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.

Body representation after a stroke in the brainstem.

BACKGROUND: Lesion occurring in the brainstem may cause a postural tilt and balance disorders, which could be due to an inaccurate perception of the body orientation. The objective of this study was to determine the effects of a brainstem stroke on body representation in horizontal and frontal plane, and links with impaired posture and neuroanatomy. METHODS: Forty patients with stroke in left brainstem (L-BS) or right (R-BS) were compared with 15 matched control subjects (C). The subjective straight-ahead (SSA) was investigated using a method disentangling lateral deviation and tilt components of error. RESULTS: The L-BS patients had contralesional lateral deviation of SSA. In addition, they showed an ipsilesional tilt, more severe for the trunk than for the head. By contrast, in R-BS patients, the representation of the body midline was fairly accurate in both the horizontal and frontal planes and did not differ from that of control subjects. CONCLUSION: This work highlights an asymmetry of representation of body associated with left brainstem lesions extending to the right cerebral hemisphere. This deviation appears only after a left lesion, which may point to a vestibular dominance. These results open a new perspective of neuro-rehabilitation of postural disorders after a stroke, with the correction of the representation of body orientation.

Ocular motor and vestibular dysfunction in central nervous system lymphoma.

BACKGROUND AND PURPOSE: Diagnosis of lymphoma involving the central nervous system (CNS) is challenging. This study aimed to explore the abnormal vestibular and ocular motor findings in CNS lymphoma. METHODS: A retrospective search of the medical records identified 30 patients with CNS lymphoma presenting ocular motor and vestibular abnormalities from four neurology clinics of university hospitals in South Korea (22 men, age range 14-81 years, mean 60.6 ± 15.2). The demographic and clinical features and the results of laboratory, radiological and pathological evaluation were analyzed. RESULTS: Patients presented with diplopia (13/30, 43%), vestibular symptoms (15/30, 50%) or both (2/30, 7%). In 15 patients with diplopia, abnormal ocular motor findings included ocular motor nerve palsy (n = 10, 67%), internuclear ophthalmoplegia (n = 2, 13%), external ophthalmoplegia (n = 2, 13%) and exophoria (n = 1, 7%). The vestibular abnormalities were isolated in 14 (82%) of 17 patients with vestibular symptoms and included combined unilateral peripheral and central vestibulopathy in three from lesions involving the vestibular nuclei. CNS lymphoma involved the brainstem (53%), cerebellum (33%), leptomeninges (30%), deep gray nuclei (23%) or cranial nerves (17%). Two patients showed the "double-panda" sign by involving the midbrain. CONCLUSIONS: This study expands the clinical and radiological spectra of CNS lymphoma. Neuro-ophthalmological and neuro-otological evaluation may guide the early diagnosis of CNS lymphoma.

Relative contribution of lateral vestibular neuron and abducens internuclear neuron inputs to the discharge activity of medial rectus motoneurons.

Medial rectus motoneurons mediate nasally directed horizontal eye movements. These motoneurons receive two major excitatory inputs, from the abducens internuclear neurons (ABD Ints) and neurons of the lateral vestibular nucleus whose axons course through the ascending tract of Deiters (ATD). In the present work, we have recorded in the alert chronic cat preparation the discharge activity of these two premotor neurons simultaneously with eye movements, to discern their relative contribution to the firing pattern of medial rectus motoneurons. ABD Int discharge was accurately correlated with eye movements, displaying high sensitivities to eye position and eye velocity. ATD neurons also discharged in relation to spontaneous and vestibular eye movements but showed significantly lower eye position and eye velocity sensitivities. Outstandingly, ATD neurons presented a significantly lower eye position threshold for recruitment compared to both ABD Ints and medial rectus motoneurons. Therefore, ATD neurons exhibited eye position and velocity signals during spontaneous and vestibular eye movements, which were of lower magnitude than those of ABD Ints, but due to their low recruitment threshold, they could play a significant role in facilitating ABD Int signal transmission onto medial rectus motoneurons.

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.

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 locus coeruleus directs sensory-motor reflex amplitude across environmental contexts.

Purposeful movement across unpredictable environments requires quick, accurate, and contextually appropriate motor corrections in response to disruptions in balance and posture.1,2,3 These responses must respect both the current position and limitations of the body, as well as the surrounding environment,4,5,6 and involve a combination of segmental reflexes in the spinal cord, vestibulospinal and reticulospinal pathways in the brainstem, and forebrain structures such as the motor cortex.7,8,9,10 These motor plans can be heavily influenced by the animal's surrounding environment, even when that environment has no mechanical influence on the perturbation itself. This environmental influence has been considered as cortical in nature, priming motor responses to a perturbation.8,11 Similarly, postural responses can be influenced by environments that alter threat levels in humans.12,13,14,15,16,17,18 Such studies are generally in agreement with work done in the mouse showing that optogenetic stimulation of the lateral vestibular nucleus (LVN) only results in motor responses when the animal is on a balance beam at height and not when walking on the stable surface of a treadmill.10 In general, this ability to flexibly modify postural responses across terrains and environmental conditions is a critically important component of the balance system.19,20 Here we show that LVN-generated motor corrections can be altered by manipulating the surrounding environment. Furthermore, environmental influence on corrections requires noradrenergic signaling from the locus coeruleus, suggesting a potential link between forebrain structures that convey sensory information about the environment and brainstem circuits that generate motor corrections.

Testosterone treatment restores vestibular function by enhancing neuronal survival in an experimental closed-head repetitive mild traumatic brain injury model.

Repetitive mild traumatic brain injury (rmTBI) results in a myriad of symptoms, including vestibular impairment. The mechanisms underlying vestibular dysfunction in rmTBI patients remain poorly understood. Concomitantly, acute hypogonadism occurs following TBI and can persist chronically in many patients. Using a repetitive mild closed-head animal model of TBI, the role of testosterone on vestibular function was tested. Male Long Evans Hooded rats were randomly divided into sham or rmTBI groups. Significant vestibular deficits were observed both acutely and chronically in the rmTBI groups. Systemic testosterone was administered after the development of chronic vestibular dysfunction. rmTBI animals given testosterone showed improved vestibular function that was sustained for 175 days post-rmTBI. Significant vestibular neuronal cell loss was, however, observed in the rmTBI animals compared to Sham animals at 175 days post-rmTBI and testosterone treatment significantly improved vestibular neuronal survival. Taken together, these data demonstrate a critical restorative role of testosterone in vestibular function following rmTBI. This study has important clinical implications because it identifies testosterone treatment as a viable therapeutic strategy for the long-term recovery of vestibular function following TBI.

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.

Properties of Deiters' neurons and inhibitory synaptic transmission in the mouse lateral vestibular nucleus.

Deiters' neurons, located exclusively in the lateral vestibular nucleus (LVN), are involved in vestibulospinal reflexes, innervate extensor motoneurons that drive antigravity muscles, and receive inhibitory inputs from the cerebellum. We investigated intrinsic membrane properties, short-term plasticity, and inhibitory synaptic inputs of mouse Deiters' and non-Deiters' neurons within the LVN. Deiters' neurons are distinguished from non-Deiters' neurons by their very low input resistance (105.8 vs. 521.8 MΩ, respectively), long axons that project as far as the ipsilateral lumbar spinal cord, and expression of the cytostructural protein nonphosphorylated neurofilament protein (NPNFP). Whole cell patch-clamp recordings in brain stem slices show that most Deiters' and non-Deiters' neurons were tonically active (>92%). Short-term plasticity was studied by examining discharge rate modulation following release from hyperpolarization [postinhibitory rebound firing (PRF)] and depolarization [firing rate adaptation (FRA)]. PRF and FRA gain were similar in Deiters' and non-Deiters' neurons (PRF 24.9 vs. 20.2 Hz and FRA gain 231.5 vs. 287.8 spikes/s/nA, respectively). Inhibitory synaptic input to both populations showed that GABAergic rather than glycinergic inhibition dominated. However, GABAA miniature inhibitory postsynaptic current (mIPSC) frequency was much higher in Deiters' neurons compared with non-Deiters' neurons (∼15.9 vs. 1.4 Hz, respectively). Our data suggest that Deiters' neurons can be reliably identified by their intrinsic membrane and synaptic properties. They are tonically active and glutamatergic, have low sensitivity or "gain," exhibit little adaptation, and receive strong GABAergic input. Deiters' neurons also have minimal short-term plasticity, and together these features suggest they are well suited to a role in encoding tonic signals for the vestibulospinal reflex.NEW & NOTEWORTHY Deiters' neurons within the lateral vestibular nucleus project the length of the spinal cord and activate antigravity extensor muscles. Deiters' neurons were characterized anatomically and physiologically in mice. Deiters' neurons are tonically active, have homogeneous intrinsic membrane properties, including low input resistance, and receive significant GABAAergic synaptic inputs. Deiters' neurons show little modulation in response to current injection. These features are consistent with Deiters' neurons responding to perturbations to maintain posture and balance.

A New Vestibular Stimulation Mode for Motion Sickness With Emphatic Analysis of Pica.

Motion sickness (MS) was frequently introduced for rodents in research work through passive motion that disturbed vestibular signals in the presence of visual and aleatory, proprioceptive inputs. Inducement of MS in this way causes conflicting signals that activate intermixed neural circuits representing multimodal stimulation. From reductionism, a lab setup to elicit rat MS via vestibular stimulation was configured in the present study for MS study in connection with dissection of the central vestibular component causally underlying MS. The individual animal was blinded to light with a custom-made restrainer, and positioned at an inclination of 30° for otolith organs to receive unusual actions by gravitoinertial vector. Following a 2-h double-axis (earth-vertical) rotation involving angular acceleration/deceleration, a suit of behaviors characterizing the MS was observed to be significantly changed including pica (eating non-nutritive substance like kaolin), conditioned taste avoidance and locomotion (p < 0.05). Notably, for the statistical hypothesis testing, the utility of net increased amount of kaolin consumption as independent variables in data processing was expounded. In addition, Fos-immunostained neurons in vestibular nucleus complex were significantly increased in number, suggesting the rotation-induced MS was closely related to the vestibular activation. In conclusion, our work indicated that the present setup could effectively elicit the MS by disturbing vestibular signals in rat in the context of well-controlled proprioceptive inputs and lack of visual afference.

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.

Calcitonin gene-related peptide receptor antagonist BIBN4096BS regulates synaptic transmission in the vestibular nucleus and improves vestibular function via PKC/ERK/CREB pathway in an experimental chronic migraine rat model.

BACKGROUND: Vestibular symptoms are frequently reported in patients with chronic migraine (CM). However, whether vestibular symptoms arise through overlapping neurobiology of migraine remains to be elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) and CGRP1 receptor play important pathological roles in facilitating central sensitization in CM. Therefore, we aimed to investigate whether CGRP1 receptor contributes to vestibular dysfunction after CM by improving synaptic transmission in the vestibular nucleus (VN). METHODS: A CM rat model was established by recurrent intermittent administration of nitroglycerin (NTG). Migraine- and vestibular-related behaviors were assessed. CGRP1 receptor specific antagonist, BIBN4096BS, and protein kinase C (PKC) inhibitor chelerythrine chloride (CHE) were administered intracerebroventricularly. The expressions of CGRP and CGRP1 receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were evaluated by western blot, immunofluorescent staining and quantitative real-time polymerase chain reaction in the vestibular nucleus (VN). Synaptic associated proteins and synaptic morphological characteristics were explored by western blot, transmission electron microscope, and Golgi-cox staining. The expressions of PKC, phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated cAMP response element-binding protein at serine 133 site (p-CREB-S133) and c-Fos were detected using western blot or immunofluorescent staining. RESULTS: The expressions of CGRP, CLR and RAMP1 were significantly upregulated in CM rats. CLR and RAMP1 were expressed mainly in neurons. BIBN4096BS treatment and PKC inhibition alleviated mechanical allodynia, thermal hyperalgesia and vestibular dysfunction in CM rats. Additionally, BIBN4096BS treatment and PKC inhibition markedly inhibited the overexpression of synaptic associated proteins and restored the abnormal synaptic structure in VN after CM. Furthermore, BIBN4096BS treatment dysregulated the expression levels of PKC, p-ERK and p-CREB-S133, and attenuated neuronal activation in VN after CM. CONCLUSIONS: The present study demonstrated that CGRP1 receptor inhibition improved vestibular function after CM by reversing the aberrant synaptic transmission via downregulating PKC/ERK/CREB signaling pathway. Therapeutic interventions by inhibiting CGRP/CGRP1 signaling may be a new target for the treatment of vestibular symptoms in CM.

Comparative study of vestibular projection pathway connectivity in cerebellar injury patients and healthy adults.

OBJECTIVE: Cerebellar injury can not only cause gait and postural instability, nystagmus, and vertigo but also affect the vestibular system. However, changes in connectivity regarding the vestibular projection pathway after cerebellar injury have not yet been reported. Therefore, in the current study, we investigated differences in the connectivity of the vestibular projection pathway after cerebellar injury using diffusion tensor imaging (DTI) tractography. METHODS: We recruited four stroke patients with cerebellar injury. Neural connectivity in the vestibular nucleus (VN) of the pons and medulla oblongata in patients with cerebellar injury was measured using DTI. Connectivity was defined as the incidence of connection between the VN on the pons and medulla oblongata and target brain regions such as the cerebellum, thalamus, parieto-insular vestibular cortex (PIVC), and parietal lobe. RESULTS: At thresholds of 10 and 30, there was lower connectivity in the ipsilateral hemisphere between the VN at the medullar level and thalamus in the patients than in healthy adults. At a threshold of 1 and 10, the patient group showed lower VN connectivity with the PIVC than healthy adults. At a threshold of 1, VN connectivity with the parietal lobe in the contralateral hemisphere was lower in the patients than in healthy adults. Additionally, at a threshold of 30, VN connectivity at the pons level with the cerebellum was lower in healthy adults than in the patients. CONCLUSION: Cerebellar injury seems to be associated with decreased vestibular projection pathway connectivity, especially in the ipsilateral thalamus, PIVC, and contralateral parietal lobe.

Signal processing in the vestibulo-ocular reflex.

In this chapter, Robinson develops models to account for the neural control of the vestibulo-ocular reflex in response to horizontal and vertical head rotations. By combining knowledge of the discharge properties of the several subpopulations of neurons that contribute to vestibular eye movements with their known anatomical connections, these models seek to explain how specific signals are combined to enable the ocular motoneurons to program vestibular eye movements that compensate for head perturbations. Details such as the integration of raw vestibular signals, differences in the neuronal processing for vertical versus horizontal reflexes, and the role of individual pathways such as the medial longitudinal fasciculus are discussed.

Neurophysiology of the optokinetic system.

This chapter provides a review of early studies into the neural substrate for optokinetic-vestibular responses. Properties and connections of retinal and brainstem neurons contributing to optokinetic responses in the afoveate rabbit are summarized. Electrophysiological and lesion studies provide support for confluence of optokinetic and vestibular signals in the vestibular nucleus to provide the brain's estimate of self-rotation. Evidence for optokinetic-vestibular symbiosis in humans comes from the observation that individuals who have lost vestibular function show no optokinetic after-nystagmus in darkness, following full-field stimulus motion. An anatomical scheme for brainstem elaboration of optokinetic responses is proposed and cerebellar contributions are reviewed.

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.

Neural Interruption by Unilateral Labyrinthectomy Biases the Directional Preference of Otolith-Related Vestibular Neurons.

BACKGROUND: The directional preference of otolith-related vestibular neurons elucidates the neuroanatomical link of labyrinths, but few direct experimental data have been provided. METHODS: The directional preference of otolith-related vestibular neurons was measured in the vestibular nucleus using chemically induced unilateral labyrinthectomy (UL). For the model evaluation, static and dynamic behavioral tests as well as a histological test were performed. Extracellular neural activity was recorded for the neuronal responses to the horizontal head rotation and the linear head translation. RESULTS: Seventy-seven neuronal activities were recorded, and the total population was divided into three groups: left UL (20), sham (35), and right UL (22). Based on directional preference, two sub-groups were again classified as contra- and ipsi-preferred neurons. There was no significance in the number of those sub-groups (contra-, 15/35, 43%; ipsi-, 20/35, 57%) in the sham (p = 0.155). However, more ipsi-preferred neurons (19/22, 86%) were observed after right UL (p = 6.056 × 10-5), while left UL caused more contra-preferred neurons (13/20, 65%) (p = 0.058). In particular, the convergent neurons mainly led this biased difference (ipsi-, 100% after right UL and contra-, 89% after left UL) (p < 0.002). CONCLUSIONS: The directional preference of the neurons depended on the side of the lesion, and its dominance was mainly led by the convergent neurons.

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.

5-HT1A receptor-mediated attenuation of synaptic transmission in rat medial vestibular nucleus impacts on vestibular-related motor function.

KEY POINTS: Chemogenetic activation of medial vestibular nucleus-projecting 5-HT neurons resulted in deficits in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. The 5-HT1A receptor mediates the vestibular-related behavioural effects of 5-HT in the vestibular nucleus. 5-HT1A receptor activation attenuated evoked excitatory postsynaptic currents and evoked inhibitory postsynaptic currents via a presynaptic mechanism in the vestibular nucleus. ABSTRACT: While the anxiolytic effects of serotonergic neuromodulation are well studied, its role in sensorimotor coordination and postural control is unclear. In this study, we show that an increase of serotonin (5-hydroxytryptamine, 5-HT) at the medial vestibular nucleus (MVN), a brainstem centre for vestibulospinal coordination, by either direct cannula administration or chemogenetic stimulation of MVN-projecting serotonergic neurons, adversely affected performance of rats in vestibular-mediated tasks, including negative geotaxis, balance beam and rota-rod tests. Application of the 5-HT1 and 5-HT7 receptor co-agonist 8-hydroxy-2-(di-n-propylamino) tetralin recapitulated the effect of 5-HT, while co-administration of the specific 5-HT1A receptor antagonist WAY 100135 effectively abolished all 5-HT-induced behavioural deficits. This indicated that 5-HT1A receptors mediated the effects of 5-HT in the rat MVN. Using whole-cell patch-clamp recording, we demonstrated that 5-HT1A receptor activation attenuated both evoked excitatory and evoked inhibitory postsynaptic currents through a presynaptic mechanism in the rat MVN. The results thus highlight the 5-HT1A receptor as the gain controller of vestibular-related brainstem circuits for posture and balance.