Selective optogenetic stimulation of glutamatergic, but not GABAergic, vestibular nuclei neurons induces immediate and reversible postural imbalance in mice.

Glutamatergic and GABAergic neurons represent the neural components of the medial vestibular nuclei. We assessed the functional role of glutamatergic and GABAergic neuronal pathways arising from the vestibular nuclei (VN) in the maintenance of gait and balance by optogenetically stimulating the VN in VGluT2-cre and GAD2-cre mice. We demonstrate that glutamatergic, but not GABAergic VN neuronal subpopulation is responsible for immediate and strong posturo-locomotor deficits, comparable to unilateral vestibular deafferentation models. During optogenetic stimulation, the support surface dramatically increased in VNVGluT2+ mice, and rapidly fell back to baseline after stimulation, whilst it remained unchanged during similar stimulation of VNGAD2+ mice. This effect persisted when vestibular tactilo kinesthesic plantar inputs were removed. Posturo-locomotor alterations evoked in VNVGluT2+ animals were still present immediately after stimulation, while they disappeared 1 h later. Overall, these results indicate a fundamental role for VNVGluT2+ neurons in balance and posturo-locomotor functions, but not for VNGAD2+ neurons, in this specific context. This new optogenetic approach will be useful to characterize the role of the different VN neuronal populations involved in vestibular physiology and pathophysiology.

Peripheral vestibular plasticity vs central compensation: evidence and questions.

Over the last few decades, several studies have been conducted to identify the mechanisms involved in spontaneous functional recovery following peripheral vestibular damage. Different reactive processes occur at both the central and peripheral levels over the first few hours after the loss of the peripheral vestibular input. The restoration of the electrophysiological homeostasis between opposite vestibular nuclei is one of the key mechanisms of central compensation. This is achieved through a mosaic of biochemical events within the vestibular nuclei that each occur with their own kinetics. At the same time, under specific conditions, strong synaptic plasticity may take place within the vestibular sensory organs. It is thought that this reactive plasticity can contribute to the repair of damaged contacts between hair cells and fibres of the vestibular nerve, thus gradually restoring peripheral sensory input. These different plastic phenomena seem to reproduce those observed during development. Research is now needed to identify the cellular and molecular mechanisms that support this spontaneous peripheral repair process, with the ambition 1 day to be able to control it and stimulate the restoration of gait and balance.

New mouse model for inducing and evaluating unilateral vestibular deafferentation syndrome.

BACKGROUND: Unilateral vestibular deafferentation syndrome (uVDS) holds a particular place in the vestibular pathology domain. Due to its suddenness, the violence of its symptoms that often result in emergency hospitalization, and its associated original neurophysiological properties, this syndrome is a major source of questioning for the otoneurology community. Also, its putative pathogenic causes remain to be determined. There is currently a strong medical need for the development of targeted and effective countermeasures to improve the therapeutic management of uVDS. NEW METHODS: The present study reports the development of a new mouse model for inducing and evaluating uVDS. Both the method for generating controlled excitotoxic-type peripheral vestibular damages, through transtympanic administration of the glutamate receptors agonist kainate (TTK), and the procedure for evaluating the ensuing clinical signs are detailed. COMPARISON WITH EXISTING METHODS: Through extensive analysis of the clinical symptoms characteristics, this new animal model provides the opportunity to better follow the temporal evolution of various uVDS specific symptoms, while better appreciating the different phases that composed this syndrome. RESULTS: The uVDS evoked in the TTK mouse model displays two main phases distinguishable by their kinetics and amplitudes. Several parameters of the altered vestibular behaviour mimic those observed in the human syndrome. CONCLUSION: This new murine model brings concrete information about how uVDS develops and how it affects global behaviour. In addition, it opens new opportunity to decipher the etiopathological substrate of this pathology by authorizing the use of genetically modified mouse models.

Neurogenesis and astrogenesis contribution to recovery of vestibular functions in the adult cat following unilateral vestibular neurectomy: cellular and behavioral evidence.

In physiological conditions, neurogenesis occurs in restricted regions of the adult mammalian brain, giving rise to integrated neurons into functional networks. In pathological or postlesional conditions neurogenesis and astrogenesis can also occur, as demonstrated in the deafferented vestibular nuclei after immediate unilateral vestibular neurectomy (UVN) in the adult cat. To determine whether the reactive cell proliferation and beyond neurogenesis and astrogenesis following UVN plays a functional role in the vestibular functions recovery, we examined the effects of an antimitotic drug: the cytosine-beta-d arabinofuranoside (AraC), infused in the fourth ventricle after UVN. Plasticity mechanisms were evidenced at the immunohistochemical level with bromodeoxyuridine, GAD67 and glial fibrillary acidic protein (GFAP) stainings. Consequences of immediate or delayed AraC infusion on the behavioral recovery processes were evaluated with oculomotor and posturo-locomotor tests. We reported that after UVN, immediate AraC infusion blocked the cell proliferation and decreased the number of GFAP-immunoreactive cells and GABAergic neurons observed in the vestibular nuclei of neurectomized cats. At the behavioral level, after UVN and immediate AraC infusion the time course of posturo-locomotor function recovery was drastically delayed, and no alteration of the horizontal spontaneous nystagmus was observed. In contrast, an infusion of AraC beginning 3 weeks after UVN had no influence neither on the time course of the behavioral recovery, nor on the reactive cell proliferation and its differentiation. We conclude that the first 3 weeks after UVN represent a possible critical period in which important neuroplasticity mechanisms take place for promoting vestibular function recovery: reactive neurogenesis and astrogenesis might contribute highly to vestibular compensation in the adult cat.

Stress axis plasticity during vestibular compensation in the adult cat.

The postural, ocular motor, perceptive and neurovegetative syndromes resulting from unilateral vestibular neurectomy (UVN) symptoms could generate a stress and thereby activate the hypothalamo-pituitary-adrenal (HPA) axis. This study was aimed at determining whether UVN causes changes in the activity of the HPA axis, and if so, evaluating the time course of changes associated with UVN syndrome. At the cellular level, corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) immunoreactivity (Ir) were analyzed and quantified in the paraventricular nucleus (PVN) and the vestibular nuclei (VN) complex of cats killed early (1 and 7 days) or late (30 and 90 days) after UVN. Dopamine-beta-hydroxylase (DbetaH), the enzyme synthesizing noradrenaline was examined in the locus coeruleus (LC) in these same cats. At the behavioral level, the time course of recovery of the postural and locomotor functions was quantified at the same postoperative delays in another group of UVN cats. Results showed a significant bilateral increase in the number of both AVP-Ir and CRF-Ir neurons in the PVN and an increase of DbetaH-Ir neurons in the LC at 1, 7 and 30 days after UVN. This increased number of neurons was no longer observed at 90 days. Conversely, a significant bilateral decrease of CRF-Ir neurons was observed in the VN at these same postlesion times, with a similar return to control values at 90 days. Our behavioral observations showed strong posturo-locomotor functional deficits early after UVN (1 and 7 days), which had recovered partially at 30 days and completely by 90 days postlesion. We demonstrate a long-lasting activation of the HPA axis, which likely reflects a chronic stress, experienced by the animals, which corresponds to the time course of full vestibular compensation, and which is no longer present when the animals are completely free of posturo-locomotor symptoms at 90 days.

Gamma amino butyric acid (GABA) immunoreactivity in the vestibular nuclei of normal and unilateral vestibular neurectomized cats.

Recent neurochemical investigations of the central vestibular pathways have demonstrated that several neurotransmitters are involved in various operations required for stabilizing posture and gaze. Neurons of the vestibular nuclei (VN) receive GABAergic inhibitory afferents, and GABAergic neurons distributed throughout the vestibular complex are implicated in inhibitory vestibulo-ocular and vestibulo-spinal pathways. The aim of this study was to analyse the modifications of GABA immunoreactivity (GABA-ir) in the cat VN after unilateral vestibular neurectomy (UVN). Indeed, compensation of vestibular deficits is a good model for studying adult central nervous system (CNS) plasticity and the GABAergic system is involved in CNS plasticity. We studied GABA-ir by using a purified polyclonal antibody raised against GABA. Light microscopic preparations of thin (20 microm) sections of cat VN were used to quantify GABA-ir by an image analysing system measuring GABA-positive punctate structures and the number of GABA-positive neurons. Both the lesioned and intact sides were analysed in three populations of UVN cats killed at different times after injury (1 week, 3 weeks and 1 year). These data were compared to those collected in normal unlesioned and sham-operated cats. Results showed a spatial distribution of GABA-ir in the control cats that confirmed previous studies. GABA-ir neurons, fibres and nerve terminals were scattered in all parts of the VN. A higher concentration of GABA-positive neurons (small cells) was detected in the medial and inferior VN (MVN and IVN) and in the dorsal part of the lateral VN (LVNd). A higher level of GABA-positive punctate structures was observed in the MVN and in the prepositus hypoglossi (PH) nucleus. Lesion-induced changes were found at each survival time. One week after injury the number of GABA-positive neurons was significantly increased in the MVN, the IVN and the dorsal part of the LVN on the lesioned side and in the ventral part of the LVN on the intact side. One year later a bilateral increase in GABA-positive neurons was detected in the MVN whilst a bilateral decrease was observed in both the SVN and the ventral part of the LVN. Changes in the GABA-staining varicosities did not strictly coincide with the distribution of GABA-ir cells, suggesting that GABA-ir fibres and nerve terminals were also modified. One week and later after injury, higher GABA-staining varicosities were seen unilaterally in the ipsilateral MVN. In contrast, bilateral increases (in PH) and bilateral decreases (in SVN and the ventral part of the LVN) were recorded in the nearly (3 weeks) or fully (1 year) compensated cats. At this stage GABA-staining varicosities were significantly increased in the lesioned side of the MVN. These findings demonstrate the reorganization of the GABAergic system in the VN and its possible role in recovery process after UVN in the cat. The changes seen during the acute stage could be causally related to the VN neuron deafferentation, contributing to the static vestibular deficits. Those found in the compensated cats would be more functionally implicated in the dynamic aspects of vestibular compensation.

Vestibular compensation in the cat: the role of the histaminergic system.

Histamine is thought to be involved in the recovery of vestibular function as histaminergic medications are effective in vestibular-related syndromes. We conducted studies in the cat to assess the effects of betahistine (a histamine-like substance) on the behavioural recovery process after unilateral vestibular neurectomy (UVN). We also investigated histamine immunoreactivity changes in the vestibular and tuberomammillary nuclei of betahistine-treated lesioned cats compared with untreated and unlesioned cats. Betahistine strongly accelerated the behavioural recovery process after UVN, with a time benefit of approximately 2 weeks for both static posture (support surface) and dynamic equilibrium function (locomotor balance) compared with untreated animals. A bilateral decrease in histamine immunoreactivity was seen in both acute and compensated UVN cats; this effect was strongly accentuated with betahistine treatment. In conclusion, the results indicate that vestibular lesion reduces histamine staining due to an increase in histamine release in the vestibular and tuberomammillary nuclei that promote vestibular recovery. Betahistine dihydrochloride should contribute to this process by acting on both the presynaptic histamine H3 and postsynaptic histamine H1 receptors.

Fos expression in the cat brainstem after unilateral vestibular neurectomy.

Immediate early genes are generally expressed in response to sensory stimulation or deprivation and can be used for mapping brain functional activity and studying the molecular events underlying CNS plasticity. We immunohistochemically investigated Fos protein induction in the cat brainstem after unilateral vestibular neurectomy (UVN), with special reference to the vestibular nuclei (VN) and related structures. Fos-like immunoreactivity was analyzed at 2, 8, and 24 h, and 1 and 3 weeks after UVN. Data from these subgroups of cats were quantified in light microscopy and compared to those recorded in control and sham-operated animals submitted to anesthesia and anesthesia plus surgery, respectively. Results showed a very low level of Fos expression in the control and sham conditions. By contrast, Fos was consistently induced in the UVN cats. Asymmetrical labeling was found in the medial, inferior, and superior VN (ipsilateral predominance) and in the prepositus hypoglossi (PH) nuclei and the beta subnuclei of the inferior olive (betaIO) (contralateral predominance). Symmetrical staining was observed in the autonomic, tegmentum pontine, pontine gray, locus coeruleus and other reticular-related nuclei. As a rule, Fos expression peaked early (2 h) and declined progressively. However, some brainstem structures including the ipsilateral inferior VN and the bilateral pontine gray nuclei displayed a second peak of Fos expression (24 h-1 week). By comparing these data to the behavioral recovery process, we conclude that the early Fos expression likely reflects the activation of neural pathways in response to UVN whereas the delayed Fos expression might underlie long-term plastic changes involved in the recovery process.

Distribution of choline acetyltransferase immunoreactivity in the vestibular nuclei of normal and unilateral vestibular neurectomized cats.

Post-lesion recovery of vestibular functions is a suitable model for studying adult central nervous system plasticity. The vestibular nuclei complex (VN) plays a major role in the recovery process and neurochemical reorganizations have been described at this brainstem level. The cholinergic system should be involved because administration of cholinergic agonists and antagonists modify the recovery time course. This study was aimed at analysing the postlesion changes in choline acetyltransferase immunoreactivity (ChAT-Ir) in the VN of cats killed 1 week, 3 weeks or 1 year following unilateral vestibular neurectomy. ChAT-positive neurons and varicosities were immunohistochemically labelled and quantified (cell count and surface measurement, respectively) by means of an image analysing system. The spatial distribution of ChAT-Ir within the VN of control cats showed darkly stained neurons and varicosities mainly located in the caudal parts of the medial (MVN) and inferior (IVN) VN, the nucleus prepositus hypoglossi (PH) and, to a lesser extent, in the medial part of the superior vestibular nucleus (SVN). Lesion-induced changes consisted in a significant increase in both the number of ChAT-positive neurons (IVN, SVN) and the surface of ChAT-positive varicosities (IVN, SVN, PH). They were observed bilaterally in the acute (1 year and 3 weeks) and compensated (1 year) cats for the SVN and PH, while they persisted only in the IVN on the lesioned side in the compensated cats. These findings demonstrate vestibular lesion-induced reorganization of the cholinergic system in the IVN, SVN and PH which could contribute to postural and oculomotor function recovery.

Nucleus- and cell-specific expression of NMDA and non-NMDA receptor subunits in monkey thalamus.

Subcortical and corticothalamic inputs excite thalamic neurons via a diversity of glutamate receptor subtypes. Differential expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptor subunits (GluR1-4; GluR5-7; NR1, NR2A-D) on a nucleus- and cell type-specific basis was examined by quantitative in situ hybridization histochemistry and by immunocytochemical staining for receptor subunits and colocalized gamma-aminobutyric acid (GABA) or calcium binding proteins. Levels of NMDA subunit expression, except NR2C, are higher than for the most highly expressed AMPA (GluR1,3,4) and kainate (GluR6) receptor subunits. Expression of NR2C, GluR2, GluR5, and GluR7 is extremely low. Major differences distinguish the reticular nucleus and the dorsal thalamus and, within the dorsal thalamus, the intralaminar and other nuclei. In the reticular nucleus, GluR4 is by far the most prominent, and NMDA receptors are at comparatively low levels. In the dorsal thalamus, NMDA receptors predominate. Anterior intralaminar nuclei are more enriched in GluR4 and GluR6 subunits than other nuclei, whereas posterior intralaminar nuclei are enriched in GluR1 and differ among themselves in relative NMDA receptor subunit expression. GABAergic intrinsic neurons of the dorsal thalamus express much higher levels of GluR1 and GluR6 receptor subunits than do parvalbumin- or calbindin-immunoreactive relay cells and low or absent NMDA receptors. Relay cells are dominated by NMDA receptors, along with GluR3 and GluR6 subunits not expressed by GABA cells. High levels of NR2B are found in astrocytes. Differences in NMDA and non-NMDA receptor profiles will affect functional properties of the thalamic GABAergic and relay cells.

Cell- and lamina-specific expression and activity-dependent regulation of type II calcium/calmodulin-dependent protein kinase isoforms in monkey visual cortex.

In situ hybridization histochemistry and immunocytochemistry were used to study localization and activity-dependent regulation of alpha, beta, gamma, and delta isoforms of type II calcium/calmodulin-dependent protein kinase (CaMKII) and their mRNAs in areas 17 and 18 of normal and monocularly deprived adult macaques. CaMKII-alpha is expressed overall at levels three to four times higher than that of CaMKII-beta and at least 15 times higher than that of CaMKII-gamma and -delta. All isoforms are expressed primarily in pyramidal cells of both areas, especially those of layers II-III, IVA (in area 17), and VI, but are also expressed in nonpyramidal, non-GABAergic cells of layer IV of both areas and in interstitial neurons of the white matter. CaMKII-alpha and -beta are colocalized, suggesting the formation of heteromers. There was no evidence of expression in neuroglial cells. Each isoform has a unique pattern of laminar and sublaminar distribution, but cortical layers or sublayers enriched for one isoform do not correlate with layers receiving inputs only from isoform-specific layers of the lateral geniculate nucleus. CaMKII-alpha and -beta mRNA and protein levels in layer IVC of area 17 are subject to activity-dependent regulation, with brief periods of monocular deprivation caused by intraocular injections of tetrodotoxin leading to a 30% increase in CaMKII-alpha mRNA and a comparable decrease in CaMKII-beta mRNA in deprived ocular dominance columns, especially of layer IVCbeta. Expression in other layers and expression of CaMKII-gamma and delta were unaffected. Changes occurring in layer IVC may influence the formation of heteromers and protect supragranular layers from CaMKII-dependent plasticity in the adult.

Cell-specific expression of type II calcium/calmodulin-dependent protein kinase isoforms and glutamate receptors in normal and visually deprived lateral geniculate nucleus of monkeys.

In situ hybridization histochemistry and immunocytochemistry were used to map distributions of cells expressing mRNAs encoding alpha, beta, gamma, and delta isoforms of type II calcium/calmodulin-dependent protein kinase (CaMKII), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA)/ kainate receptor subunits, (GluR1-7), and N-methyl-D-aspartate (NMDA) receptor subunits, NR1 and NR2A-D, or stained by subunit-specific immunocytochemistry in the dorsal lateral geniculate nuclei of macaque monkeys. Relationships of specific isoforms with particular glutamate receptor types may be important elements in neural plasticity. CaMKII-alpha is expressed only by neurons in the S laminae and interlaminar plexuses of the dorsal lateral geniculate nucleus, but may form part of a more widely distributed matrix of similar cells extending from the geniculate into adjacent nuclei. CaMKII-beta, -gamma, and -delta isoforms are expressed by all neurons in principal and S laminae and interlaminar plexuses. In principal laminae, they are down-regulated by monocular deprivation lasting 8-21 days. All glutamate receptor subunits are expressed by neurons in principal and S laminae and interlaminar plexuses. The AMPA/kainate subunits, GluR1, 2, 5, and 7, are expressed at low levels, although GluR1 immunostaining appears selectively to stain interneurons. GluR3 is expressed at weak, GluR 6 at moderate and GluR 4 at high levels. NMDA subunits, NR1 and NR2A, B, and D, are expressed at moderate to low levels. GluR4, GluR6 and NMDA subunits are down-regulated by visual deprivation. CaMKII-alpha expression is unique in comparison with other CaMKII isoforms which may, therefore, have more generalized roles in cell function. The results demonstrate that all of the isoforms are associated with NMDA receptors and with AMPA receptors enriched with GluR4 subunits, which implies high calcium permeability and rapid gating.

Histamine immunoreactivity changes in vestibular-lesioned and histaminergic-treated cats.

Histamine is likely involved in vestibular function recovery since histaminergic medications are effective in vestibular-related syndromes. We investigated the histamine immunoreactivity changes after unilateral vestibular neurectomy and the effects of betahistine (a partial histamine H1 receptor agonist and an histamine H3 receptor antagonist) and thioperamide (a pure histamine H3 receptor antagonist) treatment in cats. Histamine staining was analyzed in the tuberomammillary and vestibular nuclei through immunohistochemical methods and quantification techniques in light microscopy. Unilateral vestibular neurectomy induced a strong bilateral decrease in histamine immunoreactivity in the vestibular nuclei and a smaller reduction in the tuberomammillary nuclei in both acute (1 week) and compensated (3 weeks, 1 year) cats. One-week thioperamide or betahistine treatment led to a near-total lack of staining in these structures in both lesioned and control cats. One-month betahistine treatment had weaker effects in the compensated cats. We conclude that vestibular lesions reduce histamine staining because of an increase in histamine release in the vestibular and tuberomammillary nuclei, promoting vestibular functions recovery, and betahistine could contribute to this process by acting on both the presynaptic histamine H3 and postsynaptic histamine H1 receptors.

Distribution of histaminergic axonal fibres in the vestibular nuclei of the cat.

The histaminergic projection in the cat brain originates from neurones located in the tuberomammillary nucleus. The distribution of histaminergic axonal fibres was investigated immunohistochemically in the vestibular nuclei of the cat using an antibody to histamine. Labelled fibres were sparsely distributed in the whole vestibular nuclei complex and were typically beaded with small, darkly stained swellings. Staining density was low to moderate compared with that of other structures in the cat brain. Histaminergic fibre distribution showed spatial variations, with significantly heavier labelling in the superior and medial vestibular nuclei than in the lateral and inferior nuclei. Histamine could play a neuromodulatory role in the processing of sensory afferent information in the vestibular nuclei and in the control of vestibular functions.

Vestibular compensation: role of visual motion cues in the recovery of posturo-kinetic functions in the cat.

Vision has long been recognized as a sensorimotor system which plays a major role in substitution for functional deficits induced by unilateral or bilateral exclusion of primary vestibular afferents. Little is known, however, about the post-lesion influence of visual inputs on the recovery of posturo-kinetic balance in a situation where fine, well-coordinated locomotor adjustments are required. The present study was carried out in order to gain some insight into the role played by motion vision in the restoration of fine posturo-kinetic balance in adult cats subjected to unilateral vestibular neurectomy. Prior to the lesion, 15 adult animals were trained to cross a beam rotating at various speeds. Their best global balance performance (highest beam rotation speed that did not provoke falling) and their average locomotion speed were evaluated. After the lesion, the cats were separated into three groups: (1) five animals were placed in a normal environment (animal house) (NV cats); (2) four animals were exposed to stroboscopic illumination which eliminated visual motion cues (SV cats) for 2 weeks following the lesion; and (3) three animals were placed in a normal environment and their training was interrupted for the same period as in the SV cats (NVI cats). The possible influence of the 2-week deprivation of visual motion cues on posturo-kinetic balance was also examined in three intact cats. The present behavioral study showed that: (1) early sensory deprivation caused suspension of the posturo-kinetic balance recovery process as long as it was maintained; (2) complete restoration of global balance capacities developed following the vestibular neurectomy after a significant delay in half of the SV cats; (3) the lack of motion cues resulted in severe alterations of fine posturo-kinetic balance (inappropriate dynamic motor adjustments and irregular locomotion speed regulation) in all SV cats; and (4) the visual deprivation induced a 2-week delay in the restoration of fine locomotor balance. These findings provide evidence for a defect in the visual sensory substitution processes that normally take place within the first few weeks following exclusion of primary vestibular afferents.

Pharmacological activity of the Ginkgo biloba extract (EGb 761) on equilibrium function recovery in the unilateral vestibular neurectomized cat.

Locomotor balance recovery after unilateral vestibular neurectomy has been found strongly accelerated in the cat when the animals received a postoperative treatment with Ginkgo biloba Extract (EGb 761:50 mg/kg/d, i.p.), a result due to the improvement of plasticity mechanisms involved in vestibular compensation. The aim of this study was to determine which of the two main biochemical components (terpenes vs. flavonoids) contained in the extract was the most active in the recovery process, to test the influence of the route of administration, and to look for dose-dependent effects. Experiments were performed in six experimental groups of cats that were compared with each other and with three control groups. Comparisons were done on the recovery profile and time course of equilibrium function restoration, as quantified by the rotating beam test. Four experimental groups were treated with the standardized extract EGb 761 given orally (p.o.:2 groups; 40 mg and 80 mg/kg) or intraperitoneally (i.p.: 2 groups; 50 mg and 25 mg/kg), whereas the two others received only a special extract that did not contain the terpenes (i.p. administration: 25 mg and 10 mg/kg). Treatment was always given until complete recovery of locomotor balance function. The control groups received either no treatment (untreated cats), an oral vehicle (placebo cats), or a sham i.p. injection (sham cats). Results showed that locomotor balance recovery was significantly improved in all the experimental groups as compared to the control groups of cats, which recovered similarly and more slowly. Efficacy of the special extract without the terpenes was comparable to that of the total extract, indicating that the nonterpenic fraction was the most active biochemical constituent in this experimental model of central nervous system (CNS) plasticity. Pharmacological activity of the extract was also significantly better when given i.p. as compared to the p.o. route of administration, and dose-dependent effects were evidenced with the i.p. administration of the special extract without the terpenes, with a lower efficacy for the lowest dose (10 mg/kg). These data confirm that EGb 761 treatment serves as useful therapy in supporting brain functional recovery in this animal model of vestibular compensation and lead to a more precise understanding of the biochemical component that is active in this recovery process.

Betahistine dihydrochloride treatment facilitates vestibular compensation in the cat.

Unilateral lesion of the vestibular system induces posturo-locomotor deficits that are compensated for with time. Drug therapy is currently used to improve the recovery process and to facilitate vestibular compensation. Betahistine dihydrochloride is an histamine-like substance that has been employed in vestibular pathology; it was found effective in many forms of vertigo and in vestibular-related syndromes. Investigations performed in animal models have shown betahistine-induced neuronal modulations in the vestibular nuclei complex and interactions with the H1 and H3 histamine receptors. Potentially, this substance is therefore capable to interfere with some recovery mechanisms and to improve the behavioral adaptations. But there is at present a total lack of data concerning the influence of betahistine treatment on vestibular compensation in animal models. The aim of this study was to understand the pharmacological activity of betahistine in the restoration of posture and locomotor balance functions in unilateral vestibular neurectomized cats. Posture recovery was assessed by quantifying the surface reaction of the cat's support as measured while standing erect on its four legs, at rest. Locomotor balance recovery was determined using the rotating beam test, by measuring the maximal performance (max. P.) of the cat and its locomotion speed regulation during the postoperative time period. We have compared the recovery profile and time course of these static (posture) and dynamic (equilibrium) functions in three groups of cats. Two experimental groups were treated at daily doses of 50 mg/kg and 100 mg/kg, respectively. Betahistine dihydrochloride was given orally until complete recovery of posturolocomotor functions. One untreated control group served as the reference. Results showed that postoperative treatment strongly accelerated the recovery process in both treated groups, inducing a time benefit of around 2 weeks as compared to the controls. Maximum performance of the cats on the rotating beam as well as locomotion speed regulation were highly correlated to the postoperative development of the cat's support surface, indicating that compensation of the static vestibulospinal deficits conditioned the subsequent locomotor balance recovery. These behavioral data showed that betahistine dihydrochloride constitutes a useful drug therapy for the symptomatic treatment of central vestibular disorders in our animal model of unilateral vestibular lesion. Improvement of vestibular compensation under betahistine postoperative treatment, as evidenced here for the posture and locomotor balance functions, is discussed both in terms of aspecific effect (histamine-induced increase of the level of vigilance) or more direct action in the vestibular nuclei (histamine-induced rebalance of neuronal activity on both sides).