Cochlear Function Research Articles

Norrie disease protein is essential for cochlear hair cell maturation

Mutations in the gene for Norrie disease protein (Ndp) cause syndromic deafness and blindness. We show here that cochlear function in an Ndp knockout mouse deteriorated with age: At P3-P4, hair cells (HCs) showed progressive loss of Pou4f3 and Gfi1, key transcription factors for HC maturation, and Myo7a, a specialized myosin required for normal function of HC stereocilia. Loss of expression of these genes correlated to increasing HC loss and profound hearing loss by 2 mo. We show that overexpression of the Ndp gene in neonatal supporting cells or, remarkably, up-regulation of canonical Wnt signaling in HCs rescued HCs and cochlear function. We conclude that Ndp secreted from supporting cells orchestrates a transcriptional network for the maintenance and survival of HCs and that increasing the level of β-catenin, the intracellular effector of Wnt signaling, is sufficient to replace the functional requirement for Ndp in the cochlea.

Neuropatía Auditiva Infantil

La combinación de las otoemisiones acústicas transitorias (OEAT) y los potenciales evocados auditivos del tronco cerebral (PEATC) nos permite identificar a un grupo de pacientes con neuropatía auditiva (NA), cuyas implicaciones clínicas y terapéuticas constituyen un reto en nuestra práctica otológica. La población pediátrica estudiada por nosotros, no ha manifestado una alteración en el examen neurológico o en la resonancia nuclear magnética cerebral o de los oídos internos. Las OEAT y los timpanogramas tipo A,se registraron en el 100% de los casos. Los reflejos estapediales y los PEATC estaban ausentes en todos los pacientes. En la audiometría tonal o conductual, el grado de hipoacusia neurosensorial osciló entre leve a moderada, siendo bilateral en todos los casos. Los niños que colaboraron en las pruebas verbales, demostraron una desproporcionada disminución de la comprensión de la palabra que no correspondió a sus audiogramas tonales. Los hallazgos previos sugieren que la lesión es neurosensorial, con normofuncionalidad de las células ciliadas externas cocleares (OEAT presentes). No se puede precisar si la lesión está localizada en las células ciliadas internas, en el octavo par o en ambos. Las etiologías más probables que han justificado la NA han sido: hiperbilirrubinemia, anoxia perinatal, prematuridad o idiopáticas. El resultado de la rehabilitación del lenguaje con los audífonos demuestra una efectividad limitada. Todos los pacientes están siendo tratados por un terapeuta en el leguaje. El éxito de esta terapia depende de la precocidad en su instauración.

Los implantes cocleares en América latina

Los implantes cocleares en América latina

Revealing the actions of the human cochlear basilar membrane at low frequency

The basilar membrane (BM) is the key infrastructure that supports the microstructure of cochlear acoustic function, and its interaction with lymph in the cochlea involves a complex, highly nonlinear coupling motion and energy conversion. In 1928, Nobel Laureate Gordon von Békésy experimented and first discovered the traveling wave motion of the BM, thus uncovering the mystery of BM motion. However, with the further development of experimental technology in recent years, scientists have discovered that the traveling wave motion does not explain many experimental observations and phenomena associated with the detection of low-frequency sounds by the cochlea. Because the cochlea is very small and complex, Békésy could only obtain medium- and high-frequency motion data for the BM but not low-frequency motion data. Based on a theory of mathematical physics and biology combined with data from medical and modern light source imaging experiments, a theoretical model of the spiral cochlea and a numerical model that conforms to the real human ear were established. The results reproduce the known traveling wave motion of the BM. Meanwhile, an exciting new finding has revealed a standing wave motion pattern at low frequencies. This newly discovered motion pattern intrinsically explains many experimental observations that could not be explained by the traveling wave theory. These results not only complement the low-frequency motion characteristics of the BM, but also probably reveal the mechanism of active phonoreceptive amplification in the cochlea, which has been a difficult problem to unravel in otology medicine.

Extended high frequency hearing loss in tinnitus-positive chronic suppurative otitis media patient.

ObjectivesTo determine the association between extended high frequency hearing loss and tinnitus in normal cochlear function based on a conventional audiometry chronic suppurative otitis media (CSOM) patient.Design and methodsA cross‐sectional study was conducted on 220 ears diagnosed as having CSOM with an equal number of tinnitus and without tinnitus groups. Only those with normal cochlear function based on conventional pure tone audiometry (250 Hz to 8 kHz) were included. They were further tested for hearing at extended high frequencies of up to 16 kHz. The severity of tinnitus was tested using a tinnitus questionnaire.ResultsThe prevalence of extended high frequency hearing loss in the normal cochlear function CSOM patients with tinnitus was 81.8% (95% CI 74.5%, 89.1%), whereas the prevalence in the tinnitus negative group was 30.0% (95% CI 21.3%, 38.7%). There was a significant association between extended high frequency hearing loss and tinnitus in CSOM patients (P < .001). The average thresholds were significantly higher in the tinnitus group at all extended high frequencies tested with an increasing trend of significance toward the higher frequencies. However, this study did not observe any association between the severity of tinnitus and extended high frequency hearing loss.ConclusionThe development of tinnitus among normal cochlear function CSOM patients indicates that the damage has occurred at a higher frequency level. However, the severity of tinnitus does not predict the degree of higher frequency hearing loss. Therefore, the presence of tinnitus warrants more aggressive monitoring and treatment to prevent sensorineural hearing loss from developing into the speech frequencies.Level of Evidence4.

Effect of Caffeine on Otoacoustic Emissions

Abstract Introduction Caffeine is consumed everyday in a variety of ways by a large population around the world, including coffee, tea, and soft drinks. Therefore, there is a significant need to explore the effects of caffeine on human auditory system. The present study aimed to investigate the effect of caffeine on cochlea using distortion product otoacoustic emission (DPOAE). Materials and Methods Thirty-three young adults were recruited for the study. The effect of caffeine on cochlea was assessed using DPOAE at frequencies between 1 to 10 kHz before and after caffeine consumption. Results The signal to noise ratio of DPOAE was compared before and after coffee intake, which revealed no significant differences. Conclusion The current study results suggest that caffeine has no effect on cochlear functioning.

Auditory brainstem response: An overview of neurophysiological implications and clinical applications -A Narrative Review.

Evoked Potentials are electrical potentials that occur in a group of neurons in response to stimulation of a sensory organ which can be recorded by surface electrodes. Testing evoked potentials is useful in assessing the integrity of neuronal pathways both at sensory and motor levels of neural control. Early auditory evoked potentials include cochlear and brainstem auditory-evoked potentials, popularly known as electrocochleogram, and auditory brainstem response. Evoked potential audiometry is a neurophysiogical test to assess auditory pathway function in response to auditory stimuli. Auditory brainstem response mainly assesses brainstem functions and integrity. These evoked potentials are widely used for assessment of the cochlear functions, auditory nerve and the brainstem. Most common indications for auditory evoked potentials include routine newborn hearing screening for auditory pathway deficits, detecting retrocochlear pathologies, intraoperative and intensive care monitoring, frequency-related measurement of auditory sensitivity and for diagnosing some demyelinating disorders in initial stages. The current narrative review was planned to highlight auditory brainstem response recording's basic principles, uses and methods of interpretation in health and disease phases.

Ion channel-related hereditary hearing loss: a narrative review

Sensorineural hearing loss is the most common sensory deficit in humans, with an estimated prevalence of 1 in 500 newborns. Approximately half of childhood hearing loss is attributed to genetic factors and can be classified as syndromic or non-syndromic based on the inheritance pattern. The ion channel genes KCNQ1 , KCNE1 , KCNQ4 , P2RX2 , TMC1 , KCNJ10 , and CACNA1D have frequently been associated with genetic hearing loss. Because of the important roles these genes play in cochlear hair cell function and the auditory pathways, mutations in these genes that result in impaired ion channel function can lead to hereditary hearing loss. The main purpose of this review was to examine the latest research progress on the functional roles, inheritance pattern, gene expression, protein structure, clinical phenotypes, mouse models, and possible treatments of the most commonly studied ion channels associated with inherited deafness. A comprehensive summary could help highlight ion channels that should be investigated as potential drug targets for the treatment of inherited deafness.

Reliability of Contralateral Suppression in Evoked Distortion Product Otoacoustic Emissions.

Introduction Distortion product otoacoustic emissions (DPOAE) and their suppression may be considered useful in monitoring cochlear function and the efferent auditory pathway inhibitory effect. Nonetheless, the establishment of reliable parameters of response variations is of great importance. Objectives To verify the replicability of test and retest in the research of the inhibitory effect of the efferent pathway using contralateral suppressing stimulus during DPOAE recording for clinical applicability. Methods Cross-sectional study with 48 volunteers, aged 18 to 30 years, with normal audiometric thresholds. The procedures included were audiometric and immittance measures to overrule any conductive or sensorineural conditions and DPOAE recordings without and with contralateral suppression with a 60 dBHL white noise. Distortion product otoacoustic emissions amplitudes were analyzed and compared in both conditions with Wilcoxon test, and the Spearman correlation test was used to assess test-retest reliability. Results The comparative analysis showed differences between amplitudes in test and retest conditions only in 1,500 Hz for DPOAE measures with all other tested frequencies showing no differences, and no difference was observed in all recorded frequencies in the test and retest comparison for DPOAE suppression. The degree of correlation between test and retest of DPOAE amplitude was good at 6,000 Hz and strong (r > 0.880) at the other frequencies. For DPOAE with suppression, all frequencies presented strong correlation between test and retest: 1,500 Hz (r = 0.880), 2,000 Hz (r = 0.882), 3,000 Hz (r = 0.940), and 6,000 Hz (r = 0.957). Conclusions The study found good replicability in contralateral suppression of DPOAE with potential clinical applicability, and we recommend conducting the test from 2000Hz to higher frequencies for more reliable results.

Investigation Of Outer Hair Cell Function Of The Cochlea in Psoriasis Patients

Objective: Psoriasis has been accepted as a T-cell mediated systemic disease and systemic inflammation may also cause immune-mediated hearing loss. We aimed to evaluate cochlear function with otoacoustic emission (OAE) measurement in psoriasis patients, and to evaluate whether there is a relationship between the duration and severity of the disease and OAEs. Material and Methods: Forty-four patients diagnosed with psoriasis were included in the study. The control group consisted of 35 healthy volunteers. The patients' age, gender, onset age and duration of the disease, family history and additional diseases were questioned and psoriasis area severity index (PASI) was calculated. Audiological and otological evaluations were performed. Distortion Product Otoacoustic Emission (DPOAE) were measured at 500, 1000, 2,000, 4,000, 6000, 8000 and 10000 Hz frequencies. Results: There was no significant difference in DPOAE values at 500, 1000, 2000, 4000, 6000, 8000 and 10000 Hz between healthy volunteers and psoriasis patients. There was a significant difference between PASI score and DPOAE value at 1000 Hz, disease duration and DPAOE values at 4000 and 6000 Hz. Conclusion: Considering that psoriasis is a long-term, chronic systemic disease, patients should be follow-up closely even if they do not have hearing complaints in the early period, and as the duration and severity of the disease increases, the hearing of the patients may be affected.

Advances in hearing preservation in cochlear implant surgery.

Advancements in cochlear implant surgical approaches and electrode designs have enabled preservation of residual acoustic hearing. Preservation of low-frequency hearing allows cochlear implant users to benefit from electroacoustic stimulation, which improves performance in complex listening situations, such as music appreciation and speech understanding in noise. Despite the relative high rates of success of hearing preservation, postoperative acoustic hearing outcomes remain unpredictable. Thin, flexible, lateral wall arrays are preferred for hearing preservation. Both shortened and thin, lateral wall arrays have shown success with hearing preservation and the optimal implant choice is an issue of ongoing investigation. Electrocochleography can monitor cochlear function during and after insertion of the electrode array. The pathophysiology of hearing loss acutely after cochlear implant may differ from that involved in delayed hearing loss following cochlear implant. Emerging innovations may reduce cochlear trauma and improve hearing preservation. Hearing preservation is possible using soft surgical techniques and electrode arrays designed to minimize cochlear trauma; however, a subset of patients suffer from partial to total loss of acoustic hearing months to years following surgery despite evidence of residual apical hair cell function. Early investigations in robotic-assisted insertion and dexamethasone-eluting implants show promise.

Effect of Using N95 and Surgical Masks on Otoacoustic Emission in Cochlear Outer Hair Cells.

Distortion product otoacoustic emission (DPOAE) was measured to investigate the effect of mask use and type on oxygen saturation on cochlear function in health care professionals during the COVID-19 pandemic. Group 1 participants wore surgical masks; Group 2 participants wore N95 masks. Distortion product otoacoustic emission and oxygen saturation were measured in both groups before and after mask use. Comparison of signal-to-noise ratio (SNR) values before and after surgical mask use in DPOAE measurements of group 1 revealed statistically significant difference in the right and left ears. Comparison of the SNR values in DPOAE measurements of group 2 before and after 8 hours of N95 mask use revealed statistically significant differences in the right ear at 988, 2963, 4444, and 8000 Hz and in the left ear at 8000 Hz. We found that prolonged mask use may affect the outer hair cells in the cochlea, causing deterioration in DPOAE values.

Prophylactic nimodipine treatment for hearing preservation after vestibular schwannoma surgery: study protocol of a randomized multi-center phase III trial\u2014AkniPro 2

BackgroundA previously performed phase III trial on 112 subjects investigating prophylactic nimodipine treatment in vestibular schwannoma (VS) surgery showed no clear beneficial effects on preservation of facial and cochlear nerve functions, though it should be considered that protection of facial nerve function was the primary outcome. However, the risk for postoperative hearing loss was halved in the nimodipine group compared to the control group (OR 0.49; 95% CI 0.18–1.30; p = 0.15). Accordingly, this phase III extension trial investigates the efficacy and safety of prophylactic nimodipine for hearing preservation in VS surgery.MethodsThis is a randomized, multi-center, two-armed, open-label phase III trial with blinded expert review and two-stage with interim analysis. Three hundred thirty-six adults with the indication for microsurgical removal of VS (Koos I–IV) and serviceable preoperative hearing (Gardner-Robertson scale (GR) 1–3) are assigned to either the therapy (intravenous nimodipine 1–2 mg/h from the day before surgery until the fifth postoperative day and standard of care) or the control group (surgery only and standard of care). The primary endpoint of the trial is postoperative cochlear nerve function measured before discharge according to GR 1–3 versus GR 4–5 (binary). Hearing function will be determined by pre- and postoperative audiometry with speech discrimination, which will be evaluated by a blinded expert reviewer. Furthermore, patient-reported outcomes using standardized questionnaires will be analyzed.DiscussionProphylactic parenteral nimodipine treatment may have a positive effect on hearing preservation in VS surgery and would improve patient’s quality of life. Further secondary analyses are planned. Except for dose-depending hypotension, nimodipine is known as a safe drug. In the future, prophylactic nimodipine treatment may be recommended as a routine medication in VS surgery. VS can be considered as an ideal model for clinical evaluation of neuroprotection, since hearing outcome can be classified by well-recognized criteria. The beneficial effect of nimodipine may be transferable to other surgical procedures with nerves at risk and may have impact on basic research.Trial registrationEudraCT 2019-002317-19, DRKS00019107. 8th May 2020.

Spontaneous otoacoustic emissions are biomarkers for mice with tectorial membrane defects

Cochlear function depends on the operation of a coupled feedback loop, incorporating outer hair cells (OHCs), and structured to assure that inner hair cells (IHCs) convey frequency specific acoustic information to the brain, even at very low sound levels. Although our knowledge of OHC function and its contribution to cochlear amplification has expanded, the importance of the tectorial membrane (TM) to the processing of mechanical inputs has not been fully elucidated. In addition, there are a surprising number of genetic mutations that affect TM structure and that produce hearing loss in humans. By synthesizing old and new results obtained on several mouse mutants, we learned that animals with abnormal TMs are prone to generate spontaneous otoacoustic emissions (SOAE), which are uncommon in most wildtype laboratory animals. Because SOAEs are not produced in TM mutants or in humans when threshold shifts exceed approximately 25 dB, some degree of cochlear amplification is required. However, amplification by itself is not sufficient because normal mice are rarely spontaneous emitters. Since SOAEs reflect active cochlear operation, TM mutants are valuable for studying the oscillatory nature of the amplification process and the structures associated with its stabilization. Inasmuch as the mouse models were selected to mirror human auditory disorders, using SOAEs as a noninvasive clinical tool may assist the classification of individuals with genetic defects that influence the active mechanisms responsible for sensitivity and frequency selectivity, the hallmarks of mammalian hearing.

Dysfunction of the Auditory System in Children With Hypothyroidism: A Systematic Review and Meta-Analysis.

To examine the prevalence of hearing impairment in children with hypothyroidism, and to characterize clinical and subclinical hearing loss by examining cochlear function, auditory brainstem pathways, and integration of the auditory system as a whole. An electronic search was conducted using PubMed, Scopus, and Cochrane Library databases. This systematic review was performed in accordance with the PRISMA guidelines. Original observational studies that utilized audiological tests for auditory system evaluations in hypothyroidism were included. A total of 2004 studies were found in the search, with 23 studies meeting the inclusion criteria. The pooled prevalence of hearing loss was 16.1% [95% confidence interval 10.7, 22.4] for children with congenital hypothyroidism. Hearing thresholds at pure-tone averages (0.5-2 kHz) were 1.6 dB [95% confidence interval 1.7, 4.8] higher for children with hypothyroidism compared to age-matched controls. Cochlear dysfunction was detected at middle frequencies (1-3 kHz) by otoacoustic emission testing, indicating abnormalities of hair cell function or cochlear integration. Retrocochlear involvement was detected on auditory brainstem response (ABR), with prolonged Wave I indicating a peripheral conduction abnormality localized to the middle or inner ear and eighth cranial nerve. Children with hypothyroidism have a higher prevalence of hearing loss than children without hypothyroidism. For children with congenital hypothyroidism, evidence of subclinical abnormalities at the level of the cochlea and eighth cranial nerve are present despite early initiation of levothyroxine therapy. Dysfunction of the auditory system might begin with predominance of peripheral conduction abnormalities early in development.

Synaptic Contributions to Cochlear Outer Hair Cell Ca2+ Dynamics.

For normal cochlear function, outer hair cells (OHCs) require a precise control of intracellular Ca2+ levels. In the absence of regulatory elements such as proteinaceous buffers or extrusion pumps, OHCs degenerate, leading to profound hearing impairment. Influx of Ca2+ occurs both at the stereocilia tips and the basolateral membrane. In this latter compartment, two different origins for Ca2+ influx have been poorly explored: voltage-gated L-type Ca2+ channels (VGCCs) at synapses with Type II afferent neurons, and α9α10 cholinergic nicotinic receptors at synapses with medio-olivochlear complex (MOC) neurons. Using functional imaging in mouse OHCs, we dissected Ca2+ influx individually through each of these sources, either by applying step depolarizations to activate VGCC, or stimulating MOC axons. Ca2+ ions originated in MOC synapses, but not by VGCC activation, was confined by Ca2+-ATPases most likely present in nearby synaptic cisterns. Although Ca2+ currents in OHCs are small, VGCC Ca2+ signals were comparable in size to those elicited by α9α10 receptors, and were potentiated by ryanodine receptors (RyRs). In contrast, no evidence of potentiation by RyRs was found for MOC Ca2+ signals over a wide range of presynaptic stimulation strengths. Our study shows that despite the fact that these two Ca2+ entry sites are closely positioned, they differ in their regulation by intracellular cisterns and/or organelles, suggesting the existence of well-tuned mechanisms to separate the two different OHC synaptic functions.SIGNIFICANCE STATEMENT Outer hair cells (OHCs) are sensory cells in the inner ear operating under very special constraints. Acoustic stimulation leads to fast changes both in membrane potential and in the intracellular concentration of metabolites such as Ca2+ Tight mechanisms for Ca2+ control in OHCs have been reported. Interestingly, Ca2+ is crucial for two important synaptic processes: inhibition by efferent cholinergic neurons, and glutamate release onto Type II afferent fibers. In the current study we functionally imaged Ca2+ at these two different synapses, showing close positioning within the basolateral compartment of OHCs. In addition, we show differential regulation of these two Ca2+ sources by synaptic cisterns and/or organelles, which could result crucial for functional segregation during normal hearing.

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors.

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca2+-permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca2+-impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro, and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

EFFECTS OF AGMATINE ON ACOUSTIC STARTLE REFLEX AND AUDITORY SYSTEM IN RATS

Background: A polyamine, agmatine, has been proposed as a new neurotransmitter in the brain. Objective: The aim of this study was to evaluate the effects of acute and chronic agmatine treatment on the rat auditory system. Methods: Male Wistar albino rats weighing between 280-330 grams were used. Animals were divided into four groups (n= 8 for each group). Acute and chronic agmatine (160 mg/kg) was administered to rats. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR), distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) were evaluated in all groups. Results: Both acute and chronic agmatine treatments also significantly disrupted PPI. Chronic but not acute treatment with agmatine produced some DPOAE and ABR changes in rats. Conclusion: Our results suggested that chronic agmatine treatment for seven days resulted in some significant negative changes in cochlear function. Because the PPI of the ASR is also used as an indicator for psychoses, such as schizophrenia, in human and experimental animal studies, our findings also imply that the DPOAE and ABR tests may also be considered in the diagnosis and follow-up of patients with psychoses.

Primed to die: an investigation of the genetic mechanisms underlying noise-induced hearing loss and cochlear damage in homozygous Foxo3-knockout mice

The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3+/−), and Foxo3 knock-out (Foxo3−/−) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and caspase-independent apoptosis. Lower immunoreactivity of the calcium buffer Oncomodulin in Foxo3−/− OHCs correlated with cell loss beginning 4 h post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3−/− mice that may contribute to OHC noise susceptibility. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. As LPA reduces OHC loss after severe noise exposure, we treated noise-exposed Foxo3−/− mice with exogenous LPA. LPA treatment delayed immediate damage to OHCs but was insufficient to ultimately prevent their death or prevent hearing loss. These results suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, possibly through sustaining endogenous LPA levels.

The Effect of Different Round Window Sealants on Cochlear Mechanics Over Time.

This project investigated the effects of round window membrane (RWM) sealants after surgical incision, with a focus on audiological thresholds, ossicular mechanics, and the impact upon cochlear function and pathology. Twenty-eight guinea pigs were randomly allocated to one of three sealant groups (muscle, n = 7; fascia, n = 7, Tisseel, n = 8) or an unsealed control group (n = 6). Preoperative hearing was measured using auditory brainstem responses (ABRs). The ossicular chain and RWM were exposed surgically, and Laser Doppler Vibrometry (LDV) measurements were obtained from the long process of the incus. The RWM was incised then sealed (or left unsealed) according to group. ABR testing and LDV measurements were repeated 4 and 12 weeks after surgery. At 12 weeks all cochleae were harvested. ABR thresholds deteriorated over time in all groups. Overall, group was not statistically significant (p = 0.064). There was no significant effect by group on LDV measurements (p = 0.798). Histopathological analyses of the RWM showed that the fascia group had more extensive fibrosis than other groups (Independent-Samples Median Test, p = 0.001). However, there were minimal differences in the outer hair cell counts between the different intervention groups. All the interventions appeared to be safe while none affected the cochlear mechanics or hearing thresholds in a statistically significant manner.