Contributions of the individual domains of αβ integrin to its extension: Insights from multiscale modeling.

The platelet integrin αβ undergoes long-range conformational transitions between bent and extended conformations to regulate platelet aggregation during hemostasis and thrombosis. However, how exactly αβ transitions between conformations remains largely elusive. Here, we studied how transitions across bent and extended-closed conformations of αβ integrin are regulated by effective interactions between its functional domains.

Evidence That Ultrafast Nonquantal Transmission Underlies Synchronized Vestibular Action Potential Generation.

Amniotes evolved a unique postsynaptic terminal in the inner ear vestibular organs called the calyx that receives both quantal and nonquantal (NQ) synaptic inputs from Type I sensory hair cells. The nonquantal synaptic current includes an ultrafast component that has been hypothesized to underlie the exceptionally high synchronization index (vector strength) of vestibular afferent neurons in response to sound and vibration. Here, we present three lines of evidence supporting the hypothesis that nonquantal transmission is responsible for synchronized vestibular action potentials of short latency in the guinea pig utricle of either sex.

Stem cell-derived brain organoids for controlled studies of transcranial neuromodulation.

Transcranial neuromodulation methods have the potential to diagnose and treat brain disorders at their neural source in a personalized manner. However, it has been difficult to investigate the direct effects of transcranial neuromodulation on neurons in human brain tissue. Here, we show that human brain organoids provide a detailed and artifact-free window into neuromodulation-evoked electrophysiological effects.

Using macular velocity measurements to relate parameters of bone conduction to vestibular compound action potential responses.

To examine mechanisms responsible for vestibular afferent sensitivity to transient bone conducted vibration, we performed simultaneous measurements of stimulus-evoked vestibular compound action potentials (vCAPs), utricular macula velocity, and vestibular microphonics (VMs) in anaesthetized guinea pigs. Results provide new insights into the kinematic variables of transient motion responsible for triggering mammalian vCAPs, revealing synchronized vestibular afferent responses are not universally sensitive to linear jerk as previously thought. For short duration stimuli (< 1 ms), the vCAP increases magnitude in close proportion to macular velocity and temporal bone (linear) acceleration, rather than other kinematic elements.

A mathematical model for mechanical activation and compound action potential generation by the utricle in response to sound and vibration.

Introduction: Calyx bearing vestibular afferent neurons innervating type I hair cells in the striolar region of the utricle are exquisitely sensitive to auditory-frequency air conducted sound (ACS) and bone conducted vibration (BCV). Here, we present experimental data and a mathematical model of utricular mechanics and vestibular compound action potential generation (vCAP) in response to clinically relevant levels of ACS and BCV. Vibration of the otoconial layer relative to the sensory epithelium was simulated using a Newtonian two-degree-of-freedom spring-mass-damper system, action potential timing was simulated using an empirical model, and vCAPs were simulated by convolving responses of the population of sensitive neurons with an empirical extracellular voltage kernel.

A parametric blueprint for optimum cochlear outer hair cell design.

The present work examines the hypothesis that cochlear outer hair cell (OHC) properties vary in precise proportions along the tonotopic map to optimize electromechanical power conversion. We tested this hypothesis using a very simple model of a single isolated OHC driving a mechanical load. Results identify three non-dimensional ratios that are predicted to optimize power conversion: the ratio of the resistive-capacitive (RC) corner to the characteristic frequency (CF), the ratio of nonlinear to linear capacitance and the ratio of OHC stiffness to cochlear load stiffness.

Otolith Membrane Herniation, not Semicircular Canal Duct Dilation, Is Associated with Decreased Caloric Responses in Ménière's Disease.

Ménière's disease (MD) is a debilitating disorder with unclear pathophysiology whose diagnosis often relies on clinical judgment rather than objective testing. To complicate matters further, a dissociation has emerged between two vestibular function tests commonly used in patients with MD to examine the same end-organ (the semicircular canals): the caloric test and video head impulse testing (vHIT). Caloric responses are often abnormal, while vHIT results remain normal.

Analysis of outer hair cell electromechanics reveals power delivery at the upper-frequency limits of hearing.

Outer hair cells are the cellular motors in the mammalian inner ear responsible for sensitive high-frequency hearing. Motor function over the frequency range of human hearing requires expression of the protein prestin in the OHC lateral membrane, which imparts piezoelectric properties to the cell membrane. In the present report, electrical power consumption and mechanical power output of the OHC membrane-motor complex are determined using previously published voltage-clamp data from isolated OHCs and membrane patches.

Differential Activation of Canal and Otolith Afferents by Acoustic Tone Bursts in Rats.

Vestibular evoked myogenic potentials (VEMPs) are routinely used to test otolith function, but which specific vestibular afferent neurons and central circuits are activated by auditory frequency VEMP stimuli remains unclear. To examine this question, we analyzed the sensitivity of individual vestibular afferents in adult Sprague-Dawley rats to tone bursts delivered at 9 frequencies (125-4000 Hz) and 3 intensity levels (60, 70, 80 dB SL re: acoustic brainstem response (ABR) threshold). Afferent neuron tone sensitivity was quantified by the cumulative probability of evoking a spike (CPE).

ATP and ACh Evoked Calcium Transients in the Neonatal Mouse Cochlear and Vestibular Sensory Epithelia.

Hair cells in the mammalian inner ear sensory epithelia are surrounded by supporting cells which are essential for function of cochlear and vestibular systems. In mice, support cells exhibit spontaneous intracellular Ca transients in both auditory and vestibular organs during the first postnatal week before the onset of hearing. We recorded long lasting (>200 ms) Ca transients in cochlear and vestibular support cells in neonatal mice using the genetic calcium indicator GCaMP5.

Biomechanics of Third Window Syndrome.

Third window syndrome describes a set of vestibular and auditory symptoms that arise when a pathological third mobile window is present in the bony labyrinth of the inner ear. The pathological mobile window (or windows) adds to the oval and round windows, disrupting normal auditory and vestibular function by altering biomechanics of the inner ear. The most commonly occurring third window syndrome arises from superior semicircular canal dehiscence (SSCD), where a section of bone overlying the superior semicircular canal is absent or thinned (near-dehiscence).

The cochlear outer hair cell speed paradox.

Cochlear outer hair cells (OHCs) are among the fastest known biological motors and are essential for high-frequency hearing in mammals. It is commonly hypothesized that OHCs amplify vibrations in the cochlea through cycle-by-cycle changes in length, but recent data suggest OHCs are low-pass filtered and unable to follow high-frequency signals. The fact that OHCs are required for high-frequency hearing but appear to be throttled by slow electromotility is the "OHC speed paradox.

Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris.

Sense of motion, spatial orientation, and balance in vertebrates relies on sensory hair cells in the inner ear vestibular system. Vestibular supporting cells can regenerate hair cells that are lost from aging, ototoxicity, and trauma, although not all factors or specific cell types are known. Here we report a population of GAD2-positive cells in the mouse crista ampullaris and trace GAD2 progenitor-like cells that express pluripotent transcription factors SOX2, PROX1, and CTBP2.

Cooperativity of K7.4 channels confers ultrafast electromechanical sensitivity and emergent properties in cochlear outer hair cells.

The mammalian cochlea relies on active electromotility of outer hair cells (OHCs) to resolve sound frequencies. OHCs use ionic channels and somatic electromotility to achieve the process. It is unclear, though, how the kinetics of voltage-gated ionic channels operate to overcome extrinsic viscous drag on OHCs at high frequency.

Spontaneous and Acetylcholine Evoked Calcium Transients in the Developing Mouse Utricle.

Spontaneous calcium transients are present during early postnatal development in the mouse retina and cochlea, and play an important role in maturation of the sensory organs and neural circuits in the central nervous system (CNS). It is not known whether similar calcium transients occur during postnatal development in the vestibular sensory organs. Here we demonstrate spontaneous intracellular calcium transients in sensory hair cells (HCs) and supporting cells (SCs) in the murine utricular macula during the first two postnatal weeks.

Semicircular canal biomechanics in health and disease.

The semicircular canals are responsible for sensing angular head motion in three-dimensional space and for providing neural inputs to the central nervous system (CNS) essential for agile mobility, stable vision, and autonomic control of the cardiovascular and other gravity-sensitive systems. Sensation relies on fluid mechanics within the labyrinth to selectively convert angular head acceleration into sensory hair bundle displacements in each of three inner ear sensory organs. Canal afferent neurons encode the direction and time course of head movements over a broad range of movement frequencies and amplitudes.

Sound abnormally stimulates the vestibular system in canal dehiscence syndrome by generating pathological fluid-mechanical waves.

Individuals suffering from Tullio phenomena experience dizziness, vertigo, and reflexive eye movements (nystagmus) when exposed to seemingly benign acoustic stimuli. The most common cause is a defect in the bone enclosing the vestibular semicircular canals of the inner ear. Surgical repair often corrects the problem, but the precise mechanisms underlying Tullio phenomenon are not known.

Endothiodon cf. bathystoma (Synapsida: Dicynodontia) bony labyrinth anatomy, variation and body mass estimates.

The semicircular canal (SC) system of the inner ear detects head angular accelerations and is essential for navigation and spatial awareness in vertebrates. Because the bony labyrinth encloses the membranous labyrinth SCs, it can be used as a proxy for animal behavior. The bony labyrinth of dicynodonts, a clade of herbivorous non-mammalian synapsids, has only been described in a handful of individuals and remains particularly obscure.

ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells.

In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) it increases background afferent discharge and 2) decreases afferent sensitivity to rotational stimuli. Although the cellular mechanisms underlying these two contrasting afferent responses remain obscure, we postulated that the reduction in afferent sensitivity was attributed, in part, to the activation of α9- containing nicotinic acetylcholine (ACh) receptors (α9*nAChRs) and small-conductance potassium channels (SK) in vestibular type II hair cells, as demonstrated in the peripheral vestibular system of other vertebrates. To test this hypothesis, we examined the effects of the predominant EVS neurotransmitter ACh on vestibular type II hair cells from wild-type (wt) and α9-subunit nAChR knockout (α9) mice.

Wave Mechanics of the Vestibular Semicircular Canals.

The semicircular canals are biomechanical sensors responsible for detecting and encoding angular motion of the head in 3D space. Canal afferent neurons provide essential inputs to neural circuits responsible for representation of self-position/orientation in space, and to compensatory circuits including the vestibulo-ocular and vestibulo-collic reflex arcs. In this work we derive, to our knowledge, a new 1D mathematical model quantifying canal biomechanics based on the morphology, dynamics of the inner ear fluids, and membranous labyrinth deformability.

Low-intensity ultrasound activates vestibular otolith organs through acoustic radiation force.

The present study examined the efficacy of 5 MHz low-intensity focused ultrasound (LiFU) as a stimulus to remotely activate inner ear vestibular otolith organs. The otolith organs are the primary sensory apparati responsible for detecting orientation of the head relative to gravity and linear acceleration in three-dimensional space. These organs also respond to loud sounds and vibration of the temporal bone.

BODIPY-Conjugated Xyloside Primes Fluorescent Glycosaminoglycans in the Inner Ear of Opsanus tau.

We report on a new xyloside conjugated to BODIPY, BX and its utility to prime fluorescent glycosaminoglycans (BX-GAGs) within the inner ear in vivo. When BX is administered directly into the endolymphatic space of the oyster toadfish (Opsanus tau) inner ear, fluorescent BX-GAGs are primed and become visible in the sensory epithelia of the semicircular canals, utricle, and saccule. Confocal and 2-photon microscopy of vestibular organs fixed 4 h following BX treatment, reveal BX-GAGs constituting glycocalyces that envelop hair cell kinocilium, nerve fibers, and capillaries.

Heat pulse excitability of vestibular hair cells and afferent neurons.

In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (ΔT ≈ 0.25°C per pulse).