch, but the size of the pitch change is also affected by neural synchrony. Our data show that the cochlear frequency-place map is not fixed but can be altered by endolymphatic hydrops. Map changes should be considered in assessing hearing pathologies and treatments.

The possibility of cochlear synaptopathy in young people using a personal listening device.

OBJECTIVE: To evaluate the association of listening to music loudly through personal listening devices with cochlear synaptopathy in young adults. METHODS: Fifty healthy young adults selected among 109 volunteers were included in the study. Participants of high risk (n=25) and low risk (n=25) groups estimated according to ETDNL (estimated total daily noise level) were evaluated using pure tone audiometry, tympanometry, matrix test, electrocochleography (EcochG) and auditory brainstem response (ABR) to evaluate the occurrence of cochlear synaptopathy. RESULTS: Audiometric thresholds between the groups were not significantly different (p>0.05). High risk group participants showed poorer performance than the low-risk group on the TurMatrix test, in non-adaptive noise with -5 SNR and -7.5 SNR, and at the 50% understanding SNR level with headphones (p<0.01). There was no difference in the adaptive free field in noise test at which 50% understanding was achieved (p>0.05). The AP amplitudes on EcochG and wave V amplitudes on ABR were significantly smaller in the high-risk group (p<0.05). There was no association between ETDNL and I/V ratio on ABR. CONCLUSION: Poorer performance in TurMatrix and other electrophysiologic tests revealed the negative effect of personal listening devices on the auditory system. Our findings support the hypothesis that personal listening devices could cause cochlear synaptopathy. Long-term studies are needed to determine the effects of binaural hearing and duration of noise exposure on the auditory system.

Evaluation of cochlear functions in infants exposed to SARS-CoV-2 intrauterine.

PURPOSE: The novel coronavirus (SARS-CoV-2) caused an acute respiratory illness named COVID-19 and the disease spread all over the World. Fever, cough, fatigue, gastrointestinal infection symptoms form the main clinical symptoms. Pregnants and newborns form a vulnerable population and urgent measures must be addressed. Studies about the effect of COVID-19 on pregnant women, developing fetuses, and infants are limited. Various viral diseases can cause congenital or acquired, unilateral or bilateral hearing loss. METHODS: 37 infants whose mother was pregnant between March 2020 and December 2020 and were born after the diagnosis of COVID- 19 during pregnancy and 36 healthy infants were included in the study. Transient evoked otoacoustic emission (TEOAE), distortion product otoacoustic emission (DPOAE) and contralateral suppression of OAE (CLS OAE) tests were performed on all infants. RESULTS: According to the TEOAE results of patients and controls in the silent a statistically significant difference was observed between the two groups at 3 kHz and 4 kHz (p < 0.05). Contralateral suppression of OAE test results of patients and controls a statistically significant difference was found in all frequencies (p< 0.05). Suppression was much more effective at all frequencies in the normal group than patient group. This difference was found to be more significant at higher frequencies (2,3 and 4 kHz) (p < 0.001). CONCLUSIONS: Our results suggest an insufficiency in medial olivocochlear efferent system in infants exposed to SARS-CoV-2 intrauterine. Cochlear functions should be examined in infants whose mothers had COVID-19.

Increased cochlear otic capsule thickness and intracortical canal porosity in the oim mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI or brittle bone disease) is a group of genetic disorders of the connective tissues caused mainly by mutations in the genes encoding collagen type I. Clinical manifestations of OI include skeletal fragility, bone deformities, and severe functional disabilities, such as hearing loss. Progressive hearing loss, usually beginning in childhood, affects approximately 70% of people with OI with more than half of the cases involving the inner ear. There is no cure for OI nor a treatment to ameliorate its corresponding hearing loss, and very little is known about the properties of OI ears. In this study, we investigate the morphology of the otic capsule and the cochlea in the inner ear of the oim mouse model of OI. High-resolution 3D images of 8-week old oim and WT inner ears were acquired using synchrotron microtomography. Volumetric morphometric measurements were conducted for the otic capsule, its intracortical canal network and osteocyte lacunae, and for the cochlear spiral ducts. Our results show that the morphology of the cochlea is preserved in the oim ears at 8 weeks of age but the otic capsule has a greater cortical thickness and altered intracortical bone porosity, with a larger number and volume density of highly branched canals in the oim otic capsule. These results portray a state of compromised bone quality in the otic capsule of the oim mice that may contribute to their hearing loss.

Correlation of cochlear aperture stenosis with cochlear nerve deficiency in congenital unilateral hearing loss and prognostic relevance for cochlear implantation.

The use of neonatal hearing screening has enabled the identification of congenital unilateral sensorineural hearing loss (USNHL) immediately after birth, and today there are several intervention options available to minimize potential adverse effects of this disease, including cochlear implantation. This study aims to analyze the characteristics of the inner ear of a homogeneous group of congenital non-syndromic USNHL to highlight the features of the inner ear, which can help in clinical, surgical, and rehabilitative decision-making. A retrospective chart review was carried out at a tertiary referral center. Systematic diagnostic work-up and rigorous inclusion-exclusion criteria were applied to 126 children with unilateral hearing impairment, leading to a selection of 39 strictly congenital and non-syndromic USNHL cases, undergoing computed tomography (CT) and magnetic resonance (MR) imaging studies. The frequency and type of malformations of the inner ear in USNHL and unaffected contralateral ears were assessed, with an in-depth analysis of the deficiency of the cochlear nerve (CND), the internal auditory canal (IAC) and the cochlear aperture (CA). Inner ear anomalies were found in 18 out of 39 (46%) of the USNHL patients. In 1 subject, the anomalies were bilateral, and the CND resulted in the predominant identified defect (78% of our abnormal case series), frequently associated with CA stenosis. Only 3 out of 14 children with CND presented stenosis of the IAC. CND and CA stenosis (and to a much lesser extent IAC stenosis) are a frequent association within congenital and non-syndromic USNHL that could represent a distinct pathological entity affecting otherwise healthy infants. In the context of a diagnostic work-up, the evaluation with CT and MRI measurements should take place in a shared decision-making setting with thorough counseling. Both imaging techniques have proven useful in differentiating the cases that will most likely benefit from the cochlear implant, from those with potentially poor implant performance.

Force and pressure measurements in temporal bones.

PURPOSE: Some cochlear implant (CI) patients lose their residual hearing during surgery. Two factors that might play a role in residual hearing loss are the change in intracochlear hydraulic pressure and force on the cochlear wall during electrode insertion. The aim of this study is to investigate whether a difference in peak hydraulic pressure and peak force on the cochlear wall exists during a CI electrode insertion with different insertion techniques. MATERIALS AND METHODS: Twenty fresh frozen temporal bones were used. Hydraulic pressure and force on the cochlear wall were recorded during straight electrode insertions with 1) slow versus fast insertion speed, 2) manual versus automatic insertion method and 3) round window approach (RWA) versus extended RWA (ERWA). RESULTS: When inserting with a slow compared to a fast insertion speed, the peak hydraulic pressure is 239% (95% CI: 130-399%) higher with a RWA and 58% (95% CI: 6-137%) higher with an ERWA. However, the peak force on the cochlear wall is a factor 29% less (95% CI: 13-43%) with a slow insertion speed. No effect was found of opening and insertion method. CONCLUSIONS: As contradictory findings were found for hydraulic pressure and force on the cochlear wall on insertion speed, it remains unclear which insertion speed (slow versus fast) is less traumatic to inner ear structure.

Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity.

Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin's ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.

Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects.

Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitudes of the sound-evoked auditory nerve compound action potential (CAP). In animal models, HHL can be caused by moderate noise exposure or aging, which induces loss of inner hair cell (IHC) synapses. In contrast, recent evidence has shown that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice with similarities to HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios observed in animals and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons whose activity is driven by a well-accepted model of cochlear sound processing. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when heminodes are disorganized, i.e. they occur at different distances from the hair cell rather than at the same distance as in the normal cochlea. These results confirm that disruption of heminode positions causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. Another mechanism resulting in HHL is loss of IHC synapses, i.e., synaptopathy. For comparison, we simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, as has been observed in noise exposed animals. Thus, model results illuminate diverse disruptions caused by synaptopathy and demyelination on neural activity in auditory processing that contribute to HHL as observed in animal models and that can contribute to perceptual deficits induced by nerve damage in humans.