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.

Optogenetic fMRI interrogation of brain-wide central vestibular pathways.

Blood oxygen level-dependent functional MRI (fMRI) constitutes a powerful neuroimaging technology to map brain-wide functions in response to specific sensory or cognitive tasks. However, fMRI mapping of the vestibular system, which is pivotal for our sense of balance, poses significant challenges. Physical constraints limit a subject's ability to perform motion- and balance-related tasks inside the scanner, and current stimulation techniques within the scanner are nonspecific to delineate complex vestibular nucleus (VN) pathways. Using fMRI, we examined brain-wide neural activity patterns elicited by optogenetically stimulating excitatory neurons of a major vestibular nucleus, the ipsilateral medial VN (MVN). We demonstrated robust optogenetically evoked fMRI activations bilaterally at sensorimotor cortices and their associated thalamic nuclei (auditory, visual, somatosensory, and motor), high-order cortices (cingulate, retrosplenial, temporal association, and parietal), and hippocampal formations (dentate gyrus, entorhinal cortex, and subiculum). We then examined the modulatory effects of the vestibular system on sensory processing using auditory and visual stimulation in combination with optogenetic excitation of the MVN. We found enhanced responses to sound in the auditory cortex, thalamus, and inferior colliculus ipsilateral to the stimulated MVN. In the visual pathway, we observed enhanced responses to visual stimuli in the ipsilateral visual cortex, thalamus, and contralateral superior colliculus. Taken together, our imaging findings reveal multiple brain-wide central vestibular pathways. We demonstrate large-scale modulatory effects of the vestibular system on sensory processing.

Serum anti-neural immunoreactivity in patients with fibromyalgia. Preliminary study.

INTRODUCTION: Fibromyalgia (FM) is a non-degenerative syndrome characterized by generalized, chronic musculoskeletal pain, as well as mood, memory and sleep disorders. OBJECTIVE: To search for serum anti-neural antibodies (ANeuA) in patients with FM (FMP) in order to rule out autoimmune etiology. METHODS: The Fibromyalgia Impact Questionnaire (FIQ) and Beck's depression inventory (BDI) were applied. Immunoreactivity and the target recognized on the sera from FMPs and healthy subjects were analyzed by indirect immunofluorescence and Western blot. RESULTS: Both FIQ and BDI values were significantly altered in FMPs in comparison with those of controls (FIQ, 70 ± 25 vs. 12 ± 12, p < 0.0001; BDI, 17 ± 11 vs. 4 ± 3, p < 0.0002). Only five out of 15 FMP sera had ANeuA specifically directed against neurons from the medial vestibular nucleus of the brainstem. This immunoreactivity was not detected in the sera from the 14 controls. ANeuA recognized a 45 kDa protein. CONCLUSIONS: 30% of FMPs have ANeuA that have not been described before. In future studies, it will be necessary for anti-neural immunoreactivity to be determined in a larger sample and for the role of ANeuAs in the pathophysiology of FM to be established.

INTRODUCCIÓN: La fibromialgia (FM) es un síndrome no degenerativo caracterizado por dolor musculoesquelético crónico y generalizado; así como por alteraciones anímicas, de memoria y sueño. OBJETIVO: Buscar anticuerpos antineurales (AANeu) séricos en pacientes con FM para descartar etiología autoinmune. MÉTODOS: Se aplicó el Cuestionario de Impacto en Fibromialgia (FIQ) y el Inventario de Depresión de Beck (BDI). La inmunorreactividad y el blanco reconocido por los sueros de pacientes con FM y sujetos sanos se analizó con inmunofluorescencia indirecta y Western blot. RESULTADOS: Los valores de FIQ y BDI estuvieron significativamente alterados en los pacientes con FM, en comparación con los de los controles (FIQ, 70 ± 25 versus 12 ± 12, p < 0.0001; BDI, 17 ± 11 versus 4 ± 3, p < 0.0002). Solo cinco de 15 sueros de pacientes con FM tuvieron AANeu dirigidos específicamente contra las neuronas del núcleo vestibular medio del tronco encefálico; estos no se detectaron en los 14 sueros de los controles. Los AANeu reconocieron una proteína de 45 kDa. CONCLUSIONES: El 30 % de los pacientes con FM tiene AANeu no descritos antes. Será necesario evaluar la inmunorreactividad antineural en una muestra más grande y determinar el papel de los AANeu en la fisiopatología de la FM.

Stochastic and sinusoidal electrical stimuli increase the irregularity and gain of Type A and B medial vestibular nucleus neurons, in vitro.

Galvanic vestibular stimulation (GVS) has been shown to improve vestibular function potentially via stochastic resonance, however, it remains unknown how central vestibular nuclei process these signals. In vivo work applying electrical stimuli to the vestibular apparatus of animals has shown changes in neuronal discharge at the level of the primary vestibular afferents and hair cells. This study aimed to determine the cellular impacts of stochastic, sinusoidal, and stochastic + sinusoidal stimuli on individual medial vestibular nucleus (MVN) neurons of male and female C57BL/6 mice. All stimuli increased the irregularity of MVN neuronal discharge, while differentially affecting neuronal gain. This suggests that the heterogeneous MVN neuronal population (marked by differential expression of ion channels), may influence the impact of electrical stimuli on neuronal discharge. Neuronal subtypes showed increased variability of neuronal firing, where Type A and B neurons experienced the largest gain changes in response to stochastic and sinusoidal stimuli. Type C neurons were the least affected regarding neuronal firing variability and gain changes. The membrane potential (MP) of neurons was altered by sinusoidal and stochastic + sinusoidal stimuli, with Type B and C neuronal MP significantly affected. These results indicate that GVS-like electrical stimuli impact MVN neuronal discharge differentially, likely as a result of heterogeneous ion channel expression.

Histamine H1 Receptor Contributes to Vestibular Compensation.

Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.

Quantitative evaluations of the contribution of the excitatory ionic conductance to repetitive spiking in a mathematical model of medial vestibular nucleus neurons.

Medial vestibular nucleus neurons show spontaneous repetitive spiking. This spiking activity was reproduced by a Hodgkin-Huxley-type mathematical model, which was developed in a previous study. The present study performed computer simulations of this model to evaluate the contribution of the excitatory ionic conductance to repetitive spiking. The present results revealed the difference in the influence of the transient sodium, persistent sodium, and calcium conductance on spiking activity. The differences between the present and previous results obtained from other neuronal mathematical models were discussed.

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

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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

BACKGROUND: This study aimed to investigate the effects of unilateral labyrinthectomy (UL) on monoamine neurotransmitters in the medial vestibular nucleus (MVN) of rats. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Effects of Betahistine on the Development of Vestibular Compensation after Unilateral Labyrinthectomy in Rats.

BACKGROUND: Vestibular compensation (VC) after unilateral labyrinthectomy (UL) consists of the initial and late processes. These processes can be evaluated based on the decline in the frequency of spontaneous nystagmus (SN) and the number of MK801-induced Fos-positive neurons in the contralateral medial vestibular nucleus (contra-MVe) in rats. Histamine H3 receptors (H3R) are reported to be involved in the development of VC. OBJECTIVE: We examined the effects of betahistine, an H3R antagonist, on the initial and late processes of VC in UL rats. METHODS: Betahistine dihydrochloride was continuously administered to the UL rats at doses of 100 and 200 mg/kg/day using an osmotic minipump. MK801 (1.0 mg/kg) was intraperitoneally administered on days 7, 10, 12, and 14 after UL, while Fos-positive neurons were immunohistochemically stained in the contra-MVe. RESULTS: The SN disappeared after 42 h, and continuous infusion of betahistine did not change the decline in the frequency of SN. The number of MK801-induced Fos-positive neurons in contra-MVe significantly decreased on days 7, 10, and 12 after UL in a dose-dependent manner in the betahistine-treated rats, more so than in the saline-treated rats. CONCLUSION: These findings suggest that betahistine facilitated the late, but not the initial, process of VC in UL rats.

The intrinsic plasticity of medial vestibular nucleus neurons during vestibular compensation-a systematic review and meta-analysis.

BACKGROUND: Vestibular compensation is a homeostatic process that occurs in the central nervous system in response to peripheral vestibular dysfunction. Experimental studies in rodent models have suggested that unilateral peripheral vestibular lesions are correlated with an increase in the intrinsic excitability of central vestibular neurons. This process may be dependent on the intrinsic properties of the neurons themselves. We aimed to conduct a systematic review of the literature to survey the evidence for changes in intrinsic plasticity observed during the acute phase of vestibular compensation. METHODS: We systematically reviewed the literature regarding the electrophysiological effect of experimentally induced unilateral vestibular deafferentation (UVD) on the intrinsic membrane properties of medial vestibular nucleus neurons in animal models. We developed tools to assess the methodological quality (precision, validity and bias) of studies that met pre-determined inclusion and exclusion criteria. We extracted numerical data and performed a meta-analysis of specific quantitative data pooled from these studies. RESULTS: We identified 17 studies that satisfied the inclusion criteria. There is moderate quality evidence to suggest a statistically significant increase in the intrinsic excitability of medial vestibular nucleus neurons following unilateral vestibular deafferentation. Specifically, the spontaneous discharge rate increases by 4 spikes/s on average and the sensitivity to current stimuli increases. CONCLUSION: Using this novel approach, we demonstrate that the methodology of systematic review and meta-analysis is a useful tool in the summation of data across experimental animal studies with similar aims.

Heterogeneous vestibulocerebellar mossy fiber projections revealed by single axon reconstruction in the mouse.

A significant population of neurons in the vestibular nuclei projects to the cerebellum as mossy fibers (MFs) which are involved in the control and adaptation of posture, eye-head movements, and autonomic function. However, little is known about their axonal projection patterns. We studied the morphology of single axons of medial vestibular nucleus (MVN) neurons as well as those originating from primary afferents, by labeling with biotinylated dextran amine (BDA). MVN axons (n = 35) were classified into three types based on their major predominant termination patterns. The Cbm-type terminated only in the cerebellum (15 axons), whereas others terminated in the cerebellum and contralateral vestibular nuclei (cVN/Cbm-type, 13 axons), or in the cerebellum and ipsilateral vestibular nuclei (iVN/Cbm-type, 7 axons). Cbm- and cVN/Cbm-types mostly projected to the nodulus and uvula without any clear relationship with longitudinal stripes in these lobules. They were often bilateral, and sometimes sent branches to the flocculus and to other vermal lobules. Also, the iVN/Cbm-type projected mainly to the ipsilateral nodulus. Neurons of these types of axons showed different distribution within the MVN. The number of MF terminals of some vestibulocerebellar axons, iVN/Cbm-type axons in particular, and primary afferent axons were much smaller than observed in previously studied MF axons originating from major precerebellar nuclei and the spinal cord. The results demonstrated that a heterogeneous population of MVN neurons provided divergent MF inputs to the cerebellum. The cVN/Cbm- and iVN/Cbm-types indicate that some excitatory neuronal circuits within the vestibular nuclei supply their collaterals to the vestibulocerebellum as MFs.

Tanshinone IIA Suppresses Hypoxia-induced Apoptosis in Medial Vestibular Nucleus Cells Via a Skp2/BKCa Axis.

BACKGROUND: The aim of the present study was to investigate the protective effects of Tanshinone IIA (Tan IIA) on hypoxia-induced injury in the medial vestibular nucleus (MVN) cells. METHODS: An in vitro hypoxia model was established using MVN cells exposed to hypoxia. The hypoxia-induced cell damage was confirmed by assessing cell viability, apoptosis and expression of apoptosis-associated proteins. Oxidative stress and related indicators were also measured following hypoxia modeling and Tan IIA treatment, and the genes potentially involved in the response were predicted using multiple GEO datasets. RESULTS: The results of the present study showed that Tan IIA significantly increased cell viability, decreased cell apoptosis and decreased the ratio of Bax/Bcl-2 in hypoxia treated cells. In addition, hypoxia treatment increased oxidative stress in MVN cells, and treatment with Tan IIA reduced the oxidative stress. The expression of SPhase Kinase Associated Protein 2 (SKP2) was upregulated in hypoxia treated cells, and Tan IIA treatment reduced the expression of SKP2. Mechanistically, SKP2 interacted with large-conductance Ca2+-activated K+ channels (BKCa), regulating its expression, and BKCa knockdown alleviated the protective effects of Tan IIA on hypoxia induced cell apoptosis. CONCLUSION: The results of the present study suggested that Tan IIA had a protective effect on hypoxia-induced cell damage through its anti-apoptotic and anti-oxidative activity via an SKP2/BKCa axis. These findings suggest that Tan IIA may be a potential therapeutic for the treatment of hypoxia-induced vertigo.

A new immunohistochemical method to evaluate the development of vestibular compensation after unilateral labyrinthectomy in rats.

BACKGROUND: Unilateral labyrinthectomy (UL) causes the disappearance of ipsilateral medial vestibular nuclear (ipsi-MVe) activity and induces spontaneous nystagmus (SN), which disappears during the initial process of vestibular compensation (VC). Ipsi-MVe-activity restores in the late process of VC. OBJECTIVE: We evaluated the late process of VC after UL in rats and examined the effects of thioperamide (H3 antagonist) on VC. MATERIALS AND METHODS: MK801 (NMDA antagonist)-induced Fos-like immunoreactive (-LIR) neurons in contra-MVe, which had been suppressed by NMDA-mediated cerebellar inhibition in UL rats was used as an index. RESULTS: The number of MK801-induced Fos-LIR neurons in contra-MVe gradually decreased to the same level as that of sham-operated rats 14 days after UL. Thioperamide moved the disappearance of the MK801-induced Fos-LIR neurons 2 days earlier. The number of MK801-induced Fos-LIR neurons in thioperamide-treated rats was significantly decreased, compared with that of vehicle rats on days 7 and 12 after UL. But, thioperamide did not influence the decline of SN frequency in UL rats. CONCLUSION: These findings suggested that the number of MK801-induced Fos-LIR neurons in contra-MVe was decreased in concordance with the restoration of ipsi-MVe-activity during the late process of VC after UL and that thioperamide accelerated the late, but not the initial process of VC.

The medial vestibular nuclei, a vulnerable target in thiamine deficiency.

BACKGROUND: Bilateral medial vestibular nuclei (MVN) is a common target in thiamine depletion and results in acute vestibular failure. Involvement of the MVN was present in 27 out of 38 brainstem sections reported in the largest thiamine deficiency autopsy cohort with Wernicke's encephalopathy. METHOD: Serial clinical, imaging and vestibulo-ocular reflex gain measured with the video head impulse (vHIT) in one patient with acute thiamine deficiency. RESULTS: Low horizontal VOR gain correlated with an abnormal manual head impulse and with MRI evidence of MVN in an alcohol-dependent patient with low thiamine levels. The vertical VOR gain was either normal or mildly abnormal. Thiamine replacement and normal diet restored the VOR gain and MRI signal changes to normal. CONCLUSION: This single case study provides clinical-imaging correlation for symmetric MVN compromise in thiamine deficiency, its effect on the VOR gain and the favorable response to thiamine and diet replacement when identified early.

Role of neural integrators in oculomotor systems: a systematic narrative literature review.

PURPOSE: To evaluate the role of neural integrators (NI) in the oculomotor system. METHODS: A literature search was carried out using several electronic databases during the months of June 2014 to March 2015. The following keywords were used to generate focused results: 'neural integrators', 'gaze-holding', 'oculomotor integration', 'impaired gaze-holding', 'gaze evoked nystagmus' and 'gaze dysfunction'. Further materials were found through searching relevant articles within reference lists. Seventy-one articles were sourced for this review which analysed animal and human subjects and network models; 45 were studies of humans, 16 studies of primates, three studies of felines and one study from rats and network models. The remaining articles were literature reviews. RESULTS: The horizontal and vertical, including torsional, NI are located logically in the brainstem, nearby their appropriate target extraocular motoneuron nuclei for stable eye position in eccentric position. The nucleus prepositus hypoglossi (NPH) and medial vestibular nuclei (MVN) are closely linked at the caudal pons and dorsal rostral medulla, integrating horizontal conjugate eye movement. The interstitial nucleus of Cajal (INC) integrates vertical and torsional eye movement at the upper midbrain. The integrator time constant is averaged to 25 seconds in human horizontal and animal vertical NI to perform its function. Case reports revealed that dysfunction of horizontal NI also resulted in vertical ocular deviations, indicating some overlap of horizontal and vertical gaze control. Furthermore, pharmacological inactivation of NI exposed a population of inhibitory neurotransmitters that permits its mechanism of action; allowing for smooth conjugate movement. CONCLUSIONS: Neural integrators operate to integrate eye velocity and eye position information to provide signals to extraocular motoneurons to attain and maintain a new position. Therefore, NI allow image stabilization during horizontal and vertical eye movements at eccentric positions for comfortable single vision.

Inmunorreactividad antineural sérica en pacientes con fibromialgia. Estudio preliminar / Serum anti-neural immunoreactivity in patients with fibromyalgia. Preliminary study

Resumen Introducción: La fibromialgia (FM) es un síndrome no degenerativo caracterizado por dolor musculoesquelético crónico y generalizado; así como por alteraciones anímicas, de memoria y sueño. Objetivo: Buscar anticuerpos antineurales (AANeu) séricos en pacientes con FM para descartar etiología autoinmune. Métodos: Se aplicó el Cuestionario de Impacto en Fibromialgia (FIQ) y el Inventario de Depresión de Beck (BDI). La inmunorreactividad y el blanco reconocido por los sueros de pacientes con FM y sujetos sanos se analizó con inmunofluorescencia indirecta y Western blot. Resultados: Los valores de FIQ y BDI estuvieron significativamente alterados en los pacientes con FM, en comparación con los de los controles (FIQ, 70 ± 25 versus 12 ± 12, p < 0.0001; BDI, 17 ± 11 versus 4 ± 3, p < 0.0002). Solo cinco de 15 sueros de pacientes con FM tuvieron AANeu dirigidos específicamente contra las neuronas del núcleo vestibular medio del tronco encefálico; estos no se detectaron en los 14 sueros de los controles. Los AANeu reconocieron una proteína de 45 kDa. Conclusiones: El 30 % de los pacientes con FM tiene AANeu no descritos antes. Será necesario evaluar la inmunorreactividad antineural en una muestra más grande y determinar el papel de los AANeu en la fisiopatología de la FM.

Abstract Introduction: Fibromyalgia (FM) is a non-degenerative syndrome characterized by generalized, chronic musculoskeletal pain, as well as mood, memory and sleep disorders. Objective: To search for serum anti-neural antibodies (ANeuA) in patients with FM (FMP) in order to rule out autoimmune etiology. Methods: The Fibromyalgia Impact Questionnaire (FIQ) and BECK’s depression inventory (BDI) were applied. Immunorreactivity and the target recognized on the sera from FMPs and healthy subjects were analyzed by indirect immunofluorescence and Western blot. Results: Both FIQ and BDI values were significantly altered in FMPs in comparison with those of controls (FIQ, 70 ± 25 vs. 12 ± 12, p < 0.0001; BDI, 17 ± 11 vs. 4 ± 3, p < 0.0002). Only five out of 15 FMP sera had ANeuA specifically directed against neurons from the medial vestibular nucleus of the brainstem. This immunoreactivity was not detected in the sera from the 14 controls. ANeuA recognized a 45 kDa protein. Conclusions: 30% of FMPs have ANeuA that have not been described before. In future studies, it will be necessary for anti-neural immunoreactivity to be determined in a larger sample and for the role of ANeuAs in the pathophysiology of FM to be established.

Distribution of extracellular matrix macromolecules in the vestibular nuclei and cerebellum of the frog, Rana esculenta.

The axons of transected and re-apposed vestibulocochlear nerve of the frog, in contrast to mammalian species, regenerate and establish functional contacts within their original termination areas of the vestibular nuclear complex and the cerebellum. The lack of regenerative capability of the mammalian central nervous system (CNS) is partially attributed to various extracellular matrix (ECM) molecules, such as chondroitin sulfate proteoglycans (CSPG) and tenascin-R (TN-R), which exert inhibition on axon regeneration. In contrast to these molecules, hyaluronan (HA) was reported to be permissive for CNS regeneration. Using histochemical and immunohistochemical methods, we investigated the distribution pattern of these molecules in the medial (MVN), lateral (LVN), superior and descending vestibular nuclei and the cerebellum of the frog and detected regional differences in the organization of the ECM. In the vestibular nuclear complex, pericellular condensation of the ECM, the perineuronal nets (PNNs) were recognizable in the LVN and MVN and were positive only for HA. The neuropil of the vestibular nuclei showed either a diffuse appearance with varying intensity of reactions, or dots and ring-like structures, which may represent the perinodal ECM of the vestibular fibers. In the cerebellum, indistinct PNNs that were only labeled for HA were present in the granular layer. Our findings suggest that the HA-rich, but CSPG and TN-R-free PNNs may be associated with the high degree of plasticity and regenerative potential of the amphibian vestibular system.

Prolyl carboxypeptidase mRNA expression in the mouse brain.

Prolyl carboxypeptidase (PRCP), a serine protease, is widely expressed in the body including liver, lung, kidney and brain, with a variety of known substrates such as plasma prekallikrein, bradykinin, angiotensins II and III, and α-MSH, suggesting its role in the processing of tissue-specific substrates. In the brain, PRCP has been shown to inactivate hypothalamic α-MSH, thus modulating melanocortin signaling in the control of energy metabolism. While its expression pattern has been reported in the hypothalamus, little is known on the distribution of PRCP throughout the mouse brain. This study was undertaken to determine PRCP expression in the mouse brain. Radioactive in situ hybridization was performed to determine endogenous PRCP mRNA expression. In addition, using a gene-trap mouse model for PRCP deletion, X-gal staining was performed to further determine PRCP distribution. Results from both approaches showed that PRCP gene is broadly expressed in the brain.

Postsynaptic mechanisms underlying the excitatory action of histamine on medial vestibular nucleus neurons in rats.

BACKGROUND AND PURPOSE: Anti-histaminergic drugs have been widely used in the clinical treatment of vestibular disorders and most studies concentrate on their presynaptic actions. The present study investigated the postsynaptic effect of histamine on medial vestibular nucleus (MVN) neurons and the underlying mechanisms. EXPERIMENTAL APPROACH: Histamine-induced postsynaptic actions on MVN neurons and the corresponding receptor and ionic mechanisms were detected by whole-cell patch-clamp recordings on rat brain slices. The distribution of postsynaptic histamine H1, H2 and H4 receptors was mapped by double and single immunostaining. Furthermore, the expression of mRNAs for H1, H2 and H4 receptors and for subtypes of Na⁺ -Ca²âº exchangers (NCXs) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels was assessed by quantitative real-time RT-PCR. KEY RESULTS: A marked postsynaptic excitatory effect, co-mediated by histamine H1 and H2 receptors, was involved in the histamine-induced depolarization of MVN neurons. Postsynaptic H1 and H2 rather than H4 receptors were co-localized in the same MVN neurons. NCXs contributed to the inward current mediated by H1 receptors, whereas HCN channels were responsible for excitation induced by activation of H2 receptors. Moreover, NCX1 and NCX3 rather than NCX2, and HCN1 rather than HCN2-4 mRNAs, were abundantly expressed in MVN. CONCLUSION AND IMPLICATIONS: NCXs coupled to H1 receptors and HCN channels linked to H2 receptors co-mediate the strong postsynaptic excitatory action of histamine on MVN neurons. These results highlight an active role of postsynaptic mechanisms in the modulation by central histaminergic systems of vestibular functions and suggest potential targets for clinical treatment of vestibular disorders.

Morphologically mixed chemical-electrical synapses formed by primary afferents in rodent vestibular nuclei as revealed by immunofluorescence detection of connexin36 and vesicular glutamate transporter-1.

Axon terminals forming mixed chemical/electrical synapses in the lateral vestibular nucleus of rat were described over 40 years ago. Because gap junctions formed by connexins are the morphological correlate of electrical synapses, and with demonstrations of widespread expression of the gap junction protein connexin36 (Cx36) in neurons, we investigated the distribution and cellular localization of electrical synapses in the adult and developing rodent vestibular nuclear complex, using immunofluorescence detection of Cx36 as a marker for these synapses. In addition, we examined Cx36 localization in relation to that of the nerve terminal marker vesicular glutamate transporter-1 (vglut-1). An abundance of immunolabeling for Cx36 in the form of Cx36-puncta was found in each of the four major vestibular nuclei of adult rat and mouse. Immunolabeling was associated with somata and initial dendrites of medium and large neurons, and was absent in vestibular nuclei of Cx36 knockout mice. Cx36-puncta were seen either dispersed or aggregated into clusters on the surface of neurons, and were never found to occur intracellularly. Nearly all Cx36-puncta were localized to large nerve terminals immunolabeled for vglut-1. These terminals and their associated Cx36-puncta were substantially depleted after labyrinthectomy. Developmentally, labeling for Cx36 was already present in the vestibular nuclei at postnatal day 5, where it was only partially co-localized with vglut-1, and did not become fully associated with vglut-1-positive terminals until postnatal day 20-25. The results show that vglut-1-positive primary afferent nerve terminals form mixed synapses throughout the vestibular nuclear complex, that the gap junction component of these synapses contains Cx36, that multiple Cx36-containing gap junctions are associated with individual vglut-1 terminals and that the development of these mixed synapses is protracted over several postnatal weeks.