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.

Corticotropin-releasing factor depolarizes rat lateral vestibular nuclear neurons through activation of CRF receptors 1 and 2.

Corticotropin-releasing factor (CRF) is a neuropeptide mainly synthesized in the hypothalamic paraventricular nucleus and has been traditionally implicated in stress and anxiety. Intriguingly, genetic or pharmacological manipulation of CRF receptors affects locomotor activity as well as motor coordination and balance in rodents, suggesting an active involvement of the central CRFergic system in motor control. Yet little is known about the exact role of CRF in central motor structures and the underlying mechanisms. Therefore, in the present study, we focused on the effect of CRF on the lateral vestibular nucleus (LVN) in the brainstem vestibular nuclear complex, an important center directly contributing to adjustment of muscle tone for both postural maintenance and the alternative change from the extensor to the flexor phase during locomotion. The results show that CRF depolarizes and increases the firing rate of neurons in the LVN. Tetrodotoxin does not block the CRF-induced depolarization and inward current on LVN neurons, suggesting a direct postsynaptic action of the neuropeptide. The CRF-induced depolarization on LVN neurons was partly blocked by antalarmin or antisauvagine-30, selective antagonists for CRF receptors 1 (CRFR1) and 2 (CRFR2), respectively. Furthermore, combined application of antalarmin and antisauvagine-30 totally abolished the CRF-induced depolarization. Immunofluorescence results show that CRFR1 and CRFR2 are co-localized in the rat LVN. These results demonstrate that CRF excites the LVN neurons by co-activation of both CRFR1 and CRFR2, suggesting that via the direct modulation on the LVN, the central CRFergic system may actively participate in the central vestibular-mediated postural and motor control.

You are better off running than walking revisited: Does an acute vestibular imbalance affect muscle synergies?

It has been suggested that vestibular cues are inhibited for the benefit of spinal locomotor centres in parallel with the increase in locomotion speed. This study aimed at quantifying the influence of a transient vestibular tone imbalance (TVTI) on gait kinematics, muscle activity and muscle synergies during walking and running. Twelve participants walk or run at a self-selected speed with or without TVTI, which was generated by 10 body rotations just prior the locomotion task. Three-dimensional lower-limb kinematic was recorded simultaneously with the surface electromyographic (EMG) activity of 8 muscles to extract muscle synergies via non-negative matrix factorization. Under TVTI, there was an increased gait deviation in walking compared to running (22.8 ±â€¯8.4° and 8.5 ±â€¯3.6°, respectively; p < 0.01), while the number (n = 4) and the composition of the muscle synergies did not differ across conditions (p = 0.78). A higher increase (p < 0.05) in EMG activity due to TVTI was found during walking compared to running, especially during stance. These findings confirmed that the central nervous system inhibited misleading vestibular signals according to the increase in locomotion speed for the benefit of spinal mechanisms, expressed by the muscle synergies.

Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion.

Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex-dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico-reticulo-spinal circuit reorganization may also improve recovery in humans.

Balance Control Mediated by Vestibular Circuits Directing Limb Extension or Antagonist Muscle Co-activation.

Maintaining balance after an external perturbation requires modification of ongoing motor plans and the selection of contextually appropriate muscle activation patterns that respect body and limb position. We have used the vestibular system to generate sensory-evoked transitions in motor programming. In the face of a rapid balance perturbation, the lateral vestibular nucleus (LVN) generates exclusive extensor muscle activation and selective early extension of the hindlimb, followed by the co-activation of extensor and flexor muscle groups. The temporal separation in EMG response to balance perturbation reflects two distinct cell types within the LVN that generate different phases of this motor program. Initially, an LVNextensor population directs an extension movement that reflects connections with extensor, but not flexor, motor neurons. A distinct LVNco-activation population initiates muscle co-activation via the pontine reticular nucleus. Thus, distinct circuits within the LVN generate different elements of a motor program involved in the maintenance of balance.

The integration of neural information by a passive kinetic stimulus and galvanic vestibular stimulation in the lateral vestibular nucleus.

Despite an easy control and the direct effects on vestibular neurons, the clinical applications of galvanic vestibular stimulation (GVS) have been restricted because of its unclear activities as input. On the other hand, some critical conclusions have been made in the peripheral and the central processing of neural information by kinetic stimuli with different motion frequencies. Nevertheless, it is still elusive how the neural responses to simultaneous GVS and kinetic stimulus are modified during transmission and integration at the central vestibular area. To understand how the neural information was transmitted and integrated, we examined the neuronal responses to GVS, kinetic stimulus, and their combined stimulus in the vestibular nucleus. The neuronal response to each stimulus was recorded, and its responding features (amplitude and baseline) were extracted by applying the curve fitting based on a sinusoidal function. Twenty-five (96.2%) comparisons of the amplitudes showed that the amplitudes decreased during the combined stimulus (p < 0.001). However, the relations in the amplitudes (slope = 0.712) and the baselines (slope = 0.747) were linear. The neuronal effects by the different stimuli were separately estimated; the changes of the amplitudes were mainly caused by the kinetic stimulus and those of the baselines were largely influenced by GVS. Therefore, the slopes in the comparisons implied the neural sensitivity to the applied stimuli. Using the slopes, we found that the reduced amounts of the neural information were transmitted. Overall, the comparisons of the responding features demonstrated the linearity and the subadditivity in the neural transmission.

Deiters' Nucleus. Its Role in Cerebellar Ideogenesis : The Ferdinando Rossi Memorial Lecture.

Otto Deiters (1834-1863) was a promising neuroscientist who, like Ferdinando Rossi, died too young. His notes and drawings were posthumously published by Max Schultze in the book "Untersuchungen über Gehirn und Rückenmark." The book is well-known for his dissections of nerve cells, showing the presence of multiple dendrites and a single axon. Deiters also made beautiful drawings of microscopical sections through the spinal cord and the brain stem, the latter showing the lateral vestibular nucleus which received his name. This nucleus, however, should be considered as a cerebellar nucleus because it receives Purkinje cell axons from the vermal B zone in its dorsal portion. Afferents from the labyrinth occur in its ventral part. The nucleus gives rise to the lateral vestibulospinal tract. The cerebellar B module of which Deiters' nucleus is the target nucleus was used in many innovative studies of the cerebellum on the zonal organization of the olivocerebellar projection, its somatotopical organization, its microzones, and its role in posture and movement that are the subject of this review.

The role of the thalamus in the human subcortical vestibular system.

Most of our knowledge concerning central vestibular pathways is derived from animal studies while evidence of the functional importance and localization of these pathways in humans is less well defined. The termination of these pathways at the thalamic level in humans is even less known. In this review we summarize the findings concerning the central subcortical vestibular pathways in humans and the role of these structures in the central vestibular system with regard to anatomical localization and function. Also, we review the role of the thalamus in the pathogenesis of higher order sensory deficits such as spatial neglect, pusher syndrome or thalamic astasia and the correlation of these phenomena with findings of a vestibular tone imbalance at the thalamic level. By highlighting thalamic structures involved in vestibular signal processing and relating the different nomenclatures we hope to provide a base for future studies on thalamic sensory signal processing.

Effect of unilateral labyrinthectomy on the molecular composition of perineuronal nets in the lateral vestibular nucleus of the rat.

Disturbances in vestibular functions caused by unilateral labyrinthectomy (UL) are spontaneously restored during the process of vestibular compensation due to the plasticity of CNS. The underlying molecular background of vestibular compensation is not yet fully understood. Recent studies have shown that the extracellular matrix (ECM) molecules have either permissive or non-permissive effect on the neural plasticity. In our previous study we have demonstrated changes in the expression of hyaluronan (HA) in the vestibular nuclei (VN) of the frog following peripheral vestibular lesion. The present work was undertaken to examine the expression of the HA and chondroitin sulfate proteoglycans (CSPGs) in the lateral vestibular nucleus (LVN) of the rat following UL by using histochemical methods. On the first postoperative day, the condensation of the ECM around the neurons, the perineuronal net (PNN) was not distinguished from the surrounding neuropil on the side of UL indicating the desorganization of its molecular structure. At survival day 3, the PNN was recognizable with the HA probe, whereas its staining for the CSPGs was restored by the time of the seventh postoperative day. In the neuropil, the intensity of the HA increased on the operated side, while the CSPGs reaction almost completely disappeared. The present study have demonstrated for the first time that the UL is accompanied by the modification of the HA, and CSPG staining pattern in the PNN of the LVN in the rat. As the reorganization of the PNN corresponds to the restoration of spontaneous activity of vestibular neurons, our study implies the role of HA and CSPGs in the vestibular compensation.

Protective effects of hypothalamic proline-rich peptide and cobra venom Naja Naja Oxiana on dynamics of vestibular compensation following unilateral labyrinthectomy.

We tested the action of proline-rich peptide (PRP-1) and cobra venom Naja Naja Oxiana (NOX) on Deiters' nucleus neurons at 3rd, 15th and 35th days after unilateral labyrinthectomy (UL). Early and late tetanic, post-tetanic potentiation and depression of Deiters'neurons to bilateral high frequency stimulation of hypothalamic supraoptic and paraventricualar nuclei was studied. The analysis of spike activity was carried out by mean of on-line selection and special program. The complex averaged peri-event time and frequency histograms shows the increase of inhibitory and excitatory reactions of Deiters' neurons at early stage of vestibular compensation following PRP-1 and NOX injection, reaching the norm at the end of tests. In histochemical study the changes in Ca(2+)-dependent acidic phosphatase (AP) activity in neurons was discovered. It was shown that in UL animals the total disappearance or delay of decolorizing of Deiters' neurons lead to neurodegenerative pattern as cellular "shade". AP activity after UL and PRP-1 injection exerts more effective recovery of neurons in comparison with events, observed after the administration of NOX. The data of this study indicate that PRP-1 and NOX are protectors, which may successfully recover the disturbed vestibular functions.

Type B GABA receptors contribute to the restoration of balance during vestibular compensation in mice.

Following unilateral vestibular damage (UVD), vestibular compensation restores both static and dynamic vestibular reflexes. The cerebellar cortex provides powerful GABAergic inhibitory input to the vestibular nuclei which is necessary for compensation. Metabotropic GABA type B (GABA(B)) receptors in the vestibular nuclei are thought to be involved. However, the contribution of GABA(B) receptors may differ between static and dynamic compensation. We tested static and dynamic postural reflexes and gait in young mice, while they compensated for UVD caused by injection of air into the vestibular labyrinth. The effects of an agonist (baclofen), an antagonist (CGP56433A) and a positive allosteric modulator (CGP7930) of the GABA(B) receptor were evaluated during compensation. Static postural reflexes recovered very rapidly in our model, and baclofen slightly accelerated recovery. However, CGP56433A significantly impaired static compensation. Dynamic reflexes were evaluated by balance-beam performance and by gait; both showed significant decrements following UVD and performance improved over the next 2 days. Both CGP56433A and baclofen temporarily impaired the ability to walk on a balance beam after UVD. Two days later, there were no longer any significant effects of drug treatments on balance-beam performance. Baclofen slightly accelerated the recovery of stride length on a flat surface, but CGP7930 worsened the gait impairment following UVD. Using immunohistochemistry, we confirmed that GABA(B) receptors are abundantly expressed on the vestibulospinal neurons of Deiters in mice. Our results suggest that GABA(B) receptors contribute to the compensation of static vestibular reflexes following unilateral peripheral damage. We also conclude that impairment of the first stage of compensation, static recovery, does not necessarily result in an impairment of dynamic recovery in the long term.

Are the thalamic projections of nucleus Z of the medulla oblongata reorganized after partial deafferentation of the ventrolateral nucleus of the thalamus?

The possible plastic reorganization of projections from the somatosensory relay nucleus Z of the cat medulla oblongata to the partially deafferented ventrolateral nucleus of the thalamus was studied by retrograde labeling with horseradish peroxidase. Partial deafferentation of the ventrolateral nucleus of the thalamus was produced by prior (three months) electrolytic destruction of the contralateral cerebellar interpositus nucleus or the lateral vestibular nucleus of Deiters. The results demonstrated local intense labeling of a group of neurons in nucleus Z, and there was a small group of labeled neurons in cell group x of the vestibular complex projecting to the ventrolateral nucleus of the thalamus, where these projections were found to overlap with those from the cerebellar nuclei. After lesioning of the cerebellar interpositus nucleus or lateral vestibular nucleus of Deiters, ipsilateral projections in the monosynaptic circuit consisting of nucleus Z and the ventrolateral nucleus of the thalamus did not form. The absence of reorganization of projections from nucleus Z to the ventrolateral nucleus of the thalamus in terms of the formation of ipsilateral projections may be associated with its being part of the somatosensory relay nucleus, which is specialized for relaying and transmitting information strictly of the specific proprioceptive modality.

[Effects of various neuromediators and regulatory peptides on the impulse activity of neurons in the lateral vestibular nucleus].

The myoelectrode technique and microiontophoresis of physiologically active substances were applied to cats immobilized with neuromuscular relaxant to show that the classic neuromediators (acetylcholine, norepinephrine, GABA etc.) and regulatory peptides (enkephalins, TRHs, vasoactive intestinal peptide (VIP), somatostatin (SS) and others) can influence directly most neurons (58 to 100%) in the lateral vestibular nucleus (LVN). Enkephalins, VIP and SS retained largely their inhibitory effect on the neuron impulse activity in the presence of L-glutamate. Also, enkephalins, VIP and SS are able to stimulate or suppress the inhibitory effect of GABA and glycine. Consequently, the substances under study may act as LVN neuromediators and/or neuromodulators.

[Can the thalamic projections of medulla oblongata nucleus Z be reorganized following partial deafferentation of the ventral lateral thalamic nucleus?].

Following partial deafferentation of ventral lateral thalamic nucleus by means of HRP retrograde labeling, possible plastic reorganization of projections of the brain stem relay Z nucleus was studied in cats. The partial deafferentation of ventral lateral thalamic nucleus was evoked by preliminary (3 months before) destroying of contralateral cerebellar nucleus interpositus or Deiters' lateral vestibular nucleus. The local intensive labeling of neurons in the Z nucleus and a little group of neurons in the cellular group x of the vestibular complex projecting to ventral lateral thalamic nucleus and overlapping with those projecting from cerebellum was observed. It was shown that, following destruction of the cerebellar nucleus interpositus or Deiters' nucleus, the ipsilateral projections in the nucleus monosynaptic link are not forming. The absence of Z nucleus-ventral lateral thalamic nucleus projections reorganization similar to the formation ofipsilateral projections possibly depends on its belonging to the somatosensory relay nucleus which provides switching and transmission of specific proprioceptuve modality.

The central vestibular complex in dolphins and humans: functional implications of Deiters' nucleus.

Toothed whales (Odontocetes; e.g., dolphins) are well-known for efficient underwater locomotion and for their acrobatic capabilities. Nevertheless, in relation to other mammals including the human and with respect to body size, their vestibular apparatus is reduced, particularly the semicircular canals. Concomitantly, the vestibular nerve and most of the vestibular nuclei are thin and small, respectively, in comparison with those in terrestrial mammals. In contrast, the lateral (Deiters') vestibular nucleus is comparatively well developed in both coastal and pelagic dolphins. In the La Plata dolphin (Pontoporia blainvillei) and the Common dolphin (Delphinus delphis), all of the vestibular nuclei are present and their topographic relations are similar to those in humans. Quantitative analysis, however, revealed that in the dolphin most of the nuclei (superior, medial, descending nucleus) are minute both in absolute and relative terms. Here, the only exception is the lateral vestibular nucleus, which is of comparable size in humans and Pontoporia and decidedly more voluminous in Delphinus. While the small size of the majority of the dolphin's vestibular nuclei correlates well with miniaturization of the semicircular canals, the size of Deiters' nucleus seems to support its relative independence from the vestibular system and a close functional relationship with the cerebellum. In comparison with findings in humans and other terrestrial mammals, both of these aspects seem to be related to the physical conditions of aquatic life and locomotion in three dimensions.

Outer hair cell active force generation in the cochlear environment.

Outer hair cells are critical to the amplification and frequency selectivity of the mammalian ear acting via a fine mechanism called the cochlear amplifier, which is especially effective in the high-frequency region of the cochlea. How this mechanism works under physiological conditions and how these cells overcome the viscous (mechanical) and electrical (membrane) filtering has yet to be fully understood. Outer hair cells are electromotile, and they are strategically located in the cochlea to generate an active force amplifying basilar membrane vibration. To investigate the mechanism of this cell's active force production under physiological conditions, a model that takes into account the mechanical, electrical, and mechanoelectrical properties of the cell wall (membrane) and cochlear environment is proposed. It is shown that, despite the mechanical and electrical filtering, the cell is capable of generating a frequency-tuned force with a maximal value of about 40 pN. It is also found that the force per unit basilar membrane displacement stays essentially the same (40 pNnm) for the entire linear range of the basilar membrane responses, including sound pressure levels close to hearing threshold. Our findings can provide a better understanding of the outer hair cell's role in the cochlear amplifier.

Plasticity of auditory medullary-midbrain connectivity across metamorphic development in the bullfrog, Rana catesbeiana.

On the basis of patterns of anterograde, retrograde, and bi-directional transport of tracers from both the superior olivary nucleus (SON) and the torus semicircularis (TS), we report anatomical changes in brainstem connectivity across metamorphic development in the bullfrog, Rana catesbeiana. In early and late stages of larval development (Gosner stages 25-37), anterograde or bi-directional tracers injected into the SON produce terminal/fiber label in the contralateral SON and in the ipsilateral TS. Between stages 38-41 (deaf period), only sparse or no terminal/fiber label is visible in these target nuclei. During metamorphic climax (stages 42-46), terminal/fiber label reappears in both the contralateral SON and in the ipsilateral TS, and now also in the contralateral TS. Injections of retrograde tracers into the SON fail to label cell bodies in the ipsilateral TS in deaf period animals, mirroring the previously-reported failure of retrograde transport from the TS to the ipsilateral SON during this developmental time. Bilateral cell body label emerges in the dorsal medullary nucleus and the lateral vestibular nucleus bilaterally as a result of SON transport during the late larval period, while cell body label in the contralateral TS emerges during climax. At all larval stages, injections into the SON produce anterograde and retrograde label in the medial vestibular nucleus bilaterally. These data show anatomical stability in some pathways and plasticity in others during larval development, with the most dramatic changes occurring during the deaf period and metamorphic climax. Animals in metamorphic climax show patterns of connectivity similar to that of froglets and adults, indicating the maturation during climax of central anatomical substrates for hearing in air.

Firing patterns of rat vestibulospinal neurons during quadrupedal standing on a pitching platform.

The neuronal activity of vestibulospinal neurons projecting to the lumbar enlargement was recorded in conscious rats standing with four limbs on a pitching platform. The neurons were classified into 3 groups: up-neurons firing maximally in the head-up phase (2/8), down-neurons with maximal firing in the head-down phase (2/8), and nonmodulated neurons (4/8). The 3 groups may play differential roles in stance control.

Validity of a new feedback method for the VEMP test.

CONCLUSIONS: We used a feedback method, based on a blood pressure manometer with inflatable cuff, to control the sternocleidomastoid muscle (SCM) contraction. To obtain comparable left-right VEMP responses, it is necessary (1) to determine which cuff pressures on both sides yield identical mean rectified voltage (MRV) values of the SCM contraction and (2) to apply these cuff pressures during the VEMP test. OBJECTIVE: To investigate the effect of the SCM muscle contraction variability on the VEMP variables when applying the feedback method. MATERIALS AND METHODS: Subjects pushed with their jaw against the hand-held inflated cuff to generate cuff pressures of subsequently 30, 40 and 50 mmHg during a MRV and VEMP measurement. RESULTS: When analyzing the relationship between the applied cuff pressures and the MRV values/VEMP amplitudes, we showed that (1) there was a linear relationship, (2) there was no side effect and (3) there was an interaction effect between 'side' and 'subject'. There was neither a side effect, nor an effect of the applied cuff pressure when considering the p13 latencies. As for the n23 values, there was no side effect but there was a significant difference when comparing the n23 latencies at cuff pressures of 30 vs 40 mmHg/50 mmHg.

Morphology and physiology of the cerebellar vestibulolateral lobe pathways linked to oculomotor function in the goldfish.

Intracellular recording and single-cell labeling were combined to investigate the oculomotor circuitry of the goldfish cerebellar vestibulolateral lobe, consisting of the eminentia granularis (Egr) and caudal lobe. Purkinje cells exhibiting highly conserved vertebrate electrophysiological and morphological properties provide the direct output from the caudal lobe to the vestibular nuclei. Biocytin labeling of the Egr distinguished numerous hindbrain precerebellar sources that could be divided into either putative mechano- or vestibulosensitive nuclei based on cellular location and axon trajectories. Precerebellar neurons in a hindbrain nucleus, called Area II, were electrophysiologically characterized after antidromic activation from the Egr (>50% bilateral) and their morphology analyzed after intracellular biocytin labeling (n = 28). Bipolar spindle-shaped somas ranged widely in size with comparably scaled dendritic arbors exhibiting largely closed field configuration. Area II neurons (85%) projected to the ipsilateral Egr with most (93%) sending a collateral through the cerebellar commissure to the contralateral Egr; however, 15% projected to the contralateral Egr by crossing in the ventral hindbrain. Axon terminals in the vestibular nucleus were the only collaterals within the hindbrain. Every Area II neuron received a disynaptic EPSP after contralateral horizontal canal nerve stimulation and a disynaptic IPSP, preceded by a small EPSP (>50%), after ipsilateral activation. Vestibular synaptic potentials were of varying shape/amplitude, unrelated to neuron location in the nucleus, and thus likely a correlate of somadendritic size. The exceptional separation of eye position and eye velocity signals into two separate hindbrain nuclei represents an ideal model for understanding the precerebellar projection to the vestibulocerebellum.