Unilateral Labyrinthectomy Research Articles

Cognitive impairments and neurobiological changes induced by unilateral vestibular dysfunction in mice

The vestibular system is essential for balance and spatial orientation, and its dysfunction can lead to cognitive deficits. This study investigates the effects of unilateral vestibular dysfunction (UVL) on cognitive function and the underlying neurobiological changes in mice. We established a unilateral labyrinthectomy (UL) model in mice and assessed cognitive function at 28 days post-surgery using a comprehensive battery of behavioral tests. We found significant impairments in spatial reference memory, working memory, and synaptic plasticity in UL mice, which persisted despite compensation for vestibular and postural motor deficits. Immunofluorescence staining revealed enhanced activation of c-Fos in the hippocampal dentate gyrus (DG) at various time points post-UL, suggesting a role of the hippocampus in cognitive deficits following UVL. RNA sequencing of the DG identified differentially expressed genes (DEGs) and altered pathways related to cognitive function, synaptic plasticity, and neuronal activation. Quantitative real-time PCR (qRT-PCR) validated the expression changes of selected genes. Our findings indicate that UVL leads to persistent cognitive impairments in mice, associated with altered neuronal activation and gene expression in the hippocampus. This study offers valuable insights into the neurobiological mechanisms underlying cognitive deficits associated with UVL. Moreover, it underscores the importance of early cognitive screening in patients with vestibular diseases, as this approach is instrumental in comprehensive condition assessment, precise diagnosis, targeted treatment, and effective rehabilitation.

Molecular profile of vestibular compensation in the medial vestibular nucleus after unilateral labyrinthectomy.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the central nervous system, yet their role in vestibular compensation remains elusive. To address this knowledge gap, we employed unilateral labyrinthectomy (UL) in rats to establish animal models of peripheral vestibular dysfunction. Utilizing ribonucleic acid sequencing (RNA-seq), we comprehensively analysed the expression profiles of genes dysregulated in the medial vestibular nucleus (MVN) of these rats at distinct time points: 4 h, 4 days, and 14 days post-UL. Through trans-target prediction analysis integrating differentially co-expressed messenger RNAs (mRNAs) and lncRNAs, we constructed lncRNA-mRNA regulatory networks. Validation of selected mRNAs and lncRNAs was performed using RT-qPCR. Our RNA-seq analysis revealed significant aberrant expression of 3054 lncRNAs and 1135 mRNAs compared to control samples. By applying weighted gene co-expression network analysis (WGCNA), we identified 11 co-expressed modules encompassing all genes. Notably, within the MEmagenta module, we observed an initial upregulation of differentially expressed genes (DEGs) at 4 h, followed by downregulation at 4- and 14-days post-UL. Our findings indicated that 3068 lncRNAs positively regulated 1259 DEGs, while 1482 lncRNAs negatively regulated 433 DEGs in the MVN. The RT-qPCR results corroborated the RNA-seq data, validating our findings. This study offers novel insights into the lncRNA-mRNA expression landscape during vestibular compensation, paving the way for further exploration of lncRNA functions in this context.

The Effects of Unilateral Labyrinthectomy on Monoamine Neurotransmitters in the Medial Vestibular Nucleus of Rats.

This study aimed to investigate the effects of unilateral labyrinthectomy (UL) on monoamine neurotransmitters in the medial vestibular nucleus (MVN) of rats. Adult Sprague-Dawley rats were utilized for the vestibular impaired animal model through UL. The success of the model establishment and the recovery process were evaluated using vestibular behavioral tests, including spontaneous nystagmus, postural asymmetry, and balance beam test. Additionally, the expression levels of c-Fos protein in the MVN were assessed by immunofluorescence. Furthermore, changes in the expression levels of monoamine neurotransmitters, including 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), and histamine in the MVN, were analyzed using high-performance liquid chromatography (HPLC) at different time points after UL (4 h, 8 h, 1 day, 2 days, 4 days, and 7 days). Compared to the sham control group, the UL group exhibited the most pronounced vestibular impairment symptoms at 4 h post-UL, which significantly decreased at 4 days and almost fully recovered by 7 days. Immunofluorescence results showed a notable upregulation of c-Fos expression in the MVN subsequent to the UL-4 h, serving as a reliable indicator of heightened neuronal activity. In comparison with the sham group, HPLC analysis showed that the levels of 5-HT and NE in the ipsilesional MVN of the UL group were significantly elevated within 4 days after UL, and peaked on 1 day and 2 days, respectively. DA showed an increasing trend at different time points up to 7 days post-UL, while histamine levels significantly increased only at 1 day post-UL. UL-induced dynamic changes in monoamine neurotransmitters during the early compensation period in the rat MVN may be associated with the regulation of the central vestibular compensation mechanism by the MVN.

Parvalbumin-positive neurons in the medial vestibular nucleus contribute to vestibular compensation through commissural inhibition.

The commissural inhibitory system between the bilateral medial vestibular nucleus (MVN) plays a key role in vestibular compensation. Calcium-binding protein parvalbumin (PV) is expressed in MVN GABAergic neurons. Whether these neurons are involved in vestibular compensation is still unknown. After unilateral labyrinthectomy (UL), we measured the activity of MVN PV neurons by in vivo calcium imaging, and observed the projection of MVN PV neurons by retrograde neural tracing. After regulating PV neurons' activity by chemogenetic technique, the effects on vestibular compensation were evaluated by behavior analysis. We found PV expression and the activity of PV neurons in contralateral but not ipsilateral MVN increased 6 h following UL. ErbB4 is required to maintain GABA release for PV neurons, conditional knockout ErbB4 from PV neurons promoted vestibular compensation. Further investigation showed that vestibular compensation could be promoted by chemogenetic inhibition of contralateral MVN or activation of ipsilateral MVN PV neurons. Additional neural tracing study revealed that considerable MVN PV neurons were projecting to the opposite side of MVN, and that activating the ipsilateral MVN PV neurons projecting to contralateral MVN can promote vestibular compensation. Contralateral MVN PV neuron activation after UL is detrimental to vestibular compensation, and rebalancing bilateral MVN PV neuron activity can promote vestibular compensation, via commissural inhibition from the ipsilateral MVN PV neurons. Our findings provide a new understanding of vestibular compensation at the neural circuitry level and a novel potential therapeutic target for vestibular disorders.

Prosthetic Stimulation of the Vestibular Nerve Can Evoke Robust Eye and Head Movements Despite Prior Labyrinthectomy.

Prosthetic electrical stimulation can evoke compensatory eye and head movement despite vestibular implant electrode insertion occurring years after prior labyrinthectomy. Vestibular implants sense head rotation and directly stimulate the vestibular nerve, bypassing damaged end organs. Animal research and current clinical trials have demonstrated the efficacy of this approach. However, candidacy criteria for vestibular implants currently require presence of a patent labyrinth in the candidate ear and at least aidable hearing in the opposite ear, thus excluding patients who have undergone prior labyrinthectomy for unilateral Menière's disease that later progressed to bilateral vestibular hypofunction. Eight years after right unilateral labyrinthectomy, we implanted stimulating electrodes in the previously exenterated right ear ampullae of a rhesus macaque monkey. The left labyrinth had long-standing hypofunction due to intratympanic gentamicin injection and surgical disruption. We used three-dimensional video-oculography to measure eye movement responses to prosthetic electrical stimulation. We also measured head-movement responses to prosthetic stimulation with the head unrestrained. Bilateral vestibular hypofunction was confirmed by absence of vestibuloocular reflex responses to whole-body rotation without prosthetic stimulation. For a subset of the implanted electrodes, prosthetic vestibular stimulation evoked robust compensatory eye and head movements. One electrode reliably elicited responses aligned with the implanted ear's anterior canal nerve regardless of the return electrode used. Similarly, a second electrode also elicited responses consistent with excitation of the horizontal canal nerve. Responses grew quasilinearly with stimulation rate and current amplitude. Prosthetic electrical stimulation targeting the vestibular nerve can be effective years after labyrinthectomy, if at least some parts of the vestibular nerve's ampullary branches remain despite destruction or removal of the membranous labyrinth.

MGluR1/IP3/ERK signaling pathway regulates vestibular compensation in ON UBCs of the cerebellar flocculus.

To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal-regulated kinase (ERK) signaling pathway. First, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)-3,5-dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p-ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p-ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC-related behavior was observed. mGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p-ERK1/2 levels, while LY367385 group showed a decrease in PI and p-ERK1/2 levels in cerebellar UBC of rats. The western blot results of p-ERK and total ERK confirm and support the observations. DHPG alleviated VC-related behavior phenotypes, while LY367385 exacerbated vestibular decompensation-like behavior induced by UL. mGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.

The effects of continuous administration of diazepam on the recovery of lesion-induced nystagmus in unilaterally labyrinthectomised rats

Background Diazepam, a gamma-aminobutyric acid type A receptor agonist, is classified as a vestibular suppressant and is effective in treating acute vertigo. However, its effects on vestibular compensation (VC) remain unclear. Objectives We examined the effects of continuous administration of diazepam on the frequency of spontaneous nystagmus (SN) after unilateral labyrinthectomy (UL) as an index of the initial process of VC in rats. Materials and methods Diazepam was continuously administered at doses of 3.5 and 7.0 mg/kg/day, intraperitoneally, via an osmotic minipump. The frequency of SN beating against the lesion side after UL was measured. Potassium chloride (KCl) solution (1 M) was injected intratympanically to induce SN beating to the injection side. Results Continuous administration of diazepam significantly and dose-dependently decreased the frequency of SN after UL, and also reduced the x intercept of the nonlinear regression curve of the decline in UL-induced SN with time in rats. However, the continuous administration of diazepam did not affect the frequency of intratympanic KCl-induced SN in the rats. Conclusion These findings suggested that continuous administration of diazepam accelerates the initial process of VC; however, it does not suppress the nystagmus-driving mechanisms in rats.

Dose- and application route-dependent effects of betahistine on behavioral recovery and neuroplasticity after acute unilateral labyrinthectomy in rats.

Betahistine is widely used for the treatment of various vestibular disorders. However, the approved oral administration route and maximum daily dose are evidently not effective in clinical trials, possibly due to a major first-pass metabolism by monoamine oxidases (MAOs). The current study aimed to test different application routes (i.v./s.c./p.o.), doses, and concurrent medication (with the MAO-B inhibitor selegiline) for their effects on behavioral recovery and cerebral target engagement following unilateral labyrinthectomy (UL) in rats. Sixty rats were subjected to UL by transtympanic injection of bupivacaine/arsanilic acid and assigned to five treatment groups: i.v. low-dose betahistine (1 mg/kg bid), i.v. high-dose betahistine (10 mg/kg bid), p.o. betahistine (1 mg/kg bid)/selegiline (1 mg/kg once daily), s.c. betahistine (continuous release of 4.8 mg/day), and i.v. normal saline bid (sham treatment; days 1-3 post-UL), respectively. Behavioral testing of postural asymmetry, nystagmus, and mobility in an open field was performed seven times until day 30 post-UL and paralleled by sequential cerebral [18F]-FDG-μPET measurements. The therapeutic effects of betahistine after UL differed in extent and time course and were dependent on the dose, application route, and selegiline co-medication: Postural asymmetry was significantly reduced on 2-3 days post-UL by i.v. high-dose and s.c. betahistine only. No changes were observed in the intensity of nystagmus across groups. When compared to sham treatment, movement distance in the open field increased up to 5-fold from 2 to 30 days post-UL in the s.c., i.v. high-dose, and p.o. betahistine/selegiline groups. [18F]-FDG-μPET showed a dose-dependent rCGM increase in the ipsilesional vestibular nucleus until day 3 post-UL for i.v. high- vs. low-dose betahistine and sham treatment, as well as for p.o. betahistine/selegiline and s.c. betahistine vs. sham treatment. From 1 to 30 days post-UL, rCGM increased in the thalamus bilaterally for i.v. high-dose betahistine, s.c. betahistine, and p.o. betahistine/selegiline vs. saline treatment. Betahistine has the potential to augment the recovery of dynamic deficits after UL if the administration protocol is optimized toward higher effective plasma levels. This may be achieved by higher doses, inhibition of MAO-based metabolism, or a parenteral route. In vivo imaging suggests a drug-target engagement in central vestibular networks.

Redistribution of the astrocyte phenotypes in the medial vestibular nuclei after unilateral labyrinthectomy.

Astrocytes are highly heterogeneous and involved in different aspects of fundamental functions in the central nervous system (CNS). However, whether and how this heterogeneous population of cells reacts to the pathophysiological challenge is not well understood. To investigate the response status of astrocytes in the medial vestibular nucleus (MVN) after vestibular loss, we examined the subtypes of astrocytes in MVN using single-cell sequencing technology in a unilateral labyrinthectomy mouse model. We discovered four subtypes of astrocytes in the MVN with each displaying unique gene expression profiles. After unilateral labyrinthectomy, the proportion of the astrocytic subtypes and their transcriptional features on the ipsilateral side of the MVN differ significantly from those on the contralateral side. With new markers to detect and classify the subtypes of astrocytes in the MVN, our findings implicate potential roles of the adaptive changes of astrocyte subtypes in the early vestibular compensation following peripheral vestibular damage to reverse behavioral deficits.

Differential Modulation of Cerebellar Flocculus Unipolar Brush Cells during Vestibular Compensation.

Vestibular compensation is a natural behavioral recovery process following unilateral vestibular injury. Understanding the mechanism can considerably enhance vestibular disorder therapy and advance the adult central nervous system functional plasticity study after injury. The cerebellum, particularly the flocculonodular lobe, tightly modulates the vestibular nucleus, the center for vestibular compensation; however, it is still unclear if the flocculus on both sides is involved in vestibular compensation. Here we report that the unipolar brush cells (UBCs) in the flocculus are modulated by unilateral labyrinthectomy (UL). UBCs are excitatory interneurons targeting granule cells to provide feedforward innervation to the Purkinje cells, the primary output neurons in the cerebellum. According to the upregulated or downregulated response to the mossy fiber glutamatergic input, UBC can be classified into ON and OFF forms of UBCs. Furthermore, we discovered that the expression of marker genes of ON and OFF UBCs, mGluR1α and calretinin, was increased and decreased, respectively, only in ipsilateral flocculus 4-8 h after UL. According to further immunostaining studies, the number of ON and OFF UBCs was not altered during UL, demonstrating that the shift in marker gene expression level in the flocculus was not caused by the transformation of cell types between UBCs and non-UBCs. These findings imply the importance of ipsilateral flocculus UBCs in the acute response of UL, and ON and OFF UBCs may be involved in vestibular compensation in opposite directions.

The effects of vibration on the neuronal activity of lateral vestibular nuclei in unilaterally labyrinthectomized rats.

Unilateral labyrinthectomy causes distinct oculomotor and postural disorder syndromes that gradually deteriorate. Simultaneously, compensatory mechanisms for the suppression of pathological disorders were activated. The current study aimed to investigate the characteristics of impulse activity in the ipsilateral and contralateral neurons of the lateral vestibular nucleus of unilaterally labyrinthectomized rats during various periods of vibration exposure. A program analysis of the background impulse activity of theneurons in the right- and left-lateral vestibular nuclei of ratsunder normal condition and after right-sided labyrinthectomy was performed. The animals were subjected to different periods of vibration exposure 2days after surgery (5-, 10-, and 15-day periods). A comparison of the characteristics of the background impulse activity of neurons in both nuclei of intact rats revealed an initial asymmetry in the values of the mean impulse frequency and coefficient of variation of interimpulse intervals. After 5days of vibration exposure, the values of the mean impulse frequency of neurons in both Deiters' nuclei were almost equal in labyrinthectomized rats. The mean impulse frequency of neurons on the uninjured side was higher than that on the injured side on the days following vibration exposure. The characteristics and functional significance of the findings are discussed.

Cerebrocortical activation following unilateral labyrinthectomy in mice characterized by whole-brain clearing: implications for sensory reweighting

Posture and gait are maintained by sensory inputs from the vestibular, visual, and somatosensory systems and motor outputs. Upon vestibular damage, the visual and/or somatosensory systems functionally substitute by cortical mechanisms called “sensory reweighting”. We investigated the cerebrocortical mechanisms underlying sensory reweighting after unilateral labyrinthectomy (UL) in mice. Arc-dVenus transgenic mice, in which the gene encoding the fluorescent protein dVenus is transcribed under the control of the promoter of the immediate early gene Arc, were used in combination with whole-brain three-dimensional (3D) imaging. Performance on the rotarod was measured as a behavioral correlate of sensory reweighting. Following left UL, all mice showed the head roll-tilt until UL10, indicating the vestibular periphery damage. The rotarod performance worsened in the UL mice from UL1 to UL3, which rapidly recovered. Whole-brain 3D imaging revealed that the number of activated neurons in S1, but not in V1, in UL7 was higher than that in sham-treated mice. At UL7, medial prefrontal cortex (mPFC) and agranular insular cortex (AIC) activation was also observed. Therefore, sensory reweighting to the somatosensory system could compensate for vestibular dysfunction following UL; further, mPFC and AIC contribute to the integration of sensory and motor functions to restore balance.

The pattern of hippocampal neuronal, LTP and unilateral labyrinthectomy in male rats: the role of exercise and curcumin

A wide range of cognitive disorders, long-term potentiation (LTP) disorders, and biochemical changes have been reported in labyrinthectomy situations in the hippocampus of rodents. In order to investigate whether exercise and/or curcumin induce LTP and increase neurons in the hippocampus of unilateral labyrinthectomy male rats, after undergoing labyrinthectomy, animals were subjected to treadmill exercises after the intraperitoneal injection of curcumin five days per week, for 30 days. An increase of LTP and neuron count of the hippocampus was observed in unilateral labyrinthectomy rats. Interestingly the combination of exercise and curcumin did not enhance LTP in unilateral labyrinthectomy rats. These findings demonstrated that treadmill exercise and curcumin individually, significantly affect reinforcement of many of the pathological processes playing a role in increasing memory in unilateral labyrinthectomy situations.

A comparative study of vestibular improvement and gastrointestinal effect of betahistine and gastrodin in mice

Betahistine and gastrodin are the first-line medications for vestibular disorders in clinical practice, nevertheless, their amelioration effects on vestibular dysfunctions still lack direct comparison and their unexpected extra-vestibular effects remain elusive. Recent clinical studies have indicated that both of them may have effects on the gastrointestinal (GI) tract. Therefore, we purposed to systematically compare both vestibular and GI effects induced by betahistine and gastrodin and tried to elucidate the mechanisms underlying their GI effects. Our results showed that betahistine and gastrodin indeed had similar therapeutic effects on vestibular-associated motor dysfunction induced by unilateral labyrinthectomy. However, betahistine reduced total GI motility with gastric hypomotility and colonic hypermotility, whereas gastrodin did not influence total GI motility with only slight colonic hypermotility. In addition, betahistine, at normal dosages, induced a slight injury of gastric mucosa. These GI effects may be due to the different effects of betahistine and gastrodin on substance P and vasoactive intestinal peptide secretion in stomach and/or colon, and agonistic/anatgonistic effects of betahistine on histamine H1 and H3 receptors expressed in GI mucosal cells and H3 receptors distributed on nerves within the myenteric and submucosal plexuses. Furthermore, treatment of betahistine and gastrodin had potential effects on gut microbiota composition, which could lead to changes in host-microbiota homeostasis in turn. These results demonstrate that gastrodin has a consistent improvement effect on vestibular functions compared with betahistine but less effect on GI functions and gut microbiota, suggesting that gastrodin may be more suitable for vestibular disease patients with GI dysfunction.

Gut Microbiome and Metabolome Changes in Mice With Acute Vestibular Deficit.

Vestibular deficit is a very common disorder in clinical practice and is characterized by vertigo, spontaneous nystagmus, and autonomic nervous symptoms, including nausea, vomiting, and sweating. In addition, the comorbidity of vestibular deficit and anxiety has long been an integral component of the medical literature. Previous studies have suggested that the mechanisms underlying this comorbidity involved overlap of vestibular and cerebellar networks. Emerging evidence has shown that the microbiota–gut–brain axis plays a key role in the regulation of affective disorders. Thus, we hypothesized that the gut microbiota may be involved in the comorbidity of vestibular deficit and anxiety. To verify this, we constructed a unilateral labyrinthectomy mouse model to simulate vestibular deficit. Then, 16S rRNA gene sequencing and liquid chromatography–mass spectrometry (LC-MS) were used to analyze the microbiome and metabolome of the cecal samples collected from mice in the unilateral labyrinthectomy, sham surgery, and control groups. Notably, unilateral labyrinthectomy shaped the composition of the mouse gut microbiome, resulting in increased abundance of Lachnospiraceae NK4A136 group, Odoribacter and Roseburia and decreased abundance of Prevotella and Parasutterella at the genus level. Tax4Fun functional prediction indicated a decrease in tryptophan metabolism in mice in the unilateral labyrinthectomy group. Moreover, functional correlation of changes in gut microbes and metabolites between different groups showed that the oleamide level was negatively correlated with Odoribacter abundance (r = -0.89, p = 0.0002). The butyric acid level was positively correlated with Parasutterella abundance (r = 0.85, p = 0.0010). The propanoate level was negatively correlated with Prevotella abundance (r = -0.81, p = 0.0020). The 20-HETE level was positively correlated with Parasutterella abundance (r = 0.84, p = 0.0013). The altered microbes and metabolites were closely related to the pathogenesis of affective disorders. Our results not only offer novel insights into the vestibular deficit comorbid with anxiety but also build an important basis for future research on this etiology.

Vestibulo-Ocular Reflex Short-Term Adaptation Is Halved After Compensation for Unilateral Labyrinthectomy.

Several prior studies, including those from this laboratory, have suggested that vestibulo-ocular reflex (VOR) adaptation and compensation are two neurologically related mechanisms. We therefore hypothesised that adaptation would be affected by compensation, depending on the amount of overlap between these two mechanisms. To better understand this overlap, we examined the effect of gain-increase (gain = eye velocity/head velocity) adaptation training on the VOR in compensated mice since both adaptation and compensation mechanisms are presumably driving the gain to increase. We tested 11 cba129 controls and 6 α9-knockout mice, which have a compromised efferent vestibular system (EVS) known to affect both adaptation and compensation mechanisms. Baseline VOR gains across frequencies (0.2 to 10Hz) and velocities (20 to 100°/s) were measured on day 28 after unilateral labyrinthectomy (UL) and post-adaptation gains were measured after gain-increase training on day 31 post-UL. Our findings showed that after chronic compensation gain-increase adaptation, as a percentage of baseline, in both strains of mice (~14%), was about half compared to their previously reported healthy, non-operated counterparts (~32%). Surprisingly, there was no difference in gain-increase adaptation between control and α9-knockout mice. These data support the notion that adaptation and compensation are separate but overlapping processes. They also suggest that half of the original adaptation capacity remained in chronically compensated mice, regardless of EVS compromise associated with α9-knockout mice, and strongly suggest VOR adaptation training is a viable treatment strategy for vestibular rehabilitation therapy and, importantly, augments the compensatory process.

The Effect of Coenzyme Q10 on Vestibular Compensation Process after Unilateral Labyrinthectomy in Rats Using Behavioral Tests

Objective: To determine the effect of coenzyme Q10 on the vestibular compensation process after unilateral labyrinthectomy. Material and Methods: Thirty Wistar rats were randomly assigned to 3 equal groups: the negative control group, the experimental group and the control group. Labyrinthectomy surgeries were performed in all 3 groups. After the labyrinthectomy, findings such as nystagmus with its fast phase directed to the undamaged side, deviation of the head to the side operated on, impairment in walking, and decreased tonus of the extensor muscles on the same side were observed. Results: The values of Group EG and Group CG were somewhat higher than those of Group NCG in terms of the degree of head tilt, but there was no statistically significant difference among the three groups. Although Group EG and Group CG were found to differ statistically significantly from Group NCG on certain days in terms of postural deficit values and nystagmus, this significance remained limited to those particular days. Conclusion: The effect of CoQ10 on the vestibular compensation process was limited may be due to its limited dose, short duration of administration, and the limited number of rats. We believe that the effects of CoQ10 on the vestibular compensation process after labyrinthectomy should not be neglected. Despite the fact that we administered it at limited doses for a short term on a limited number of rats, CoQ10 should be used in larger samples, in higher doses, and for a longer time because CoQ10 has positive, though limited effects, on the vestibular compensation process.

A Once-Daily High Dose of Intraperitoneal Ascorbate Improves Vestibulo-ocular Reflex Compensation After Unilateral Labyrinthectomy in the Mouse.

Ascorbate potentiates the response of nicotinic-acetylcholine-receptors containing α9 and α10 subunits found predominantly in the efferent systems of the inner ear, such as the efferent vestibular system (EVS). Prior mouse studies have shown that an attenuated EVS results in reduced vestibulo-ocular reflex (VOR) gain (=eye_velocity/head_velocity) plasticity in intact (VOR adaptation) and surgically-lesioned (VOR compensation) mice. We sought to determine whether ascorbate-treatment could improve VOR recovery after vestibular organ injury, possibly through potentiation of the EVS pathway. We tested 10 cba129 mice, 5 received ascorbate-treatment and 5 did not, but otherwise experienced the same conditions. Ascorbate-treatment comprised a once-daily intraperitoneal injection of L-form reduced ascorbate (4 g/kg) in 0.2 ml saline starting 1 week before, and ending 4 weeks after, unilateral labyrinthectomy surgery. These were deliberately high doses to determine the ascorbate effects on recovery. Baseline, acute, and chronic sinusoidal VOR gains (frequency and velocity ranges: 0.2-10 Hz, 20-100 deg/s) were measured 3-5 days before, 3-5 days after, and 28-31 days after labyrinthectomy. Mice treated with ascorbate had acute ipsilesional VOR gains 12 % higher compared to control mice (+45.2 ± 14.9 % from baseline versus +33.7 ± 15.4 %, P < 0.001). Similarly, chronic ipsilesional and contralesional VOR gains were respectively 16 % (+74.3 ± 16.3 % from baseline versus +58.1 ± 15.8 %, P < 0.001) and 13 % (+78.6 ± 16.0 % versus +65.6 ± 10.9 %, P < 0.001) higher compared to control mice. These data suggest ascorbate-treatment had a prophylactic effect reducing acute loss, and helped recovery during acute to chronic stages of compensation. One possible mechanism is that an ascorbate-enhanced EVS drives an increase in the number and sensitivity of irregular-discharging primary vestibular afferents, important for VOR plasticity.

Effect and mechanism of BDNF/TrkB signaling on vestibular compensation

ABSTRACT Brain-derived neurotrophic factor (BDNF) regulates neuronal plasticity by targeting the tyrosine kinase B receptor (TrkB) receptor, but limited researches concentrate on the role of BDNF/TrkB signaling in vestibular compensation. In this study, rats with unilateral vestibular dysfunction were established by unilateral labyrinthectomy (UL) and infusion with siBDNF or 7, 8-Dihydroxyflavone (7,8-DHF, a TrkB receptor agonist). The behavioral scores of rats with vestibular deficits were determined and the rotarod test was performed after UL. BDNF and TrkB levels after UL were determined by western blot and quantitative reverse transcription PCR (qRT-PCR). 5-bromo-2ʹ-deoxyuridine (BrdU)-positive cells (newly generated cells) and GAD67-positive cells (GABAergic neurons) were identified by immunohistochemistry. Glial fibrillary acidic protein (GFAP) (astrocyte marker)-positive cells were identified and GABA type A receptor (GABAAR) expression was detected by immunofluorescence. We found that after UL, BDNF and TrkB levels were up-regulated with a maximum value at 4 h, and then progressively down-regulated during 4 h ~ 7 d. Blocking BDNF/TrkB signaling inhibited the recovery from vestibular deficits, decreased the numbers of newly generated cells and astrocytes in medial vestibular nucleus (MVN), inferior vestibular nerve (IVN), superior vestibular nerve (SVN) and lateral vestibular nucleus (LVN), and disrupted the balances of GABAergic neurons and GABAAR expressions in the left (lesioned) side and right (intact) side of MVN, whereas activation of BDNF/TrkB signaling caused opposite results. The current study indicated that BDNF/TrkB signaling avails vestibular compensation, depending on the number of newly generated cells and astrocytes, the rebalance of GABAergic neurons, and GABAAR expression in bilateral MVN.

The Differential Effects of Acute Right- vs. Left-Sided Vestibular Deafferentation on Spatial Cognition in Unilateral Labyrinthectomized Mice.

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group (p < 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side.