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Otology & Neurotology Open Mar 2023Proteins enriched in the perilymph proteome of Meńier̀e disease (MD) patients may identify affected cell types. Utilizing single-cell transcriptome datasets from the...
HYPOTHESIS
Proteins enriched in the perilymph proteome of Meńier̀e disease (MD) patients may identify affected cell types. Utilizing single-cell transcriptome datasets from the mammalian cochlea, we hypothesize that these enriched perilymph proteins can be localized to specific cochlear cell types.
BACKGROUND
The limited understanding of human inner ear pathologies and their associated biomolecular variations hinder efforts to develop disease-specific diagnostics and therapeutics. Perilymph sampling and analysis is now enabling further characterization of the cochlear microenvironment. Recently, enriched inner ear protein expression has been demonstrated in patients with MD compared to patients with other inner ear diseases. Localizing expression of these proteins to cochlear cell types can further our knowledge of potential disease pathways and subsequent development of targeted therapeutics.
METHODS
We compiled previously published data regarding differential perilymph proteome profiles amongst patients with MD, otosclerosis, enlarged vestibular aqueduct, sudden hearing loss, and hearing loss of undefined etiology (controls). Enriched proteins in MD were cross-referenced against published single-cell/single-nucleus RNA-sequencing datasets to localize gene expression to specific cochlear cell types.
RESULTS
In silico analysis of single-cell transcriptomic datasets demonstrates enrichment of a unique group of perilymph proteins associated with MD in a variety of intracochlear cells, and some exogeneous hematologic and immune effector cells. This suggests that these cell types may play an important role in the pathology associated with late MD, suggesting potential future areas of investigation for MD pathophysiology and treatment.
CONCLUSIONS
Perilymph proteins enriched in MD are expressed by specific cochlear cell types based on in silico localization, potentially facilitating development of disease-specific diagnostic markers and therapeutics.
PubMed: 38516320
DOI: 10.1097/ONO.0000000000000027 -
Cell Death & Disease Mar 2024Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of mA modifications in various...
Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of mA modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3-knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA mA methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of mA-modified PSEN1, while decreased METTL3-mediated mA methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.
Topics: Animals; beta Catenin; Methylation; Methyltransferases; RNA, Messenger; Wnt Signaling Pathway; Zebrafish; Presenilin-1; Zebrafish Proteins
PubMed: 38509077
DOI: 10.1038/s41419-024-06606-9 -
Journal of Cellular and Molecular... Apr 2024Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research...
Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1β. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.
Topics: Animals; Mice; Cisplatin; NF-E2-Related Factor 2; Reactive Oxygen Species; Antioxidants; Ferroptosis; Apoptosis; Hearing Loss; Anti-Inflammatory Agents; Succinates
PubMed: 38506087
DOI: 10.1111/jcmm.18207 -
Fish and Fisheries (Oxford, England) Jul 2023Ernst Weber stated in 1819, based on dissections, that the swimbladder in the European wels (, Siluridae) and related cyprinids serves as an eardrum and that the...
Ernst Weber stated in 1819, based on dissections, that the swimbladder in the European wels (, Siluridae) and related cyprinids serves as an eardrum and that the ossicles connecting it to the inner ear function as hearing ossicles similar to mammals. In the early 20th century, K. von Frisch showed experimentally that catfishes and cyprinids (otophysines) indeed hear excellently compared to fish taxa lacking auxiliary hearing structures (ossicles, eardrums). Knowledge on hearing in catfishes progressed in particular in the 21st century. Currently, hearing abilities (audiograms) are known in 28 species out of 13 families. Recent ontogenetic and comparative studies revealed that the ability to detect sounds of low-level and high frequencies (4-6 kHz) depends on the development of Weberian ossicles. Species with a higher number of ossicles and larger bladders hear better at higher frequencies (>1 kHz). Hearing sensitivities are furthermore affected by ecological factors. Rising temperatures increase, whereas various noise regimes decrease hearing. Exposure to high-noise levels (>150 dB) for hours result in temporary thresholds shifts (TTS) and recovery of hearing after several days. Low-noise levels reduce hearing abilities due to masking without a TTS. Furthermore, auditory evoked potential (AEP) experiments reveal that the temporal patterns of fish-produced pulsed stridulation and drumming sounds are represented in their auditory pathways, indicating that catfishes are able to extract important information for acoustic communication. Further research should concentrate on inner ears to determine whether the diversity in swimbladders and ossicles is paralleled in the inner ear fine structure.
PubMed: 38505404
DOI: 10.1111/faf.12751 -
European Neuropsychopharmacology : the... Jun 2024Trait anxiety is a well-established risk factor for anxiety and depressive disorders, yet its neural correlates are not clearly understood. In this study, we...
Trait anxiety is a well-established risk factor for anxiety and depressive disorders, yet its neural correlates are not clearly understood. In this study, we investigated the neural correlates of trait anxiety in a large sample (n = 179) of individuals who completed the trait and state versions of the State-Trait Anxiety Inventory and underwent resting-state functional magnetic resonance imaging. We used independent component analysis to characterize individual resting-state networks (RSNs), and multiple regression analyses to assess the relationship between trait anxiety and intrinsic connectivity. Trait anxiety was significantly associated with intrinsic connectivity in different regions of three RSNs (dorsal attention network, default mode network, and auditory network) when controlling for state anxiety. These RSNs primarily support attentional processes. Notably, when state anxiety was not controlled for, a different pattern of results emerged, highlighting the importance of considering this factor in assessing the neural correlates of trait anxiety. Our findings suggest that trait anxiety is uniquely associated with resting-state brain connectivity in networks mainly supporting attentional processes. Moreover, controlling for state anxiety is crucial when assessing the neural correlates of trait anxiety. These insights may help refine current neurobiological models of anxiety and identify potential targets for neurobiologically-based interventions.
Topics: Humans; Male; Female; Magnetic Resonance Imaging; Anxiety; Attention; Adult; Young Adult; Brain; Nerve Net; Brain Mapping; Adolescent; Neural Pathways
PubMed: 38492550
DOI: 10.1016/j.euroneuro.2024.02.013 -
Scientific Reports Mar 2024Electrically evoked frequency-following responses (eFFRs) provide insight in the phase-locking ability of brainstem of cochlear-implant (CI) users. eFFRs can potentially...
Electrically evoked frequency-following responses (eFFRs) provide insight in the phase-locking ability of brainstem of cochlear-implant (CI) users. eFFRs can potentially be used to gain insight in the individual differences in the biological limitation on temporal encoding of the electrically stimulated auditory pathway, which can be inherent to the electrical stimulation itself and/or the degenerative processes associated with hearing loss. One of the major challenge of measuring eFFRs in CI users is the process of isolating the stimulation artifact from the neural response, as both the response and the artifact overlap in time and have similar frequency characteristics. Here we introduce a new artifact removal method based on template subtraction that successfully removes the stimulation artifacts from the recordings when CI users are stimulated with pulse trains from 128 to 300 pulses per second in a monopolar configuration. Our results show that, although artifact removal was successful in all CI users, the phase-locking ability of the brainstem to the different pulse rates, as assessed with the eFFR differed substantially across participants. These results show that the eFFR can be measured, free from artifacts, in CI users and that they can be used to gain insight in individual differences in temporal processing of the electrically stimulated auditory pathway.
Topics: Humans; Evoked Potentials, Auditory; Cochlear Implants; Cochlear Implantation; Deafness; Hearing Loss; Electric Stimulation
PubMed: 38486005
DOI: 10.1038/s41598-024-56047-9 -
PloS One 2024Salidroside (SAL) is a phenol glycoside compound found in plants of the Rhodiola genus which has natural antioxidant and free radical scavenging properties. SAL are able...
Therapeutic potential of salidroside in preserving rat cochlea organ of corti from gentamicin-induced injury through modulation of NRF2 signaling and GSK3β/NF-κB pathway.
Salidroside (SAL) is a phenol glycoside compound found in plants of the Rhodiola genus which has natural antioxidant and free radical scavenging properties. SAL are able to protect against manganese-induced ototoxicity. However, the molecular mechanism by which SAL reduces levels of reactive oxygen species (ROS) is unclear. Here, we established an in vitro gentamicin (GM) ototoxicity model to observe the protective effect of SAL on GM-induced hair cells (HC) damage. Cochlear explants of postnatal day 4 rats were obtained and randomly divided into six groups: two model groups (treatment with 0.2 mM or 0.4 mM GM for 24 h); two 400 μmol/L SAL-pretreated groups pretreatment with SAL for 3 h followed by GM treatment (0.2 mM or 0.4 mM) for 24 h; 400 μmol/L SAL group (treatment with SAL for 24 h); control group (normal cultured cochlear explants). The protective effects of SAL on GM-induced HC damage, and on mRNA and protein levels of antioxidant enzymes were observed. HC loss occurred after 24 h of GM treatment. Pretreatment with SAL significantly reduced GM-induced OHC loss. In cochlear tissues, mRNA and protein levels of NRF2 and HO-1 were enhanced in the GM alone group compared with the SAL pretreatment GM treatment group. SAL may protect against GM-induced ototoxicity by regulating the antioxidant defense system of cochlear tissues; SAL can activate NRF2/HO-1 signaling, inhibit NF-κB activation, activate AKT, and increase inhibitory phosphorylation of GSK3β to decrease GSK3 activity, all of which exert antioxidant effects.
Topics: Rats; Animals; Gentamicins; NF-kappa B; Antioxidants; NF-E2-Related Factor 2; Glycogen Synthase Kinase 3 beta; Ototoxicity; Glycogen Synthase Kinase 3; Hair Cells, Auditory; Cochlea; Phenols; RNA, Messenger; Glucosides
PubMed: 38483863
DOI: 10.1371/journal.pone.0298529 -
International Journal of Molecular... Feb 2024In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea...
In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea via specialized ribbon synapses. Auditory nerve fibers of different physiological types differ subtly in their synaptic location and morphology. Low-spontaneous-rate auditory nerve fibers typically connect on the modiolar side of the inner hair cell, while high-spontaneous-rate fibers are typically found on the pillar side. In aging and noise-damaged ears, this fine-tuned balance between auditory nerve fiber populations can be disrupted and the functional consequences are currently unclear. Here, using immunofluorescent labeling of presynaptic ribbons and postsynaptic glutamate receptor patches, we investigated changes in synaptic morphology at three different tonotopic locations along the cochlea of aging gerbils compared to those of young adults. Quiet-aged gerbils showed about 20% loss of afferent ribbon synapses. While the loss was random at apical, low-frequency cochlear locations, at the basal, high-frequency location it almost exclusively affected the modiolar-located synapses. The subtle differences in volumes of pre- and postsynaptic elements located on the inner hair cell's modiolar versus pillar side were unaffected by age. This is consistent with known physiology and suggests a predominant, age-related loss in the low-spontaneous-rate auditory nerve population in the cochlear base, but not the apex.
Topics: Animals; Gerbillinae; Cochlea; Synapses; Cochlear Nerve; Hair Cells, Auditory, Inner
PubMed: 38473985
DOI: 10.3390/ijms25052738 -
International Journal of Molecular... Feb 2024Congenital cytomegalovirus (CMV) infection is the main cause of non-hereditary sensorineural hearing loss (SNHL). In order to shed light on SNHL pathophysiology, we...
Congenital cytomegalovirus (CMV) infection is the main cause of non-hereditary sensorineural hearing loss (SNHL). In order to shed light on SNHL pathophysiology, we examined the auditory pathway in CMV-infected fetuses; the temporal lobe, in particular the auditory cortex, and the inner ear. We investigated both inner ears and temporal lobes of 20 human CMV-infected fetuses at 21 weeks of gestation. As a negative group, five fetuses from spontaneous miscarriages without CMV infection were studied. Inner ears and temporal lobes were histologically examined, immunohistochemistry for CMV and CMV-PCR were performed. On the auditory cortex, we evaluated the local microglial reaction to the infection. CMV-positive cells were found in 14/20 brains and the damage was classified as severe, moderate, or mild, according to histological features. Fetuses with severe brain damage had a statistically higher temporal lobe viral load and a higher number of activated microglial cells in the auditory cortex compared to fetuses with mild brain damage (: 0.01; : 0.01). In the inner ears, the marginal cells of the stria vascularis were the most CMV positive. In our study, CMV affected the auditory pathway, suggesting a tropism for this route. In addition, in the auditory cortex, microglial activation may favor further tissue damage contributing to hearing loss.
Topics: Humans; Cytomegalovirus; Auditory Pathways; Cytomegalovirus Infections; Hearing Loss, Sensorineural; Fetus
PubMed: 38473883
DOI: 10.3390/ijms25052636 -
ENeuro Mar 2024Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds...
Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium, NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recorded in vivo awake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly in females. Behaviorally, we trained birds using operant conditioning and tested their ability to detect songs in scenes after administering FAD orally or injected bilaterally into NCM. Oral FAD increased response bias and decreased correct rejections in females, but not in males. FAD in NCM did not affect performance. Thus, FAD in the NCM impaired neuronal ASA but that did not lead to behavioral disruption suggesting the existence of resilience or compensatory responses. Moreover, impaired performance after systemic FAD suggests involvement of other aromatase-rich networks outside the auditory pathway in ASA. This work highlights how transient estrogen synthesis disruption can modulate higher-order processing in an animal model of vocal communication.
Topics: Female; Animals; Male; Finches; Aromatase; Reproducibility of Results; Vocalization, Animal; Acoustic Stimulation; Auditory Pathways; Auditory Perception; Auditory Cortex
PubMed: 38467426
DOI: 10.1523/ENEURO.0423-23.2024