The α9-nicotinic acetylcholine receptor (α9-nAChR) subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic efferent vestibular system (EVS). A recent study has shown that α9-nAChRs play an important role in short-term vestibulo-ocular reflex (VOR) adaptation. We hypothesize that α9-nAChRs could also be important for other forms of vestibular plasticity, such as that needed for VOR recovery after vestibular organ injury. We measured the efficacy of VOR compensation in α9 knockout mice. These mice have deletion of most of the gene () encoding the nAChR and thereby lack α9-nAChRs. We measured the VOR gain (eye velocity/head velocity) in 20 α9 knockout mice and 16 cba129 controls. We measured the sinusoidal (0.2-10 Hz, 20-100°/s) and transient (1,500-6,000°/s) VOR in complete darkness before (baseline) unilateral labyrinthectomy (UL) and then 1, 5, and 28 days after UL. On after UL, cba129 mice retained ~50% of their initial function for contralesional rotations, whereas α9 knockout mice only retained ~20%. After 28 days, α9 knockout mice had ~50% lower gain for both ipsilesional and contralesional rotations compared with cba129 mice. Cba129 mice regained ~75% of their baseline function for ipsilesional and ~90% for contralesional rotations. In contrast, α9 knockout mice only regained ~30% and ~50% function, respectively, leaving the VOR severely impaired for rotations in both directions. Our results show that loss of α9-nAChRs severely affects VOR compensation, suggesting that complimentary central and peripheral EVS-mediated adaptive mechanisms might be affected by this loss. Loss of the α9-nicotinic acetylcholine receptor (α9-nAChR) subunit utilized by the efferent vestibular system (EVS) has been shown to significantly affect vestibulo-ocular reflex (VOR) adaptation. In our present study we have shown that loss of α9-nAChRs also affects VOR compensation, suggesting that the mammalian EVS plays an important role in vestibular plasticity, in general, and that VOR compensation is a more distributed process than previously thought, relying on both central and peripheral changes.

Hübner PP, Khan SI, Migliaccio AA. The mammalian efferent vestibular system plays a crucial role in the high-frequency response and short-term adaptation of the vestibuloocular reflex. J Neurophysiol 114: 3154 -3165, 2015. First published September 30, 2015 doi:10.1152/jn.00307.2015.-Although anatomically well described, the functional role of the mammalian efferent vestibular system (EVS) remains unclear. Unlike in fish and reptiles, the mammalian EVS does not seem to play a role in modulation of primary afferent activity in anticipation of active head movements. However, it could play a role in modulating long-term mechanisms requiring plasticity such as vestibular adaptation. We measured the efficacy of vestibuloocular reflex (VOR) adaptation in ␣9-knockout mice. These mice carry a missense mutation of the gene encoding the ␣9 nicotinic acetylcholine receptor (nAChR) subunit. The ␣9 nAChR subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic EVS. We measured the VOR gain (eye velocity/head velocity) in 26 ␣9-knockout mice and 27 cba129 control mice. Mice were randomly assigned to one of three groups: gain-increase adaptation (1.5ϫ), gain-decrease adaptation (0.5ϫ), or no adaptation (baseline, 1ϫ). After adaptation training (horizontal rotations at 0.5 Hz with peak velocity 20°/s), we measured the sinusoidal (0.2-10 Hz, 20 -100°/s) and transient (1,500 -6,000°/s 2 ) VOR in complete darkness. ␣9-Knockout mice had significantly lower baseline gains compared with control mice. This difference increased with stimulus frequency (ϳ5% Ͻ1 Hz to ϳ25% Ͼ1 Hz). Moreover, vestibular adaptation (difference in VOR gain of gain-increase and gain-decrease adaptation groups as % of gain increase) was significantly reduced in ␣9-knockout mice (17%) compared with control mice (53%), a reduction of ϳ70%. Our results show that the loss of ␣9 nAChRs moderately affects the VOR but severely affects VOR adaptation, suggesting that the EVS plays a crucial role in vestibular plasticity. efferent vestibular system; vestibular adaptation; vestibular plasticity; vestibuloocular reflex; ␣9-knockout mice DESPITE CONSIDERABLE EFFORT, the functional role of the mammalian efferent vestibular system (EVS) is poorly understood.

Dizziness and imbalance are clinically poorly defined terms, which affect ~30% of people over 65 years of age. In these people, it is often difficult to define the primary cause of dizziness, as it can stem from cardiovascular, vestibular, psychological, and neuromuscular causes. However, identification of the primary cause is vital in determining the most effective treatment strategy for a patient. Our aim is to accurately identify the prevalence of benign paroxysmal positional vertigo (BPPV), peripheral, and central vestibular hypofunction in people aged over 50 years who had experienced dizziness within the past year. Seventy-six participants aged 51–92 (mean ± SD = 69 ± 9.5 years) were tested using the head thrust dynamic visual acuity (htDVA) test, dizziness handicap inventory (DHI), as well as sinusoidal and unidirectional rotational chair testing, in order to obtain data for htDVA score, DHI score, sinusoidal (whole-body, 0.1–2 Hz with peak velocity at 30°/s) vestibulo-ocular reflex (VOR) gain and phase, transient (whole-body, acceleration at 150°/s2 to a constant velocity rotation of 50°/s) VOR gain and time constant (TC), optokinetic nystagmus (OKN) gain, and TC (whole-body, constant velocity rotation at 50°/s). We found that BPPV, peripheral and central vestibular hypofunction were present in 38 and 1% of participants, respectively, suggesting a likely vestibular cause of dizziness in these people. Of those with a likely vestibular cause, 63% had BPPV; a figure higher than previously reported in dizziness clinics of ~25%. Our results indicate that htDVA, sinusoidal (particularly 0.5–1 Hz), and transient VOR testing were the most effective at detecting people with BPPV or vestibular hypofunction, whereas DHI and OKN were effective at only detecting non-BPPV vestibular hypofunction.