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Animal models suggest that cochlear afferent nerve endings may be more vulnerable than sensory hair cells to damage from acoustic overexposure and aging. Because neural degeneration without hair-cell loss cannot be detected in standard clinical audiometry, whether such damage occurs in humans is hotly debated. Here, we address this debate through co-ordinated experiments in at-risk humans and a wild-type chinchilla model. Cochlear neuropathy leads to large and sustained reductions of the wideband middle-ear muscle reflex in chinchillas. Analogously, human wideband reflex measures revealed distinct damage patterns in middle age, and in young individuals with histories of high acoustic exposure. Analysis of an independent large public dataset and additional measurements using clinical equipment corroborated the patterns revealed by our targeted cross-species experiments. Taken together, our results suggest that cochlear neural damage is widespread even in populations with clinically normal hearing.

Different cellular mechanisms contribute to the hearing sense, so it is obvious that any disruption in such processes leads to hearing impairment that greatly influences the global economy and quality of life of the patients and their relatives. In the past two decades, transmembrane inner ear (TMIE) protein has received a great deal of research interest because its impairments cause hereditary deafness in humans. This evolutionarily conserved membrane protein contributes to a fundamental complex that plays role in the maintenance and function of the sensory hair cells. Although the critical roles of the TMIE in mechanoelectrical transduction or hearing procedures have been discussed, there are little to no review papers summarizing the roles of the TMIE in the auditory system. In order to fill this gap, herein, we discuss the important roles of this protein in the auditory system including its role in mechanotransduction, olivocochlear synapse, morphology and different signalling pathways; we also review the genotype‐phenotype correlation that can per se show the possible roles of this protein in the auditory system.

International audience; We recognize sounds by analyzing their frequency content. Different frequency components evoke distinct mechanical waves that each travel within the hearing organ, or cochlea, to a frequency-specific place. These signals are detected by hair cells, the ear's sensory receptors, in response to vibrations of mechanically sensitive antennas termed hair bundles. An active process enhances the sensitivity, sharpens the frequency tuning, and broadens the dynamic range of hair cells through several mechanisms, including active hair-bundle motility. A dynamic interplay between negative stiffness mediated by ion channels' gating forces and delayed force feedback owing to myosin motors and channel reclosure by calcium ions brings the hair bundle to the vicinity of an oscillatory instability-a Hopf bifurcation. Operation near a Hopf bifurcation provides nonlinear generic features that are characteristic of hearing. Multiple gradients at molecular, cellular, and supercellular scales tune hair cells to characteristic frequencies that cover our auditory range.

Insects fall prey to the Venus flytrap (Dionaea muscipula) when they touch the sensory hairs located on the flytrap lobes, causing sudden trap closure. The mechanical stimulus imparted by the touch produces an electrical response in the sensory cells of the trigger hair. These cells are found in a constriction near the hair base, where a notch appears around the hair&rsquo, s periphery. There are mechanosensitive ion channels (MSCs) in the sensory cells that open due to a change in membrane tension, however, the kinematics behind this process is unclear. In this study, we investigate how the stimulus acts on the sensory cells by building a multi-scale hair model, using morphometric data obtained from &mu, CT scans. We simulated a single-touch stimulus and evaluated the resulting cell wall stretch. Interestingly, the model showed that high stretch values are diverted away from the notch periphery and, instead, localized in the interior regions of the cell wall. We repeated our simulations for different cell shape variants to elucidate how the morphology influences the location of these high-stretch regions. Our results suggest that there is likely a higher mechanotransduction activity in these &rsquo, hotspots&rsquo, which may provide new insights into the arrangement and functioning of MSCs in the flytrap.

Sensory hair cells of the inner ear are exposed to continuous mechanical stress, causing damage over time. The maintenance of hair cells is further challenged by damage from a variety of other ototoxic factors, including loud noise, aging, genetic defects, and ototoxic drugs. This damage can manifest in many forms, from dysfunction of the hair cell mechanotransduction complex to loss of specialized ribbon synapses, and may even result in hair cell death. Given that mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. Here, we discuss how several key hair cell structures can be damaged, and what is known about how they are repaired.

A high performance electronic hair (EH) sensor with multiple responsibilities is fabricated via fully mimicking the sensory hair cell structure and properties of human skin. The designed EH sensor consists of nylon fibers as hairs for mechanical signal amplification and polydimethylsiloxane (PDMS) resin as the human skin for sensor encapsulation. Two carbonized papers are used as piezo-resistive mechanoreceptors (M1 and M2). The nylon fibers used have a diameter and Young's modulus close to those of hairs and PDMS has a Young's modulus close to that of human skin. The structure of human hairs is verified to be optimal for maximizing the sensing ability, and the structure of the EH sensor is then optimized in terms of the structure of human hairs. Unlike conventional single-mode EH sensors, the EH sensor obtained by fully mimicking human skin is capable of detecting multiple signals of pressure, surface roughness, the airflow rate, etc. just like human skin. Moreover, the EH sensor is also effective in identifying the airflow direction. Because of its simple structure, low cost, good flexibility and multiple functionalities, the EH sensor is expected to find widespread application in e-skins, wearable devices, robotics, human machine interfaces, etc.

The sensory hairs of the Venus flytrap (Dionaea muscipula Ellis) detect mechanical stimuli imparted by their prey and fire bursts of electrical signals called action potentials (APs). APs are elicited when the hairs are sufficiently stimulated and two consecutive APs can trigger closure of the trap. Earlier experiments have identified thresholds for the relevant stimulus parameters, namely the angular displacement $$\theta $$ θ and angular velocity $$\omega $$ ω . However, these experiments could not trace the deformation of the trigger hair’s sensory cells, which are known to transduce the mechanical stimulus. To understand the kinematics at the cellular level, we investigate the role of two relevant mechanical phenomena: viscoelasticity and intercellular fluid transport using a multi-scale numerical model of the sensory hair. We hypothesize that the combined influence of these two phenomena and $$\omega $$ ω contribute to the flytrap’s rate-dependent response to stimuli. In this study, we firstly perform sustained deflection tests on the hair to estimate the viscoelastic material properties of the tissue. Thereafter, through simulations of hair deflection tests at different loading rates, we were able to establish a multi-scale kinematic link between $$\omega $$ ω and the cell wall stretch $$\delta $$ δ . Furthermore, we find that the rate at which $$\delta $$ δ evolves during a stimulus is also proportional to $$\omega $$ ω . This suggests that mechanosensitive ion channels, expected to be stretch-activated and localized in the plasma membrane of the sensory cells, could be additionally sensitive to the rate at which stretch is applied.

Insects fall prey to the Venus flytrap (Dionaea muscipula) when they touch the sensory hairs located on the flytrap lobes, causing sudden trap closure. The mechanical stimulus imparted by the touch produces an electrical response in the sensory cells of the trigger hair. These cells are found in a constriction near the hair base, where a notch appears around the hair’s periphery. There are mechanosensitive ion channels (MSCs) in the sensory cells that open due to a change in membrane tension; however, the kinematics behind this process is unclear. In this study, we investigate how the stimulus acts on the sensory cells by building a multi-scale hair model, using morphometric data obtained from μ-CT scans. We simulated a single-touch stimulus and evaluated the resulting cell wall stretch. Interestingly, the model showed that high stretch values are diverted away from the notch periphery and, instead, localized in the interior regions of the cell wall. We repeated our simulations for different cell shape variants to elucidate how the morphology influences the location of these high-stretch regions. Our results suggest that there is likely a higher mechanotransduction activity in these ’hotspots’, which may provide new insights into the arrangement and functioning of MSCs in the flytrap. Dataset: 10.3929/ethz-b-000448954

This research examined the impacts of acoustic stress in peled (Coregonus peled Gmelin, 1788), a species commonly cultivated in Russia. This study presents a comparative analysis of the macula sacculi and otoliths, as well as primary hematological and secondary telomere stress responses, in control and sound-exposed peled. The authors measured the effects of long-term (up to 18 days) exposure to a 300 Hz tone at mean sound pressure levels of 176–186 dB re 1 μPa (SPLpk–pk); the frequency and intensity were selected to approximate loud acoustic environments associated with cleaning equipment in aquaculture settings. Acoustic exposure resulted in ultrastructure changes to otoliths, morphological damage to sensory hair cells of the macula sacculi, and a gradual decrease in the number of functionally active mitochondria in the red blood cells but no changes to telomeres. Changes were apparent following at least ten days of acoustic exposure. These data suggest that acoustic exposure found in some aquaculture settings could cause stress responses and auditory damage to peled and, potentially, other commercially important species. Reducing sound levels in fish rearing facilities could contribute to the formation of effective aquaculture practices that mitigate noise-induced stress in fishes.

Decades-old model of slow adaptation in sensory hair cells of the auditory and vestibular systems requires revamp., Hair cells detect sound and motion through a mechano-electric transduction (MET) process mediated by tip links connecting shorter stereocilia to adjacent taller stereocilia. Adaptation is a key feature of MET that regulates a cell’s dynamic range and frequency selectivity. A decades-old hypothesis proposes that slow adaptation requires myosin motors to modulate the tip-link position on taller stereocilia. This “motor model” depended on data suggesting that the receptor current decay had a time course similar to that of hair-bundle creep (a continued movement in the direction of a step-like force stimulus). Using cochlear and vestibular hair cells of mice, rats, and gerbils, we assessed how modulating adaptation affected hair-bundle creep. Our results are consistent with slow adaptation requiring myosin motors. However, the hair-bundle creep and slow adaptation were uncorrelated, challenging a critical piece of evidence upholding the motor model. Considering these data, we propose a revised model of hair cell adaptation.

Sound intensity is encoded by auditory neuron subgroups that differ in thresholds and spontaneous rates. Whether variations in neuronal biophysics contributes to this functional diversity is unknown. Because intensity thresholds correlate with synaptic position on sensory hair cells, we combined patch clamping with fiber labeling in semi-intact cochlear preparations in neonatal rats from both sexes. The biophysical properties of auditory neurons vary in a striking spatial gradient with synaptic position. Neurons with high thresholds to injected currents contact hair cells at synaptic positions where neurons with high thresholds to sound-intensity are found in vivo. Alignment between in vitro and in vivo thresholds suggests that biophysical variability contributes to intensity coding. Biophysical gradients were evident at all ages examined, indicating that cell diversity emerges in early post-natal development and persists even after continued maturation. This stability enabled a remarkably successful model for predicting synaptic position based solely on biophysical properties.

Synopsis The lateral line of fishes and aquatic amphibians demonstrates robust regenerative capacity. Following selective ablation of sensory hair cells, subsets of surrounding supporting cells proliferate to repopulate the neuromast. This regenerative response restores lateral line mediated behaviors, although the time course of morphological regeneration does not always parallel functional recovery. Aquatic pollutants can negatively impact regeneration, suggesting that fishes in polluted environments may have compromised sensory input. This chapter examines ethological and biomedical studies of lateral line regeneration and highlights unanswered questions in both realms.

Analysis of mechanotransduction among ensembles of sensory hair cells in vivo is challenging in many species. To overcome this challenge, we used optical indicators to investigate mechanotransduction among collections of hair cells in intact zebrafish. Our imaging reveals a previously undiscovered disconnect between hair-cell mechanosensation and synaptic transmission. We show that saturating mechanical stimuli able to open mechanically gated channels are unexpectedly insufficient to evoke vesicle fusion in the majority of hair cells. Although synaptically silent, latent hair cells can be rapidly recruited after damage, demonstrating that they are synaptically competent. Therefore synaptically silent hair cells may be an important reserve that acts to maintain sensory function. Our results demonstrate a previously unidentified level of complexity in sculpting sensory transmission from the periphery., Hair cells of the inner ear are mechanosensors that detect sound, and synapse onto afferent neurons. Here, the authors used calcium imaging to find that not all hair cells are synaptically engaged, but after damage these silent cells are synaptically engaged.

The ear can be subdivided into three distinct parts, each with significantly distinct structural and functional differences, the outer, middle, and inner ear, the latter housing the specialized sensory hair cells that act as transducers. There are numerous manuscripts documenting the anatomical development of the inner, middle, and outer ear in humans, rodents, chick, and zebrafish, dating back to the early 20th Century, and these developmental processes of these components are further compared in a number of review articles (Anthwal & Thompson, ; Basch, Brown, Jen, & Groves, ; Sai & Ladher, ). This article presents a review of both pre- and postnatal development of the inner ear, discusses recent molecular genetic advances toward our understanding of hair cells responsible for the sensory functions of the inner ear. Finally, a survey of comparative ear biology is used to pull together our understanding of the species differences, similarities, and key time points of definitive organ development of the ear.

Hair cells mediating the senses of hearing and balance rely on active mechanisms for amplification of mechanical signals. In amphibians, hair cells exhibit spontaneous self-sustained mechanical oscillations of their hair bundles. We study the response of the mechanical oscillations to perturbation of the cell’s membrane potential in a model for hair bundle of bullfrog saccular hair cells. We identify bifurcation mechanism leading to mechanical oscillations using the membrane potential and the strength of fast adaptation as control parameters and then compute static and dynamic sensitivity of mechanical oscillations to voltage variations. We show that fast adaptation results in the static sensitivity of oscillating hair bundles in the range 0.1–0.2 nm/mV, consistent with recent experimental work. Predicted dynamic response of oscillating hair bundle to voltage variations is characterized by the values of sensitivity of up to 2 nm/mV, enhanced by the presence of fast adaptation.

Summary: Hypotonic stress causes the activation of swelling-activated nonselective cation channels (NSCCs), which leads to Ca2+-dependent regulatory volume decrease (RVD) and adaptive maintenance of the cell volume; however, the molecular identities of the osmosensitive NSCCs remain unclear. Here, we identified TMEM63B as an osmosensitive NSCC activated by hypotonic stress. TMEM63B is enriched in the inner ear sensory hair cells. Genetic deletion of TMEM63B results in necroptosis of outer hair cells (OHCs) and progressive hearing loss. Mechanistically, the TMEM63B channel mediates hypo-osmolarity-induced Ca2+ influx, which activates Ca2+-dependent K+ channels required for the maintenance of OHC morphology. These findings demonstrate that TMEM63B is an osmosensor of the mammalian inner ear and the long-sought cation channel mediating Ca2+-dependent RVD.

This paper proposes an acoustic frequency selective curtain composed of two membranes and periodically connected elastic pillars. This new architecture, which was inspired by the structure of sensory hair cells in human auditory system, generates a pass band at a certain frequency, and can be used as a curtain which allows only a specific sound pass through.

International audience; Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2 clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our indepth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.

The carnivorous Venus flytrap catches prey by an ingenious snapping mechanism. Based on work over the past 190 years, it has become generally accepted that two touches of the trap’s sensory hairs within 30 seconds, each one generating an action potential, are required to trigger closure of the trap. We developed an electromechanical model which, however, suggests that under certain circumstances one touch is sufficient to generate two action potentials. Using a force-sensing microrobotics system, we precisely quantified the sensory hair deflection parameters necessary to trigger trap closure, and correlated them with the elicited action potentials in vivo. Our results confirm the model’s predictions, suggesting that the Venus flytrap may be adapted to a wider range of prey movement than previously assumed.

Mutations in transmembrane inner ear (TMIE) cause deafness in humans; previous studies suggest involvement in the mechano-electrical transduction (MET) complex in sensory hair cells, but TMIE’s precise role is unclear. In tmie zebrafish mutants, we observed that GFP-tagged Tmc1 and Tmc2b, which are subunits of the MET channel, fail to target to the hair bundle. In contrast, overexpression of Tmie strongly enhances the targeting of Tmc1-GFP and Tmc2b-GFP to stereocilia. To identify the motifs of Tmie underlying the regulation of the Tmcs, we systematically deleted or replaced peptide segments. We then assessed localization and functional rescue of each mutated/chimeric form of Tmie in tmie mutants. We determined that the first putative helix was dispensable and identified a novel critical region of Tmie, the extracellular region and transmembrane domain, which is required for both mechanosensitivity and Tmc2b-GFP expression in bundles. Collectively, our results suggest that Tmie’s role in sensory hair cells is to target and stabilize Tmc channel subunits to the site of MET., Author summary Hair cells mediate hearing and balance through the activity of a mechanosensitive channel in the cell membrane. The transmembrane inner ear (TMIE) protein is an essential component of the protein complex that gates this so-called mechanotransduction channel. While it is known that loss of TMIE results in deafness, the function of TMIE within the complex is unclear. Using zebrafish as a deafness model, Pacentine and Nicolson demonstrate that Tmie is required for the localization of the channel subunits, transmembrane channel-like (Tmc) proteins Tmc1/2b. They then evaluate thirteen unique versions of Tmie, each containing mutations in different domains of Tmie. This analysis reveals that specific mutated versions of Tmie reduce hair cell activity, and that these same dysfunctional versions also cause reduced Tmc expression at the normal site of the channel. These findings link hair cell activity with the levels of Tmc in the bundle, reinforcing the notion that the Tmcs are the pore-forming subunits of the mechanotransduction channel. The authors conclude that Tmie, through distinct regions, is involved in both trafficking and stabilizing the channels at the site of mechanotransduction.

Normal hearing and synaptic transmission at afferent auditory inner hair cell (IHC) synapses require otoferlin. Deafness DFNB9, caused by mutations in the OTOF gene encoding otoferlin, might be treated by transferring wild‐type otoferlin cDNA into IHCs, which is difficult due to the large size of this transgene. In this study, we generated two adeno‐associated viruses (AAVs), each containing half of the otoferlin cDNA. Co‐injecting these dual‐AAV2/6 half‐vectors into the cochleae of 6‐ to 7‐day‐old otoferlin knock‐out (Otof −/−) mice led to the expression of full‐length otoferlin in up to 50% of IHCs. In the cochlea, otoferlin was selectively expressed in auditory hair cells. Dual‐AAV transduction of Otof −/− IHCs fully restored fast exocytosis, while otoferlin‐dependent vesicle replenishment reached 35–50% of wild‐type levels. The loss of 40% of synaptic ribbons in these IHCs could not be prevented, indicating a role of otoferlin in early synapse maturation. Acoustic clicks evoked auditory brainstem responses with thresholds of 40–60 dB. Therefore, we propose that gene delivery mediated by dual‐AAV vectors might be suitable to treat deafness forms caused by mutations in large genes such as OTOF.

This invited talk introduces how extraordinary acoustic transmission plays an important role to detect sounds in human hearing system. This new approach from engineering point of view is totally different from that of V. Bekesy's traveling wave theory which has been widely accepted up to today. To elucidate human hearing mechanism, we focus on architecture of sensory hair cells. That is, the wall of the cell has three-layered structure consisting of plasma membrane, cortical lattice, and subsurface cisternae. Our theoretical study indicates that the plasma membrane and cortical lattice form an extraordinary acoustic transmission system to detect sounds with extremely high resolution and sensitivity, and subsurface cisternae works as a sound reflector to protect DNA in nucleus against damages caused by higher sound pressures for resonance.

Sensory hair cells are highly specialized cells that form the basis for our senses of hearing, orientation to gravity, and perception of linear acceleration (head translation in space) and angular acceleration (head rotation). In many species of fish and aquatic amphibians, hair cells mediate perception of water movement through the lateral line system, and electroreceptors derived from hair cell precursors mediate electric field detection. In tunicates, cells of the mechanosensory coronal organ on the incurrent siphon meet the structural, functional, and developmental criteria to be described as hair cells, and they function to deflect large particles from entering the animal. The past two decades have witnessed significant breakthroughs in our understanding of hair cell biology and how their specialized structures influence their functions. This symposium combines the approaches of developmental biology, evolutionary biology, and physiology to share the gains of recent research in understanding hair cell function in different model systems. We brought together researchers working on sensory hair cells in organisms spanning the chordates in order to examine the depth and breadth of hair cell evolution. It is clear that these specialized cells serve a range of functions in different animals, due to evolutionary tinkering with a basic specialized cell type. This collection of papers will serve to mark the progress that has been made in this field and also stimulate the next wave of progress in this exciting field.

Sensory hair cells are specialized secondary sensory cells that mediate our senses of hearing, balance, linear acceleration, and angular acceleration (head rotation). In addition, hair cells in fish and amphibians mediate sensitivity to water movement through the lateral line system, and closely related electroreceptive cells mediate sensitivity to low-voltage electric fields in the aquatic environment of many fish species and several species of amphibian. Sensory hair cells share many structural and functional features across all vertebrate groups, while at the same time they are specialized for employment in a wide variety of sensory tasks. The complexity of hair cell structure is large, and the diversity of hair cell applications in sensory systems exceeds that seen for most, if not all, sensory cell types. The intent of this review is to summarize the more significant structural features and some of the more interesting and important physiological mechanisms that have been elucidated thus far. Outside vertebrates, hair cells are only known to exist in the coronal organ of tunicates. Electrical resonance, electromotility, and their exquisite mechanical sensitivity all contribute to the attractiveness of hair cells as a research subject.

The ant Ondontomuchus kuroiwae has a trap jaw that snaps quickly to capture a prey. The ant opens the trap jaw, locks it and closes quickly if it detects a prey using a sensory hair on the jaw. We here analyze 3-dimensional structure of the trap jaw muscles by using a micro volume imaging with an X-ray micro-computed tomography (micro-CT) to elucidate the mechanism of the exoskeletal muscular system to realize ultra-high speed movement of the trap jaw.

Otoconia are bio-crystals which couple mechanic forces to the sensory hair cells in the utricle and saccule, a process essential for us to sense linear acceleration and gravity for the purpose of maintaining bodily balance. In fish, structurally similar bio-crystals called otoliths mediate both balance and hearing. Otoconia abnormalities are common and can cause vertigo and imbalance in humans. However, the molecular etiology of these illnesses is unknown, as investigators have only begun to identify genes important for otoconia formation in recent years. To date, in-depth studies of selected mouse otoconial proteins have been performed, and about 75 zebrafish genes have been identified to be important for otolith development. This review will summarize recent findings as well as compare otoconia and otolith development. It will provide an updated brief review of otoconial proteins along with an overview of the cells and cellular processes involved. While continued efforts are needed to thoroughly understand the molecular mechanisms underlying otoconia and otolith development, it is clear that the process involves a series of temporally and spatially specific events that are tightly coordinated by numerous proteins. Such knowledge will serve as the foundation to uncover the molecular causes of human otoconia-related disorders.