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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 -
Medicina (Kaunas, Lithuania) Nov 2023There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur... (Review)
Review
There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.
Topics: Humans; Neurobiology; Polyphenols; Cochlea; Aging; Deafness
PubMed: 38004094
DOI: 10.3390/medicina59112045 -
International Journal of Molecular... Nov 2023Tinnitus is the perception of noise in the absence of acoustic stimulation (phantom noise). In most patients suffering from chronic peripheral tinnitus, an alteration of... (Review)
Review
Tinnitus is the perception of noise in the absence of acoustic stimulation (phantom noise). In most patients suffering from chronic peripheral tinnitus, an alteration of outer hair cells (OHC) starting from the stereocilia (SC) occurs. This is common following ototoxic drugs, sound-induced ototoxicity, and acoustic degeneration. In all these conditions, altered coupling between the tectorial membrane (TM) and OHC SC is described. The present review analyzes the complex interactions involving OHC and TM. These need to be clarified to understand which mechanisms may underlie the onset of tinnitus and why the neuropathology of chronic degenerative tinnitus is similar, independent of early triggers. In fact, the fine neuropathology of tinnitus features altered mechanisms of mechanic-electrical transduction (MET) at the level of OHC SC. The appropriate coupling between OHC SC and TM strongly depends on autophagy. The involvement of autophagy may encompass degenerative and genetic tinnitus, as well as ototoxic drugs and acoustic trauma. Defective autophagy explains mitochondrial alterations and altered protein handling within OHC and TM. This is relevant for developing novel treatments that stimulate autophagy without carrying the burden of severe side effects. Specific phytochemicals, such as curcumin and berberin, acting as autophagy activators, may mitigate the neuropathology of tinnitus.
Topics: Humans; Tinnitus; Hair Cells, Auditory, Outer; Stereocilia; Sound; Acoustic Stimulation
PubMed: 38068993
DOI: 10.3390/ijms242316664 -
Communications Biology Jun 2023The human auditory system is designed to capture and encode sounds from our surroundings and conspecifics. However, the precise mechanisms by which it adaptively...
The human auditory system is designed to capture and encode sounds from our surroundings and conspecifics. However, the precise mechanisms by which it adaptively extracts the most important spectro-temporal information from sounds are still not fully understood. Previous auditory models have explained sound encoding at the cochlear level using static filter banks, but this vision is incompatible with the nonlinear and adaptive properties of the auditory system. Here we propose an approach that considers the cochlear processes as envelope interpolations inspired by cochlear physiology. It unifies linear and nonlinear adaptive behaviors into a single comprehensive framework that provides a data-driven understanding of auditory coding. It allows simulating a broad range of psychophysical phenomena from virtual pitches and combination tones to consonance and dissonance of harmonic sounds. It further predicts the properties of the cochlear filters such as frequency selectivity. Here we propose a possible link between the parameters of the model and the density of hair cells on the basilar membrane. Cascaded Envelope Interpolation may lead to improvements in sound processing for hearing aids by providing a non-linear, data-driven, way to preprocessing of acoustic signals consistent with peripheral processes.
Topics: Humans; Hearing; Cochlea; Sound; Basilar Membrane
PubMed: 37355702
DOI: 10.1038/s42003-023-05040-5