[The adult brain produces new neurons to restore balance after vestibular loss]. / Le cerveau adulte produit de nouveaux neurones pour restaurer l'équilibre après une perte vestibulaire.

Following partial or total loss of peripheral vestibular inputs, a phenomenon called central vestibular compensation takes place in the hours and days following the injury. This neuroplasticity process involves a mosaic of profound rearrangements within the brain stem vestibular nuclei. Among them, the setting of a new neuronal network is maybe the most original and unexpected, as it involves an adult reactive neurogenesis in a brain area not reported as neurogenic so far. Both the survival and functionality of this newly generated neuronal network will depend on its integration to pre-existing networks in the deafferented structure. Far from being aberrant, this new structural organization allows the use of inputs from other sensory modalities (vision and proprioception) to promote the restoration of the posture and equilibrium. We choose here to detail this model, which does not belong to the traditional niches of adult neurogenesis, but it is the best example so far of the reparative role of the adult neurogenesis. Not only it represents an original neuroplasticity mechanism, interesting for basic neuroscience, but it also opens new medical perspectives for the development of therapeutic approaches to alleviate vestibular disorders.

TITLE: Le cerveau adulte produit de nouveaux neurones pour restaurer l'équilibre après une perte vestibulaire. ABSTRACT: Un phénomène appelé « compensation vestibulaire ¼ se produit après une atteinte vestibulaire périphérique. Ce processus, qui permet un retour progressif de l'équilibre, se produit principalement au sein des noyaux vestibulaires du tronc cérébral, et met en jeu une mosaïque de réarrangements structurels. Parmi ceux-ci, la neurogenèse vestibulaire réactionnelle (NGVR) adulte est peut-être la plus inattendue, car elle se produit dans une région du cerveau qui n'a jamais été signalée auparavant comme neurogène. La survie et la fonctionnalité de ce réseau neuronal nouvellement généré dépendent de son intégration dans les réseaux préexistants des noyaux désafférentés. Cette organisation permet au cerveau d'utiliser les apports d'autres modalités sensorielles pour faciliter le rétablissement de la posture et de l'équilibre. C'est à ce jour le meilleur exemple du rôle réparateur de la neurogenèse adulte. Ces observations soulèvent de nombreuses questions sur la pertinence physiologique de la NGVR.

Compensación vestibular / Vestibular compensation

INTRODUCCIÓN Y OBJETIVO: La compensación vestibular es el conjunto de procesos que se ponen en marcha cuando tiene lugar una lesión a nivel vestibular sea cual sea el origen y la magnitud de la misma. a vez establecida la lesión los mecanismos de compensación del daño son variados y se establecen diferentes líneas de actuación. Para conocer cómo mejorar el estado de nuestros pacientes es importante saber cómo funciona la compensación vestibular y a qué niveles podemos actuar para acelerar el proceso de recuperación. CONCLUSIONES: Es importante conocer los mecanismos de compensación vestibular para adecuar la terapia a cada paciente y así mejorar su calidad de vida

INTRODUCTION AND OBJECTIVE: Vestibular compensation is the term used to describe the mechanisms triggered when there is damage in the vestibular system regardless of its origin. When suffering from an injure in vestibular area there are a wide range of compensatory responses that will involve different approaches. In order to improve the quality of life for our patients and to correctly work with them to accelerate the restoration process it is important to become acquainted with how vestibular compensation works. CONCLUSIONS: Vestibular compensation mechanisms are important to adapt the therapy to each patient and thus improve their quality of life

BDNF Signaling Promotes Vestibular Compensation by Increasing Neurogenesis and Remodeling the Expression of Potassium-Chloride Cotransporter KCC2 and GABAA Receptor in the Vestibular Nuclei.

UNLABELLED: Reactive cell proliferation occurs rapidly in the cat vestibular nuclei (VN) after unilateral vestibular neurectomy (UVN) and has been reported to facilitate the recovery of posturo-locomotor functions. Interestingly, whereas animals experience impairments for several weeks, extraordinary plasticity mechanisms take place in the local microenvironment of the VN: newborn cells survive and acquire different phenotypes, such as microglia, astrocytes, or GABAergic neurons, whereas animals eventually recover completely from their lesion-induced deficits. Because brain-derived neurotrophic factor (BDNF) can modulate vestibular functional recovery and neurogenesis in mammals, in this study, we examined the effect of BDNF chronic intracerebroventricular infusion versus K252a (a Trk receptor antagonist) in our UVN model. Results showed that long-term intracerebroventricular infusion of BDNF accelerated the restoration of vestibular functions and significantly increased UVN-induced neurogenesis, whereas K252a blocked that effect and drastically delayed and prevented the complete restoration of vestibular functions. Further, because the level of excitability in the deafferented VN is correlated with behavioral recovery, we examined the state of neuronal excitability using two specific markers: the cation-chloride cotransporter KCC2 (which determines the hyperpolarizing action of GABA) and GABAA receptors. We report for the first time that, during an early time window after UVN, significant BDNF-dependent remodeling of excitability markers occurs in the brainstem. These data suggest that GABA acquires a transient depolarizing action during recovery from UVN, which potentiates the observed reactive neurogenesis and accelerates vestibular functional recovery. These findings suggest that BDNF and/or KCC2 could represent novel treatment strategies for vestibular pathologies. SIGNIFICANCE STATEMENT: In this study, we report for the first time that brain-derived neurotrophic factor potentiates vestibular neurogenesis and significantly accelerates functional recovery after unilateral vestibular injury. We also show that specific markers of excitability, the potassium-chloride cotransporter KCC2 and GABAA receptors, undergo remarkable fluctuations within vestibular nuclei (VN), strongly suggesting that GABA acquires a transient depolarizing action in the VN during the recovery period. This novel plasticity mechanism could explain in part how the system returns to electrophysiological homeostasis between the deafferented and intact VN, considered in the literature to be a key parameter of vestibular compensation. In this context, our results open new perspectives for the development of therapeutic approaches to alleviate the vestibular symptoms and favor vestibular function recovery.

[Discovering a new functional neurogenic zone: the vestibular nuclei of the brainstem]. / Une nouvelle zone de neurogenèse fonctionnelle: les noyaux vestibulaires du tronc cérébral.

The adult mammal brain is mostly considered as non-neurogenic, except in the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus, where ongoing neurogenesis occurs. However, anti-neurogenic influences can be removed in pathological conditions or after specific injury. That is what happens in a model of unilateral vestibular neurectomy (UVN) that mimics human pathology in adult cats. We showed for the first time that a UVN promoted an intense reactive cell proliferation in the deafferented vestibular nuclei located in the brainstem. The new cells survived up to one month, differentiated into glial cells - microglia or astrocytes - or GABAergic neurons, so highlighting a GABAergic neurogenesis. Surprisingly, we further showed that post-UVN reactive cell proliferation contributed successfully to fine restoration of vestibular posturo-locomotor functions. In conclusion, these pioneering studies bring new pieces of a promising puzzle in both stem cell and vestibular therapy domains.

Adaptation of chicken vestibular nucleus neurons to unilateral vestibular ganglionectomy.

Vestibular compensation refers to the behavioral recovery after a unilateral peripheral vestibular lesion. In chickens, posture and balance deficits are present immediately following unilateral vestibular ganglionectomy (UVG). After three days, most operated chickens begin to recover, but severe deficits persist in others. The tangential nucleus is a major avian vestibular nucleus whose principal cells are vestibular reflex projection neurons. From patch-clamp recordings on brain slices, the percentage of spontaneous spike firing principal cells, spike discharge rate, ionic conductances, and spontaneous excitatory postsynaptic currents (sEPSCs) were investigated one and three days after UVG. Already by one day after UVG, sEPSC frequency increased significantly on the lesion side, although no differences were detected in the percentage of spontaneous spike firing cells or discharge rate. In compensated chickens three days after UVG, the percentage of spontaneous spike firing cells increased on the lesion side and the discharge rate increased bilaterally. In uncompensated chickens three days after UVG, principal cells on the lesion side showed increased discharge rate and increased sEPSC frequency, whereas principal cells on the intact side were silent. Typically, silent principal cells exhibited smaller persistent sodium conductances and higher activation thresholds for the fast sodium channel than spiking cells. In addition, silent principal cells on the intact side of uncompensated chickens had larger dendrotoxin-sensitive potassium conductance, with a higher ratio of Kv1.1 surface/cytoplasmic expression. Increased sEPSC frequency in principal cells on the lesion side of uncompensated chickens was accompanied by decreased Kv1.2 immunolabeling of presynaptic terminals on principal cell bodies. Thus, both intrinsic ionic conductances and excitatory synaptic inputs play crucial roles at early stages after lesions. Unlike the principal cells in compensated chickens which showed similar percentages of spontaneous spike firing cells, discharge rates, and sEPSC frequencies bilaterally, principal cells in uncompensated chickens displayed gross asymmetry in these properties bilaterally.

Synaptic protein expression in the medial temporal lobe and frontal cortex following chronic bilateral vestibular loss.

Several studies have reported that bilateral vestibular deafferentation (BVD) results in the disruption of place cell function and theta activity in the hippocampus. Recent magnetic resonance imaging (MRI) studies in humans demonstrated that bilateral but not unilateral vestibular loss is associated with a bilateral atrophy of the hippocampus. In this study we investigated whether BVD in rats resulted in changes in the expression of four proteins related to neuronal plasticity, synaptophysin, SNAP-25, drebrin and neurofilament-L, in the hippocampal subregions (CA1, CA2/3, the DG) and the entorhinal (EC), perirhinal (PRC) and frontal cortices (FC), using western blotting. At 6 months following BVD, there were no significant differences in the expression of synaptophysin in any region. There were also no significant differences in SNAP-25 expression in CA1, CA2/3, EC, PRC, or the FC; however, there was a significant increase in SNAP-25 expression in the DG compared to sham controls. Drebrin A and E expression was significantly reduced in the EC and drebrin A was significantly reduced in the FC of BVD animals. NF-L expression was not significantly different in CA1, CA2/3, DG, EC, or the PRC. However, its expression was significantly reduced in the FC of BVD animals. These data suggest that circumscribed neurochemical changes in SNAP-25, drebrin and NF-L expression occur in the DG, EC, and the FC over 6 months following BVD.

Vestibulosympathetic reflex mediates the pressor response to hypergravity in conscious rats: contribution of the diencephalon.

To investigate the mechanism of arterial pressure (AP) regulation during hypergravity, the AP response to gravitational force was examined in conscious rats and the AP was found to increase, depending on the degree of gravity load induced by centrifugation. At 20 s after application of 2, 3, or 5 G, the AP increased by 9+/-2, 20+/-3, or 24+/-3 mm Hg, respectively. The AP increase during first 60 s was suppressed by vestibular lesion or pretreatment with hexamethonium, suggesting that the vestibular system and sympathetic nerve system be involved, respectively, in the afferent and efferent pathways. To further examine the central pathway of this response, Fos expression in the brain was examined after exposure to 5 G for 90 min. Intense Fos expression was seen in the medial vestibular nucleus, paraventricular hypothalamic nucleus, autonomic nuclei in the brain stem in intact rats, but not in rats with vestibular lesion. To examine the involvement of the diencephalic nuclei in this pressor response, AP was measured under hypergravity in rats with midcollicular transection. In these rats, the AP change was minimal at 2, 3, and 5 G, indicating that nuclei rostral to the transection level were involved in the pressor response. These results indicate that output from the vestibular system project to the diencephalon, and activation of diencephalic nuclei is indispensable to the pressor response via the sympathetic nerve system.

Time course of eye nystagmus and body movement after peripheral vestibular lesions in guinea pigs.

Body movement of guinea pigs was measured using a force platform at various times before and after unilateral end organ ablation and before and after sham surgery. Both spontaneous and drop-evoked movement patterns differed in the same animal after vestibular ablation and from control animals that received sham lesions. Whereas measures of eye nystagmus disappeared by 48 h postablation, measures of body movement indicated persistent differences even at 72 h. We conclude that the force platform can differentiate between movement patterns of normal and vestibular-lesioned animals and, in fact, measures a vestibular deficiency that is independent of eye nystagmus. The force platform appears to be a useful addition to evaluate vestibular deficits as well as to detect any benefits of pharmacological or surgical therapies.

Effects on the vestibulo- and opto-oculomotor system in rats by lesions of the commissural vestibular fibres.

Eye movements were recorded from rats with a magnetic search coil system before and after sectioning of the midline commissural pathways in the brain stem at the level of the vestibular nuclei. After lesion, the findings were as follows: 1) During sinusoidal vestibular stimulation the eyes moved in a sinusoidal way similar to the head movement without any regular saccades. There was a reduced gain and a phase lead. 2) During optokinetic stimulation the eyes moved in the stimulus direction to an excentric position and stayed there until stimulation ceased. 3) During acceleratory/deceleratory rotation in the light there was a drift of the eyes in the direction of the expected slow phase movement to an excentric position. In some animals there was a directional asymmetry. The findings may be explained by a failure of the central neural integrator for horizontal eye movements. The results support the hypothesis that vestibular commissural fibres are of crucial importance for the function of this integrator system.

Cholinergic mechanisms related to REM sleep. III. Tonic and phasic inhibition of monosynaptic reflexes induced by an anticholinesterase in the decerebrate cat.

The depression of the postural activity induced by intravenous injection of eserine sulphate (0.1 mg/kg), an anticholinesterase, has been studied in precollicular decerebrate cats. The extensor and flexor monosynaptic reflexes elicited by single shock stimulation of the GS, P1-FDHL and DP nerves are tonically depressed during the episodes of postural atonia induced by the anticholinesterase. A further phasic depression of the monosynaptic reflexes occurs during the bursts of rapid eye movements (REM) typical of these episodes. These changes in spinal reflex activity closely resemble the tonic depression of the spinal reflexes described in the unrestrained cats during the desynchronized sleep as well as the phasic depression of the spinal reflexes characteristic of the hypnic bursts of REM. Results obtained after spinal cord section indicate that both the tonic and the phasic depression of the spinal reflexes induced by eserine are due to active inhibitory influences originating from supraspinal structures. A complete bilateral destruction of the vestibular nuclei or limited to the medial and descending vestibular nuclei abolishes not only the cholinergically induced bursts of REM, as reported in a previous paper, but also the related phasic depression of the monosynaptic reflexes. These findings can be related with previous observations showing that a bilateral lesion of the vestibular nuclei abolishes the REM bursts of desynchronized sleep, as well as the related phasic inhibition of the spinal reflexes. The tonic depression of the monosynaptic reflexes induced by the anticholinesterase, on the other hand, remains unmodified by this vestibular lesion. This depression, therefore, can be attributed to supraspinal descending inhibitory volleys originating from extravestibular structures.