Neuroembryol Aging 2004–05;3:183–193 DOI: 10.1159/000096796

Published online: November 3, 2006

Cellular Mechanisms of Vestibular Compensation Janet M. Paterson John R.W. Menzies Filip Bergquist Mayank B. Dutia Center for Integrative Physiology, Edinburgh University College of Medicine and Veterinary Medicine, School of Biomedical Sciences, Edinburgh, UK

Key Words Brainstem
Cerebellum
Deafferentation
Labyrinth
Plasticity
Stress

Abstract Vestibular compensation, the behavioral recovery that takes place after unilateral vestibular deafferentation, is a complex and multifactorial process involving synaptic and neuronal plasticity in the vestibular nuclei, cerebellum and related structures. Recent experimental evidence suggests that changes in the intrinsic properties of the vestibular nucleus neurons, changes in the efficacy of their inhibitory synaptic inputs, activity-dependent rewiring of synaptic connectivity in the vestibular brainstem, and changes in the cerebellar control of the brainstem neurons are involved in the rebalancing of resting activity of the vestibular neurons after deafferentation. In this article, we review recent advances in understanding the cellular and molecular mechanisms of vestibular compensation. Copyright © 2005 S. Karger AG, Basel

The vestibular system plays a fundamental role in the control of eye movements and stabilization of gaze, the control of posture and locomotion, and in cognitive aspects of balance, self-orientation and spatial navigation. Inputs from the vestibular, visual and proprioceptive sys-

© 2005 S. Karger AG, Basel 1661–3406/05/0034–0183$22.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/nba

tems converge in the first instance on second-order neurons in the brainstem vestibular nuclei (VN). VN neurons transform these inputs into motor commands for eye and head movements, and also project to higher brain areas including the hippocampus, thalamus and vestibular cortex. An appropriate temporal and spatial integration of vestibular and related signals by brainstem VN neurons is therefore critical both for oculomotor and postural reflex function as well as spatial cognition and navigation. Damage to the peripheral vestibular receptors in the inner ear of one side, or to the vestibular nerve, precipitates a complex and debilitating syndrome of oculomotor, postural and cognitive deficits. Remarkably however, many of the initial consequences of peripheral vestibular loss ameliorate rapidly, through a process of behavioral recovery known as ‘vestibular compensation’ (VC). Since there is no regeneration of the damaged vestibular receptors or nerve, the behavioral recovery after vestibular damage is attributed to neural and synaptic plasticity in the brainstem VN, cerebellum, and related areas of the brain. There is considerable interest in understanding the cellular and molecular mechanisms of VC, not only because of their potential clinical importance in the management of patients with balance disorders, but also because VC represents an attractive experimental model in which to investigate brain plasticity underlying behav-

Mayank B. Dutia, Center for Integrative Physiology Edinburgh University College of Medicine and Veterinary Medicine School of Biomedical Sciences, Hugh Robson Building, George Square Edinburgh, EH8 9XD (UK) Tel. +44 131 650 3252, Fax +44 131 650 6527, E-Mail [email protected]

MRM

LRM

OMN

ABN

MVN

MVN

I

I I

n. VIII

I

II

II

n. VIII

Midline

directly related to the behavioral recovery, or indeed ‘compensatory’ in nature [4]. Thus VC may be accompanied by various changes in the processing of spatial, visual, proprioceptive and cognitive information, but some of these may be secondary and not necessarily directly involved in the neuronal plasticity that underlies compensation. It is therefore a challenge to understand the processes involved in VC, and determine the interactions between them that eventually bring about the overall behavioral recovery. Much recent research has investigated the effects of UVD on neurons in the medial VN (MVN), which are primarily involved in mediating the horizontal vestibulo-ocular reflex (hVOR; fig. 1). This review will accordingly focus to a large extent on currently proposed mechanisms of plasticity in MVN neurons and in the hVOR pathways, which are likely to be most directly involved in the compensation of spontaneous ocular nystagmus (SN) after UVD.

Fig. 1. Simplified, schematic diagram of the organization of the

MVN projections involved in mediating hVOR. Primary vestibular afferents from the horizontal semicircular canals travel in the VIIIth cranial nerve (n. VIII) and synapse with second-order, ‘type I’ MVN neurons in the brainstem. ‘Type II’ MVN neurons are inhibitory interneurons, which receive excitation from the contralateral MVN. Connections between the MVN neurons of the left and right sides form a reciprocal, commissural inhibitory system. Projections of the type I MVN neurons to the abducens nucleus (ABN) and thence to the oculomotor nucleus (OMN) lead to the reflex activation of the medial and lateral rectus muscles (MRM and LRM, respectively).

ioral recovery. Many studies have investigated the effects of unilateral vestibular deafferentation (UVD) on neurons in the VN, and possible mechanisms of deafferentation-induced plasticity in the VN and cerebellum, in various species [reviewed in ref. 1–8]. At the same time, detailed studies of the behavioral deficits that follow UVD in animals and humans have emphasized that VC is by no means a single process. There are wide differences in the time course and ultimate level of compensation for the range of oculomotor, postural and cognitive deficits that follow UVD [1, 2, 5]. Thus although VC refers to the overall behavioral recovery that takes place after vestibular damage it is clear that the underlying physiological processes are diverse, with differences in the signals that initiate and drive them, their time course and end points. In addition, it is probably the case that not all physiological processes that take place in the brain after UVD are 184

Neuroembryol Aging 2004–05;3:183–193

Behavioral Consequences of UVD

Static and Dynamic Signs and Symptoms of Unilateral Vestibular Loss The profound effects of UVD on eye movements and posture, and the subsequent behavioral recovery that occurs as VC takes place, were first described in 1824 by Flourens [cited in ref. 9]. The signs and symptoms that follow UVD have since been characterized in a range of species using a wide range of techniques, including posturography, video oculography, 3D search coil recordings of eye movements and X-ray cinematography. Although there are species differences, the nature of the vestibular deafferentation syndrome and the subsequent behavioral recovery are broadly similar in various animals from the goldfish and frog to monkey and man, indicating that the underlying processes share many commonalities [1, 2, 4, 10]. The deficits observed immediately after UVD can be divided into two categories on the basis of their relationship to head movement. ‘Static’ signs are observed in the absence of head movement, affecting head and body posture and eye movements. In addition ‘dynamic’ signs are observed during head movements (that is, in response to vestibular stimulation), and result from abnormalities in the amplitude and timing of the vestibulo-ocular, vestibulo-collic and vestibulo-spinal reflexes. In general, static symptoms show a rapid recovery following UVD, with many of the initial severe static symptoms disapPaterson/Menzies/Bergquist/Dutia

pearing within a few days, while compensation of the dynamic symptoms is much slower and incomplete. In mammals, the most prominent static symptom is a high-frequency horizontal SN, seen as a slow drift of the eyes towards the lesioned side (slow phase) followed by a fast beat towards the intact side (quick phase). Soon after unilateral labyrinthectomy, the frequency of SN in rats and guinea pigs is around 80–180 beats per minute [2, 10–15]. The frequency of SN begins to decrease soon after unilateral labyrinthectomy, declining to about half of its initial value within 6 h in the rat and disappearing completely within about 60 h. In the monkey and man, SN may persist for up to a week [16, 17]. In amphibians, SN does not occur [3]. UVD also results in disturbances in the position of the eyes, head and body. Ocular torsion and ocular skew deviation cause the eye on the affected side to rotate and deviate downwards in its orbit relative to the eye on the intact side [1, 3]. The deviated position of the eyes causes a systematic error in the perception of horizontal and vertical lines, which are seen as being rotated towards the affected ear in proportion to the ocular torsion [1–3, 5]. Humans show relatively little head and body rotation after unilateral vestibular loss, but common to many other species is a tilting of the head towards the lesioned side in the roll plane (‘roll head tilt’), and a turning of the head towards the lesioned side in the yaw plane (‘yaw head tilt’). Other static postural symptoms in animals include a curvature of the upper spine towards the lesioned side, circular walking and barrel rolling, and an asymmetric extensor muscle tone with a tendency to fall to the lesioned side [1, 9, 10, 18]. Along with the disappearance of SN after UVD, the majority of these static signs ameliorate remarkably rapidly: barrel rolling and circular walking subside within 4 h in the rat, while ocular torsion, skew deviation and yaw head tilt have largely disappeared within a few days. By contrast, the recovery of dynamic symptoms is slow and incomplete. UVD results in severe abnormalities in the gain, symmetry and phase of the hVOR [1, 2, 17, 19]. After UVD hVOR gain is significantly lower than its normal value of approximately 1.0, and is severely asymmetric: hVOR gain in response to rotations towards the side of the lesioned ear (the ‘ipsilesional’ side) is much lower than that in response to rotations towards the intact side (the ‘contralesional’ side). During rotations towards the ipsilesional side the hVOR gain falls to approximately 0.3–0.4 in humans and guinea pigs, while during contralesional rotations hVOR gain is higher, around 0.7–0.8. These abnormalities in hVOR performance appear to be

permanent – they do not significantly compensate in the long term, and can be observed months and years following labyrinthectomy [2, 5]. The lack of recovery of the dynamic deficits in vestibular reflex performance contrasts with the apparently complete behavioral recovery that is seen in the majority of animals or patients, who are able to return to a nearnormal lifestyle after unilateral vestibular loss. Presumably, high-level, cognitive and behavioral strategies are developed in order to minimize the effects of the permanently compromised vestibular reflexes such as the hVOR. Thus patients may learn to minimize head turns, or to blink or fixate on a visual target during head rotations so as to suppress the VOR, or generate compensatory saccades during voluntary head rotations towards the deficient side. Indeed, such strategies may be an important requirement for compensation, as recent evidence shows that ‘rewiring’ of the connectivity of the vestibular networks after deafferentation may give rise to new, inappropriate reflex responses to head rotations [4, 20]. Potentially, different subjects may develop individual compensatory strategies, and indeed use different strategies in particular circumstances, and these strategies may be learnt and refined over varying times during VC. Thus the behavioral compensation of dynamic deficits after UVD is a complex, multifactorial and potentially individualistic process, and the underlying mechanisms are at present largely unexplored. Instead, much of the fundamental research into the mechanisms of VC has concentrated on the adaptive processes in the VN and cerebellum that may bring about the initial, rapid amelioration of the static symptoms.

Mechanisms of Vestibular Compensation

Neuroembryol Aging 2004–05;3:183–193

Effects of UVD on Neuronal Activity in the VN Unilateral vestibular loss has profound effects on the activity of neurons in the brainstem VN, and the severe behavioral symptoms induced by UVD are believed to arise directly from these effects. Of the four main VN in the brainstem, the most extensively studied is the MVN. The MVN, particularly its rostral part, is largely concerned with afferent inputs from the horizontal semicircular canals and with the hVOR (fig. 1). A number of studies have shown that immediately after UVD, the normally high resting discharge rate of the majority of MVN neurons (‘type I’ neurons, fig. 1) on the ipsilesional side is virtually abolished, while the activity of MVN neurons on the contralesional side is either normal or increased (fig. 2) [21–29]. Furthermore, the amelioration of the static symptoms is broadly correlated with a recovery of the resting activity of the ipsilesional MVN neurons to 185

a n. VIII

Balanced commissural inhibitory system

+

+

Unilateral vestibular deafferentation

b Resting activity of MVN neurons

Imbalanced commissural inhibitory system

Hyperactive

Silent

+

Normal Ipsilesional MVN

Contralesional MVN

Vestibular compensation:

c Rebalanced commissural inhibitory system

Intrinsic excitability Inhibitory receptor sensitivity +

In ipsilesional neurons

Cerebellar inhibition of contralesional neurons Activity-dependent synaptic reorganization

Ipsilesional MVN

Contralesional MVN

Fig. 2. Schematic representation of the effects of UVD on the

brainstem commissural inhibitory system that links the MVN of the two sides. a In the normal situation there is a balanced resting activity of MVN neurons of the two sides, and a balanced commissural inhibition. b After the loss of the left vestibular labyrinth (left UVD), there is a marked imbalance in resting activity of the MVN neurons on the ipsi- (left) and contralesional (right) sides. This is due to the disfacilitation of the ipsilesional MVN neurons, which causes a decrease in their inhibition of the contralesional MVN cells. These become hyperactive and increase their inhibition of the ipsilesional cells. Rapidly after UVD, this imbalance in commissural inhibition causes the silencing of the ipsilesional

near-normal levels. MVN neurons are the major CNS target of primary vestibular afferents from the semicircular canals; they occupy a central position in the VOR pathway providing a major input to abducens motoneurons, and also project to the cervical spinal cord and the forebrain, relaying information to the vestibular cortex. It is therefore generally accepted that the profound loss of resting activity in these neurons immediately after UVD is an important factor in generating the initial static symptoms, as well as the behavioral and cognitive deficits 186

Neuroembryol Aging 2004–05;3:183–193

neurons, while the contralesional cells are hyperactive. This imbalance in MVN activity is the likely cause of the initial static symptoms that appear after UVD. c ‘Rebalancing’ of the commissural inhibitory system in the hours and days after UVD is thought to be achieved by a range of cellular plasticity mechanisms involving mainly the vestibular nuclei and the cerebellar flocculus. These mechanisms include changes in the efficacy of GABA and glycine receptors in ipsilesional MVN cells, and changes in their intrinsic excitability, as well as adaptations in the inhibitory control of the MVN neurons by the flocculus, and the reorganization of synaptic connectivity in the vestibular.

that immediately follow UVD. Much research has therefore focused on understanding the causes of the initial silencing of the resting discharge of ipsilesional MVN cells after UVD, and the mechanisms that may bring about the recovery of their resting activity early in VC. However it should be borne in mind that other brain centers may also be important in the early behavioral recovery after UVD [27]. Interestingly, recent experiments have shown that after bilateral labyrinthectomy, where the MVN neurons of Paterson/Menzies/Bergquist/Dutia

the two sides are equally disfacilitated by the interruption of the primary vestibular afferents on both sides, the resting activity of MVN cells is not abolished; instead, it decreases to only about 50% of normal on both sides [29]. This implies that after UVD, the reason for the silencing of the ipsilesional MVN neurons is not the deafferentation itself, since one would then expect the resting activity in both MVN to be abolished after bilateral deafferentation. Instead, the likely explanation for the silencing of the ipsilesional MVN neurons after UVD is that these cells are subjected to not only the loss of excitatory input from the lesioned primary vestibular afferents, but also a continued and enhanced commissural inhibition from contralesional MVN neurons, which tend to become hyperactive because of the collapse of inhibitory drive from the lesioned side (fig. 2b). Normally, the reciprocal commissural inhibitory pathways that link the MVN of the two sides are important in optimizing the dynamic responsiveness of the MVN neurons to head movements, and the time constant of the brainstem neural integrator [30, 31]. After UVD however, the commissural inhibitory system is pushed into marked imbalance as a result of the disfacilitation of the ipsilesional MVN cells (fig. 2b). Thus a fundamental cause of the silencing of the deafferented MVN neurons appears to be the commissural inhibitory input to the ipsilesional cells. In this light, it is reasonable to hypothesize that cellular mechanisms that may relieve the ipsilesional MVN cells from excessive commissural inhibition after UVD would promote the recovery of their resting discharge and the restoration of their inhibitory control of the contralesional MVN neurons, and this would help to ‘rebalance’ the levels of neuronal activity in the MVN of the two sides. Mechanisms Involved in the Recovery of Ipsilesional Vestibular Neuronal Activity after UVD Experimental evidence accumulated over the past 10 years has indicated at least four candidate mechanisms, which may operate in parallel and synergistically, to bring about the restoration of resting activity in the deafferented ipsilesional MVN neurons after UVD. These are discussed in turn below. Changes in the Responsiveness of VN Neurons to Inhibitory Synaptic Inputs Evidence for adaptive changes in the intrinsic properties of MVN neurons after UVD has come from studies of brain slice preparations of the brainstem in vitro. Such in vitro studies have significantly increased our understanding of the electrophysiological characteristics of Mechanisms of Vestibular Compensation

MVN neurons, and the actions of many neurotransmitters that influence vestibular function [for reviews see ref. 6–8, 32]. Yamanaka et al. [33] and Vibert et al. [34] compared the responsiveness of MVN neurons to the inhibitory neurotransmitters GABA and glycine (which are the main transmitters involved in the commissural inhibitory system), in slices prepared from normal animals and animals that had compensated for various times after UVD. These experiments revealed that the sensitivity of the ipsilesional MVN neurons to GABA and glycine is significantly downregulated after UVD, so that the same doses of the inhibitory neurotransmitters cause a much smaller inhibition of MVN neurons from animals after UVD than normal MVN neurons. This reduction in the sensitivity of ipsilesional MVN cells to inhibitory inputs is appropriate to counteract the enhanced commissural inhibition to which these cells are subjected after UVD (fig. 2b), which is a likely cause of the silencing of their resting discharge after UVD. Thus the downregulation of the functional efficacy of inhibitory neurotransmitter receptors in the ipsilesional MVN neurons is a plausible mechanism that may help to restore their resting discharge early in VC (fig. 2c). Interestingly, MVN neurons possess both the muscimol-sensitive GABA-A subtype and the baclofen-sensitive GABA-B subtype of GABA receptors, and both subtypes are downregulated immediately after UVD [33]. However, GABA-A receptor-mediated inhibition recovers within a few days, while the responsiveness of the MVN neurons to the GABA-B receptor-mediated inhibition remains downregulated [35]. The functional importance of the altered function of GABA-B receptors in compensated animals has been confirmed in behavioral experiments, in which the GABA-B receptor agonist baclofen was administered to animals that had partially or fully compensated after UVD [13–15]. Baclofen given systemically to animals acutely after UVD (while spontaneous nystagmus was still present), suppressed it, while baclofen given to animals that had compensated for 1 week after UVD, caused the reappearance of nystagmus (‘decompensation’). By contrast, administration of the GABA-A receptor agonist THIP was ineffective, other than causing a general suppression of reflex excitability at higher doses. These effects are consistent with the longterm changes in the efficacy of GABA-B receptors in the ipsilesional MVN neurons observed in slices, though, as suggested by Magnusson et al. [15], the presynaptic actions of baclofen may also be important in vivo.

Neuroembryol Aging 2004–05;3:183–193

187

c

a

100 ms

b

d

100 ms

Fig. 3. Examples of low-threshold calcium spikes (a, b) and plateau potentials (c, d) in intracellular recordings from MVN neurons in slices from animals that had compensated after UVD for 2 weeks. Action potentials fired by these two MVN cells in response to depolarizing current pulses (a, b) and their responses to hyperpolarizing current pulses (c, d) are shown. Note the lowthreshold calcium spikes (a, b ; arrows) and the plateau potentials (c, d ; arrows) elicited by depolarization and by the release of hyperpolarization. Such membrane electrophysiological responses in the MVN neurons after compensation will tend to increase the ability of these neurons to fire action potentials in response to excitatory synaptic inputs, and may therefore help to restore excitability in the deafferented cells during compensation.

Changes in the Electrophysiological Excitability of VN Neurons after Deafferentation In parallel with the changes in their sensitivity to inhibitory neurotransmitters after UVD, the deafferented ipsilesional MVN cells also upregulate their intrinsic, electrophysiological excitability (fig. 2c). This was first observed simply as an increase in the mean spontaneous discharge rate of the ipsilesional MVN cells in brain slices taken from animals that had compensated for various times after UVD [36]. Subsequent studies using intracellular recordings have shown that not only does the spontaneous activity of the cells increase as a result of chang188

Neuroembryol Aging 2004–05;3:183–193

es in their input resistance and resting membrane potentials, but their responsiveness to synaptic inputs is also potentiated through the upregulation of appropriate ion channels [37]. In particular, there is an increase in the number of cells that show low-threshold calcium spikes after UVD. This ionic conductance is of interest because it can be strongly activated by small depolarizing inputs when the membrane potential is hyperpolarized below normal (fig. 3). Thus the increased expression of lowthreshold calcium spikes in ipsilesional MVN neurons, which are indeed hyperpolarized and silent immediately after UVD, is likely to significantly increase their responsiveness to excitatory synaptic inputs from other, nonvestibular sources. In addition, plateau potentials in MVN cells (fig. 3) also enhance the firing of trains of action potentials in response to excitatory synaptic inputs. In the longer term, these changes in intrinsic electrophysiology of the ipsilesional MVN neurons persist, and additional changes also occur in the electrophysiological properties of contralesional MVN neurons [38, 39]. The excitability and signal-processing characteristics of the vestibular neurons are therefore permanently modified after deafferentation [8]. Postlesional Changes in Synaptic Connectivity in the Vestibular Reflex Networks In addition to the changes in the properties of MVN neurons after deafferentation Dieringer [4] and Goto et al. [40–42] have shown that after UVD, the synaptic connectivity of excitatory and inhibitory pathways in the brainstem VN undergoes gradual, activity-dependent reorganization. Thus 2 months after unilateral vestibular neurectomy, the strength of excitatory synaptic inputs to the ipsilesional MVN neurons from the contralesional, intact side was significantly increased. In addition, after partial vestibular neurectomy in which only one branch of the vestibular nerve is sectioned leaving the innervation of the remaining end-organs intact, there is an expansion of the excitatory synaptic inputs from the intact afferents to the ipsilesional MVN cells. Thus, MVN neurons that are deprived of their original synaptic inputs as a result of the sectioning of the vestibular nerve branch that normally supplies them, become responsive to excitatory inputs from the other, remaining intact vestibular afferents. This substitution of inputs through the reorganization of synaptic connectivity is similar to that seen in other sensory systems after partial deafferentation: for example, the area of the somatosensory cortex concerned with a particular body part gradually becomes responsive to inputs from adjacent regions, if its normal input region Paterson/Menzies/Bergquist/Dutia

is deafferented [43]. In the VN, such ‘rewiring’ of synaptic connectivity has the beneficial effect that the deafferented MVN neurons receive substitute excitatory inputs that may help to restore and maintain their resting discharge [4]. However the rewired connections may now generate quite inappropriate vestibular reflexes, since the MVN neurons which were previously concerned with, for example, horizontal canal afferent inputs may now receive synaptic excitation from utricular afferents, and so generate horizontal eye movements in response to head movements in the vertical plane [4, 20]. Thus, while synaptic rewiring may help to the restoration of resting activity in the deafferented MVN neurons and contribute to their long-term survival after UVD, the generation of new and inappropriate reflexes as a consequence of rewiring indicates that the suppression of such reflexes, by for example alternative non-vestibular strategies for gaze stabilization, may be an important part of the overall process of VC. Postlesional Changes in the Control of VN Neurons by the Cerebellum While the cerebellum and in particular the flocculus has long been known to be important in calibrating the gaze-stabilizing function of the hVOR, the role of the flocculus in VC has been unclear. In a recent review, Kitahara et al. [44] have demonstrated that the flocculus plays an important role in the early compensation of static symptoms, particularly ocular nystagmus. An important role for the flocculus is also indicated by the finding that in a knockout mouse lacking the delta-2 subunit of the glutamate receptor, which is selectively localized in cerebellar Purkinje cells and which is essential for cerebellar cortical plasticity, the severity of ocular nystagmus after UVD is exaggerated, and the time course of recovery is prolonged [45]. Consistent with this are the findings that indicate that cerebellar cortical plasticity in the flocculus occurs after UVD, and is required for compensation [46–50]. However, the flocculus is not essential for VC, as even in flocculectomized animals the ocular nystagmus eventually disappears completely; thus, other processes, such as the changes in intrinsic properties of MVN neurons, and synaptic reorganization of the brainstem vestibular pathways, may be sufficient to achieve compensation but over a longer recovery time. For the normal development of VC and the relatively rapid subsidence of nystagmus within a few days however, the flocculus appears to play an important but as yet unclear role. As proposed by Kitahara et al. [12, 44, 51], the flocculus may act to inhibit the activity of contralesional MVN Mechanisms of Vestibular Compensation

neurons (fig. 2b), and so reduce the commissural inhibition they project to the deafferented ipsilesional MVN cells after UVD. At present, the effects of UVD on the activity of Purkinje cells in the ipsi- and contralesional flocculi have not been investigated in any detail, and further experiments are necessary to clarify the role played by the cerebellum in the early stages of VC.

Interactions between Stress, the Neuroendocrine System and Brain Plasticity in VC

Recent research has also shown that the development of VC after UVD is significantly affected by stress, stressrelated steroids as well as conditions such as anxiety and depression, where the normal function of the hypothalamo-pituitary-adrenal stress axis is altered. Glucocorticoids released by the adrenal cortex in response to stressinduced hypothalamo-pituitary-adrenal activation have widespread actions throughout the body; in addition, they have important modulatory effects on the function of neurons and synapses in the brain. Glucocorticoids may act directly on membrane ion channels and neurotransmitter receptors to regulate their function, or they may alter gene expression in neurons through specific intracellular receptors [glucocorticoid receptors (GRs) or mineralocorticoid receptors], and they may be rapidly converted by a range of enzymes to active neurosteroids. In addition to stress steroids, neurosteroids derived from the sex steroid progesterone also affect neuronal and synaptic function in the vestibular system and cerebellum [for a review see ref. 52]. A number of studies suggest that glucocorticoids and neurosteroids may have an important role in modulating the process of VC [52–55]. Anxiety and stress in patients with vertigo significantly delays the recovery from vestibular symptoms [56]. Conversely, treatment with methylprednisolone has been reported to improve VC in animal models [57], and promote recovery from acute vertigo or vestibular neuritis in humans [58, 59]. Yamanaka et al. [60] showed that administration of the synthetic GR agonist dexamethasone facilitated the behavioral recovery following UVD in the rabbit; in contrast, administration of the GR antagonist RU38486 delayed compensation. Glucocorticoids and neurosteroids have direct excitatory actions on MVN neurons [61–63]. However in a recent study, systemic administration of dexamethasone was found to have no effect on the rate of compensation of spontaneous nystagmus in the guinea pig [64].

Neuroembryol Aging 2004–05;3:183–193

189

At the neuronal level, the development of the increase in excitability of MVN neurons after UVD (fig. 1c) is dependent on the activation of GRs. Thus the increase in excitability of the ipsilesional MVN neurons was prevented by administration of the GR antagonist RU38486, and did not develop in animals that remained anesthetized after UVD. However, in anesthetized animals that were treated with the synthetic GR agonist dexamethasone simultaneously with UVD, the increase in excitability did occur [65]. These findings suggest that the acute stress that normally accompanies the behavioral symptoms immediately after UVD may have a role in facilitating the cellular plasticity in MVN neurons. An important site of action of glucocorticoids during VC would appear to be the cerebellar flocculus [50]. However, a critical optimal level of GR activation appears to be required, since additional stress in the form of restraint applied to a compensating animal after UVD causes a retardation of the behavioral recovery [66, reviewed in ref. 52]. The interactions between the stress axis, glucocorticoids and vestibular plasticity may have potentially important implications for the treatment and management of patients with balance disorders. Perhaps a factor in the known effectiveness of vestibular rehabilitation exercises in promoting VC may be the acute stress that accompanies the performance of initially aversive movements, which may facilitate the plasticity mechanisms in the brain that are necessary for VC. It is also possible that patients who are unable to compensate adequately after UVD may have preexisting alterations in their stress axis function through depression or anxiety, or develop changes in their stress axis as a result of the vestibular dysfunction and the associated symptoms. This may result in too low or too high levels of stress responses to vestibular, visual and postural challenges, that may impede the cellular plasticity in the vestibular pathways necessary for VC. Further investigations to reveal the cellular mechanisms of action of stress steroids on VC are necessary in animal models, as well as studies of stress axis function in patients with balance disorders.

Studies of Changes in Gene and Protein Expression in the MVN during VC

In a search for the molecular mechanisms of plasticity in MVN neurons during VC, a number of studies have looked for changes in gene and/or protein expression after UVD. The changes in amino acid neurotransmitter receptor efficacy, the intrinsic properties of MVN neu190

Neuroembryol Aging 2004–05;3:183–193

Table 1. Summary of studies investigating changes in gene and protein expression in the MVN during VC

Main finding

Ref.

Asymmetric changes in c-fos expression during VC in the rat

71, 72

Increased phosphorylation of several likely PKC substrates in the MVN + prepositus hypoglossi 10–53 h after UVD

73

Intracerebroventricular administration of PKC inhibitors retards recovery of spontaneous nystagmus in the rat for up to 8 h after UVD

48

Upregulation of three unidentified proteins in guinea pig ipsilateral VN, 1 week after UVD

74

No change in PKC-mediated phosphorylation in guinea pig MVN, but increased phosphorylation in contralesional prepositus hypoglossi, 10–53 h after UVD

75

Increased immunoreactivity for the phosphorylated form of cAMP/calcium response element binding protein bilaterally in the rat VN, 1–24 h after UVD

76

Inhibition of PKC, but not Ca2+/calmodulin-dependent kinase II, in the VN affects recovery from spontaneous nystagmus but not postural symptoms in the guinea pig

70

No change in GAP-43 protein or mRNA in the rat VN after UVD

77

Downregulation of NR2A, GluR2 and GluR7 mRNA in ipsilesional MVN 6 h after UVD, but not 50 h after UVD, in the rat

78

Increase in expression of GAD65 mRNA bilaterally, and GABA-A receptor ␣1 subunit mRNA ipsilaterally, in rat VN 6–50 h after UVD

79

No change in voltage-gated Na channels or Ca-activated K channels in VN after UVD

69

Microarray analysis showed differing gene expression between ipsi- and contralesional rat VN complex, 6 h after UVD

80

Increased asymmetrical expression of extracellular signal-regulated kinase 1/2 in the rat VN 5–90 min after UVD

81

No change in glycine receptors and gephyrin protein in VN after UVD in the rat Change in histamine H3 receptor mRNA expression in rat ipsilesional VN 24 h after UVD

67

No change in GABA-A and GABA-B receptor mRNA after UVD in the rat

68

PKC = Protein kinase C.

Paterson/Menzies/Bergquist/Dutia

82

rons, and the reorganization of neural connectivity that are implicated in VC, as reviewed above, may be brought about by a range of molecular mechanisms. These include changes dependent on alterations in gene expression, e.g. changes in neurotransmitter receptor subunit expression or composition, or the expression of molecules regulating neural growth and axon guidance, and changes not necessarily dependent on alterations of gene expression, e.g. involving changes in protein phosphorylation or other posttranslational modifications of proteins. A number of studies have reported such changes in the MVN after UVD (table 1), but no clear picture has yet emerged which appears to link many of the individual findings. In particular, painstaking and detailed analyses by Eleore et al. [67, 68] on glycine and GABA receptor gene expression in the MVN after UVD have not detected significant changes that might account for the functional downregulation of these receptors during VC. Similarly, no significant changes in voltage-gated Na channels and calciumactivated K channels, which might correlate with the changes in intrinsic excitability of MVN neurons, were detected at the gene level [69]. On the other hand, administration of protein kinase C (PKC) inhibitors has been shown to retard VC [48, 70], implying that protein phosphorylation in the MVN or related sites, is necessary. At present, the molecular mechanisms of VC remain intriguing but largely unclear.

the lesioned and intact sides which is seen immediately after unilateral labyrinthectomy, with the ipsilesional neurons falling silent while the contralesional neurons are hyperactive. The compensation of many static symptoms, such as spontaneous ocular nystagmus, is related to the ‘rebalancing’ of the resting firing rate of the VN neurons on the two sides. Experimental evidence from studies in animal models has indicated several parallel adaptive processes that may help to ‘rebalance’ the activity of the vestibular neurons of the two sides. These include adaptive changes in the sensitivity of the ipsilesional vestibular neurons to the inhibitory neurotransmitter receptors for GABA and glycine, changes in their intrinsic electrophysiological excitability, changes in the inhibitory control of the brainstem vestibular networks by the cerebellar flocculus, and an activity-dependent reorganization of the synaptic connectivity of the vestibular reflex pathways. By contrast, the dynamic deficits in the vestibular reflexes that follow unilateral vestibular damage do not show much functional recovery, even over the long term. Instead, compensation for the permanently compromised vestibular reflexes appears to be achieved by the development of new behavioral strategies such as minimizing head turns, blinking during rotations, and the suppression of inappropriate reflex responses evoked by vestibular stimulation. The brain mechanisms involved in compensation for dynamic deficits are complex, involving many structures in addition to the VN, and are largely unexplored.

Conclusion

VC, the overall behavioral recovery after peripheral vestibular damage, is a complex and multifactorial process. An important factor causing prominent initial static symptoms in the vestibulo-oculomotor system is the large imbalance in the firing rate of the VN neurons on

Acknowledgment Research in the laboratory of M.B.D. is supported by the Wellcome Trust, BBSRC and EPSRC.

References 1 Curthoys IS, Halmagyi GM: Vestibular compensation: a review of the oculomotor, neural, and clinical consequences of unilateral vestibular loss. J Vestib Res 1995;5:67–107. 2 Curthoys IS, Halmagyi GM: Vestibular compensation. Adv Otorhinolaryngol 1999; 55: 82–110. 3 Dieringer N: ‘Vestibular compensation’: neural plasticity and its relations to functional recovery after labyrinthine lesions in frogs and other vertebrates. Prog Neurobiol 1995;46:97–129.

Mechanisms of Vestibular Compensation

4 Dieringer N: Activity-related postlesional vestibular reorganization. Ann NY Acad Sci 2003;1004:50–60. 5 Curthoys IS: Vestibular compensation and substitution. Curr Opin Neurol 2000;13:27– 30. 6 Darlington CL, Dutia MB, Smith PF: The contribution of the intrinsic excitability of vestibular nucleus neurons to recovery from vestibular damage. Eur J Neurosci 2002; 15: 1719–1727.

7 Darlington CL, Smith PF: Molecular mechanisms of recovery from vestibular damage in mammals: recent advances. Prog Neurobiol 2000;62:313–325. 8 Straka H, Vibert N, Vidal PP, Moore LE, Dutia MB: Intrinsic membrane properties of vertebrate vestibular neurons: function, development and plasticity. Prog Neurobiol 2005;76:349–392. 9 Schaefer KP, Meyer DL: Compensation of vestibular lesions; in Kornhuber HH (ed): Handbook of Sensory Physiology. Berlin, Springer, 1974, pp 463–490.

Neuroembryol Aging 2004–05;3:183–193

191

10 Vidal PP, de Waele C, Vibert N, Muhlethaler M: Vestibular compensation revisited. Otolaryngol Head Neck Surg 1998;119:34–42. 11 Kitahara T, Takeda N, Saika T, Kubo T, Kiyama H: Effects of MK801 on Fos expression in the rat brainstem after unilateral labyrinthectomy. Brain Res 1995;700:182–190. 12 Kitahara T, Fukushima M, Takeda N, Saika T, Kubo T: Effects of pre-flocculectomy on Fos expression and NMDA receptor-mediated neural circuits in the central vestibular system after unilateral labyrinthectomy. Acta Otolaryngol 2000;120:866–871. 13 Magnusson AK, Eriksson B, Tham R: Effects of the GABA agonists baclofen and THIP on long-term compensation in hemilabyrinthectomised rats. Brain Res 1998; 795: 307– 311. 14 Magnusson AK, Lindstrom S, Tham R: GABA(B) receptors contribute to vestibular compensation after unilateral labyrinthectomy in pigmented rats. Exp Brain Res 2000; 134:32–41. 15 Magnusson AK, Ulfendahl M, Tham R: Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABA(B) receptor function. Neuroscience 2002;111:625–634. 16 Cass SP, Kartush JM, Graham MD: Patterns of vestibular function following vestibular nerve section. Laryngoscope 1992; 102: 388– 394. 17 Fetter M, Zee DS: Recovery from unilateral labyrinthectomy in rhesus monkey. J Neurophysiol 1988;59:370–393. 18 Smith PF, Curthoys IS: Mechanisms of recovery following unilateral labyrinthectomy: a review. Brain Res Brain Res Rev 1989; 14:155–180. 19 Gilchrist DP, Curthoys IS, Cartwright AD, Burgess AM, Topple AN, Halmagyi M: High acceleration impulsive rotations reveal severe long-term deficits of the horizontal vestibulo-ocular reflex in the guinea pig. Exp Brain Res 1998;123:242–254. 20 Rohregger M, Dieringer N: Postlesional vestibular reorganization improves the gain but impairs the spatial tuning of the maculo-ocular reflex in frogs. J Neurophysiol 2003;90: 3736–3749. 21 Shimazu H, Precht W: Inhibition of central vestibular neurons from the contralateral labyrinth and its mediating pathway. J Neurophysiol 1966; 29:467–492. 22 Dieringer N, Precht W: Mechanisms of compensation for vestibular deficits in the frog. I. Modification of the excitatory commissural system. Exp Brain Res 1979;36:311–328. 23 Dieringer N, Precht W: Mechanisms of compensation for vestibular deficits in the frog. II. Modification of the inhibitory pathways. Exp Brain Res 1979;36:329–357. 24 Smith PF, Curthoys IS: Neuronal activity in the ipsilateral medial vestibular nucleus of the guinea pig following unilateral labyrinthectomy. Brain Res 1988;444:308–319.

192

25 Smith PF, Curthoys IS: Neuronal activity in the contralateral medial vestibular nucleus of the guinea pig following unilateral labyrinthectomy. Brain Res 1988;444:295–307. 26 Newlands SD, Perachio AA: Compensation of horizontal canal related activity in the medial vestibular nucleus following unilateral labyrinth ablation in the decerebrate gerbil. II. Type II neurons. Exp Brain Res 1990; 82: 373–383. 27 Ris L, Capron B, de Waele C, Vidal PP, Godaux E: Dissociations between behavioural recovery and restoration of vestibular activity in the unilabyrinthectomized guinea-pig. J Physiol (Lond) 1997;500:509–522. 28 Ris L, de Waele C, Serafin M, Vidal PP, Godaux E: Neuronal activity in the ipsilateral vestibular nucleus following unilateral labyrinthectomy in the alert guinea pig. J Neurophysiol 1995;74:2087–2099. 29 Ris L, Godaux E: Neuronal activity in the vestibular nuclei after contralateral or bilateral labyrinthectomy in the alert guinea pig. J Neurophysiol 1998; 80:2352–2367. 30 Arnold DB, Robinson DA: The oculomotor integrator: testing of a neural network model. Exp Brain Res 1997;113:57–74. 31 Graham BP, Dutia MB: Cellular basis of vestibular compensation: analysis and modelling of the role of the commissural inhibitory system. Exp Brain Res 2001;137:387–396. 32 de Waele C, Muhlethaler M, Vidal PP: Neurochemistry of the central vestibular pathways. Brain Res Brain Res Rev 1995; 20: 24– 46. 33 Yamanaka T, Him A, Cameron SA, Dutia MB: Rapid compensatory changes in GABA receptor efficacy in rat vestibular neurones after unilateral labyrinthectomy. J Physiol (Lond) 2000;523:413–424. 34 Vibert N, Beraneck M, Bantikyan A, Vidal PP: Vestibular compensation modifies the sensitivity of vestibular neurones to inhibitory amino acids. Neuroreport 2000; 11: 1921–1927. 35 Johnston AR, Him A, Dutia MB: Differential regulation of GABA(A) and GABA(B) receptors during vestibular compensation. Neuroreport 2001;12:597–600. 36 Cameron SA, Dutia MB: Cellular basis of vestibular compensation: changes in intrinsic excitability of MVN neurones. Neuroreport 1997;8:2595–2599. 37 Him A, Dutia MB: Intrinsic excitability changes in vestibular nucleus neurons after unilateral deafferentation. Brain Res 2001; 908:58–66. 38 Beraneck M, Hachemaoui M, Idoux E, Ris L, Uno A, Godaux E, Vidal PP, Moore LE, Vibert N: Long-term plasticity of ipsilesional medial vestibular nucleus neurons after unilateral labyrinthectomy. J Neurophysiol 2003;90:184–203.

Neuroembryol Aging 2004–05;3:183–193

39 Beraneck M, Idoux E, Uno A, Vidal PP, Moore LE, Vibert N: Unilateral labyrinthectomy modifies the membrane properties of contralesional vestibular neurons. J Neurophysiol 2004;92:1668–1684. 40 Goto F, Straka H, Dieringer N: Expansion of afferent vestibular signals after the section of one of the vestibular nerve branches. J Neurophysiol 2000; 84:581–584. 41 Goto F, Straka H, Dieringer N: Postlesional vestibular reorganization in frogs: evidence for a basic reaction pattern after nerve injury. J Neurophysiol 2001; 85:2643–2646. 42 Goto F, Straka H, Dieringer N: Gradual and reversible central vestibular reorganization in frog after selective labyrinthine nerve branch lesions. Exp Brain Res 2002;147:374– 386. 43 Pons TP, Garraghty PE, Ommaya AK, Kaas JH, Taub E, Mishkin M: Massive cortical reorganization after sensory deafferentation in adult macaques. Science 1991; 252: 1857– 1860. 44 Kitahara T, Takeda N, Kiyama H, Kubo T: Molecular mechanisms of vestibular compensation in the central vestibular system – review. Acta Otolaryngol Suppl 1998; 539: 19–27. 45 Murai N, Tsuji J, Ito J, Mishina M, Hirano T: Vestibular compensation in glutamate receptor delta-2 subunit knockout mice: dynamic property of vestibulo-ocular reflex. Eur Arch Otorhinolaryngol 2004; 261: 82– 86. 46 Kitahara T, Takeda N, Saika T, Kubo T, Kiyama H: Role of the flocculus in the development of vestibular compensation: immunohistochemical studies with retrograde tracing and flocculectomy using Fos expression as a marker in the rat brainstem. Neuroscience 1997;76:571–580. 47 Kitahara T, Takeda N, Kubo T, Kiyama H: An implication of protein phosphatase 2Abeta in the rat flocculus for lesion-induced vestibular plasticity. Acta Otolaryngol 1998; 118:685–691. 48 Balaban CD, Freilino M, Romero GG: Protein kinase C inhibition blocks the early appearance of vestibular compensation. Brain Res 1999;845:97–101. 49 Barmack NH, Qian ZY, Kim HJ, Yoshimura J: Activity-dependent distribution of protein kinase C-delta within rat cerebellar Purkinje cells following unilateral labyrinthectomy. Exp Brain Res 2001;141:6–20. 50 Johnston AR, Seckl JR, Dutia MB: Role of the flocculus in mediating vestibular nucleus neuron plasticity during vestibular compensation in the rat. J Physiol 2002; 545: 903– 911. 51 Kitahara T, Takeda N, Kubo T, Kiyama H: Nitric oxide in the flocculus works the inhibitory neural circuits after unilateral labyrinthectomy. Brain Res 1999;815:405–409. 52 Seemungal BM, Gresty MA, Bronstein AM: The endocrine system, vertigo and balance. Curr Opin Neurol 2001;14:27–34.

Paterson/Menzies/Bergquist/Dutia

53 Jacob RG, Furman JM: Psychiatric consequences of vestibular dysfunction. Curr Opin Neurol 2001;14:41–46. 54 Balaban CD, Thayer JF: Neurological bases for balance-anxiety links. J Anxiety Disord 2001;15:53–79. 55 Balaban CD: Neural substrates linking balance control and anxiety. Physiol Behav 2002;77:469–475. 56 Yardley L, Beech S, Zander L, Evans T, Weinman J: A randomized controlled trial of exercise therapy for dizziness and vertigo in primary care (see comments). Br J Gen Pract 1998;48:1136–1140. 57 Jerram AH, Darlington CL, Smith PF: Methylprednisolone reduces spontaneous nystagmus following unilateral labyrinthectomy in guinea pig. Eur J Pharmacol 1995; 275: 291– 293. 58 Ariyasu L, Byl FM, Sprague MS, Adour KK: The beneficial effect of methylprednisolone in acute vestibular vertigo. Arch Otolaryngol Head Neck Surg 1990;116:700–703. 59 Strupp M, Zingler VC, Arbusow V, Niklas D, Maag KP, Dieterich M, Bense S, Theil D, Jahn K, Brandt T: Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J Med 2004;351:354–361. 60 Yamanaka T, Sasa M, Amano T, Miyahara H, Matsunaga T: Role of glucocorticoid in vestibular compensation in relation to activation of vestibular nucleus neurons. Acta Otolaryngol Suppl 1995; 519:168–172. 61 Yamamoto T, Yamanaka T, Matsunaga T: Effects of the neurosteroid dehydroepiandrosterone sulfate on medial vestibular nucleus neurons. Acta Otolaryngol 1998; 118: 185– 191. 62 Yamamoto T, Yamanaka T, Miyahara H, Matsunaga T: The neurosteroid pregnenolone sulfate excites medial vestibular nucleus neurons. Acta Otolaryngol Suppl 1998; 533: 22–25. 63 Yamanaka T, Amano T, Sasa M, Matsunaga T: Prednisolone excitation of medial vestibular nucleus neurons in cats. Eur Arch Otorhinolaryngol 1995; 252:112–118. 64 Alice C, Paul AE, Sansom AJ, Maclennan K, Darlington CL, Smith PF: The effects of steroids on vestibular compensation and vestibular nucleus neuronal activity in the guinea pig. J Vestib Res 1998;8:201–207.

Mechanisms of Vestibular Compensation

65 Cameron SA, Dutia MB: Lesion-induced plasticity in rat vestibular nucleus neurones dependent on glucocorticoid receptor activation. J Physiol 1999;518(Pt 1):151–158. 66 Yamamoto T, Yamanaka T, Matsunaga T: The effect of stress application on vestibular compensation. Acta Otolaryngol 2000; 120: 504–507. 67 Eleore L, Vassias I, Vidal PP, de Waele C: An in situ hybridization and immunofluorescence study of glycinergic receptors and gephyrin in the vestibular nuclei of the intact and unilaterally labyrinthectomized rat. Exp Brain Res 2004;154:333–344. 68 Eleore L, Vassias I, Bernat I, Vidal PP, de Waele C: An in situ hybridization and immunofluorescence study of GABA(A) and GABA(B) receptors in the vestibular nuclei of the intact and unilaterally labyrinthectomized rat. Exp Brain Res 2005;160:166–179. 69 Patko T, Vassias I, Vidal PP, De Waele C: Modulation of the voltage-gated sodiumand calcium-dependent potassium channels in rat vestibular and facial nuclei after unilateral labyrinthectomy and facial nerve transsection: an in situ hybridization study. Neuroscience 2003;117:265–280. 70 Sansom AJ, Smith PF, Darlington CL, Laverty R: The effects of protein kinase C and calmodulin kinase II inhibitors on vestibular compensation in the guinea pig. Brain Res 2000;882:45–54. 71 Kaufman GD, Anderson JH, Beitz AJ: Brainstem Fos expression following acute unilateral labyrinthectomy in the rat. Neuroreport 1992;3:829–832. 72 Cirelli C, Pompeiano M, D’Ascanio P, Arrighi P, Pompeiano O: c-fos expression in the rat brain after unilateral labyrinthectomy and its relation to the uncompensated and compensated stages. Neuroscience 1996; 70: 515–546. 73 Sansom AJ, Brent VA, Jarvie PE, Darlington CL, Smith PF, Laverty R, Rostas JA: In vitro phosphorylation of medial vestibular nucleus and prepositus hypoglossi proteins during behavioural recovery from unilateral vestibular deafferentation in the guinea pig. Brain Res 1997;778:166–177. 74 Ris L, Wattiez R, Falmagne P, Godaux E: Changes in protein expression in the vestibular nuclei during vestibular compensation. Neuroreport 1999;10:3333–3339.

75 Kerr DR, Sansom AJ, Smith PF, Darlington CL: Comparison of protein kinase activity and protein phosphorylation in the medial vestibular nucleus and prepositus hypoglossi in labyrinthine-intact and labyrinthectomized guinea pigs. J Vestib Res 2000;10:107– 117. 76 Kim MS, Kim JH, Lee MY, Chun SW, Lee SH, Park BR: Identification of phosphorylated form of cAMP/calcium response element binding protein expression in the brain stem nuclei at early stage of vestibular compensation in rats. Neurosci Lett 2000; 290: 173– 176. 77 de Waele C, Loquet G, Campos Torres A, Vidal PP: Lack of growth-associated protein43 reemergence or of growth-associated protein-43 mRNA modulation in deafferented vestibular nuclei during the first 6 weeks after unilateral inner ear lesion. Exp Brain Res 2000;132:464–475. 78 Horii A, Smith PF, Darlington CL: Quantitative changes in gene expression of glutamate receptor subunits/subtypes in the vestibular nucleus, inferior olive and flocculus before and following unilateral labyrinthectomy in the rat: real-time quantitative PCR method. Exp Brain Res 2001;139:188–200. 79 Horii A, Kitahara T, Smith PF, Darlington CL, Masumura C, Kubo T: Effects of unilateral labyrinthectomy on GAD, GAT1 and GABA receptor gene expression in the rat vestibular nucleus. Neuroreport 2003; 14: 2359–2363. 80 Horii A, Masumura C, Smith PF, Darlington CL, Kitahara T, Uno A, Mitani K, Kubo T: Microarray analysis of gene expression in the rat vestibular nucleus complex following unilateral vestibular deafferentation. J Neurochem 2004; 91:975–982. 81 Kim MS, Choi MA, Choi DO, Lee MY, Kim KY, Rhee JK, Jin YZ, Park BR: Asymmetric activation of extracellular signal-regulated kinase 1/2 in rat vestibular nuclei by unilateral labyrinthectomy. Brain Res 2004; 1011: 238–242. 82 Lozada AF, Aarnisalo AA, Karlstedt K, Stark H, Panula P: Plasticity of histamine H3 receptor expression and binding in the vestibular nuclei after labyrinthectomy in rat. BMC Neurosci 2004;5:32.

Neuroembryol Aging 2004–05;3:183–193

193