Context-independent encoding of passive and active self-motion in vestibular afferent fibers during locomotion in primates

The vestibular system detects head motion to coordinate vital reflexes and provide our sense of balance and spatial orientation. A long-standing hypothesis has been that projections from the central vestibular system back to the vestibular sensory organs (i.e., the efferent vestibular system) mediate adaptive sensory coding during voluntary locomotion. However, direct proof for this idea has been lacking. Here we recorded from individual semicircular canal and otolith afferents during walking and running in monkeys. Using a combination of mathematical modeling and nonlinear analysis, we show that afferent encoding is actually identical across passive and active conditions, irrespective of context. Thus, taken together our results are instead consistent with the view that the vestibular periphery relays robust information to the brain during primate locomotion, suggesting that context-dependent modulation instead occurs centrally to ensure that coding is consistent with behavioral goals during locomotion.

The mammalian efferent vestibular system utilizes cholinergic mechanisms to excite primary vestibular afferents

Electrical stimulation of the mammalian efferent vestibular system (EVS) predominantly excites primary vestibular afferents along two distinct time scales. Although roles for acetylcholine (ACh) have been demonstrated in other vertebrates, synaptic mechanisms underlying mammalian EVS actions are not well-characterized. To determine if activation of ACh receptors account for efferent-mediated afferent excitation in mammals, we recorded afferent activity from the superior vestibular nerve of anesthetized C57BL/6 mice while stimulating EVS neurons in the brainstem, before and after administration of cholinergic antagonists. Using a normalized coefficient of variation (CV*), we broadly classified vestibular afferents as regularly- (CV* < 0.1) or irregularly-discharging (CV* > 0.1) and characterized their responses to midline or ipsilateral EVS stimulation. Afferent responses to efferent stimulation were predominantly excitatory, grew in amplitude with increasing CV*, and consisted of fast and slow components that could be identified by differences in rise time and post-stimulus duration. Both efferent-mediated excitatory components were larger in irregular afferents with ipsilateral EVS stimulation. Our pharmacological data show, for the first time in mammals, that muscarinic AChR antagonists block efferent-mediated slow excitation whereas the nicotinic AChR antagonist DHβE selectively blocks efferent-mediated fast excitation, while leaving the efferent-mediated slow component intact. These data confirm that mammalian EVS actions are predominantly cholinergic.

A review of efferent cholinergic synaptic transmission in the vestibular periphery and its functional implications

It has been over 60 years since peripheral efferent vestibular terminals were first identified in mammals, and yet the function of the efferent vestibular system remains obscure. One reason for the lack of progress may be due to our deficient understanding of the peripheral efferent synapse. Although vestibular efferent terminals were identified as cholinergic less than a decade after their anatomical characterization, the cellular mechanisms that underlie the properties of these synapses have had to be inferred. In this review we examine how recent mammalian studies have begun to reveal both nicotinic and muscarinic effects at these terminals and therefore provide a context for fast and slow responses observed in classic electrophysiological studies of the mammalian efferent vestibular system, nearly 40 years ago. Although incomplete, these new results together with those of recent behavioral studies are helping to unravel the mysterious and perplexing action of the efferent vestibular system. Armed with this information, we may finally appreciate the behavioral framework in which the efferent vestibular system operates.

New advances regarding adaptation of the vestibulo-ocular reflex

This is a review summarizing the development of vestibulo-ocular reflex (VOR) adaptation behavior with relevance to rehabilitation over the last 10 years and examines VOR adaptation using head-on-body rotations, specifically the influence of training target contrast, position and velocity error signal, active vs. passive head rotations, and sinusoidal vs. head impulse rotations. This review discusses optimization of the single VOR adaptation training session, consolidation between repeated training sessions, and dynamic incremental VOR adaptation. Also considered are the effects of aging and the roles of the efferent vestibular system, cerebellum, and otoliths on angular VOR adaptation. Finally, this review examines VOR adaptation findings in studies using whole body rotations.

The mammalian efferent vestibular system plays a crucial role in vestibulo-ocular reflex compensation after unilateral labyrinthectomy

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 ( chrna9) 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°/s2) VOR in complete darkness before (baseline) unilateral labyrinthectomy (UL) and then 1, 5, and 28 days after UL. On day 1 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. NEW & NOTEWORTHY 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.

The mammalian efferent vestibular system plays a crucial role in the high-frequency response and short-term adaptation of the vestibuloocular reflex

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 α9-knockout mice. These mice carry a missense mutation of the gene encoding the α9 nicotinic acetylcholine receptor (nAChR) subunit. The α9 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 α9-knockout mice and 27 cba129 control mice. Mice were randomly assigned to one of three groups: gain-increase adaptation (1.5×), gain-decrease adaptation (0.5×), or no adaptation (baseline, 1×). 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°/s2) VOR in complete darkness. α9-Knockout mice had significantly lower baseline gains compared with control mice. This difference increased with stimulus frequency (∼5% <1 Hz to ∼25% >1 Hz). Moreover, vestibular adaptation (difference in VOR gain of gain-increase and gain-decrease adaptation groups as % of gain increase) was significantly reduced in α9-knockout mice (17%) compared with control mice (53%), a reduction of ∼70%. Our results show that the loss of α9 nAChRs moderately affects the VOR but severely affects VOR adaptation, suggesting that the EVS plays a crucial role in vestibular plasticity.