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Environmental Research Dec 2023Meniere's disease (MD) is a severe inner ear condition known by debilitating symptoms, including spontaneous vertigo, fluctuating and progressive hearing loss, tinnitus,... (Review)
Review
Meniere's disease (MD) is a severe inner ear condition known by debilitating symptoms, including spontaneous vertigo, fluctuating and progressive hearing loss, tinnitus, and aural fullness or pressure within the affected ear. Prosper Meniere first described the origins of MD in the 1860s, but its underlying mechanisms remain largely elusive today. Nevertheless, researchers have identified a key histopathological feature called Endolymphatic Hydrops (ELH), which refers to the excessive buildup of endolymph fluid in the membranous labyrinth of the inner ear. The exact root of ELH is not fully understood. Still, it is believed to involve several biological and bioenvironmental etiological factors such as genetics, autoimmunity, infection, trauma, allergy, and new theories, such as saccular otoconia blocking the endolymphatic duct and sac. Regarding treatment, there are no reliable and definitive cures for MD. Most therapies focus on managing symptoms and improving the overall quality of patients' life. To make significant advancements in addressing MD, it is crucial to gain a fundamental understanding of the disease process, laying the groundwork for more effective therapeutic approaches. This paper provides a comprehensive review of the pathophysiology of MD with a focus on old and recent theories. Current treatment strategies and future translational approaches (with low-level evidence but promising results) related to MD are also discussed, including patents, drug delivery, and nanotechnology, that may provide future benefits to patients suffering from MD.
Topics: Humans; Meniere Disease; Endolymphatic Hydrops; Otolithic Membrane
PubMed: 37648189
DOI: 10.1016/j.envres.2023.116972 -
Proceedings of the National Academy of... Jun 2023The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional...
The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional network governing cochlear late-stage maturation and particularly the differentiation of its lateral nonsensory region. Here, we establish ZBTB20 as an essential transcription factor required for cochlear terminal differentiation and maturation and hearing. ZBTB20 is abundantly expressed in the developing and mature cochlear nonsensory epithelial cells, with transient expression in immature hair cells and spiral ganglion neurons. Otocyst-specific deletion of causes profound deafness with reduced endolymph potential in mice. The subtypes of cochlear epithelial cells are normally generated, but their postnatal development is arrested in the absence of ZBTB20, as manifested by an immature appearance of the organ of Corti, malformation of tectorial membrane (TM), a flattened spiral prominence (SP), and a lack of identifiable Boettcher cells. Furthermore, these defects are related with a failure in the terminal differentiation of the nonsensory epithelium covering the outer border Claudius cells, outer sulcus root cells, and SP epithelial cells. Transcriptome analysis shows that ZBTB20 regulates genes encoding for TM proteins in the greater epithelial ridge, and those preferentially expressed in root cells and SP epithelium. Our results point to ZBTB20 as an essential regulator for postnatal cochlear maturation and particularly for the terminal differentiation of cochlear lateral nonsensory domain.
Topics: Animals; Mice; Cochlea; Hair Cells, Auditory; Hearing; Mammals; Spiral Ganglion; Transcription Factors
PubMed: 37279265
DOI: 10.1073/pnas.2220867120 -
BMC Medical Genomics Jun 2023The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular...
BACKGROUND
The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular contributions of specific cell types remain poorly characterized. Therefore, we aimed to identify pH regulators in pendrin-expressing cells that may contribute to the homeostasis of endolymph pH and define the cellular pathogenic mechanisms that contribute to the dysregulation of cochlear endolymph pH in Slc26a4 mice.
METHODS
We used single-cell RNA sequencing to identify both Slc26a4-expressing cells and Kcnj10-expressing cells in wild-type (WT, Slc26a4) and Slc26a4 mice. Bioinformatic analysis of expression data confirmed marker genes defining the different cell types of the stria vascularis. In addition, specific findings were confirmed at the protein level by immunofluorescence.
RESULTS
We found that spindle cells, which express pendrin, contain extrinsic cellular components, a factor that enables cell-to-cell communication. In addition, the gene expression profile informed the pH of the spindle cells. Compared to WT, the transcriptional profiles in Slc26a4 mice showed downregulation of extracellular exosome-related genes in spindle cells. Immunofluorescence studies in spindle cells of Slc26a4 mice validated the increased expression of the exosome-related protein, annexin A1, and the clathrin-mediated endocytosis-related protein, adaptor protein 2.
CONCLUSION
Overall, cell isolation of stria vascularis from WT and Slc26a4 samples combined with cell type-specific transcriptomic analyses revealed pH-dependent alternations in spindle cells and intermediate cells, inspiring further studies into the dysfunctional role of stria vascularis cells in SLC26A4-related hearing loss.
Topics: Mice; Animals; Stria Vascularis; Anion Transport Proteins; Cochlea; Deafness; Sulfate Transporters; RNA
PubMed: 37322474
DOI: 10.1186/s12920-023-01549-0 -
Magnetic Resonance in Medical Sciences... Apr 2024The endolymph of the inner ear, vital for balance and hearing, has long been considered impermeable to intravenously administered gadolinium-based contrast agents...
PURPOSE
The endolymph of the inner ear, vital for balance and hearing, has long been considered impermeable to intravenously administered gadolinium-based contrast agents (GBCAs) due to the tight blood-endolymph barrier. However, anecdotal observations suggested potential GBCA entry in delayed heavily T2-weighted 3D-real inversion recovery (IR) MRI scans. This study systematically investigated GBCA distribution in the endolymph using this 3D-real IR sequence.
METHODS
Forty-one patients suspected of endolymphatic hydrops (EHs) underwent pre-contrast, 4-h, and 24-h post-contrast 3D-real IR imaging. Signal intensity in cerebrospinal fluid (CSF), perilymph, and endolymph was measured and analyzed for temporal dynamics of GBCA uptake, correlations between compartments, and the influence of age and presence of EH.
RESULTS
Endolymph showed a delayed peak GBCA uptake at 24h, contrasting with peaks in perilymph and CSF at 4h. Weak to moderate positive correlations between endolymph and CSF contrast effect were observed at both 4 (r = 0.483) and 24h (r = 0.585), suggesting possible inter-compartmental interactions. Neither the presence of EH nor age significantly influenced endolymph enhancement. However, both perilymph and CSF contrast effects significantly correlated with age at both time points.
CONCLUSION
This study provides the first in vivo systematic confirmation of GBCA entering the endolymph following intravenous administration. Notably, endolymph uptake peaked at 24h, significantly later than perilymph and CSF. The lack of a link between endolymph contrast and both perilymph and age suggests distinct uptake mechanisms. These findings shed light on inner ear fluid dynamics and their potential implications in Ménière's disease and other inner ear disorders.
PubMed: 38569839
DOI: 10.2463/mrms.mp.2024-0011 -
Frontiers in Neurology 2023Vestibular loss and dysfunction has been associated with cognitive deficits, decreased spatial navigation, spatial memory, visuospatial ability, attention, executive...
BACKGROUND
Vestibular loss and dysfunction has been associated with cognitive deficits, decreased spatial navigation, spatial memory, visuospatial ability, attention, executive function, and processing speed among others. Superior semicircular canal dehiscence (SSCD) is a vestibular-cochlear disorder in humans in which a pathological third mobile window of the otic capsule creates changes to the flow of sound pressure energy through the perilymph/endolymph. The primary symptoms include sound-induced dizziness/vertigo, inner ear conductive hearing loss, autophony, headaches, and visual problems; however, individuals also experience measurable deficits in basic decision-making, short-term memory, concentration, spatial cognition, and depression. These suggest central mechanisms of impairment are associated with vestibular disorders; therefore, we directly tested this hypothesis using both an auditory and visual decision-making task of varying difficulty levels in our model of SSCD.
METHODS
Adult Mongolian gerbils ( = 33) were trained on one of four versions of a Go-NoGo stimulus presentation rate discrimination task that included standard ("easy") or more difficult ("hard") auditory and visual stimuli. After 10 days of training, preoperative ABR and c+VEMP testing was followed by a surgical fenestration of the left superior semicircular canal. Animals with persistent circling or head tilt were excluded to minimize effects from acute vestibular injury. Testing recommenced at postoperative day 5 and continued through postoperative day 15 at which point final ABR and c+VEMP testing was carried out.
RESULTS
Behavioral data (d-primes) were compared between preoperative performance (training day 8-10) and postoperative days 6-8 and 13-15. Behavioral performance was measured during the peak of SSCD induced ABR and c + VEMP impairment and the return towards baseline as the dehiscence began to resurface by osteoneogenesis. There were significant differences in behavioral performance (d-prime) and its behavioral components (Hits, Misses, False Alarms, and Correct Rejections). These changes were highly correlated with persistent deficits in c + VEMPs at the end of training (postoperative day 15). The controls demonstrated additional learning post procedure that was absent in the SSCD group.
CONCLUSION
These results suggest that aberrant asymmetric vestibular output results in decision-making impairments in these discrimination tasks and could be associated with the other cognitive impairments resulting from vestibular dysfunction.
PubMed: 37905188
DOI: 10.3389/fneur.2023.1259030