Reconsidering the role of neuronal intrinsic properties and neuromodulation in vestibular homeostasis

Abstract

The sensorimotor transformations performed by central vestibular neurons constantly adapt as the animal faces conflicting sensory information or sustains injuries. To ensure the homeostasis of vestibular-related functions, neural changes could in part rely on the regulation of 2° VN intrinsic properties. Here we review evidence that demonstrates modulation and plasticity of central vestibular neurons' intrinsic properties. We first present the partition of Rodents' vestibular neurons into distinct subtypes, namely type A and type B. Then, we focus on the respective properties of each type, their putative roles in vestibular functions, fast control by neuromodulators and persistent modifications following a lesion. The intrinsic properties of central vestibular neurons can be swiftly modulated by a wealth of neuromodulators to adapt rapidly to temporary changes of ecophysiological surroundings. To illustrate how intrinsic excitability can be rapidly modified in physiological conditions and therefore be therapeutic targets, we present the modulation of vestibular reflexes in relation to the variations of the neuromodulatory inputs during the sleep/wake cycle. On the other hand, intrinsic properties can also be slowly, yet permanently, modified in response to major perturbations, e.g., after unilateral labyrinthectomy (UL). We revisit the experimental evidence, which demonstrates that drastic alterations of the central vestibular neurons' intrinsic properties occur following UL, with a slow time course, more on par with the compensation of dynamic deficits than static ones. Data are interpreted in the framework of distributed processes that progress from global, large-scale coping mechanisms (e.g., changes in behavioral strategies) to local, small-scale ones (e.g., changes in intrinsic properties). Within this framework, the compensation of dynamic deficits improves over time as deeper modifications are engraved within the finer parts of the vestibular-related networks. Finally, we offer perspectives and working hypotheses to pave the way for future research aimed at understanding the modulation and plasticity of central vestibular neurons' intrinsic properties.

Keywords: central vestibular neurons; intrinsic properties; neuromodulation; postlesional plasticity; vestibular compensation.

Figure 1

Basic intrinsic membrane properties of type A versus type B medial 2° VN (MVN). (A) Static properties of MVN. Superimposed averaged spike traces illustrate the differences in the electrophysiological signatures of type A (blue traces) and type B (green traces) neurons. The most salient characteristics such as the differences in the afterhyperpolarization are summarized. Transient A-type K⁺ channels (I_A) in neurons are implicated in the delay of the spike onset and the decrease in the firing frequency. (B) and (C), dynamic properties of MVN. (B) In response to ramps of currents (I), type A neurons show linear firing responses, while most type B neurons display a non-linear overshoot in their instantaneous frequency (IF). Similarly, when stimulated with sine waves of current (C), the transfer functions of type A and B neurons differs, type A neurons showing less of a resonance but at higher frequency than type B neurons; t, time. F, stimulation frequency.

Figure 2

Physiological changes of neuromodulators during sleep/wake cycle alter vestibular functions. (A) Schematic of the variations of neuromodulatory concentration between wakefulness and the first NREM/REM episode of sleep. ACh, acetylcholine; NAd, Noradrenaline; 5HT, serotonin. (Adapted from McCarley, 2007). (B) Diagram of eye movements in response to head rotations during vestibulo-ocular reflex in dark. Both the amplitude and phase of the eye movements generated in response to sinusoidal stimulations are increasingly altered as deeper levels of sleep are reached. (Adapted from Jones and Sugie, ; and Kasper et al., 1992).

Figure 3

Vestibular nuclei activity at control, acute, or compensated stage. For (A–C), Left panels: resting condition; right panels: during sinusoidal movement. Top, middle, and bottom panels represent respectively the average discharge in left and right vestibular nuclei, the excitatory/inhibitory relations between 1° and 2° VN (MVN) as well as the influence of commissural inhibition, and finally the resting balanced activity (left) and global modulation of activity (right) within vestibular nuclei. (A) Control. Vestibular nuclei work as a symmetrical, push–pull system, with a balanced activity at rest and a differential perception of the movement: movements elicit both ipsilateral excitation and contralateral disfacilitation (1° VN to 2° VN) which are amplified by the commissural inhibition (increased inhibition from the ipsilateral side to the contralateral side and conversely disinhibition from contralateral to ipsilateral). (B) Acute. Schematics represent the activity typically recorded 24 h after the lesion. The ipsilesional neurons lose their excitatory drive and are therefore silenced by the commissural inhibition. In turn, the contralesional side is disinhibited, which causes a strong imbalance in the absence of movements. During movements, the balanced activity used as a carrier signal cannot be modulated anymore by the reciprocal connections of both vestibular nuclei. Thus only movements toward the contralesional side can be detected, however with a decreased sensitivity. (C) Compensated. Schematics represent the activity typically recorded 1 month after the lesion and is “compensated” from a static point of view (see Behavioral Correlates of Vestibular Compensation). In the absence of movement, the balanced activity is restored between both sides. When a rotation is applied, this basal activity can be modulated by the sensory inputs from the contralesional side through the inhibitory commissural system. The system has evolved from an initial symmetrical push–pull organization to a new regime where the ipsilesional side restores a tonic discharge which is more or less inhibited by the contralesional side during respectively contra and ipsilesional movements: the ipsilateral “carrier” activity is modulated by the contralateral phasic signals, at the expenses of the signal-to-noise ratio.

Figure 4

Dynamic of vestibular compensation and neural correlates. Compensation of static and dynamic deficits is presented in gray scales. Static deficits get compensated in about a week while dynamic compensation follows a slower time course over several months or years. Neural correlates associated to sensory substitution (red) depend on structures distributed throughout the entire central nervous system (CNS) and encompass all kinds of structural plasticities. Synaptic (green) and intrinsic (blue) scales represent the neural correlates at the level of the vestibular nuclei based on in vitro works. With time, deeper modifications are engraved within the finer parts of the vestibular-related networks. Importantly, there is no causal relationship postulated between the parallel processes. Instead, the hypothesis is to be understood as a “basic reaction pattern” which includes all the cellular events initially triggered by the lesion.

Figure 5

Long-term modifications in vestibular phasico-tonic and tonic neuronal filters after 1 month of vestibular compensation. (A) Central vestibular neurons (2° VN) about equally split between type A and type B neurons. Both sides of the brainstem are linked through direct connections via the commissural system, or indirect polysynaptic connections through the efferent system which contact the sensory neurons located on each side. (B) One month after UL, membrane properties of 2° VN are bilaterally modified. The ipsilesional side is dominated by tonic, type A and type A-like neurons. On the contralesional side, both the vestibular afferents and central vestibular neurons evolve toward more phasic properties. Modifications of the vestibular afferents through the efferent pathway are hypothesized from Sadeghi et al. (2007b). Note that irregular dimorphic afferents were omitted for sake of clarity.