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Proceedings of the National Academy of... Jun 2023Functional molecular characterization of the cochlea has mainly been driven by the deciphering of the genetic architecture of sensorineural deafness. As a result, the...
Functional molecular characterization of the cochlea has mainly been driven by the deciphering of the genetic architecture of sensorineural deafness. As a result, the search for curative treatments, which are sorely lacking in the hearing field, has become a potentially achievable objective, particularly cochlear gene and cell therapies. To this end, a complete inventory of cochlear cell types, with an in-depth characterization of their gene expression profiles right up to their final differentiation, is indispensable. We therefore generated a single-cell transcriptomic atlas of the mouse cochlea based on an analysis of more than 120,000 cells on postnatal day 8 (P8), during the prehearing period, P12, corresponding to hearing onset, and P20, when cochlear maturation is almost complete. By combining whole-cell and nuclear transcript analyses with extensive in situ RNA hybridization assays, we characterized the transcriptomic signatures covering nearly all cochlear cell types and developed cell type-specific markers. Three cell types were discovered; two of them contribute to the modiolus which houses the primary auditory neurons and blood vessels, and the third one consists in cells lining the scala vestibuli. The results also shed light on the molecular basis of the tonotopic gradient of the biophysical characteristics of the basilar membrane that critically underlies cochlear passive sound frequency analysis. Finally, overlooked expression of deafness genes in several cochlear cell types was also unveiled. This atlas paves the way for the deciphering of the gene regulatory networks controlling cochlear cell differentiation and maturation, essential for the development of effective targeted treatments.
Topics: Animals; Mice; Transcriptome; Cochlea; Basilar Membrane; Hearing; Deafness
PubMed: 37339214
DOI: 10.1073/pnas.2221744120 -
Journal of the Association For Research... Oct 2014The mouse has become an important animal model in understanding cochlear function. Structures, such as the tectorial membrane or hair cells, have been changed by gene...
The mouse has become an important animal model in understanding cochlear function. Structures, such as the tectorial membrane or hair cells, have been changed by gene manipulation, and the resulting effect on cochlear function has been studied. To contrast those findings, physical properties of the basilar membrane (BM) and tectorial membrane (TM) in mice without gene mutation are of great importance. Using the hemicochlea of CBA/CaJ mice, we have demonstrated that tectorial membrane (TM) and basilar membrane (BM) revealed a stiffness gradient along the cochlea. While a simple spring mass resonator predicts the change in the characteristic frequency of the BM, the spring mass model does not predict the frequency change along the TM. Plateau stiffness values of the TM were 0.6 ± 0.5, 0.2 ± 0.1, and 0.09 ± 0.09 N/m for the basal, middle, and upper turns, respectively. The BM plateau stiffness values were 3.7 ± 2.2, 1.2 ± 1.2, and 0.5 ± 0.5 N/m for the basal, middle, and upper turns, respectively. Estimations of the TM Young's modulus (in kPa) revealed 24.3 ± 25.2 for the basal turns, 5.1 ± 4.5 for the middle turns, and 1.9 ± 1.6 for the apical turns. Young's modulus determined at the BM pectinate zone was 76.8 ± 72, 23.9 ± 30.6, and 9.4 ± 6.2 kPa for the basal, middle, and apical turns, respectively. The reported stiffness values of the CBA/CaJ mouse TM and BM provide basic data for the physical properties of its organ of Corti.
Topics: Animals; Basilar Membrane; Biomechanical Phenomena; Guinea Pigs; Mice; Mice, Inbred CBA; Tectorial Membrane
PubMed: 24865766
DOI: 10.1007/s10162-014-0463-y -
Hearing Research Mar 2018The motion along the basilar membrane in the cochlea is due to the interaction between the micromechanical behaviour of the organ of Corti and the fluid movement in the... (Review)
Review
The motion along the basilar membrane in the cochlea is due to the interaction between the micromechanical behaviour of the organ of Corti and the fluid movement in the scalae. By dividing the length of the cochlea into a finite number of elements and assuming a given radial distribution of the basilar membrane motion for each element, a set of equations can be separately derived for the micromechanics and for the fluid coupling. These equations can then be combined, using matrix methods, to give the fully coupled response. This elemental approach reduces to the classical transmission line model if the micromechanics are assumed to be locally-reacting and the fluid coupling is assumed to be entirely one-dimensional, but is also valid without these assumptions. The elemental model is most easily formulated in the frequency domain, assuming quasi-linear behaviour, but a time domain formulation, using state space method, can readily incorporate local nonlinearities in the micromechanics. Examples of programs are included for the elemental model of a human cochlea that can be readily modified for other species.
Topics: Acoustic Stimulation; Auditory Pathways; Cochlea; Computer Simulation; Finite Element Analysis; Hearing; Humans; Hydrodynamics; Models, Theoretical; Motion; Sound; Time Factors
PubMed: 29174619
DOI: 10.1016/j.heares.2017.10.013 -
Cold Spring Harbor Perspectives in... Jun 2019This review summarizes paleontological data as well as studies on the morphology, function, and molecular evolution of the cochlea of living mammals (monotremes,... (Review)
Review
This review summarizes paleontological data as well as studies on the morphology, function, and molecular evolution of the cochlea of living mammals (monotremes, marsupials, and placentals). The most parsimonious scenario is an early evolution of the characteristic organ of Corti, with inner and outer hair cells and nascent electromotility. Most remaining unique features, such as loss of the lagenar macula, coiling of the cochlea, and bony laminae supporting the basilar membrane, arose later, after the separation of the monotreme lineage, but before marsupial and placental mammals diverged. The question of when hearing sensitivity first extended into the ultrasonic range (defined here as >20 kHz) remains speculative, not least because of the late appearance of the definitive mammalian middle ear. The last significant change was optimizing the operating voltage range of prestin, and thus the efficiency of the outer hair cells' amplifying action, in the placental lineage only.
Topics: Animals; Biological Evolution; Cochlea; Hair Cells, Auditory, Outer; Humans; Mammals; Microscopy, Electron, Scanning; Monotremata
PubMed: 30181353
DOI: 10.1101/cshperspect.a033241 -
BioMed Research International 2014The cochlea plays a crucial role in mammal hearing. The basic function of the cochlea is to map sounds of different frequencies onto corresponding characteristic... (Review)
Review
The cochlea plays a crucial role in mammal hearing. The basic function of the cochlea is to map sounds of different frequencies onto corresponding characteristic positions on the basilar membrane (BM). Sounds enter the fluid-filled cochlea and cause deflection of the BM due to pressure differences between the cochlear fluid chambers. These deflections travel along the cochlea, increasing in amplitude, until a frequency-dependent characteristic position and then decay away rapidly. The hair cells can detect these deflections and encode them as neural signals. Modelling the mechanics of the cochlea is of help in interpreting experimental observations and also can provide predictions of the results of experiments that cannot currently be performed due to technical limitations. This paper focuses on reviewing the numerical modelling of the mechanical and electrical processes in the cochlea, which include fluid coupling, micromechanics, the cochlear amplifier, nonlinearity, and electrical coupling.
Topics: Basilar Membrane; Biomechanical Phenomena; Hair Cells, Auditory; Hearing; Humans; Models, Biological
PubMed: 25136555
DOI: 10.1155/2014/150637 -
Frontiers in Cellular Neuroscience 2023Age-related hearing loss (ARHL) is the most common sensory degenerative disease and can significantly impact the quality of life in elderly people. A previous study...
Age-related hearing loss (ARHL) is the most common sensory degenerative disease and can significantly impact the quality of life in elderly people. A previous study using GeneChip miRNA microarray assays showed that the expression of miR-29a changes with age, however, its role in hearing loss is still unclear. In this study, we characterized the cochlear phenotype of miR-29a knockout () mice and found that miR-29a-deficient mice had a rapid progressive elevation of the hearing threshold from 2 to 5 months of age compared with littermate controls as measured by the auditory brainstem response. Stereocilia degeneration, hair cell loss and abnormal stria vascularis (SV) were observed in mice at 4 months of age. Transcriptome sequencing results showed elevated extracellular matrix (ECM) gene expression in mice. Both Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the key differences were closely related to ECM. Further examination with a transmission electron microscope showed thickening of the basilar membrane in the cochlea of mice. Five Col4a genes () and two laminin genes () were validated as miR-29a direct targets by dual luciferase assays and miR-29a inhibition assays with a miR-29a inhibitor. Consistent with the target gene validation results, the expression of these genes was significantly increased in the cochlea of mice, as shown by RT-PCR and Western blot. These findings suggest that miR-29a plays an important role in maintaining cochlear structure and function by regulating the expression of collagen and laminin and that the disturbance of its expression could be a cause of progressive hearing loss.
PubMed: 37275774
DOI: 10.3389/fncel.2023.1191740 -
Proceedings of the National Academy of... Aug 2016It is commonly believed that the exceptional sensitivity of mammalian hearing depends on outer hair cells which generate forces for amplifying sound-induced basilar...
It is commonly believed that the exceptional sensitivity of mammalian hearing depends on outer hair cells which generate forces for amplifying sound-induced basilar membrane vibrations, yet how cellular forces amplify vibrations is poorly understood. In this study, by measuring subnanometer vibrations directly from the reticular lamina at the apical ends of outer hair cells and from the basilar membrane using a custom-built heterodyne low-coherence interferometer, we demonstrate in living mouse cochleae that the sound-induced reticular lamina vibration is substantially larger than the basilar membrane vibration not only at the best frequency but surprisingly also at low frequencies. The phase relation of reticular lamina to basilar membrane vibration changes with frequency by up to 180 degrees from ∼135 degrees at low frequencies to ∼-45 degrees at the best frequency. The magnitude and phase differences between reticular lamina and basilar membrane vibrations are absent in postmortem cochleae. These results indicate that outer hair cells do not amplify the basilar membrane vibration directly through a local feedback as commonly expected; instead, they actively vibrate the reticular lamina over a broad frequency range. The outer hair cell-driven reticular lamina vibration collaboratively interacts with the basilar membrane traveling wave primarily through the cochlear fluid, which boosts peak responses at the best-frequency location and consequently enhances hearing sensitivity and frequency selectivity.
Topics: Acoustic Stimulation; Animals; Basement Membrane; Basilar Membrane; Cochlea; Female; Hair Cells, Auditory, Outer; Hearing; Interferometry; Male; Mechanotransduction, Cellular; Mice, Inbred CBA; Sound; Vibration
PubMed: 27516544
DOI: 10.1073/pnas.1607428113 -
ELife Sep 2018Auditory sensory outer hair cells are thought to amplify sound-induced basilar membrane vibration through a feedback mechanism to enhance hearing sensitivity. For...
Auditory sensory outer hair cells are thought to amplify sound-induced basilar membrane vibration through a feedback mechanism to enhance hearing sensitivity. For optimal amplification, the outer hair cell-generated force must act on the basilar membrane at an appropriate time at every cycle. However, the temporal relationship between the outer hair cell-driven reticular lamina vibration and the basilar membrane vibration remains unclear. By measuring sub-nanometer vibrations directly from outer hair cells using a custom-built heterodyne low-coherence interferometer, we demonstrate in living gerbil cochleae that the reticular lamina vibration occurs after, not before, the basilar membrane vibration. Both tone- and click-induced responses indicate that the reticular lamina and basilar membrane vibrate in opposite directions at the cochlear base and they oscillate in phase near the best-frequency location. Our results suggest that outer hair cells enhance hearing sensitivity through a global hydromechanical mechanism, rather than through a local mechanical feedback as commonly supposed.
Topics: Animals; Basilar Membrane; Cochlea; Female; Gerbillinae; Male; Postmortem Changes; Sound; Time Factors; Vibration
PubMed: 30183615
DOI: 10.7554/eLife.37625