Molecular mechanisms of recovery from vestibular damage in mammals: recent advances

doi:10.1016/S0301-0082(00)00002-2

Progress in Neurobiology

Volume 62, Issue 3, 31 October 2000, Pages 313-325

https://doi.org/10.1016/S0301-0082(00)00002-2 Get rights and content

Abstract

The aim of this review is to summarise and critically evaluate studies of vestibular compensation published over the last 2 years, with emphasis on those concerned with the molecular mechanisms of this process of lesion-induced plasticity. Recent studies of vestibular compensation have confirmed and extended the previous findings that: (i) compensation of the static ocular motor and postural symptoms occurs relatively rapidly and completely compared to the dynamic symptoms, many of which either do not compensate substantially or else compensate variably due to sensory substitution and the development of sensori-motor strategies which suppress or minimize symptoms; (ii) static compensation is associated with, and may be at least partially caused by a substantial recovery of resting activity in the ipsilateral vestibular nucleus complex (VNC), which starts to develop very quickly following the unilateral vestibular deafferentation (UVD) but does not correlate perfectly with the development of some aspects of static compensation (e.g., postural compensation); and (iii) many complex biochemical changes are occurring in the VNC, cerebellum and even areas of the central nervous system like the hippocampus, following UVD. However, despite many recent studies which suggest the importance of excitatory amino acid receptors such as the N-methyl-D-aspartate receptor, expression of immediate early gene proteins, glucocorticoids, neurotrophins and nitric oxide in the vestibular compensation process, how these various factors are linked and which of them may have a causal relationship with the physiological changes underlying compensation, remains to be determined.

Introduction

Damage to the peripheral vestibular system, as a consequence of destruction of the vestibular receptor cells or transection of the vestibular nerve itself, results in a syndrome of ocular motor and postural disorders due to the disruption of central vestibulo-ocular and vestibulo-spinal pathways. In the case of unilateral vestibular deafferentation (UVD), the symptoms are particularly dramatic, as a result of the severe imbalance in neuronal activity between the ipsilateral and contralateral vestibular nucleus complexes (VNCs). However, over time, many but not all of these symptoms subside in a process of behavioural recovery known as ‘vestibular compensation’. Vestibular compensation is a complex, heterogeneous process, in which many of the ocular motor and postural symptoms (i.e., ‘static symptoms’, such as spontaneous ocular nystagmus (SN), yaw head tilt (YHT) and roll head tilt (RHT)) related to the imbalance in spontaneous resting activity between the bilateral VNCs, gradually subside within a few days to a week, whereas those symptoms related to the loss of dynamic sensitivity of VNC neurons to head movement (i.e., ‘dynamic symptoms’, such as abnormal gain and phase of the vestibulo-ocular and vestibulospinal reflexes), compensate much less completely, more variably and over a longer period of time. To the extent that vestibular compensation does occur, it appears to be relatively independent of any recovery in the deafferented vestibular nerve, and therefore is attributed to plasticity in the central nervous system (CNS) (e.g., see Smith and Curthoys, 1989, Smith and Darlington, 1991, Curthoys and Halmagyi, 1995, Curthoys and Halmagyi, 1999, Dieringer, 1995, Vidal et al., 1998, Kitahara et al., 1998c for reviews).

Vestibular compensation is of interest for three main reasons: (1) the way in which the vestibular system changes following damage reveals a great deal about how it functions normally; (2) understanding the processes and mechanisms of vestibular compensation is important for developing the best treatments for humans who suffer UVD as a result of accidental injury, ototoxicity or disease, or who receive UVD as a surgical treatment for disease (e.g., Meniere’s disease); and (3) vestibular compensation is an interesting model of CNS plasticity, in a system which is relatively simple and has well-identified inputs and outputs. For all of these reasons, vestibular compensation has been the focus of a tremendous amount of research over the last 30 years. Nonetheless, there are still many aspects of the compensation process which are poorly understood, in particular, the exact mechanism of vestibular compensation and where in the CNS it resides.

Because many reviews on vestibular compensation are already available, the aim of the present review is to summarise and critically evaluate only recent developments (i.e., since 1997) in this area, with particular emphasis on molecular mechanisms in order to identify some key areas which may be important for further investigation. For an overview of other aspects of the vestibular compensation literature, the reader is referred to one of the many reviews available (e.g., Smith and Curthoys, 1989, Smith and Darlington, 1991, Curthoys and Halmagyi, 1995, Curthoys and Halmagyi, 1999, Dieringer, 1995, Vidal et al., 1998, Kitahara et al., 1998c).

Section snippets

Static symptoms

Recent research relating to the static symptoms of UVD has emphasised the complexity and species-specific nature of vestibular compensation, as well as the stratified nature of the ocular motor and postural compensation processes. Hamann et al. (1998) have reported deficits in vertical eye position in rats in response to lateral static tilt in darkness, even six months post-UVD. Similarly, the 90° YHT toward the lesioned side, which is observed shortly following UVD, was seen whenever the

Neurophysiological substrates of vestibular compensation

During the 1980s and early 1990s, there was considerable controversy regarding the extent of the recovery of resting activity in the ipsilateral VNC during the development of vestibular compensation (e.g., Smith and Curthoys, 1991). Since most of the available studies had used anesthetised preparations or decerebrate or spinally-transected preparations, it was conceivable that the results observed had been substantially affected by the methodology used. However, in the last few years, Godaux

Theories of vestibular compensation

Theories of vestibular compensation can be generally divided into pre- and post-synaptic categories. Presynaptic theories have traditionally suggested that changes in synaptic input to the ipsilateral VNC are responsible for the recovery of resting activity underlying static vestibular compensation, e.g., changes in the efficacy of synaptic inputs from the spinal cord resulting from axonal sprouting or increased transmitter release (e.g., Dieringer, 1995, Ris and Godaux, 1998a, Ris and Godaux,

Biochemical mechanisms of static vestibular compensation

Whichever combination of different pre- and post-synaptic changes account for the neuronal plasticity underlying the static vestibular compensation process, all of the proposed mechanisms would require biochemical changes, and these biochemical changes would almost certainly have to include changes in second messenger levels, the activity of protein kinases and phosphatases and consequent changes in protein phosphorylation and dephosphorylation, since phosphorylation and dephosphorylation have

Conclusions

Recent studies of vestibular compensation have confirmed and extended the previous findings that: (i) compensation of the static ocular motor and postural symptoms occurs relatively rapidly and completely compared to the dynamic symptoms, many of which either do not compensate substantially or else compensate variably due to sensory substitution and the development of sensori-motor strategies which suppress or minimize symptoms; (ii) static compensation is associated with, and may be at least

Acknowledgements

This research was supported by a Project Grant from the Health Research Council of New Zealand (to CD and PS).

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In the process of dynamic vestibular compensation after UL, the sensitivity of ipsi-MVe neurons to head velocity and acceleration is restored due to synaptic changes such as long-term potentiation and sprouting of commissures, resulting in the restoration of the dynamic vestibulo-ocular and vestibulo-spinal reflexes. To facilitate dynamic vestibular compensation, early ambulation and subsequent vestibular rehabilitation exercise are recommended for the treatment of chronic vertigo in patients with uncompensated unilateral vestibular dysfunction.
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Experience-dependent brain circuit plasticity underlies various sensorimotor learning and memory processes. Recently, a novel set-point adaptation mechanism was identified that accounts for the pronounced negative optokinetic afternystagmus (OKAN) following a sustained period of unidirectional optokinetic nystagmus (OKN) in larval zebrafish. To investigate the physiological significance of optokinetic set-point adaptation, animals in the current study were exposed to a direction-alternating optokinetic stimulation paradigm that better resembles their visual experience in nature. Our results reveal that not only was asymmetric alternating stimulation sufficient to induce the set-point adaptation and the resulting negative OKAN, but most strikingly, under symmetric alternating stimulation some animals displayed an inherent bias of the OKN gain in one direction, and that was compensated by the similar set-point adaptation. This finding, supported by mathematical modeling, suggests that set-point adaptation allows animals to cope with asymmetric optokinetic behaviors evoked by either external stimuli or innate oculomotor biases.
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Unilateral Vestibular Neurectomy (UVN) induces a postural syndrome whose compensation over time is underpinned by multimodal sensory substitution processes. However, at a chronic stage of compensation, UVN rats exhibit an enduring postural asymmetry expressed by an increase in the body weight on the ipsilesional paws. Given the anatomo-functional links between the vestibular nuclei and the primary somatosensory cortex (S1), we explored the interplay of vestibular and somatosensory cortical inputs following acute and chronic UVN. We determined whether the enduring imbalance in tactilo-plantar inputs impacts response properties of S1 cortical neurons and organizational features of somatotopic maps. We performed electrophysiological mapping of the hindpaw cutaneous representations in S1, immediately and one month after UVN. In parallel, we assessed the posturo-locomotor imbalance during the compensation process. UVN immediately induces an expansion of the cortical neuron cutaneous receptive fields (RFs) leading to a partial dedifferentiation of somatotopic maps. This effect was demonstrated for the ventral skin surface representations and was greater on the contralesional hindpaw for which the neuronal threshold to skin pressure strongly decreased. The RF enlargement was amplified for the representation of the ipsilesional hindpaw in relation to persistent postural asymmetries, but was transitory for the contralesional one. Our study shows, for the first time, that vestibular inputs exert a modulatory influence on S1 neuron’s cutaneous responses. The lesion-induced cortical malleability highlights the influence of vestibular inputs on tactile processing related to postural control.
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Citation Excerpt :
Activation of the contralesional vestibular cortex was found also in patients with vestibular neuritis in the acute stage (Becker-Bense et al., 2014; Bense et al., 2004). In our study, an rCGM increase was found bilaterally in the cerebellum, which is known to contribute to the early stages of vestibular compensation (Beraneck et al., 2008; Darlington and Smith, 2000; Kitahara et al., 1997; Zwergal et al., 2016). Similarly, patients with a unilateral strategic medullary vestibular lesion showed bilateral cerebellar activation (Becker-Bense et al., 2013).
Unilateral damage to the inner ear results in an acute vestibular syndrome, which is compensated within days to weeks due to adaptive cerebral plasticity. This process, called central vestibular compensation (VC), involves a wide range of functional and structural mechanisms at the cellular and network level. The short-term dynamics of whole-brain functional network recruitment and recalibration during VC has not been depicted in vivo. The purpose of this study was to investigate the interplay of separate and distinct brain regions and in vivo networks in the course of VC by sequential [¹⁸F]-FDG-PET-based statistical and graph theoretical analysis with the aim of revealing the metabolic connectome before and 1, 3, 7, and 15 days post unilateral labyrinthectomy (UL) in the rat. Temporal changes in metabolic brain connectivity were determined by Pearson's correlation (|r| > 0.5, p < 0.001) of regional cerebral glucose metabolism (rCGM) in 57 segmented brain regions. Metabolic connectivity analysis was compared to univariate voxel-wise statistical analysis of rCGM over time and to behavioral scores of static and dynamic sensorimotor recovery. Univariate statistical analysis revealed an ipsilesional relative rCGM decrease (compared to baseline) and a contralesional rCGM increase in vestibular and limbic networks and an increase in bilateral cerebellar and sensorimotor networks. Quantitative analysis of the metabolic connections showed a maximal increase from baseline to day 3 post UL (interhemispheric: 2-fold, ipsilesional: 3-fold, contralesional: 12-fold) and a gradual decline until day 15 post UL, which paralleled the dynamics of vestibular symptoms. In graph theoretical analysis, an increase in connectivity occurred especially within brain regions associated with brainstem-cerebellar and thalamocortical vestibular networks and cortical sensorimotor networks. At the symptom peak (day 3 post UL), brain networks were found to be organized in large ensembles of distinct and highly connected hubs of brain regions, which separated again with progressing VC. Thus, we found rapid changes in network organization at the subcortical and cortical level and in both hemispheres, which may indicate an initial functional substitution of vestibular loss and subsequent recalibration and reorganization of sensorimotor networks during VC.

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Molecular mechanisms of recovery from vestibular damage in mammals: recent advances

Abstract

Introduction

Section snippets

Static symptoms

Neurophysiological substrates of vestibular compensation

Theories of vestibular compensation

Biochemical mechanisms of static vestibular compensation

Conclusions

Acknowledgements

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