Angular vestibuloocular reflex responses in Otop1 mice. II. Otolith sensor input improves compensation after unilateral labyrinthectomy

Abstract

The role of the otoliths in mammals in the normal angular vestibuloocular reflex (VOR) was characterized in an accompanying study based on the Otopetrin1 (Otop1) mouse, which lacks functioning otoliths because of failure to develop otoconia but seems to have otherwise normal peripheral anatomy and neural circuitry. That study showed that otoliths do not contribute to the normal horizontal (rotation about Earth-vertical axis parallel to dorso-ventral axis) and vertical (rotation about Earth-vertical axis parallel to interaural axis) angular VOR but do affect gravity context-specific VOR adaptation. By using these animals, we sought to determine whether the otoliths play a role in the angular VOR after unilateral labyrinthectomy when the total canal signal is reduced. In five Otop1 mice and five control littermates we measured horizontal and vertical left-ear-down and right-ear-down sinusoidal VOR (0.2–10 Hz, 20–100°/s) during the early (3–5 days) and plateau (28–32 days) phases of compensation after unilateral labyrinthectomy and compared these measurements with baseline preoperative responses from the accompanying study. From similar baselines, acute gain loss was ~25% less in control mice, and chronic gain recovery was ~40% more in control mice. The acute data suggest that the otoliths contribute to the angular VOR when there is a loss of canal function. The chronic data suggest that a unilateral otolith signal can significantly improve angular VOR compensation. These data have implications for vestibular rehabilitation of patients with both canal and otolith loss and the development of vestibular implants, which currently only mimic the canals on one side. NEW & NOTEWORTHY This is the first study examining the role of the otoliths (defined here as the utricle and saccule) on the acute and chronic angular vestibuloocular reflex (VOR) after unilateral labyrinthectomy in an animal model in which the otoliths are reliably inactivated and the semicircular canals preserved. This study shows that the otolith signal is used to augment the acute angular VOR and help boost VOR compensation after peripheral injury.

Improvement After Vestibular Rehabilitation Not Explained by Improved Passive VOR Gain

“…Our data is the first behavioral evidence to show correlations between improved DVA (putative semicircular canal function) and preserved otolith function (smaller magnitude asymmetry ratio) as measured by ocular and cervical VEMP. It has recently been shown that labyrinthectomized mice also missing otolith function (otopetrin 1), are unable to adapt their angular VOR gain as well as healthy mice (45). Our data support the murine evidence that otolith function does appear to have a critical role in compensation to semicircular canal damage.…”

The Growing Evidence for the Importance of the Otoliths in Spatial Memory

“…Although the otoliths do not encode angular acceleration themselves, they are known to be important in velocity storage (e.g., Angelaki et al, 1992; Koizuka et al, 1996; Mittelstaedt and Mittelstaedt, 1996; Wearne et al, 1999). Recent studies using Otop1 mice show that although the otoliths do not appear to contribute to the baseline angular velocity of the VOR in mice, they are necessary for its adaptation to changes in gravitational stimulation (Khan et al, 2019a, b). As Shinder and Taube (2014) noted, the fact that the otoliths are known to be important for HD cell firing, suggests that linear acceleration information from the otoliths and rotational acceleration information from the semi-circular canals, must converge by the time they reach the thalamus.…”

“…Het–/– mice exhibit a complete and specific loss of utricular and saccular otoconia (Bergstrom et al, 1998). Another model is the –/–; B6.Cg- Otop1tlt/j tilted mouse (Jackson Laboratories, Bar Harbor, ME; Jones et al, 2008; Kim et al, 2010), which exhibits a similar deletion of the otoliths (de Caprona et al, 2004; Blankenship et al, 2017; Khan et al, 2019a, b).…”

Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists

“…The crude product was purified by reverse phase HPLC (H 2 O/acetonitrile 10 to 90%) to afford the title compound 8 as a white solid (374.6 mg, 1.26 mmol, 60%). General Procedure B: N-(1-((3,5-Dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-hydroxybenzamide (19). The amine hydrochloride 6 (227 mg, 1.0 mmol), 3-hydroxybenzoic acid (138 mg, 1.0 mmol), PyBop (624 mg, 1.2 mmol), and triethylamine (0.28 mL, 2.0 mmol) were stirred in dimethylformamide (2 mL) at ambient temperature for 8 h under a nitrogen atmosphere.…”

“…However, Horio et al later demonstrated that PKDs only contribute partly to the detection of sour taste in mice, thus pointing at the involvement of other receptors in sour taste mediation . More recently, the work by Tu et al identified otopetrin1 (OTOP1), a proton permeable protein that also plays a key role in the formation of gravity-sensing calcium carbonate crystals in the utricle of the ear, as being the sour taste receptor. ,,− For salt taste perception in rodents, ENaC has been shown to participate, at least partially, but it does not seem to play a significant role in human salt taste perception . Other candidate salt receptors are still under evaluation.…”