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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, GABA

A major cause of morbidity in Parkinson’s disease (PD) is postural instability. The neuropathology underlying postural instability is unknown. Postural control is mediated by Deiters’ neurons of the lateral vestibular nucleus (LVN), which are the brainstem origin of descending vestibulospinal reflexes. Deiters’ neurons express the cytostructural protein, non-phosphorylated neurofilament protein (NPNFP). In PD, reduced expression of NPNFP in substantia nigra (SN) neurons is believed to contribute to dysfunction. It was the aim of this study to determine if there is altered expression of NPNFP in the LVN in PD. We immunolabeled NPNFP in brainstem sections of six aged controls (mean age 92 yo) and six PD donors (mean age 83 yo). Our results show there was a ~ 50% reduction in NPNFP-positive Deiters’ neurons compared to controls (13 ± 2.0/section vs 25.7 ± 3.0/section; p

Summary: 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. : Murray et al. study how the nervous system generates an appropriate motor response following a postural perturbation. They identify two distinct cell types in the lateral vestibular nucleus that act together to maintain posture when a mouse undergoes a perturbation on a balance beam. Keywords: neural circuits, vestibular system, postural control, motor transition, lateral vestibular nucleus, neuronal diversity, balance control

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.

Water deprivation (WD) induces changes in plasma volume and osmolality, which in turn activate several responses, including thirst, the activation of the renin-angiotensin system (RAS) and vasopressin (AVP) and oxytocin (OT) secretion. These systems seem to be influenced by oestradiol, as evidenced by the expression of its receptor in brain areas that control fluid balance. Thus, we investigated the effects of oestradiol treatment on behavioural and neuroendocrine changes of ovariectomized rats in response to WD. We observed that in response to WD, oestradiol treatment attenuated water intake, plasma osmolality and haematocrit but did not change urinary volume or osmolality. Moreover, oestradiol potentiated WD-induced AVP secretion, but did not alter the plasma OT or angiotensin II (Ang II) concentrations. Immunohistochemical data showed that oestradiol potentiated vasopressinergic neuronal activation in the lateral magnocellular PVN (PaLM) and supraoptic (SON) nuclei but did not induce further changes in Fos expression in the median preoptic nucleus (MnPO) or subfornical organ (SFO) or in oxytocinergic neuronal activation in the SON and PVN of WD rats. Regarding mRNA expression, oestradiol increased OT mRNA expression in the SON and PVN under basal conditions and after WD, but did not induce additional changes in the mRNA expression for AVP in the SON or PVN. It also did not affect the mRNA expression of RAS components in the PVN. In conclusion, our results show that oestradiol acts mainly on the vasopressinergic system in response to WD, potentiating vasopressinergic neuronal activation and AVP secretion without altering AVP mRNA expression.

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

Through whole-cell patch recordings in brainstem slices, the effects of histamine on neuronal activity of the lateral vestibular nucleus (LVN) were investigated. Bath application of histamine elicited a concentration-dependent excitation of both spontaneous firing (n=19) and silent (n=7) LVN neurons. Moreover, histamine induced a stable inward current in the LVN neurons (n=5) and the histamine-induced depolarization of membrane potential persisted in the presence of tetrodotoxin (n=4), indicating a direct post-synaptic effect of the histamine on the LVN neurons. Selective histamine H2 receptor antagonist ranitidine effectively blocked the histamine-evoked excitatory responses on the LVN neurons (n=4), but selective histamine H1 receptor antagonist triprolidine did not (n=4). In addition, selective histamine H2 receptor agonist dimaprit (n=3) rather than 2-pyridylethylamine (n=4), a selective histamine H1 receptor agonist, mimicked the excitatory action of histamine on LVN neurons. The results demonstrate that histamine excites the LVN neurons via post-synaptic histamine H2 receptors and suggest that the central histaminergic projection arising from the hypothalamus may modulate LVN neurons activity and actively influence the vestibular reflexes and functions.

Chicken (Gallus gallus) brains were used to investigate the typology and the immunolabel pattern for the subunits composing the AMPA-type glutamate receptors (GluR) of hindbrain neurons of the dorsal (dND) and ventral nuclei (vND) of the Deiter's vestibular complex (CD), which is the avian correspondent of the lateral vestibular nucleus (LVN) of mammals. Our results revealed that neurons of both divisions were poor in GluR1. The vND, the GluR2/3+ and GluR4+ label presented no area or neuronal size preference, although most neurons were around 75%. The dND neurons expressing GluR2/3 are primarily around 85%, medium to large-sized 85%, and predominantly 60% located in the medial portion of the rostral pole and in the lateral portion of the caudal pole. The majority of dND neurons containing GluR4 are also around 75%, larger (70% are large and giant), exhibiting a distribution that seems to be complementary to that of GluR2/3+ neurons. This distinct arrangement indicates functional differences into and between the DC nuclei, also signaling that such variation could be attributed to the diverse nature of the subunit composition of the GluRs. Discussion addresses the morphological and functional correlation of the avian DC with the LVN of mammals in addition to the high morphological correspondence, To include these data into the modern comparative approach we propose to adopt a similar nomenclature for the avian divisions dND and vND that could be referred as dLVN and vLVN.

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.

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.

A method based on the retrograde axonal transport of horseradish peroxidase after preliminary (three months) lesioning of the contralateral intermediate nucleus of the cerebellum or lateral vestibular nucleus of Deiters in adult cats demonstrated the formation of new ipsilateral thalamic projections from all three central nuclei of the cerebellum and the nuclei of the vestibular complex.

In vitro intracellular recordings of central vestibular neurons have been restricted so far to the medial vestibular nucleus (MVN). We performed intracellular recordings of large Deiters' neurons in the lateral vestibular nucleus (LVN) to determine their static and dynamic membrane properties, and compare them with those of type A and type B neurons identified in the MVN. Unlike MVN neurons (MVNn), the giant-size LVN neurons (LVNn) form a homogeneous population of cells characterized by sharp spikes, a low-amplitude, biphasic after-hyperpolarization like type B MVNn, but also an A-like rectification like type A MVNn. In accordance with their lower membrane resistance, the sensitivity of LVNn to current injection was lower than that of MVNn over a large range of frequencies. The main difference between LVNn and MVNn was that the Bode plots showing the sensitivity of LVNn as a function of stimulation frequency were flatter than those of MVNn, and displayed a weaker resonance. Furthermore, most LVNn did not show a gradual decrease of their firing rate modulation in the frequency range where it was observed in MVNn. LVNn synchronized their firing with the depolarizing phase of high-frequency sinusoidal current injections. In vivo studies have shown that the MVN would be mainly involved in gaze control, whereas the giant LVNn that project to the spinal cord are involved in the control of posture. We suggest that the difference in the membrane properties of LVNn and MVNn may reflect their specific physiological roles.

Extracellular recording was used to investigate spontaneously active neurons in all four major nuclei of the rat vestibular nuclear complex (VNC) in brainstem slices. The density of spontaneously active neurons was highest in the medial vestibular nucleus (MVN), slightly lower in the superior (SuVN) and spinal (SpVN) nuclei, and lowest in the lateral vestibular nucleus (LVN). We compared the effects of acetylcholine agonists and antagonists on spontaneously discharging neurons in MVN, SuVN, and SpVN with those in the nearby dorsal cochlear nucleus (DCN). The proportion of neurons responding to carbachol was greatest in DCN and smallest in SpVN. Unlike in DCN, some neurons in MVN, SuVN, and SpVN showed decreased firing during carbachol or muscarine. Magnitudes of responses to carbachol and muscarine were closely correlated (P0.01). MVN neurons possessed nicotinic as well as muscarinic receptors. Activation of either type was unaffected by blocking synaptic transmission. The IC(50) values for the muscarinic subtype-preferential antagonists were compared, and tropicamide, preferential for M(4), was the most potent. Our results suggest that: (1) the relative numbers of spontaneously active neurons in rat VNC differ among nuclei; (2) acetylcholine agonists elicit changes in mean firing rates of neurons in MVN, SuVN and SpVN, but fewer neurons respond, and responses are smaller than in DCN; (3) both muscarinic and nicotinic acetylcholine receptors are present on MVN neurons, but muscarinic receptors may be more prominent.

This study examined the extent of axon retraction (dieback) exhibited by injured brain stem neurons in a chronic spinal cord injury (SCI) condition. Adult female rats subjected to a cervical (C3) hemisection lesion were sacrificed 1, 4, 8, or 14 weeks after injury and the spinal cord from C1 to the lesion cavity was removed. One week prior to sacrifice, a microinjection of biotinylated dextran amine (BDA, 0.5 microliter) was made into the red nucleus, lateral vestibular nucleus, or medullary reticular formation of each animal. Horizontal cryostat sections were processed with avidin-HRP to detect supraspinal axons anterogradely labeled with BDA. Terminal end bulbs of axons were identified and their distance from the lesion site was measured by a computerized image analysis program. At all postinjury intervals, numerous rubrospinal, vestibulospinal, and reticulospinal tract axons were found immediately adjacent to the lesion site and over 60% of all terminals were within 500 micrometer at 1 and 4 weeks. The mean axonal distance of 450-500 micrometer from the lesion indicated that many injured axons had retracted farther than 500 micrometer from the lesion site; however, long-term maintenance of the mean axonal distance from the lesion at less than 500 micrometer indicated the absence of progressive dieback after SCI. While some modest changes occur in specific supraspinal pathways following SCI, axonal retraction does not appear to be a contributing factor to the diminished regenerative effort by certain brain stem neurons that has been observed at long postinjury intervals.

The data concerning the effects of age on the brainstem are scarce and few works are devoted to the human vestibular nuclear complex. The study of the effects of aging in the vestibular nuclei could have clinical interest due to the high prevalence of balance control and gait problems in the elderly. We have used in this work eight human brainstems of different ages sectioned and stained by the formaldehyde-thionin technique. The neuron's profiles were drawn with a camera lucida and Abercrombie's method was used to estimate the total number of neurons. The test of Kolmogorov-Smirnov with the correction of Lilliefors was used to evaluate the fit of our data to a normal distribution and a regression analysis was done to determine if the variation of our data with age was statistically significant. Aging does not affect the volume or length of the vestibular nuclear complex. Our results clearly show that neuronal loss occurs with aging in the descending (DVN), medial (MVN), and lateral (LVN) vestibular nuclei, but not in the superior (SVN). There are changes in the proportions of neurons of different sizes but they are not statistically significant. The neuronal loss could be related with the problems that elderly people have to compensate unilateral vestibular lesions and the alterations of the vestibulospinal reflexes. The preservation of SVN neurons can explain why vestibulo-ocular reflexes are compensated after unilateral vestibular injuries.

The vestibular nuclear complex (VNC) consists of a collection of sensory relay nuclei that integrates and relays information essential for coordination of eye movements, balance, and posture. Spanning the majority of the hindbrain alar plate, the rhombomere (r) origin and projection pattern of the VNC have been characterized in descriptive works using neuroanatomical tracing. However, neither the molecular identity nor developmental regulation of individual nucleus of the VNC has been determined. To begin to address this issue, we found that Hoxb1 is required for the anterior-posterior (AP) identity of precursors that contribute to the lateral vestibular nucleus (LVN). Using a gene-targeted Hoxb1-GFP reporter in the mouse, we show that the LVN precursors originate exclusively from r4 and project to the spinal cord in the stereotypic pattern of the lateral vestibulospinal tract that provides input into spinal motoneurons driving extensor muscles of the limb. The r4-derived LVN precursors express the transcription factors Phox2a and Lbx1, and the glutamatergic marker Vglut2, which together defines them as dB2 neurons. Loss of Hoxb1 function does not alter the glutamatergic phenotype of dB2 neurons, but alters their stereotyped spinal cord projection. Moreover, at the expense of Phox2a, the glutamatergic determinants Lmx1b and Tlx3 were ectopically expressed by dB2 neurons. Our study suggests that the Hox genes determine the AP identity and diversity of vestibular precursors, including their output target, by coordinating the expression of neurotransmitter determinant and target selection properties along the AP axis.

1. Cl− ion outward permeation across microdissected Deiters' neuron plasma membranes is augmented by GABA on the membrane cytoplasmic side. When these neurons are preincubated with a PKC activator, phorbol-12,13-dibutyrate (PdBu), there is a complex pattern of effects on basal and GABA-activated36Cl− in → out permeation. A distinct fact is an increase in basal Cl− passage and a disappearance of the 10−6M GABA effect at [PdBu] = 0.1µM. 2. Likewise, 0.1µM oleylacetylglycerol (OAG) treatment erases the effect completely, further supporting a role for PKC in modulating GABA-stimulated Cl− in → out permeation. 3. The inactive ester, phorbol-12,13-didecanoate (Pdd), at 0.1µM, does not affect GABA stimulation of Cl− passage. 4. High concentrations (15-20µM) of OAG and PdBu block the “intracellular” GABA effect. However, the 20µM PdBu effect is reversed by 30µM H7. 5. These results indicate a role of endogenous PKC in Cl− extrusion by GABAA receptors on the cytoplasmic side of the Deiters' neuron membrane.

SummaryThe absence of orexin results in narcolepsy-cataplexy. While the function of the central orexinergic system in sleep regulation has been well studied, the role of orexin in motor control is largely unknown. Here, we show that orexin-A acts via OX1 and OX2 receptors to directly depolarize neurons in the rat lateral vestibular nucleus (LVN), a subcortical motor center, and enhance their sensitivity. A dual ionic mechanism involving both Na+-Ca2+ exchangers and inward rectifier K+ channels underlies these effects. Furthermore, orexin-A regulates central vestibular-mediated posture, motor balance and negative geotaxis. Orexin is critical when an animal is facing a major motor challenge as opposed to during rest and general movements. Therefore, orexin participates not only in sleep and emotion (nonsomatic) but also in motor (somatic) regulation, suggesting that the central orexinergic system plays an important role in somatic-nonsomatic integration. These findings may account for why the absence of orexin results in narcolepsy-cataplexy.

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.

Antidromic and orthodromic action potentials of neurons located in the lateral vestibular nucleus of Deiters' evoked by stimulation of red nucleus were studied in anaesthetized cats. Vestibulospinal neurons were identified by stimulation of the lateral vestibulospinal tract. The 'second-order' vestibular neurons were revealed by mean of stimulation of the ipsilateral VIIIth nerve. Stimulation of the red nucleus is shown to lead mainly to antidromic, as well as mono-, oligo- and polysynaptic activation of Deiters' neurons. Not any inhibitory reaction was observed in vestibular neurons in response to stimulation of the red nucleus. Ascending axon collaterals of the vestibulospinal neurons to this brainstem structure were revealed. The peculiarities and functional significance of the effects mentioned are discussed.

The lateral vestibular nucleus consists of multipolar isodendritic neurons of various sizes The distal segments of some dendrites display broad expansions packed with slender mitochondria and glycogen particles. These distinctive formations are interpreted as being growing tips of dendrites, and the suggestion is advanced that they are manifestations of architectonic plasticity in the mature central nervous system. Unlike large neurons elsewhere, the giant cells (Deiters) contain small Nissl bodies interconnected in a dense mesh-work. The Nissl substance is characterized by randomly arranged cisterns of the endoplasmic reticulum and by a high proportion of free ribosomes. Whether attached or free, ribosomes usually cluster in groups of four to six, and larger polysomal arrays are rare. Free ribosomal clusters also occur in the axon hillock and the initial segment. The neuronal perikarya contain distinctive inclusions consisting of a ball of neurofilaments enveloped by a complex honeycombed membrane. The failure of these fibrillary inclusions to stain with silver suggests that the putative argyrophilia of neurofilaments may reside in an inconstant matrix surrounding them. Giant cells of Deiters are in intimate contact with two kinds of cellular elements-astroglial processes and synaptic terminals. Oligodendroglial cells are only rarely satellites of giant cells; in contrast, they are frequently satellites of small and medium-sized cells.

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.

1. In this commentary we discuss results obtained by a micromethod for the study of Cl− permeability across single nerve membranes from rabbit Deiters' neurons. 2. These results showed the presence of GABAA receptors on the nerve cell membrane cytoplasmic side. 3. We could show that these receptor complexes have a higher affinity for GABA than their extracellularly facing counterparts. Moreover, they present a phenomenon of desensitization. Another distinct property is that upon activation by GABA, they expose positive charges at their cytoplasmic mouths. 4. We propose that these receptor complexes could functionin situ as a device for extruding Cl− anions from the nerve cell interior. This phenomenon would create an electrochemical gradient for Cl− penetration into the cell upon the action of extracellular GABA, after its presynaptic release.

Interplay between migraine and balance disorder morbidities has been a topic of interest for many years. Serotonin (5-HT) receptor is closely related with migraine and is associated with vestibular symptoms. The mechanism underlying migrainous vertigo, however, has not been determined. 5.HT 1F receptor has recently attracted attention in the treatment of migraine, and the release of glutamate from trigeminal neurons has been implicated in migraine. In this study, the authors observed the colocalization of 5-HT 1F receptor and glutamate in the vestibular nuclei of rats using double immunofluorescence, which suggests that 5-HT 1F receptor might modulate glutamate release from the vestibular nuclei. The results of this study suggest that 5.HT 1F receptor agonists represent a potential therapeutic strategy for migraine and balance disorders by blocking the elease of glutamate.

The presence of gamma-aminobutyric acid (GABA) in two brainstem nuclei is demonstrated by using a pre-embedding immunohistochemical procedure followed by staining intensification. Firstly, immunoreactivity was found in numerous cell bodies and profiles of the medial nucleus of the trapezoid body (MNTB). Secondly, numerous neurons including giant Deiters' cells, terminals and fibers were strongly labelled within the lateral vestibular nucleus (LVN). These observations suggest that the inhibitory part of the efferent innervation of outer hair cells in the cochlea can originate from the MNTB, and that GABAergic neurons in the LVN may contribute to information processing within this nucleus.

The vestibular portion of the eighth cranial nerve informs the brain about the linear and angular movements of the head in space and the position of the head with respect to gravity. The termination sites of these eighth nerve afferents define the territory of the vestibular nuclei in the brainstem. (There is also a subset of afferents that project directly to the cerebellum.) This chapter reviews the anatomical organization of the vestibular nuclei, and the anatomy of the pathways from the nuclei to various target areas in the brain. The cytoarchitectonics of the vestibular brainstem are discussed, since these features have been used to distinguish the individual nuclei. The neurochemical phenotype of vestibular neurons and pathways are also summarized because the chemical anatomy of the system contributes to its signal-processing capabilities. Similarly, the morphologic features of short-axon local circuit neurons and long-axon cells with extrinsic projections are described in detail, since these structural attributes of the neurons are critical to their functional potential. Finally, the composition and hodology of the afferent and efferent pathways of the vestibular nuclei are discussed. In sum, this chapter reviews the morphology, chemoanatomy, connectivity, and synaptology of the vestibular nuclei.

Changes of spontaneous unit activity in the lateral vestibular nucleus of the rat following 5-, 10- and 15-day vibration (60 Hz, 2 hrs. Daily), were studied. Averaged histogramz and autocorrelograms were analysed following computerized interspike intervals. The data obtained revealed a variety of the unit activity in its direct or mediated effects exerted through several structures of the central nervous system.

This article is a review of work in three species, squirrel monkey, cat, and rat studying the inputs and outputs from the lateral vestibular nucleus (LVN). Different electrophysiological shock paradigms were used to determine the synaptic inputs derived from thick to thin diameter vestibular nerve afferents. Angular and linear mechanical stimulations were used to activate and study the combined and individual contribution of inner ear organs and neck afferents. The spatio-temporal properties of LVN neurons in the decerebrated rat were studied in response to dynamic acceleration inputs using sinusoidal linear translation in the horizontal head plane. Outputs were evaluated using antidromic identification techniques and identified LVN neurons were intracellularly injected with biocytin and their morphology studied.

The aims of the study were twofold: (1) to verify the hypothesis that neurons in the fastigial nucleus excite and inhibit hindlimb α-motoneurons and (2) to determine both the supraspinal and spinal relays of these actions. Axons of fastigial neurons were stimulated at the level of their decussation in the cerebellum, within the hook bundle of Russell, in deeply anesthetized cats with only the right side of the spinal cord intact. The resulting excitatory postsynaptic potentials and inhibitory postsynaptic potentials were analyzed in motoneurons on the left side of the lumbar enlargement. Postsynaptic potentials evoked by the first effective stimulus were induced at latencies

Vestibular Deiters' neurons have been isolated from bovine brain by the Hydén's freehand dissection technique and challenged with monoclonal antibodies directed toward the alpha 1 and beta 2/3 subunits of the GABAA receptors. Subsequent challenge with fluorescent secondary antibodies and confocal microscopy allowed the study of the cellular distribution of such subunits. In Deiters' neurons the beta 2/3 subunit displayed a clear presence all along the cell body profile and the initial parts of the dendrites. The alpha 1 subunit was found highly present all over the cell interior except the nuclear profiles. The strong presence inside the cells possibly masked its presence on the plasma membrane. However, in part of the cells studied a distinct presence on the plasma membrane was evident. This subunit was visualized also all along the long dendrites of these neurons. The approach we describe here, involving freehand isolated mature neurons from adult animals, may allow a better characterization of the tridimensional distribution of different types of neuronal GABAA receptors in the respect of the approach with brain slices.

The permeation of labelled gamma-aminobutyric acid (GABA) across single microdissected Deiters' membranes has been studied in a microchamber system. The GABA permeation is via pores which are blocked by 4,4'-diisothiocyanato stilbene-2-2'disulphonic acid (DIDS). As this substance blocks as well chloride permeation across these membranes we tested whether GABA and chloride permeate across the same pores. Membrane pre-treatment with different doses of corticotropin releasing factor (CRF), a membrane permeant cyclic AMP analogue and phalloidin parallelly block the permeation of the two substances. Thus, it is most probable that GABA and chloride pass across the same pores. These pores may be swelling activated ones, opened by the mechanical stress on the membranes in the microchamber system. The passage of GABA across these pores may be of physiological importance in the termination of GABA inhibitory action on the vestibular Deiters' neurones.

Free hand isolation of adult rabbit vestibular Deiters’ neurons and dissection of their single membranes allows the study of their ionic permeability characteristics in a microchambers device. In the case of hare-like rabbits, the dissection of such membranes presents evidence of a high basal permeation of labelled chloride, possibly related to mechanical disturbance of the plasma membrane-related cytoskeleton and activation of chloride channels. This did not apply to the laboratory strain of white New Zealand rabbits. However, membranes from hare-like rabbits which were stressed by being rotated on a platform before the experiment, behaved like those from the New Zealand strain. Vice versa, habituation to handling day after day of New Zealand rabbits resulted in a chloride permeation equal to that of unstressed hare-like rabbits. We propose that the stressful conditions result in the release of neurochemical messages to the vestibular Deiters’ cells which influence their electrophysiological behavior. The corticotropin releasing factor (CRF), a stress-related peptide present in the climbing fibers, actually blocks the basal chloride permeation across the Deiters’ membranes and this effect is partially reversed by its receptor antagonist, α-helical CRF [9–41].

It has been the goal of this review to describe the functional interrelations between Deiters' vestibular nucleus and numerous brain structures. Emphasis is placed on dynamic and integrative properties of linkages between the neurons of Deiters' nucleus and many other brain structures in order to begin considering the capabilities of the loops in the light of motor control and coordination of movement. The problem of somatotopy within the loops is also considered. Putting this information together, the possible roles of Deiters' nucleus in the control of movements are described. It is suggested that Deiters' nucleus in co-operation with cerebral cortex, cerebellum, subcortical and brainstem structures are responsible for the integration and realization of different movements.

We are interested in studying the co-localization of NMDA glutamate receptor subunits (NR1, NR2A/B) and AMPA glutamate receptor subunits (GluR1, GluR2, GluR2/3 and GluR4) in individual neurons of the rat vestibular nuclei. Immunoreactivity for NR1, NR2A/B, GluR1, GluR2, GluR2/3 and GluR4 was found in the somata and dendrites of neurons in the four major subdivisions (superior, medial, lateral, and spinal vestibular nuclei) and in two minor groups (groups x and y) of the vestibular nuclei. Double immunofluorescence showed that all the NR1-containing neurons exhibited NR2A/B immunoreactivity, indicating that native NMDA receptors are composed of NR1 and NR2A/B in a hetero-oligomeric configuration. Co-expression of NMDA receptor subunits and AMPA receptor subunits was demonstrated by double labeling of NR1/GluR1, NR1/GluR2/3, NR1/GluR4 and NR2A/B/GluR2 in individual vestibular nuclear neurons. All NR1-containing neurons expressed GluR2/3 immunoreactivity, and all NR2A/B-containing neurons expressed GluR2 immunoreactivity. However, only about 52% of NR1-immunoreactive neurons exhibited GluR1 immunoreactivity and 46% of NR1-containing neurons showed GluR4 immunoreactivity. The present data reveal that NMDA receptors are co-localized with variants of AMPA receptors in a large proportion of vestibular nuclear neurons. These results suggest that cross-modulation between NMDA receptors and AMPA receptors may occur in individual neurons of the vestibular nuclei during glutamate-mediated excitatory neurotransmission and may in turn contribute to synaptic plasticity within the vestibular nuclei.

The time course of c-jun expression and the effect of a peripheral nerve (PN) graft on axonal regeneration and c-jun expression in the lateral vestibular nucleus (LVN) were investigated in this study. c-Jun was found in LVN neurons 1 day after hemisection of the spinal cord at C3, with weak immunoreactivity. Strong c-Jun positive immunoreactivity was found 3 days post-injury. The expression of c-jun reached its maximum level (45% +/- 2.5, mean +/- SD) 1 week post-injury and gradually decreased to about a third of its peak value 6 weeks after the inflicted lesion. The PN graft implanted at the lesion site significantly enhanced the number of neurons expressing c-jun 4 weeks after PN transplantation (from 20% of LVN neurons in axotomy alone to 30% in PN graft transplantation, P0. 05). The PN graft induced injured neurons to regrow into the PN graft. About 91 FG-labeled neurons were found in the LVN and approximately 87% of these neurons showed c-Jun positive immunoreactivity. The high percentage of regenerating neurons expressing c-jun suggested that c-Jun might be involved in the regenerative process. The result of double staining for c-Jun and NOS showed that approximately 93% NOS positive neurons co-expressed c-Jun. Comparing the time course of the appearance of c-Jun with that of NOS, the expression of c-jun preceded that of NOS. Although a high percentage of NOS reactive neurons expressed c-jun, the expression of NOS in damaged LVN neurons needs to be further investigated.

Electrocoagulation of lateral vestibular nucleus (NVL) reduces inhibitory effect of the motor and somatosensory areas and enhances the inhibitory effect of limbic, vestibular, and orbital cortical areas. Facilitating effect was enhanced by electrostimulation of the motor area and reduced by the stimulation of other cortical areas. Following the coagulation of the NVL, the ascending afferent flow to the cortex seems to be reduced. This results in diminishing of the cortical neurones tone and readjusts the descending influences upon the NVL neurones activity.

1. Data obtained studying permeability characteristics of single Deiters' membranes in a microchamber system show that intracellular GABA can activate chloride in--out passage with a GABAA pharmacology. 2. The overall data suggest the presence of a chloride extrusion pump in these neurons based on intracellular GABA activated chloride channels. 3. This conclusion takes up a previous theoretical suggestion that ionic channels could work as ionic pumps provided an energy input modifies the energy profile along the permeation path. 4. According to our quantitative evaluation, this pumping mechanism works with a low yield and along a cycle with a strongly asymmetric behavior, being far from equilibrium due to powerful "leakage" pathways for chloride in these neurons.

Single plasma membranes were microdissected from Deiters' neurons freshly obtained from the lateral vestibular nucleus of the rabbit and their chloride permeability was studied in a microchamber system. The basal in→out 36 Cl − permeation initially found was brought to zero by Zn 2+ , 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid and iodide. GABA on the membrane cytoplasmic side resulted in a measurable in→out 36 Cl − passage, which was blocked by the GABA A antagonists bicuculline and picrotoxin. This effect peaked at 1 μ M GABA on the inner side of the membrane. At higher GABA concentrations, a strong desensitization of the effect was found. Stimulation of Cl − permeability by GABA on the extracellular side of the membrane peaked at much higher GABA concentrations, 10–100 μ M. This excludes an effect due to passage of the neurotransmitter from the inner to the outer compartment in our microchamber device. Moreover, this possibility is also dismissed by the fact that 1 μ M GABA on the membrane outside did not evoke any 36 Cl − in→out permeation. In addition, pentobarbitone by itself could also stimulate 36 Cl − in→out permeation when added on the cytoplasmic side of Deiters' membrane. On these bases and in agreement with our previous reports, we propose that structures behaving pharmacologically as GABA A receptors respond to low levels of GABA on the cytoplasmic side of these neurons' membranes. We suggest that these structures are devices that, at the expense of ATP consumed in their phosphorylation, extrude Cl − after postsynaptic GABA uptake into the Deiters' neuron.

In acute experiments in rabbits the influence of stimulation of the ventromedial hypothalamic nucleus on the activity of neurons of vestibular Deiters' nucleus was studied under conditions of 15-day exposure to vibration (60 Hz, 0.8 mm, 3 h daily). The mechanisms are discussed which underlie the observed phenomena.

The peculiarities of the effect of vestibular, somatosensory, motor and limbic areas of brain cortex on the activity of neurons of lateral vestibular nucleus (LVN) are studied in the nembutal and chloralose anesthetized rabbits by the extracellular lead method before and after vibration exposure. It is found that the responses of neurons of Deiters's nucleus at all frequency ranges to stimulation of different areas of the cortex were predominantly of inhibitory type, being more pronounced during stimulation of the vestibular and motor areas. The facilitating corticofugal effect was noted in 20-30 % of cells and more pronounced influence was during stimulation of somatosensory and limbic areas of the cortex. During vibration there was a multidirectional effect of cortical areas on the neuronal activity of LVN. The vibration stimulus decreases an inhibitory effect and increases stimulating influence of vestibular cortex on the activity of Deiters's nucleus. The noted effect was more pronounced in neurons with low frequency of initial activity. On stimulation of other areas of the cortex an increase of inhibitory and suppression of facilitating descending effects were noted. The greatest amount of inhibited neurons was recorded during stimulation of motor cortex. The peculiarities and functional significance of the observed effects are discussed.

Recovery of head postural control after unilateral vestibular neurectomy was investigated in the alert cat by chronically recording the spontaneous neck muscle EMG activity from splenius capitis on both sides and the vestibulocollic reflexes evoked during roll and pitch tilts. Neuronal correlates occurring within the lateral (Deiters) vestibular nuclei (LVN) were also recorded during the time-course of recovery. During the acute phase (1-2 weeks), the cats exhibited strong imbalance in spontaneous neck muscle activity, characterized by increased muscular tone in the ipsilateral splenius capitis muscle and hypoactivity in the contralateral one. At the same time, the mean resting activity of Deiters' neurons strongly decreased on the deafferented side, while a slight but significant decrease was observed on the intact side. Vestibulocollic reflexes were totally lacking during the acute phase, whatever the direction and the amplitude of tilt. Recovery developed in the following weeks, leading to complete rebalance of spontaneous EMG activity as well as near to normal static vestibulocollic reflexes 5 weeks after the lesion. However, compensation remained sub-normal during roll tilts while overcompensation was found during pitch tilts, suggesting that the intact labyrinth would play a leader role in the recovery process but that bilateral cooperation of the two labyrinths is required for proper head postural control. Five weeks are also needed for a partial rebalancing of resting activity between both LVN. These results indicate that changes in neck muscle activity observed in the acute cats and that recovery found in the compensated animals could result from modifications in neural networks controlling neck musculature, such as the LVN.

The effects of stimulation of the vestibular nerve and five different cerebral cortex areas on the neuronal activity of the lateral vestibular nucleus of Deiters were studied. Stimulation of the cerebral cortex is shown to lead to antidromic and synaptic activation of Deiters neurons. The synaptic potentials of Deiters neurons evoked from the cerebral cortex were of mono- and polysynaptic origin. In particular, stimulation of the cerebral cortex evoked in Deiters neurons mono- and polysynaptic excitatory postsynaptic potentials. Collaterals of vestibulospinal neurons reaching different cortex fields as well as convergence of influences from these cortex fields on Deiters neurons were revealed. Inhibitory effects of the cerebral cortex on Deiters neurons were of polysynaptic origin and occurred rarely. The topical correlation between Deiters nucleus and different areas of the cerebral cortex was found. The peculiarities and functional significance of the effects obtained are discussed.

1. In addition to giant cells, originally described by Deiters, the lateral vestibular nucleus contains also medium- and small-size cells. The role that these neurons exert in the static control of posture has been investigated in precollicular decerebrate cats in which the resting discharge of spontaneously active vestibulospinal neurons projecting to lumbosacral segments of the spinal cord (IVS neurons) has been related to the cell size inferred on the basis of the conduction velocity of their axons. 2. In control experiments, the IVS neurons with slower axonal conduction velocity and, by inference, having thinner axons and smaller cell bodies differed from those having faster conduction velocity by displaying a higher resting discharge rate and a relatively regular interspike interval distribution, i.e. a lower coefficient of variation (CV). 3. The resting discharge of the IVS neurons, which corresponded on the average to 24.5 +/- 15.7, S.D. imp./sec, in control experiments, increased significantly to 44.1 +/- 23.8, S.D. imp./sec after ablation of the cerebellar vermis and the fastigial nuclei, leading to a great increase in postural activity, while the proportion of regularly discharging units (with the lowest CV) increased. Moreover, the negative correlation between resting discharge of all the recorded IVS neurons and the conduction velocity of the corresponding axons, which was quite slight in the experiments with the cerebellum intact, greatly increased after partial cerebellectomy. This finding was due to a prominent increase in resting discharge of the small-size IVS neurons, while the discharge of the large-size IVS neurons was, on the average, comparable to that obtained in the controls. It appears, therefore, that the cerebellum exerts a prominent tonic inhibitory influence on the small-size IVS neurons, which are thus responsible for the great increase in decerebrate rigidity after cerebellectomy. 4. The resting discharge rate of the IVS neurons was not, on the average, greatly modified after ipsilateral acute (aVN) and chronic vestibular neurectomy (cVN) with respect to the controls. However, the proportion of regularly discharging units (with the lowest CV) decreased after aVN, but increased after cVN. The relation found in control experiments, i.e. the faster the conduction velocity of VS axon the lower was the unit discharge at rest, was lost after aVN, due to a decrease in resting discharge rate of the slow neurons. The mean discharge rate of these units, however, recovered after cVN, so that the negative correlation between resting discharge rate and axonal conduction velocity was reestablished.(ABSTRACT TRUNCATED AT 400 WORDS)

The permeation of labeled Cl- ions across single plasma membranes from Deiters' neurons has been studied in the presence of various concentrations of phosphatidylserine (PS) on their extracellular side. PS reduces significantly basal Cl- permeation only at 10(-5) M on the membrane exterior. No effect was found at other concentrations. GABA activable 36Cl- permeation is heavily reduced and almost abolished at 10(-11) - 10(-5) M phosphatidylserine. This exogenous phosphatidylserine effect is difficult to interpret in relation to the function of the endogenous phospholipid. However, it may be involved in the epileptogenic effect in vivo of exogenous phosphatidylserine administration to rats.

A new micromethod for studying the interaction of gamma-aminobutyric acid (GABA) with its post-synaptic uptake in a defined type of nerve cell is described. The method involves the isolation by free hand microdissection of Deiters' nerve cells from the rabbit lateral vestibular nucleus and their incubation with tritiated GABA in the presence of 100 mM Na+ at 4 degrees C. From the binding data a Kd was calculated for this interaction of 104 nM and a BMax of 8.4 X 10(5) sites/neuron. The method was applied to the study of the modifications of the binding of GABA to Deiters' neurons from control rats and rats trained to balance on a steel wire in order to reach food. This performance is a powerful stimulation to the vestibular system. The results show that, in the binding experiment with 100 nM [3H]GABA, the amount of GABA which specifically binds to the Deiters' neurons is increased by 38% in the trained rats. Analogously, when the incubation with GABA was performed at 37 degrees C, involving an intake of GABA into the neurons, the amount of GABA taken up increases by 50% in the trained group. No GABA-binding or uptake increase was found when animals were subjected to intense vestibular stimulation for a short period without learning. These results indicate that when rats learn a behavioral test which involves an improved vestibular control, there is a specific neurochemical modification in the neurons of the lateral vestibular nucleus. This modification seems to be of importance for the physiology of the neuronal circuits controlling the vestibular function in the rat.