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We have used sinusoidal and band-limited Gaussian noise stimuli along with information measures to characterize the linear and non-linear responses of morpho-physiologically identified posterior canal (PC) afferents and to examine the relationship between mutual information rate and other physiological parameters. Our major findings are: 1) spike generation in most PC afferents is effectively a stochastic renewal process, and spontaneous discharges are fully characterized by their first order statistics; 2) a regular discharge, as measured by normalized coefficient of variation (cv*), reduces intrinsic noise in afferent discharges at frequencies below the mean firing rate; 3) coherence and mutual information rates, calculated from responses to band-limited Gaussian noise, are jointly determined by gain and intrinsic noise (discharge regularity), the two major determinants of signal to noise ratio in the afferent response; 4) measures of optimal non-linear encoding were only moderately greater than optimal linear encoding, indicating that linear stimulus encoding is limited primarily by internal noise rather than by non-linearities; and 5) a leaky integrate and fire model reproduces these results and supports the suggestion that the combination of high discharge regularity and high discharge rates serves to extend the linear encoding range of afferents to higher frequencies. These results provide a framework for future assessments of afferent encoding of signals generated during natural head movements and for comparison with coding strategies used by other sensory systems. This article is part of a Special Issue entitled: Neural Coding., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Multiunit activity during horizontal sinusoidal motion was recorded from pairs of oculomotor, trochlear, or abducens nerves of an in vitro turtle brainstem preparation that received inputs from intact semicircular canals. Responses of left oculomotor, right trochlear and right abducens nerves were approximately aligned with leftward head velocity, and that of the respective contralateral nerves were in-phase with rightward velocity. We examined the effect of sectioning or injecting lidocaine (1-2 microL of 0.5%) into the right vestibular nerve. Nerve block caused a striking phase shift in the evoked response of right oculomotor and left trochlear nerves, in which (rightward) control responses were replaced by a smaller-amplitude response to leftward table motion. Such "phase-reversed" responses were poorly defined in abducens nerve recordings. Frequency analysis demonstrated that this activity was advanced in phase relative to post-block responses of the respective contralateral nerves, which were in turn phase-advanced relative to pre-block controls. Phase differences were largest (approximately 10 degrees) at low frequencies (approximately 0.1 Hz) and statistically absent at 1 Hz. The phase-reversed responses were further investigated by eliminating individual canal input from the left labyrinth following right nVIII block, which indicated that the activation of the vertical canal afferents is the source of this activity.

Although the effectiveness of histamine-related drugs in the treatment of peripheral and central vestibular disorders may be explained by their action on the vestibular nuclei, it has also been shown that antivertigo effects can take place at the peripheral level. In this work, we examined the actions of H3 histaminergic agonists and antagonists on the afferent neuron electrical discharge in the isolated inner ear of the axolotl. Our results indicate that H3 antagonists such as thioperamide, clobenpropit, and betahistine (BH) decreased the electrical discharge of afferent neurons by interfering with the postsynaptic response to excitatory amino acid agonists. These results lend further support to the idea that the antivertigo action of histamine-related drugs may be caused, at least in part, by a decrease in the sensory input from the vestibular endorgans. The present data show that the inhibitory action of the afferent neurons discharge previously described for BH is not restricted to this molecule but is also shared by other H3 antagonists.

The low voltage gain in type I hair cells implies that neurotransmitter release at their afferent synapse should be mediated by low voltage activated calcium channels, or that some peculiar mechanism should be operating in this synapse. With the patch clamp technique, we studied the characteristics of the Ca(2+) current in type I hair cells enzymatically dissociated from rat semicircular canal crista ampullaris. Calcium current in type I hair cells exhibited a slow inactivation (during 2-s depolarizing steps), was sensitive to nimodipine and was blocked by Cd(2+) and Ni(2+). This current was activated at potentials above -60 mV, had a mean half maximal activation of -36 mV, and exhibited no steady-state inactivation at holding potentials between -100 and -60 mV. This data led us to conclude that hair cell Ca(2+) current is most likely of the L type. Thus, other mechanisms participating in neurotransmitter release such as K(+) accumulation in the synaptic cleft, modulation of K(+) currents by nitric oxide, participation of a Na(+) current and possible metabotropic cascades activated by depolarization should be considered.

The horizontal and vertical vestibulo ocular reflex (VOR) of head tilted (het) mutant mice was compared to C57BL/6 controls. Eye movements were recorded in darkness using a temporarily attached search coil. Contributions of semicircular canal versus otolith organ signals were investigated by providing a canal only (vertical axis) or canal plus otolith organ (horizontal axis) stimulus. In controls, rotations that stimulated only the canals (upright yaw and on tail roll) produced accurate VOR timing during middle frequency rotations at 0.5 Hz (gain 0.27, phase error 6 degrees), and a phase advanced VOR during low frequency rotations at 0.05 Hz (0.05, 115 degrees). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.11, 42 degrees) and 0.05 Hz (0.01, 36 degrees). In controls, rotations that stimulated both the otolith organs and semicircular canals (upright roll and on tail yaw) produced higher VOR gains overall than were elicited during vertical axis rotations, with phase accurate VOR at both 0.5 Hz (0.52, 4 degrees) and 0.05 Hz (0.34, 9 degrees). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.14, 51 degrees) and 0.05 Hz (0.01, 43 degrees). During constant velocity rotations about an earth horizontal axis, eye velocity bias and modulation were virtually absent in het mutant mice, while robust in controls. Control mice produced compensatory ocular deviations in response to static head tilt, but responses in het mice were weak and inconsistent. These results show that het mice not only lack all aspects of otolith mediated VOR, but also are deficient in canal mediated VOR. Because semicircular canals are normal in het mice, we conclude that central neurons of the canal VOR are dependent on otolith organ signals for normal performance.

Vestibular nerve branches innervating the sensory epithelia of the three semicircular canals or of the three otolith organs of frogs were selectively labeled in-vitro with biocytin. Labeled afferent fibers from the semicircular canals, utricle, and lagena were encountered in each of the four vestibular nuclei and their projections overlapped considerably. Saccular afferent fibers projected to the dorsal (acoustic) nuclei and smaller projections to the vestibular nuclei were regionally restricted. Per semicircular canal or otolith organ about equal numbers (11-14) of medium sized vestibular neurons (between 7.5 and 17 microm in diameter) were dye-coupled to afferent fibers. Most of these dye-coupled vestibular neurons were located in the lateral and descending vestibular nuclei between the VIIIth and IXth nerves. The superior vestibular nucleus was relatively free of dye-coupled vestibular neurons. The location of this subpopulation of central vestibular neurons supports the notion that these neurons are part of a particular vestibulospinal pathway. In addition, from each of the canal and/or otolith organs about 3-4 efferent vestibular neurons were labeled retrogradely. These neurons (between 15 and 26 microm in diameter) were located ventral to the vestibular nuclear complex. The branching of efferent vestibular neurons was shown by the presence of neurons that were double labeled by two different fluorescent dyes applied in the same experiment to the anterior and posterior ramus of the same VIIIth nerve, respectively. The branching of these efferent neuron axons explained the presence of collaterals and terminals in the sensory epithelia of a number of untreated ipsilateral endorgans.

Immunolabeling patterns of the immediate early gene-related protein Fos in the gerbil brainstem were studied following stimulation of the sacculus by both hypergravity and galvanic stimulation. Head-restrained, alert animals were exposed to a prolonged (1 h) inertial vector of 2 G (19.6 m/s2) head acceleration directed in a dorso-ventral head axis to maximally stimulate the sacculus. Fos-defined immunoreactivity was quantified, and the results compared to a control group. The hypergravity stimulus produced Fos immunolabeling in the dorsomedial cell column (dmcc) of the inferior olive independently of other subnuclei. Similar dmcc labeling was induced by a 30 min galvanic stimulus of up to -100 microA applied through a stimulating electrode placed unilaterally on the bony labyrinth overlying the posterior canal (PC). The pattern of vestibular afferent firing activity induced by this galvanic stimulus was quantified in anesthetized gerbils by simultaneously recording from Scarpa's ganglion. Only saccular and PC afferent neurons exhibited increases in average firing rates of 200-300%, suggesting a pattern of current spread involving only PC and saccular afferent neurons at this level of stimulation. These results suggest that alteration in saccular afferent firing rates are sufficient to induce Fos-defined genomic activation of the dmcc, and lend further evidence to the existence of a functional vestibulo-olivary-cerebellar pathway of adaptation to novel gravito-inertial environments.

Responses of 35 Purkinje cells in decerebrate cats were recorded during 0.5 Hz rotations in 4-11 vertical planes and the horizontal plane to determine their semicircular canal input. Most neurons received convergent input from two canals (21 neurons) or 3 canals (5 neurons). Few Purkinje cells were maximally sensitive to rotations about an axis appropriate to their inferior olivary input as determined by Gerrits and Voogd [15,24,27,49].

In the inner ear, calcium appears to play a major role in different processes including mechanoelectrical transduction, adaptation during prolonged stimulation and electrical resonance. The aim of the present study was to investigate the effect of an increase of the cytosolic calcium content and a reduction of the perilymphatic concentration of calcium, on the bioelectrical activity of the isolated frog semicircular canal. Under resting conditions, the spontaneous activity of the afferent fibers and the difference of potential between the endolymphatic and perilymphatic compartments, called endolymphatic potential, were recorded. When the sensory epithelium was mechanically stimulated three additional parameters were investigated: the variations of the endolymphatic potential (ampullar direct current), the variations of the ampullar nerve potential (nerve direct current) and the frequency of the evoked afferent spikes. Increase of the intracellular calcium concentration by administration of the calcium ionophore A23187 (3 x 10(-6) M, 20 min) into the perilymphatic compartment, caused a biphasic effect on the spontaneous activity of the ampullar nerve which increased rapidly, reaching a maximum within 15 min, and then gradually declined to stabilize at 74% of the control 1 h after withdrawal of A23187. A23187 did not induce any modifications of the endolymphatic potential, the ampullar direct current or the frequency of the evoked afferent spikes. In contrast, A23187 induced a significant reduction of the nerve direct current which decreased by 31% of the control 1 h after withdrawal of the ionophore. Gradual reduction of the perilymphatic concentration of calcium (from 2 to 1 mM) induced a dose-dependent increase of the spontaneous activity of the ampullar nerve and the frequency of the evoked afferent spikes. Reduction of the perilymphatic calcium concentration from 1.6 to 1.2 mM caused a transient increase of the endolymphatic potential, while 1 mM Ca2+ induced a decrease to 88% of the control. The nerve direct current slightly increased for calcium concentrations ranging from 1.8 to 1.4 mM and decreased in the presence of 1.2 mM CaCl2. These data suggest that an increase of calcium into the cytosol induces an alteration of the mechanisms responsible for the spontaneous release of the afferent neurotransmitter and the electrogenic spreading of the postsynaptic potentials. In contrast, an excess of calcium does not impair the mechanisms involved in the generation of the action potentials. Our results also suggest that reduction of the perilymphatic calcium concentration may lead to modifications of the physical and electrical properties of the cell membranes of the labyrinthine epithelium and/or the ampullar afferent fibers.

To investigate the neural substrate of vestibulo-sympathetic reflexes, we studied the responses of neurons in the rostral ventrolateral medulla (RVLM) of decerebrate cats to natural stimulation of the labyrinth in vertical and horizontal planes. The RVLM is a major source of excitatory inputs to sympathetic preganglionic neurons. The animals used in these studies were baroreceptor-denervated and vagotomized and had a cervical spinal transection so that inputs from tilt-sensitive receptors outside of the labyrinth did not influence the units we recorded. Of the 38 neurons whose type of vertical vestibular inputs could be classified, the majority (27) received signals mainly from otolith organs. Only 4 of the neurons received inputs predominantly from vertical semicircular canals, and 7 were classified as having convergent inputs from otoliths and canals that were spatially aligned (2 cells) or misaligned (5 cells). In addition, only 2 of 68 neurons tested responded to sinusoidal horizontal rotations in a manner typical of brainstem neurons that receive inputs from the horizontal semicircular canals. Thus, the vestibular inputs to the RVLM appear to come mainly from otolith receptors. In labyrinthectomized cats, we were unable to locate neurons with responses to tilt similar to those of cells recorded in labyrinth-intact cats, confirming that the responses attributed to vertical vestibular inputs were produced by signals from the labyrinth. In animals whose semicircular canals had been rendered dysfunctional by plugging, we only recorded responses similar to those of neurons classified as having mainly otolith inputs in canal-intact animals, indicating that the dynamic behavior of these cells does not depend upon canal inputs. The presence of otolith inputs to the RVLM is consistent with the hypothesis that this region mediates vestibulo-sympathetic reflexes involved in correcting posturally-related changes in blood pressure.

Alert cats were rotated sinusoidally (0.25 Hz) in their sagittal plane while viewing optokinetic motion in their horizontal plane. Vertical and horizontal vestibulo-ocular reflex (VOR) was measured in the dark before and after 2 h of these adaptation stimuli in upright or onside orientation of the cat. Onside exposure produced maximal adaptive horizontal VOR at the training frequency. Upright exposure produced highest gain at lower frequencies. A cat with inoperative vertical canals adapted only to upright exposure. We conclude that in the presence of horizontal image rotation either vertical canal or otolith stimulation can produce adaptation in VOR direction and stimulation of both produces complex adaptation dynamics.

Selective labyrinthine lesions were made to study the origin of excitation in the labyrinth during off-vertical axis rotation. Plugging the semicircular canals abolishes the response to rotation about a vertical axis, but optokinetic after-nystagmus (OKAN) and the sustained horizontal nystagmus induced by off-vertical axis rotation (OVAR) are maintained. After cutting the nerves of the lateral semicircular canals, neither horizontal OKAN nor the continuous horizontal nystagmus associated with off-axis rotation can be induced, although vertical OKN, OKAN and vestibular nystagmus are intact. This supports the theory that labyrinthine activity responsible for the nystagmus induced by OVAR arises in the otolith organs and couples to the oculomotor system through the velocity storage mechanism.

Responses to rotation in many vertical and horizontal planes were studied in electrically identified secondary vestibular neurons of alert cats. This report concerns secondary neurons that gave responses which could not be explained as due to a summation of semicircular canal inputs. These cells responded to sinusoidal rotation of the cat in any vertical plane, and response phase depended on the plane of rotation. The responses were modeled as the result of summation of two inputs that differed in their spatial orientations and dynamics. Response dynamics and a comparison of responses to vertical and horizontal rotations showed that some cells were sensitive to rotation with respect to gravity. Their responses both to gravity and horizontal rotations argue that these secondary neurons received convergent otolith and canal inputs. Some cells also had oculomotor related discharges and/or responded weakly to neck rotation.

The gain (slow-phase eye velocity/head velocity) of the vestibulo-ocular reflex (VOR) of 6 alert cats was sequentially adapted to values between 0.2 and 1.66 by the chronic wearing of visual reversing or 2 X magnifying spectacles, combined with forced rotation in the light. Gain was measured during sinusoidal oscillation in darkness at 0.05 Hz at a peak velocity of about 30 degrees/s. In each state of VOR gain adaptation, optokinetic nystagmus (OKN) and optokinetic afternystagmus (OKAN) were measured in a full-field optokinetic drum at velocities of 20-80 degrees/s. Steady-state, slow-phase, optokinetic eye velocity nearly equaled low drum velocities, but saturated at higher velocities and declined when drum velocity further increased. The saturation velocity varied in relation to VOR gain, ranging from 10-20 degrees/s at a VOR gain of 0.2-0.4, to 65 degrees/s at a VOR gain of 1.66. The means that the variable gain element of the VOR is shared by the optokinetic system (OKS). OKAN, measured in darkness, had a roughly exponential decay. The time constant of OKAN (Tokan) also varied with VOR gain, ranging form about 2 s at a VOR gain of 0.2, to 10 s at a VOR gain of 1.66. This is a novel finding which suggests that the velocity-storage mechanism was also affected by gain changes. A model is proposed in which a neural, variable-gain element is located in a positive-feedback, velocity-storage loop common to both the VOR and the OKS. Computer simulation showed that this hypothesis could account for most of the observed changes in OKN saturation and Tokan with changes in VOR gain. The model also predicts that low frequency VOR phase lead in darkness should increase with decreasing VOR gain. Experimental VOR phase lead at 0.05 Hz varied from about 10 degrees for VOR gains above 1.1 to about 50 degrees for VOR gains below 0.3. Such phase-lead data agree with the trend predicted by the model.

The technique of principal-component analysis was used to define anatomically the semicircular canal planes of the rhesus and squirrel monkeys with respect to the stereotaxic coordinate system. The analyses were performed on a series of points obtained from the dissected osseous labyrinths. A planar equation was defined for each canal plane in the stereotaxic coordinate system and angles were calculated between the 3 ipsilateral canal planes, between synergistic canal pairs and between each canal plane and the stereotaxic planes. The data from both species are similar: the ipsilateral canal planes are nearly orthogonal; synergistic pairs of canal planes are approximately parallel with angles of 2 degrees-12 degrees between pairs in the rhesus monkey and 13 degrees-16 degrees between pairs in the squirrel monkey. The horizontal canal planes form angles of 22 degrees and 18 degrees with the horizontal stereotaxic plane in the rhesus and squirrel monkeys, respectively. A head position of 15 degrees (pitch nose-down) was calculated to produce an optimal head position in both species for maximally stimulating the horizontal canals and minimally stimulating the vertical canals during horizontal angular acceleration. The radii of curvature (R) of the horizontal, anterior and posterior canals were also measured for both species using a calibrated reticle. These measurements indicate that the anterior canal of both species has the largest radius of curvature. This anatomical information is discussed in relation to the available physiological data.

The orientation of the rat semicircular canals was determined using one of two techniques. Null point analysis was used to define physiologically the planar equations of the anterior (n = 15) and posterior canals (n = 15); equations for the horizontal canal (n = 19) were determined using an anatomical dissection technique. Canal orientation was defined with respect to stereotaxic coordinate system and, for comparison, relative to head position during freeze (startle) behavior. Results show that ipsilateral canal planes are orthogonal within 4-8 degrees, and pairs of right-left synergistic pairs are essentially co-planar. The horizontal canals are inclined upwards 35 degrees with respect to the horizontal plane, but a head position of 43 degrees nose-down was determined to produce near optimal horizontal canal and minimal vertical canal activation with horizontal rotation. Finally, a loud or unexpected auditory stimulus initiates a freeze (startle) response in rat characterized by an transient followed by a sustained head position lasting several seconds. Transients are complete within 300-400 ms. Thereafter, the head becomes momentarily stabilized in the startle position which averaged 14 +/- 8 degrees (nose-down with respect to horizontal stereotaxic zero) across the population (n = 14). The response habituated only slightly, but the final position was sufficiently variable so as to limit the usefulness of the freeze (startle) position as a reference of semicircular canal position in the rat.

The discharge activity of first-order vestibular neurons was recorded in anesthetized or decerebrated gerbils from the post-ganglionic fibers of the vestibular nerve. Semicircular canal afferents were distinguished from otolith afferents on the basis of their responses to linear and angular head acceleration. In decerebrated preparations, canal afferents exhibited significantly faster discharge activity (average = 87.8 impulses/s) than that of canal afferents in anesthetized preparations (average = 66.2 impulses/s), when the head was held to position the lateral semicircular canals coplanar with the earth horizontal plane (standard position). The effects of changes in linear forces on vestibular afferent activity were determined by statically tilting the head +/- 10 degrees about either the fore-aft and/or left-right head axes. A change in activity, from that recorded in the standard position, of 10% or greater was considered significant. Using this criterion, significant changes in the tilt response in anesthetized animals were observed in both anterior (23 of 48 neurons, 48%) and lateral (22 of 31, 71%) canal afferents as well as otolith (18 of 25, 72%) afferents. In decerebrated preparations for tilts around the pitch (left-right) axis, comparable effects were measured in (19 of 36, 53%) anterior and (17 of 30, 57%) lateral canal afferents. Neurons with irregular firing activity were more likely than regularly firing canal afferents to change their average discharge rate during static tilt. No significant differences in response magnitude to +/- 10 degrees head tilt were found between canal and otolith afferents in anesthetized animals. Mechanisms to account for the responses to linear acceleration of canal afferents are discussed.

The contribution from different pairs of semicircular canals to the generation of horizontal vestibular nystagmus was examined in monkeys. Animals with different pairs of semicircular canals surgically plugged were accelerated sinusoidally at 1 Hz (a predictive stimulus) or with steps of angular velocity (a non-predictive stimulus) about an earth vertical axis while the head was placed in various static pitch positions. In normal animals, and in animals with only the lateral canals intact, horizontal nystagmus elicited with angular velocity steps is maximal at a static pitch angle of 15 degrees nose-down (relative to the horizontal stereotaxic plane). The response follows a cosine function of the pitch angle, approaches zero at an angle of 90 degrees to the optimal orientation, and finally reverses. In animals with only the vertical canals operating, direction specific horizontal nystagmus can still be elicited. Using velocity steps, a null plane at which nystagmus reverses can be determined. It is found at about 32 degrees nose-down and thus is different from the optimal plane of the lateral canals. Consequently, it is not possible to stimulate the lateral canals maximally without stimulating the vertical canals simultaneously. Using sinusoidal rotation, nystagmus is attenuated at the static pitch position of 32 degrees nose-down, but does not reverse direction with further pitching.

Responses to natural stimulation were studied in electrically identified secondary vestibular neurons of awake cats. A class of neurons was identified whose response dynamics and responses to rotations in several vertical and horizontal planes indicated that they received semicircular canal input. Each canal neuron had clearly defined planes of maximal and null sensitivity to rotation. The orientation of these planes indicated that 44% of the neurons received input from one pair of canals, 40% from two, and 16% from all 3 canal pairs. Many cells also had oculomotor-related discharges and/or responded weakly to neck rotation.

The response to angular acceleration of units in the superior vestibular nucleus (SVN) of barbiturate-anesthetized, cerebellectomized squirrel monkeys was used to study the distribution of semicircualr-canal inputs to the nucleus. Some so-called intact animals had 6 active semicircular canals. In other animals, the 3 canals on one side were rendered nonresponsive by plugging. In plugged animals, superior, posterior, and horizontal-canal units were encountered on both the plugged and unplugged sides, showing that all 6 canals influence the nucleus. Most units responded bilaterally to labyrinthine polarization; 92.5% of units in intact animals responded to angular acceleration, and this incidence was not decreased in plugged animals. These results suggest that most units in the superior nucleus receive bilateral canal inputs. Convergence of influences arising in orthogonally related canals was detected in less than 10% of units, so the bilateral ampullary influences must arise in parallel canals. Most SVN canal units on the plugged and unplugged sides gave type I responses, indicating that the contralateral canal influence is carried by a crossed inhibitory pathway. Most units influenced by the ipsilateral superior canal were located in the lateral half of the SVN. Posterior-canal units were in the medial half. There was no clear localization of the relatively few horizontal-canal units which were encountered.

Sinusoidal pitch while rotating about a vertical axis in darkness causes continuous horizontal compensatory nystagmus in the monkey which persists for the duration of stimulation. The steady-state velocity sums with post-rotatory nystagmus to reduce or cancel it, suggesting involvement of the velocity storage mechanism. Analysis of the labyrinthine excitation during pitch while rotating suggests that the vertical canals play a predominant role in generating the response. Effects of selective labyrinthine lesions are in agreement with this hypothesis. Plugging the lateral canals, leaving the vertical canals intact, blocked the initial rapid response at the onset of rotation, but did not interrupt the continuous nystagmus induced by pitch while rotating. On the other hand, plugging the vertical canals abolished the response. If the lateral canal nerves were cut so that the velocity storage mechanism was inactivated, the continuous response to pitch while rotating also disappeared. The dominant labyrinth activation responsible for the nystagmus during pitching while rotating appears to arise in the vertical semicircular canals and to couple to the oculomotor system through the velocity storage mechanism.