Implication of Vestibular Hair Cell Loss of Planar Polarity for the Canal and Otolith-Dependent Vestibulo-Ocular Reflexes in Celsr1–/– Mice

Introduction: Vestibular sensory hair cells are precisely orientated according to planar cell polarity (PCP) and are key to enable mechanic-electrical transduction and normal vestibular function. PCP is found on different scales in the vestibular organs, ranging from correct hair bundle orientation, coordination of hair cell orientation with neighboring hair cells, and orientation around the striola in otolithic organs. Celsr1 is a PCP protein and a Celsr1 KO mouse model showed hair cell disorganization in all vestibular organs, especially in the canalar ampullae. The objective of this work was to assess to what extent the different vestibulo-ocular reflexes were impaired in Celsr1 KO mice.Methods: Vestibular function was analyzed using non-invasive video-oculography. Semicircular canal function was assessed during sinusoidal rotation and during angular velocity steps. Otolithic function (mainly utricular) was assessed during off-vertical axis rotation (OVAR) and during static and dynamic head tilts.Results: The vestibulo-ocular reflex of 10 Celsr1 KO and 10 control littermates was analyzed. All KO mice presented with spontaneous nystagmus or gaze instability in dark. Canalar function was reduced almost by half in KO mice. Compared to control mice, KO mice had reduced angular VOR gain in all tested frequencies (0.2–1.5 Hz), and abnormal phase at 0.2 and 0.5 Hz. Concerning horizontal steps, KO mice had reduced responses. Otolithic function was reduced by about a third in KO mice. Static ocular-counter roll gain and OVAR bias were both significantly reduced. These results demonstrate that canal- and otolith-dependent vestibulo-ocular reflexes are impaired in KO mice.Conclusion: The major ampullar disorganization led to an important reduction but not to a complete loss of angular coding capacities. Mildly disorganized otolithic hair cells were associated with a significant loss of otolith-dependent function. These results suggest that the highly organized polarization of otolithic hair cells is a critical factor for the accurate encoding of the head movement and that the loss of a small fraction of the otolithic hair cells in pathological conditions is likely to have major functional consequences. Altogether, these results shed light on how partial loss of vestibular information encoding, as often encountered in pathological situations, translates into functional deficits.

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 Ca2+ transients in both auditory and vestibular organs during the first postnatal week before the onset of hearing. We recorded long lasting (>200 ms) Ca2+ transients in cochlear and vestibular support cells in neonatal mice using the genetic calcium indicator GCaMP5. Both cochlear and vestibular support cells exhibited spontaneous intracellular Ca2+ transients (GCaMP5 ΔF/F), in some cases propagating as waves from the apical (endolymph facing) to the basolateral surface with a speed of ∼25 μm per second, consistent with inositol trisphosphate dependent calcium induced calcium release (CICR). Acetylcholine evoked Ca2+ transients were observed in both inner border cells in the cochlea and vestibular support cells, with a larger change in GCaMP5 fluorescence in the vestibular support cells. Adenosine triphosphate evoked robust Ca2+ transients predominantly in the cochlear support cells that included Hensen’s cells, Deiters’ cells, inner hair cells, inner phalangeal cells and inner border cells. A Ca2+ event initiated in one inner border cells propagated in some instances longitudinally to neighboring inner border cells with an intercellular speed of ∼2 μm per second, and decayed after propagating along ∼3 cells. Similar intercellular propagation was not observed in the radial direction from inner border cell to inner sulcus cells, and was not observed between adjacent vestibular support cells.

The History of Research in Vestibular Organ and Benign Paroxysmal Positional Vertigo

Since B.C., vertigo had been described as a condition closely related to migraines or epilepsy. This perception remained during the 14th-16th century and vertigo was considered to be a symptom of brain disease. Until the 18th century, the perception remained that the vestibular organ would be in charge of hearing. However, during the 19th century, it was understood that the sense of equilibrium and vertigo might have been related to vestibular organs. Barany first mentioned positional vertigo and otolithic disease in 1921, and Dix and Hallpike defined their clinical characteristics in 1952. After studies from numerous otologists and neurologists, including Schuknecht and Epley, which identified benign paroxysmal positional vertigo (BPPV) has emerged as one of today’s most common diseases. The development of various test methods enabled more detailed diagnosis of BPPV. The treatment performance also improved significantly as various canalith repositioning procedures were introduced.

A gradient of Wnt activity positions the neurosensory domains of the inner ear

The auditory and vestibular organs of the inner ear and the neurons that innervate them originate from Sox2-positive and Notch-active neurosensory domains specified at early stages of otic development. Sox2 is initially present throughout the otic placode and otocyst, and then it becomes progressively restricted to a ventro-medial domain. Using gain- and loss-of-function approaches in the chicken otocyst, we show that these early changes in Sox2 expression are regulated in a dose-dependent manner by Wnt/beta-catenin signalling. Both high and very low levels of Wnt activity repress Sox2 and neurosensory competence. However, intermediate levels allow the maintenance of Sox2 expression and sensory organ formation. We propose that a dorso-ventral (high-to-low) gradient and wave of Wnt activity initiated at the dorsal rim of the otic placode progressively restricts Sox2 and Notch activity to the ventral half of the otocyst, thereby positioning the neurosensory competent domains in the inner ear.

El tiempo de tránsito del pulso detecta cambios en la presión arterial en respuesta a estimulación eléctrica vestibular y cambio de postura

The interaction of the vestibular organs with the cardiovascular system is a relevant research field with clinical applications that contribute to the understanding of cardiovascular modulation due to movement and posture. The current noninvasive measurement of blood pressure (BP) consists of an inflatable cuff that is unsuitable to perform movement tasks. However, Pulse-Transit Time (PTT), an indirect method that estimates BP from electrocardiographic (ECG) and photoplethysmographic (PPG) recordings, may detect BP variations during dynamic experiments. Galvanic vestibular stimulation (GVS) is considered an analog to mechanical stimulation. Research with GVS has been done involving static and dynamic tasks. Our study aims to determine if PTT is a suitable method to be included in GVS experiments to detect BP modulation. PTT was calculated from 16 healthy subjects during GVS; stimulation was applied while seated and standing. PTT increased during the stimulation period in both positions. The increase was statistically significant only for subjects standing. These findings are following previous GVS studies that monitor BP invasively in animal models. As we expected, an increase in PTT during GVS was observed. Additionally, the increase was slightly different for subjects seated and standing. Overall, results indicate that PTT is an effective method to estimate transient BP changes during GVS.

Endolymphatic Potential Measured From Developing and Adult Mouse Inner Ear

The mammalian inner ear has two major parts, the cochlea is responsible for hearing and the vestibular organ is responsible for balance. The cochlea and vestibular organs are connected by a series of canals in the temporal bone and two distinct extracellular fluids, endolymph and perilymph, fill different compartments of the inner ear. Stereocilia of mechanosensitive hair cells in the cochlea and vestibular end organs are bathed in the endolymph, which contains high K+ ions and possesses a positive potential termed endolymphatic potential (ELP). Compartmentalization of the fluids provides an electrochemical gradient for hair cell mechanotransduction. In this study, we measured ELP from adult and neonatal C57BL/6J mice to determine how ELP varies and develops in the cochlear and vestibular endolymph. We measured ELP and vestibular microphonic response from saccules of neonatal mice to determine when vestibular function is mature. We show that ELP varies considerably in the cochlear and vestibular endolymph of adult mice, ranging from +95 mV in the basal turn to +87 mV in the apical turn of the cochlea, +9 mV in the saccule and utricle, and +3 mV in the semicircular canal. This suggests that ELP is indeed a local potential, despite the fact that endolymph composition is similar. We further show that vestibular ELP reaches adult-like magnitude around post-natal day 6, ~12 days earlier than maturation of cochlear ELP (i.e., endocochlear potential). Maturation of vestibular ELP coincides with the maturation of vestibular microphonic response recorded from the saccular macula, suggesting that maturation of vestibular function occurs much earlier than maturation of hearing in mice.

Why There Is a Vestibular Sense, or How Metacognition Individuates the Senses

Should the vestibular system be counted as a sense? This basic conceptual question remains surprisingly controversial. While it is possible to distinguish specific vestibular organs, it is not clear that this suffices to identify a genuine vestibular sense because of the supposed absence of a distinctive vestibular personal-level manifestation. The vestibular organs instead contribute to more general multisensory representations, whose name still suggest that they have a distinct ‘sensory’ contribution. The vestibular case shows a good example of the challenge of individuating the senses when multisensory interactions are the norm, neurally, representationally and phenomenally. Here, we propose that an additional metacognitive criterion can be used to single out a distinct sense, besides the existence of specific organs and despite the fact that the information coming from these organs is integrated with other sensory information. We argue that it is possible for human perceivers to monitor information coming from distinct organs, despite their integration, as exhibited and measured through metacognitive performance. Based on the vestibular case, we suggest that metacognitive awareness of the information coming from sensory organs constitutes a new criterion to individuate a sense through both physiological and personal criteria. This new way of individuating the senses accommodates both the specialised nature of sensory receptors as well as the intricate multisensory aspect of neural processes and experience, while maintaining the idea that each sense contributes something special to how we monitor the world and ourselves, at the subjective level.