Adult and endemic neurogenesis in the vestibular nuclei after unilateral vestibular neurectomy.

We previously revealed adult reactive neurogenesis in deafferented vestibular nuclei following unilateral vestibular neurectomy (UVN) in the feline model. We recently replicated the same surgery in a rodent model and aimed to elucidate the origin and fate of newly generated cells following UVN. We used specific markers of cell proliferation, glial reaction, and cell differentiation in the medial vestibular nucleus (MVN) of adult rats. UVN induced an intense cell proliferation and glial reaction with an increase of GFAP-Immunoreactive (Ir), IBA1-Ir and Olig2-Ir cells 3 days after the lesion in the deafferented MVN. Most of the newly generated cells survived after UVN and differentiated into oligodendrocytes, astrocytes, microglial cells and GABAergic neurons. Interestingly, UVN induced a significant increase in a population of cells colocalizing SOX2 and GFAP 3 days after lesion in the deafferented MVN indicating the probable presence of multipotent cells in the vestibular nuclei. The concomitant increase in BrdU- and SOX2-Ir cells with the presence of SOX2 and GFAP colocalization 3 days after UVN in the deafferented MVN may support local mitotic activity of endemic quiescent neural stem cells in the parenchyma of vestibular nuclei.

The tangential nucleus controls a gravito-inertial vestibulo-ocular reflex.

BACKGROUND: Although adult vertebrates sense changes in head position by using two classes of accelerometer, at larval stages zebrafish lack functional semicircular canals and rely exclusively on their otolithic organs to transduce vestibular information. RESULTS: Despite this limitation, we find that larval zebrafish perform an effective vestibulo-ocular reflex (VOR) that serves to stabilize gaze in response to pitch and roll tilts. By using single-cell electroporations and targeted laser ablations, we identified a specific class of central vestibular neurons, located in the tangential nucleus, that are essential for the utricle-dependent VOR. Tangential nucleus neurons project contralaterally to extraocular motoneurons and in addition to multiple sites within the reticulospinal complex. CONCLUSIONS: We propose that tangential neurons function as a broadband inertial accelerometer, processing utricular acceleration signals to control the activity of extraocular and postural neurons, thus completing a fundamental three-neuron circuit responsible for gaze stabilization.

Cerebellar grafting in the oculomotor system as a model to study target influence on adult neurons.

In the last decades, there have been many efforts directed to gain a better understanding on adult neuron-target cell relationships. Embryonic grafts have been used for the study of neural circuit rewiring. Thus, using several donor neuronal tissues, such as cerebellum or striatum, developing grafted cells have been shown to have the capability of substituting neural cell populations and establishing reciprocal connections with the host. In addition, different lesion paradigms have also led to a better understanding of target dependence in neuronal cells. Thus, for example, axotomy induces profound morphofunctional changes in adult neurons, including the loss of synaptic inputs and discharge alterations. These alterations are probably due to trophic factor loss in response to target disconnection. In this review, we summarize the different strategies performed to disconnect neurons from their targets, and the effects of target substitution, performed by tissue grafting, upon neural properties. Using the oculomotor system-and more precisely the abducens internuclear neurons-as a model, we describe herein the effects of disconnecting a population of central neurons from its natural target (i.e., the medial rectus motoneurons at the mesencephalic oculomotor nucleus). We also analyze target-derived influences in the structure and physiology of these neurons by using cerebellar embryonic grafts as a new target for the axotomized abducens internuclear neurons.

Effects of bilateral vestibular nucleus lesions on cardiovascular regulation in conscious cats.

The vestibular system participates in cardiovascular regulation during postural changes. In prior studies (Holmes MJ, Cotter LA, Arendt HE, Cas SP, and Yates BJ. Brain Res 938: 62-72, 2002, and Jian BJ, Cotter LA, Emanuel BA, Cass SP, and Yates BJ. J Appl Physiol 86: 1552-1560, 1999), transection of the vestibular nerves resulted in instability in blood pressure during nose-up body tilts, particularly when no visual information reflecting body position in space was available. However, recovery of orthostatic tolerance occurred within 1 wk, presumably because the vestibular nuclei integrate a variety of sensory inputs reflecting body location. The present study tested the hypothesis that lesions of the vestibular nuclei result in persistent cardiovascular deficits during orthostatic challenges. Blood pressure and heart rate were monitored in five conscious cats during nose-up tilts of varying amplitude, both before and after chemical lesions of the vestibular nuclei. Before lesions, blood pressure remained relatively stable during tilts. In all animals, the blood pressure responses to nose-up tilts were altered by damage to the medial and inferior vestibular nuclei; these effects were noted both when animals were tested in the presence and absence of visual feedback. In four of the five animals, the lesions also resulted in augmented heart rate increases from baseline values during 60 degrees nose-up tilts. These effects persisted for longer than 1 wk, but they gradually resolved over time, except in the animal with the worst deficits. These observations suggest that recovery of compensatory cardiovascular responses after loss of vestibular inputs is accomplished at least in part through plastic changes in the vestibular nuclei and the enhancement of the ability of vestibular nucleus neurons to discriminate body position in space by employing nonlabyrinthine signals.

Plasticity of histamine H3 receptor expression and binding in the vestibular nuclei after labyrinthectomy in rat.

BACKGROUND: In rat, deafferentation of one labyrinth (unilateral labyrinthectomy) results in a characteristic syndrome of ocular and motor postural disorders (e.g., barrel rotation, circling behavior, and spontaneous nystagmus). Behavioral recovery (e.g., diminished symptoms), encompassing 1 week after unilateral labyrinthectomy, has been termed vestibular compensation. Evidence suggesting that the histamine H3 receptor plays a key role in vestibular compensation comes from studies indicating that betahistine, a histamine-like drug that acts as both a partial histamine H1 receptor agonist and an H3 receptor antagonist, can accelerate the process of vestibular compensation. RESULTS: Expression levels for histamine H3 receptor (total) as well as three isoforms which display variable lengths of the third intracellular loop of the receptor were analyzed using in situ hybridization on brain sections containing the rat medial vestibular nucleus after unilateral labyrinthectomy. We compared these expression levels to H3 receptor binding densities. Total H3 receptor mRNA levels (detected by oligo probe H3X) as well as mRNA levels of the three receptor isoforms studied (detected by oligo probes H3A, H3B, and H3C) showed a pattern of increase, which was bilaterally significant at 24 h post-lesion for both H3X and H3C, followed by significant bilateral decreases in medial vestibular nuclei occurring 48 h (H3X and H3B) and 1 week post-lesion (H3A, H3B, and H3C). Expression levels of H3B was an exception to the forementioned pattern with significant decreases already detected at 24 h post-lesion. Coinciding with the decreasing trends in H3 receptor mRNA levels was an observed increase in H3 receptor binding densities occurring in the ipsilateral medial vestibular nuclei 48 h post-lesion. CONCLUSION: Progressive recovery of the resting discharge of the deafferentated medial vestibular nuclei neurons results in functional restoration of the static postural and occulomotor deficits, usually occurring within a time frame of 48 hours in rats. Our data suggests that the H3 receptor may be an essential part of pre-synaptic mechanisms required for reestablishing resting activities 48 h after unilateral labyrinthectomy.

Modulation of the beta1-3 voltage-gated sodium channels in rat vestibular and facial nuclei after unilateral labyrinthectomy and facial nerve section: an in situ hybridization study.

We investigated whether the production of the mRNAs for the auxiliary beta subunits of the Na channels are modulated in deafferented medial vestibular nucleus (MVN) and in axotomized facial motoneurons. No beta1-3 mRNAs modulation was detected at any time following unilateral labyrinthectomy in the deafferented and intact medial vestibular nucleus. In contrast, beta1 gene expression in the axotomized facial nucleus decreased compared to controls as soon as day post-lesion 3.

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.

Transneuronal down regulation of vestibulo-ocular neurons following vestibular ablation.

Unilateral ablation of vestibular input causes lasting morphological changes bilaterally in superior vestibulo-ocular neurons (SVON). The present study was performed to see if these changes in SVON are more pronounced after bilateral vestibular neurectomy. Twenty-three SVON from both vestibular nuclei of 2 cats sacrificed 8 weeks after bilateral ablation were examined utilizing morphometric ultrastructural techniques. There was a significantly greater somal atrophy, loss of synaptic profiles, rough endoplasmic reticulum and polyribosomes compared to unilateral neurectomy. These changes indicate a down regulation that is proportional to the level of deafferentation and may account for functional deficits seen in the vestibulo-ocular reflex after peripheral ablation.

Quantitative changes of amino acid distributions in the rat vestibular nuclear complex after unilateral vestibular ganglionectomy.

Changes of amino acid concentrations in the vestibular nuclear complex (VNC) during lesion-induced vestibular compensation were studied in rats after unilateral vestibular ganglionectomy. Distributions of 12 amino acids within the VNC were measured at 2,4,7, and 30 days after surgery, using microdissection of freeze-dried brain sections and HPLC. Glutamate decreased on the lesioned side in nearly all VNC regions. Changes were fully developed 2 days after lesion and persisted through 30 days. In some regions, glutamate decreased also on the unlesioned side, especially at longer survival times, so that bilateral asymmetries became reduced. Aspartate changes were similar to those of glutamate on either side. Lesion-induced glutamine asymmetry was usually opposite to that of glutamate. Although GABA concentration decreased at early survival times, it recovered at later times and sometimes increased in dorsal parts of lateral and medial nuclei. Taurine changes were similar to those of GABA in most regions. Glycine change was primarily limited to a bilateral decrease in the dorsal part of the lateral vestibular nucleus. Concentrations of other amino acids were much lower, but some showed postlesion changes.

Recovery of head postural control following unilateral vestibular neurectomy in the cat. Neck muscle activity and neuronal correlates in Deiters' nuclei.

Recovery of head postural control after unilateral vestibular neurectomy was investigated in the alert cat by chronically recording the spontaneous neck muscle EMG activity from splenius capitis on both sides and the vestibulocollic reflexes evoked during roll and pitch tilts. Neuronal correlates occurring within the lateral (Deiters) vestibular nuclei (LVN) were also recorded during the time-course of recovery. During the acute phase (1-2 weeks), the cats exhibited strong imbalance in spontaneous neck muscle activity, characterized by increased muscular tone in the ipsilateral splenius capitis muscle and hypoactivity in the contralateral one. At the same time, the mean resting activity of Deiters' neurons strongly decreased on the deafferented side, while a slight but significant decrease was observed on the intact side. Vestibulocollic reflexes were totally lacking during the acute phase, whatever the direction and the amplitude of tilt. Recovery developed in the following weeks, leading to complete rebalance of spontaneous EMG activity as well as near to normal static vestibulocollic reflexes 5 weeks after the lesion. However, compensation remained sub-normal during roll tilts while overcompensation was found during pitch tilts, suggesting that the intact labyrinth would play a leader role in the recovery process but that bilateral cooperation of the two labyrinths is required for proper head postural control. Five weeks are also needed for a partial rebalancing of resting activity between both LVN. These results indicate that changes in neck muscle activity observed in the acute cats and that recovery found in the compensated animals could result from modifications in neural networks controlling neck musculature, such as the LVN.

Partial glycinergic denervation induces transient changes in the distribution of a glycine receptor-associated protein in a central neuron.

The effect of partial glycinergic denervation on the cellular distribution of the 93 kDa peripheral polypeptide associated with the glycine receptor was studied at the level of the teleost Mauthner cell, an identified neuron of the goldfish brain (Carassius auratus). Previous studies using monoclonal antibodies raised against purified glycine receptors and immunoperoxidase staining have shown that these proteins are localized in clusters on the entire surface of this neuron. Specifically, the 93 kDa polypeptide was situated only on the cytoplasmic side of the postsynaptic membrane facing active zones. Unilateral electrolytic lesions of the vestibular complex caused the degeneration of some glycinergic afferents to this neuron. When the first signs of this response appeared, 3 d after the surgery, there was also a change in the ultrastructural distribution of the 93 kDa polypeptide in the deafferented cell. The synaptic protein apposed to degenerating axons did not spread onto adjacent extrasynaptic membranes, and it disappeared a few hours after the disruption of its presynaptic element. At the same time, a cytoplasmic immunoreactivity appeared as randomly distributed clusters in the deafferented Mauthner cell; these aggregates, not seen in control preparations, were never found inside membrane-bound organelles. In some preparations these clusters were localized along arrays at a relatively constant distance from the plasma membrane. The intracellular immunoreaction product was found in the soma and the initial part of the dendrites, gradually decreasing in number and intensity toward the extremities of these processes. At later postoperative stages, 10-15 d after surgery, the 93 kDa immunoreactivity remained only at postsynaptic membranes facing intact terminals. Similar alterations following denervation were observed in reticular neurons, at the level at which degenerating presynaptic terminals were also detected. In contrast, continuous 3-d blockade of synaptic transmission by strychnine, an antagonist of the glycine receptor, had no effect on either the distribution of the surface receptor clusters, or the 93 kDa peripheral protein linked to these receptors. Taken together, our results suggest that the ultrastructural distribution of the glycine receptor complex is regulated by "trophic" factors rather than by transmitter-evoked synaptic activity.

Ultrastructural changes in vestibulo-ocular neurons following vestibular neurectomy in the cat.

Vestibulo-ocular (VO) neurons in the superior vestibular nucleus were labeled retrogradely with horseradish peroxidase and studied quantitatively using electron microscopy to determine the morphologic correlates of vestibular compensation. Eleven VO neurons from three normal cats were compared to 26 VO neurons in four animals killed 8 weeks after vestibular neurectomy and 13 VO cells from two animals killed 1 year after vestibular neurectomy. The results demonstrated a marked reduction (74%) in the number of synaptic profiles (SPs) on the VO cell soma in both experimental groups. Synaptic vesicles in the remaining SPs on VO neurons were fewer, smaller, and rounder than vesicles in control animals. The residual SPs also were associated with more asymmetric synapses. The experimental VO neuron showed a significant decrease in soma and organelles associated with protein synthesis.

Locomotor dysfunction after surgical lesions in the unilateral vestibular nuclei region in squirrel monkeys.

The present experimental results in squirrel monkeys indicated that the performance of psycho-physically advanced locomotor task (squirrel monkey rail test) was severely impaired after the placement of the medium to relatively large surgical lesions in the unilateral vestibular nuclei area, and therefore, confirmed that this brain-stem structure is essential for the signal relay and/or input coordination. The severest locomotor disability was found 10-14 days after the surgery; thereafter, squirrel monkeys showed very gradual and only limited degree of performance recovery. The post-ablative performance levels were no better than 1/5 of their pre-ablative performance levels.