The Vestibular System

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The Vestibular System P.P. Vidal1, K. Cullen2, I.S. Curthoys3, S. Du Lac4, G. Holstein5, E. Idoux1, A. Lysakowski6, K. Peusner7, A. Sans8, P. Smith9 1CESeM

– UMR8194, Université Paris Descartes, CNRS, Paris, France; 2Department of Physiology, McGill University, Montreal, Canada; 3Vestibular Research Laboratory, University of Sydney, School of Psychology, Camperdown, Sydney, Australia; 4Howard Hughes Medical Institute, La Jolla, CA, USA; 5Department of Neurology, Neuroscience, Anatomy, and Cell Biology, Mount Sinai School Medicine, New York, NY, USA; 6Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA; 7George Washington University Medical Center, Ross Hall, George Washington University, Washington D.C., USA; 8Retired; 9Department of Pharmacology and Toxicology, School of Medical Sciences, and the Brain Health Research Center, University of Otago, Dunedin, New Zealand

O U T L I N E The Vestibular Receptors

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Primary Vestibular Afferents Regular and Irregular Neurons Responses to Sound and Vibration Ionic Currents in 1°VN Postnatal Maturation of 1°VN Active Versus Passive Stimuli

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Anatomy of the Vestibular Nuclei

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Vestibular Processing in Alert Animals Vestibular Pathways and Multimodal Integration VOR Pathways: General Organization Multimodal Integration in VOR Pathways: Gaze Dependent Processing

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Multimodal Integration in Vestibular Pathways: Posture and Perception Implications for the Observed Integration of Signals

Postnatal Maturation

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Semicircular Canals-Related Vestibular Neurons 819 Otolith-Related Vestibular Neurons 819

Vestibular Pharmacology Classic Vestibular Pharmacology A. The Excitatory Amino Acids

The Rat Nervous System, Fourth Edition http://dx.doi.org/10.1016/B978-0-12-374245-2.00028-0

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Excitatory Amino Acid Receptors Pharmacological Analysis of Excitatory Amino Acid Mediated Synaptic Transmission in the MVe Functional Roles of NMDA Receptors in the Vestibular Nuclei: Correlation with In Vivo Data

The Inhibitory Amino Acids

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Anatomical Studies Electrophysiological Studies Functional Considerations

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Cholinergic Neurotransmission

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Anatomical Evidence Electrophysiological Evidence Behavioral Evidence

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Modulation of Central Vestibular Neurons by Monoamines Histaminergic Modulation of the Vestibular System Serotoninergic Modulation of the Vestibular System Dopaminergic Modulation of the Vestibular System Noradrenergic Modulation of the Vestibular System Functional Speculations

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© 2015 Elsevier Inc. All rights reserved.

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Neuropeptides in the Central Vestibular Network825 Somatostatin826 Opioid Peptides 826 Substance P and the Tachykinins 826

Adrenocorticotropin (ACTH), Growth Factors and Other Neuropeptides Presence of Purine Receptors in the Vestibular Nuclei Vestibular Pharmacology Update

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Overview827 Excitatory Amino Acid Neurotransmitters 827 Immunolabeling Studies 827 Electrophysiological Studies 828 Inhibitory Amino Acid Neurotransmitters 828 Monoaminergic and Neuropeptidergic Neurotransmitters830

Vestibular Pharmacology Summary Membrane and Firing Properties of Central Vestibular Neurons Firing Properties

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Ten years ago, George Paxinos asked A. Sans and me to write the chapter on the vestibular system for his book on the rat nervous system. By the time the fourth edition was planned my former coauthor had retired and did not wish to contribute anything further to the chapter. Because of his absence and the explosion of knowledge in the field during the past ten years, I decided in agreement with George, to replace the former two-author chapter by a new collective one. Parts of the previous chapter are still included because the morphology of the vestibular nuclei, unsurprisingly, has not been modified during the past ten years and the extensive review of the neuropharmacology of the vestibular system was still informative, at least in my view. On the other hand, additional contributions were needed to update the former chapter, and I would like here to warmly thank the new contributors, who agreed to participate in that collective task. They are listed alphabetically in the title. For vertebrates, maintaining their body equilibrium in the gravitational field and being capable of orienting themselves in their environment are fundamental aspects of survival. These constraints imply permanent control of the head and trunk positions in space but also control of the head in relation to the trunk. Three sensory modalities are strongly implicated: vision, proprioception and vestibular function. Gaze and postural stabilization are therefore the result of complex multisensory integration. This integration can be defined as the process of matching multiple internal representations of an external event (head and/or

Ion Channels

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Vestibulo-Autonomic Interactions

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Vestibular Plasticity Vestibular Compensation: An Example of Plastic Recovery Lesions: Symptoms and Recovery The Whole Nucleus The Synapses Secondary Vestibular Neurons (2°VN) Modulation of Plasticity Visual Inputs Hormones and Other Chemical Modulators Conclusions on Plasticity

839 840 840 841 841 842 843 843 844 844

The Vestibular System and Spatial Navigation 844 Relationship to Human Studies 845 Non-Spatial Cognitive Effects of Vestibular Damage 846 Relationship to Hippocampal Function 847 Spatial Navigation and Memory Beyond the Hippocampus 848 References848

trunk rotation), obtained from different sensory modalities, into a unique intrinsic frame of reference in which appropriate motor commands can be coded (Gdowski and McCrea, 1999, 2000; Roy and Cullen, 1998, 2001). Past studies have demonstrated that well-defined neuronal networks in the central nervous system implement these complex sensorimotor transformations, known as the vestibuloocular, vestibulocollic and optokinetic reflexes. In the rat, vestibulospinal reflexes have not been studied in detail while a considerable amount of data is available in other species (for review, see Wilson et al., 1995, 1999). On the other hand, eye–head coordination (Fuller, 1985; Dieringer and Meier, 1993; Meier and Dieringer and 1993; Sirkin, 2012), the angular vestibulo-ocular reflex (VOR) (Lannou et al., 1982; Hess et al., 1989; Reber et al., 1996) and the maculo-ocular reflex (Hess and Dieringer, 1991) have been well described in the rat, as has the effect of gravity on the horizontal and vertical VOR (Brettler et al., 2000; Plotnik et al., 1999). The optokinetic reflex (Hess et al., 1985, 1989; Sirkin et al., 1985; Niklasson et al., 1990) and the cervicoocular reflex (Niklasson et al., 1990) had also been well described in that species. In addition, the functional plasticity of the rat VOR had also been investigated following adaptation to visuovestibular conflicts (Tempia et al., 1991; Gauthier et al., 1995; see du Lac et al., 1995 for a review across species) and habituation (Tempia et al., 1991; see Kawato and Gomi, 1992, for a review across species). The post-lesional plasticity of the rat vestibular system has been investigated in

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a variety of models: following unilateral ablation of the labyrinth (Hamann et al., 1998 in the rat; see Curthoys and Halmagyi, 1995; Dieringer, 1995; for reviews across species, Magnusson et al., 2002; Magnusson and Tham, 2003), in a strain of mutant rat (Rabbath et al., 2001), following lesions of the commissural vestibular fibers (Tham et al., 1989), the frontal eye field (Bahring et al., 1994), the nucleus reticularis tegmenti pontis (Hess et al., 1989) and after exposition to toxic agents (Tham et al., 1982, 1984; Larsby et al., 1986; Niklasson et al., 1993; Magnusson et al., 1998). The vestibular reflexes have been also investigated following exposure to hypergravity (Wubbels and de Jong, 2001a, b; Abe et al., 2007; Morita et al., 2007) and microgravity (Shipov and Aizikov, 1992). These behavioral studies will not be summarized here, given the limited scope of the review. If interested, the reader should refer to the above-mentioned papers. In the following chapters, the main characteristics of the vestibular system will be exposed, including the physiologic properties related to the anatomic features of the peripheral and central vestibular system. In this case, we have included the electrophysiological aspects and the neurotransmitters related to each vestibular nuclei, focusing on the medial vestibular nucleus, which

has been the main subject of these studies. Although an attempt has been made to focus the review on rat data, the results obtained in other species have also been included when required. Finally, I would like to thank E. Idoux, who not only contributed to the writing of this chapter but very kindly spent time helping me to edit the final manuscript. I would like also to thank A. Lysakowski, for her extensive review of the manuscript and P. Renouf for his help correcting the reference list.

THE VESTIBULAR RECEPTORS A. Lysakowski The vestibular labyrinth consists of five distinct sensory organs (Fig. 1): three cristae ampullares (horizontal, anterior and posterior) located inside the semicircular canals and two otolith organs (the utricular and saccular maculae). The former are sensitive to angular acceleration (head rotations); the latter to linear acceleration, such as motion in a vehicle or an elevator (Goldberg et al., 2012). In terms of orientation, the horizontal canal is tilted upwards 30° from the horizontal plane, whereas the anterior and posterior vertical canals are oriented orthogonal to each FIGURE 1  Schematic illustration of how the afferents from the various sense organs course in the vestibular nerve.

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other, angled about 45° outward from the midline. The two maculae are also positioned orthogonal to each other, with the utricular macula in the horizontal plane and the saccular macula in the vertical plane. In both maculae, the anterior portions are curved away from the plane of the remainder of the macula (Curthoys et al., 2009). Vestibular sensory epithelia are similar in mammals, birds and reptiles, and comparative aspects have been extensively described (Wersäll and Bagger-Sjöback, 1974; Baird, 1974; Lysakowski, 1996). Embedded in an epithelial matrix of supporting cells are two types of sensory receptors, called hair cells: the flask-shaped type I hair cell enveloped by a large afferent nerve ending called a calyx and the cylindrical-shaped type II hair cell contacted by small afferent endings termed “boutons” (Fig. 2). The neurotransmitter present in hair cell synaptic vesicles is glutamate. Immunogold evidence for AMPA glutamate receptors (Matsubara et al., 1996) and transporters (Takumi et al., 1997; Dalet et al., 2012) has been found in rodent vestibular afferents and supporting cells, respectively, and immunohistochemical studies in the rat have shown NMDA receptors in the rat vestibular periphery (Ishiyama et al., 2002). Physiological studies in turtle vestibular organs have provided supporting evidence for both AMPA and NMDA receptors (Bonsaquet et al., 2006; Holt et al., 2006,

2007). Lending support to the idea that glutamate is the neurotransmitter for vestibular hair cells, is a new study on glutamate-transporter- (GLAST-) null mice, which has demonstrated that in addition to the absence of GLAST (shown by Takumi et al., 1997, to be present in vestibular supporting cells), these mice exhibit circling behavior and other signs of vestibular dysfunction (Schraven et al., 2012). The presence of both small clear vesicles and dense core vesicles has been shown at the apex of the afferent calyx, suggesting neurotransmitter or neuromodulator release (Scarfone et al., 1988; Demêmes et al., 2000; Lysakowski and Goldberg, 2008). Sensory transduction in type I hair cells is possibly controlled by neurotransmitters included in these apically-located vesicles (Sans and Scarfone, 1996), since presynaptic Ca2+ channels and components of the presynaptic SNARE proteins involved in synaptic vesicle docking and calcium-dependent exocytosis (Demêmes et al., 2000) are found there. The electrophysiological characteristics of the two types of vestibular hair cells are varied (for reviews, see Eatock and Lysakowski, 2006; Eatock and Songer, 2011). Several types of ionic currents are present in rodents. Both hair cell types possess mechanotransduction channels and L-type calcium currents (reviewed in Eatock and Lysakowski, 2006). Type I hair cells are clearly identified

FIGURE 2  Schematic of two types of vestibular hair cells and their afferent endings. Both hair cells have ribbon synapses, similar to those found in retinal photoreceptors. Type I hair cells have a large calyx ending enveloping their entire basolateral surface, while type II hair cells are contacted by afferent bouton endings. Efferent endings contact the outer surface of the calyx around type I hair cells, contact type II hair cells directly, and in some cases contact their bouton endings postsynaptically. Figure modified by Dr. Sapan S. Desai, from Wersäll (1956).

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The Vestibular Receptors

by large stereotypical delayed outward potassium currents with voltage-dependant activation kinetics (first discovered and named IKI in the pigeon by Correia and Lang, 1990) and later renamed IK,L in rodents (L for low voltage activation, Rüsch and Eatock, 1996, Rüsch et al., 1998). In addition, type I hair cells also possess sodium and other potassium currents. INa1 and INa2 (NaV1.2 and 1.6) have been found in type I hair cells (Chabbert et al., 2003) and afferents (Lysakowski et al., 2011) with the specific isoform depending upon their location in the sensory epithelium, and NaV1.5 has been found on the inner surface of calyx terminals (Wooltorton et al., 2007; Lysakowski et al., 2011). Several delayed rectifiers, such as the M-current (KCNQ, ERG) and KV1 families of channels have also been demonstrated on the inner surface of calyces by electrophysiological and immunohistochemical studies (Hurley et al., 2006; Lysakowski et al., 2011; Spitzmaul et al., 2013), along with the inward rectifier isoform, Kir4.1 (Udagawa et al., 2012). Mammalian type II hair cells also possess a mixture

809

of different currents: a delayed rectified potassium current (IKII), a potassium-activated calcium current IKCa, a fast inactivating current IA, and an inward rectifier, Kir2.1, in addition to both L-type and non-L-type calcium currents (Rennie and Correia, 1994; Rüsch and Eatock, 1996; Dou et al., 2004; Levin and Holt, 2012). Type I and type II hair cells do not operate in isolation, but rather as part of a well-organized cytoarchitecture (Fig. 3) within each vestibular sensory organ (­Lindeman, 1969; reviewed in Lysakowski and Goldberg, 2004). This cytoarchitecture consists of a central part, where the most sensitive, phasically-activated afferents are located, and a peripheral part, housing the less sensitive, tonicallyactivated afferents. An elegant series of studies described the morphological and physiological properties of 3 classes of vestibular afferents in relation to this cytoarchitecture (­Fernández et al., 1988, 1990; Baird et al., 1988; Goldberg et al., 1990a, 1990b) in a rodent species, the chinchilla. The three classes of afferents are calyx afferents,

FIGURE 3  Composite sketch illustrating afferent and efferent innervation of the vestibular sensory epithelia. At bottom center is a cross section at the level of the vestibular brainstem, showing the location of the vestibular efferent nucleus lateral the the facial nerve genu. Efferent fibers (green) emerging from this nucleus innervate either the striolar/central zone of the otolith or crista organs or the extrastriolar/peripheral zone, depending upon whether they contact acetylcholine (alpha-9), ATP (P2X2), or CGRP receptors. Afferent fibers (red, blue, purple) from the otolith and canal sensory epithelia (lower left and right corners, respectively, modified from Fernandez et al., 1988, 1990), show three types of morphology and two distinct types of electrophysiology (either a linear relationship between discharge regularity and sensitivity at 2 Hz, as in the bouton and dimorphic afferents, or a reduced gain in crista calyx afferents). Pure calyx fibers (blue) innervate the striolar/central zones, bouton fibers (red) innervate the extrastriolar/peripheral zone, and dimorphic fibers (purple) are found throughout the macular and crista sensory epithelia, as seen in cross-sections at top left and top right, respectively. Portions of the figure are original artwork produced by Dr. Sapan S. Desai, based on suggestions from Anna Lysakowski. VI.   SYSTEMS

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which contact only type I hair cells and are found in the central part of the sensory epithelia, bouton afferents, which contact only type II hair cells and are found in the peripheral part of the epithelium, and dimorphic afferents, which contact both types of hair cells and are found throughout the sensory epithelia (Figs. 3 & 4). In the chinchilla, calyx, bouton and dimorphic afferents make up 10%, 20% and 70% of the total number of afferents, respectively. Morphological studies have confirmed these findings in other rodents (Desai et al., 2005a, 2005b; Li et al., 2008; Schweizer et al., 2009). The latter two papers have demonstrated an intriguing finding in the rat and mouse utricle, which is that the majority of striolar hair cells are medial to the reversal line, the line across which the kinocilia reverse polarity. This reversal line is determined by specific planar cell polarity genes (Montcouquiol et al., 2006; for review, see May-Simera and Kelley, 2012). The same does not appear to be true in the saccular macula (Songer and Eatock, 2013). Finally, across six rodent species, an allometric study confirms that the numbers of vestibular afferents and hair cells, as well as the areas of the sensory epithelia, are correlated with body weight, except for the rat, in which all values are low for its size (Desai et al., 2005a, 2005b). This cytoarchitectural finding suggests that the rat vestibular periphery is not very well-suited for vestibular studies. Numerous features distinguish the central (striolar zone of macular organs) and the peripheral (extrastriolar zone of macular organs) zones in the rat. Central zones have a slightly higher proportion of type I hair cells,

approximately half of which are enclosed in complex calyces that enclose more than one type I hair cell (Fernández et al., 1988, 1990). In the rat and mouse, most of the complex calyces are thought to be calyx, as opposed to dimorphic, afferents (Li et al., 2008; Songer and Eatock, 2013). Calcium binding proteins can distinguish among afferent types. Desmadryl and Dechesne (1992) were the first to make the correlation that calretinin antibody selectively labels the calyx class of afferents in the guinea pig and chinchilla cristae. About half of the striolar calyces of both simple and complex type are calyx afferents and immunoreactive for calretinin (Fernández et al., 1988, 1990; Desai et al., 2005a, 2005b), while all central calyces are calbindin-positive (including both the calyx afferents and central dimorphic afferents). Calbindin also labels medium-sized ganglion cells and juxtrastriolar dimorphic afferents in the gerbil (Kevetter and Leonard, 2002; Leonard and Kevetter 2002). Small fibers, corresponding to the bouton afferents, contain peripherin (Lysakowski et al., 1999) and substance P (Demêmes and Rhyzhova, 1997; Sans et al., 2001). Recent studies also suggest that certain antibodies specifically label striolar type I hair cells. In the developing rat, antibodies to BK label central type I hair cells (Schweizer et al., 2009), while in the adult mouse, oncomodulin, another calcium binding protein, also labels central type I hair cells (Simmons et al., 2010). Finally, the majority of peripheral type II hair cells contain calretinin in the rat and mouse (Sans et al., 2001; Desai et al., 2005a, 2005b).

FIGURE 4  Schematic representations of calyx, dimorphic and bouton afferent nerve endings.

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There are also regional differences in the control of afferent input to the vestibular nuclei. Efferent terminals were once considered to be highly concentrated at the peripheral parts of the sensory epithelium and rare in the central parts (Raymond and Demêmes, 1983; Purcell and Perachio, 1997), but an ultrastructural study showed the same number of efferent boutons per hair cell regardless of zone (Lysakowski and Goldberg, 1997). There may, however, be more efferent boutons contacting the unmyelinated portions of afferent fibers in the neuropil below the hair cells in the peripheral zone. Efferent fibers directly contact type II hair cells and afferent boutons as well as the outer surfaces of the calyces surrounding type I hair cells. Vestibular efferent cell bodies are located in the brainstem, below the 4th ventricle (Warr, 1975; Goldberg and Fernández, 1980; for review, see Holt et al., 2011). As discussed in the review, several studies have demonstrated the presence of acetylcholine (ACh), calcitonin gene-related peptide (CGRP), nitric oxide (NO), adenosine triphosphate and their receptors related to efferent fibers. In the mammalian vestibular system, efferent innervation of the periphery produces an excitatory effect (Goldberg and Fernández, 1980), which differs from that observed in the auditory system and from the effects observed in lower vertebrates (Holt et al., 2011), except for the toadfish (Boyle and Highstein, 1990). ACh likely exerts its effect through nicotinic (Holt et al., 2006) and muscarinic (Pérez et al., 2010; Drescher et al., 1999) receptors, while the physiological effects of CGRP in the vestibular periphery are still unknown, although it has been shown to be excitatory in Xenopus lateral line hair cells (Sewell and Starr, 1991). The physiological effects and presence of nitric oxide (NO) in vestibular efferent neurons and endings have also been demonstrated (Chen and Eatock, 2000; Lysakowski and Singer, 2000).

PRIMARY VESTIBULAR AFFERENTS I.S. Curthoys

Regular and Irregular Neurons The projection of afferents in the vestibular nerve of the rat is similar to that of all mammalian species (de Burlet, 1929). The first-order vestibular afferent neurons (1°VN) are bipolar cells (Gacek, 1969), which contact the hair cells of the labyrinth and the second-order vestibular neurons (2°VN). Their somas are located in Scarpa’s ganglion which in rodents lies just at the junction of the temporal bone and the brainstem (Curthoys, 1981). The vestibular nerve and ganglion each has two divisions. The afferents in the superior division supply the horizontal and anterior canal ampullae and the entire utricular macula (Fig. 1). In the superior division there is also a small component (called Voit’s nerve) from the anterior (“hook”) region of the saccular macula (Gacek and Rasmussen, 1961). The afferents in the inferior division supply the posterior canal ampulla and the main part (the “shank”) of the saccular macula (de Burlet, 1929). Gacek and Rasmussen counted a total of around 2700 afferents in the guinea pig inferior vestibular nerve; and about 5500 in the superior nerve. For the otoliths, there were 1700 from the utricular macula and a total of about 1530 from the saccular macula (about 270 in Voit’s nerve and 1260 in the main saccular division of the inferior nerve). Each ampulla contributed around 1600 afferents (see Desai et al., 2005a, 2005b for numbers of receptors in many rodent species). Most vestibular afferents are characterized by a resting discharge that permits the afferents to respond bidirectionally (Goldberg, 1991, 2000; Goldberg et al., 2012, for reviews). The resting discharges can be regular or irregular. Regular 1°VN are commonly referred to as tonic afferents and are sensitive to the mechanical displacement of the cupula or, in the case of otolithic neurons, to the mechanical

FIGURE 5  Time series of activation by a utricular neuron to BCV and ACS. The adjacent image shows an image of such a cell labelled by neurobiotin terminating in 3 calyx endings with boutons. Reproduced with permission from Curthoys et al. (2012).

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displacement of the otolithic membrane. For the canals, the tonic afferents encode angular head velocity, and for the otoliths, they encode gravito-inertial acceleration of the head—linear accelerations and tilts with respect to gravity. Irregular afferents are often referred to as phasic 1°VN and they are sensitive to both the mechanical displacement of the mechanoreceptors and also to the velocity of their displacement, so they encode changes in head velocity and changes in head linear acceleration, as well as being responsive to the acceleration itself (Goldberg, 1991, 2000; Goldberg et al., 2011, 2012; Eatock and Songer, 2011). Across the afferents there is a range of different physiological characteristics. There is a range of regularity of resting discharge of the afferents from highly regular to highly irregular. This regularity is quantified by the corrected coefficient of variation of interspike intervals at rest. The research from the Goldberg laboratory over many years has shown that this range is related to the morphology of the termination of the afferent neuron on the receptors—bouton afferents contacting many type II receptors tend to be regular, calyx afferents contacting type I receptors are irregular and dimorphic afferents have intermediate values of regularity (Figs. 3 & 4). Within the nerve from each sense organ there is a range of axon diameters and there are corresponding variations in physiological characteristics—regularity of spontaneous discharge, conduction velocity, sensitivity to acceleration stimulation, sensitivity to galvanic vestibular stimulation (GVS), which is DC or low frequency electrical stimulation of the sense organs. Afferents from all vestibular sense organs are activated by GVS at approximately equal thresholds (Kim and Curthoys, 2004), although irregular afferents have a significantly lower threshold for GVS activation than regular neurons. Importantly, afferents from different regions within each sense organ show differential selectivity to various temporal aspects of the acceleration stimuli. Also the afferents from different spatial locations of the otoliths show preferences for accelerations in particular directions. Figure 1 gives the impression that each vestibular sense organ is a uniform structure but in fact the opposite is the case. Within each sense organ there are specialized areas for detecting different temporal and spatial aspects of the acceleration stimulus (Fig. 3). The acceleration stimulus or the change in acceleration is processed differently in the central and peripheral zones of each sense organ. This channeling of temporal and spatial information is a fundamental principle of operation of the vestibular system and it serves to explain the large number of seemingly redundant receptors and afferents in each sense organ. Far from being redundant, different neurons are tuned to different stimulus aspects. Regular 1°VN are comprised of bouton and dimorphic units in the peripheral zone of the cristae and in

the extrastriolar zone of the otolithic maculae. They are characterized by thin or medium-sized, slow-conducting axons and by a low sensitivity to head rotation and to galvanic (DC electrical) vestibular stimulation. Irregular 1°VN are comprised of calyx and dimorphic units, which innervate the central cristae and the striolar zones of the otolithic maculae. They are characterized by large or medium-sized, fast-conducting axons and by large excitatory responses to efferent system stimulation (Baird et al., 1988; Goldberg et al., 1990a). Their sensitivity to linear or angular head rotations and electrical stimulation is on average six times higher than that of the regular afferents (Goldberg et al., 1984). Primary afferents activated from the horizontal semicircular canal have been recorded in anaesthetized rats by Curthoys (1982a). Regular 1°VN (43% of the cells) displayed higher spontaneous activity (63 spike/s versus 18 spike/s) to maintained angular accelerations, and had lower sensitivity (0.79 versus 1.1 (spike/s)/(deg/s2)) and longer time constants (3.4 s versus 2.3 s) than the irregular 1°VN, when tested with constant angular acceleration. Some irregular 1°VN were more sensitive to increasing accelerations than to decreasing ones, which was not the case for regular 1°VN. When challenged with sinusoidal angular acceleration (0.01–1.5 Hz), regular 1°VN also have lower gain (0.83 versus 1 (spike/s)/ (deg/s2) at 0.5 Hz), smaller phase leads re. velocity and longer time constants (4.36 versus 4.03 s) than irregular 1°VN. However, for both types of stimulations, there was considerable overlap between the characteristics of the two populations of cells. Clearly, there is a continuum of regularity of spiking in 1°VN (as is the case for 2°VN, see below). It is now clear that membrane channels within the afferent neurons are responsible for the regularity of spontaneous activity (Eatock et al., 2008; Iwasaki et al., 2008; Kalluri et al., 2010).

Responses to Sound and Vibration Angular and linear acceleration of the whole animal have been the usual stimuli in studies of vestibular physiology. However it is now clear that some vestibular afferents can also respond to [loud?] sound and vibration (Fig. 5). A 500 Hz vibration of the skull causes a series of rapidly changing linear accelerations at the mastoids and there is clear evidence from guinea pigs and rats that irregular otolithic afferents from the striolar region of the utricular and saccular maculae are activated by such stimuli, as might be expected from their preference for changes in linear acceleration (Curthoys and Vulovic, 2011; Curthoys et al., 2012). At 500 Hz irregular otolithic afferents are strongly activated with low threshold and high sensitivity—in some cases the stimulus intensity at threshold is around 0.1g, which is the level required for an ABR threshold. A 500 Hz vibration is selective: afferents

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from the semicircular canals (irregular or regular) are not detectably affected by this stimulus, whereas irregular otolithic afferents respond strongly. At low frequencies (around 100 Hz) both otolith and canal irregular neurons can be activated by vibration (Curthoys, 2012). Presumably the vibration is causing a deflection of the receptor cilia and it seems that even air-conducted sound can also cause such a deflection since the afferents activated by vibration are usually activated in similar fashion by high intensity air-conducted sound. This selectivity has been used to develop new clinical tests of otolith function – the cervical and the ocular vestibular evoked myogenic potentials (Curthoys, 2010; Curthoys, 2012).

Ionic Currents in 1°VN Ultrastructural characteristics lead to classifying vestibular ganglion neurons in two main types: large and small neurons (Rosenbluth, 1962). On the basis of neurochemical components, i.e., calbindin-D28K (CaBP), calretinin (CaR) and neurofilament (NF) proteins, three subpopulations were identified: (1) CaBP and CaR positive 1°VN corresponding to the largest neurons (16%); (2) exclusively NF-positive 1°VN; and (3) 1°VN unlabeled by CaBP, CaR, NF antibodies (70%) (Demêmes et al., 1992; Dechesne et al., 1993). These different types of neurons express glutamate, ARIA or acetylcholine receptor inducing activity (Morley, 1998), glycine (Baurle et al., 1997) choline acetyltransferase and different receptors, such as glutamate (Fujita et al., 1994; Doi et al.,1995; Usami et al., 1995; Niedzielski and Wenthold, 1995) and purinergic (P2X) receptors (Xiang et al., 1999). Analysis of voltage-activated conductances recorded in 1°VN revealed the presence, in all vestibular neurons, of two types of sodium current (Chabbert et al., 1997; Wooltorton et al., 2007), five calcium currents (Desmadryl et al., 1997, Chambard et al., 1999), one type of hyperpolarization-activated inward current (IH) (Chabbert et al., 2001), a TEA-sensitive potassium current (IK) (Chabbert et al., 2001; Eatock and Songer, 2011). However, the properties of these currents and their distributions cannot account for the various electrical activities recorded in primary afferents. More interestingly, considerable variability in the expression of two fast-activating potassium currents (IA and ID) (Chabbert et al., 2001b; Eatock and Songer, 2011) suggest that, if they are involved in shaping action potential, a variation in their relative expression could explain the heterogeneity of the 1°VN.

Postnatal Maturation of 1°VN In the rat, head accelerations can be transduced by the 1°VN (Curthoys, 1978, 1979, 1982b) and encoded by the 2°VN at birth (Lannou et al., 1979; Eatock and Lysakowski,

2006 in the mouse). The semicircular canals reach their adult size by P20 and vestibular hair cells appear to be mature at two weeks following birth. During the first two weeks, 1°VN (Desmadryl, 1991; Curthoys, 1978, 1979, 1982a) and 2°VN (Lannou et al., 1979) also progressively mature. As a result, the vestibulo-ocular reflexes, which are already present at birth, increase in sensitivity during the first postnatal month (Curthoys, 1979). Irregular 1°VN have been recorded at birth. They respond to head accelerations with a gain similar to the adult rat at P6, while their phase lead re. velocity continues to decrease up to P30. Regular afferents are absent at birth and begin to appear at P5. Then, their number and their resting discharge rise steadily to reach adult values around P30. In contrast to irregular cells, regular 1°VN display low sensitivity and long phase lag as in the adult, as soon as they appear. These data can be compared with the results of previous studies in mice concerning the maturation of the 1°VN (Demêmes and Sans, 1985; Desmadryl et al., 1986, 1997, 1998; Desmadryl, 1991; Chambard et al., 1999; Dutia et al., 1995; Dutia and Johnston, 1998).

Active Versus Passive Stimuli It has been suggested that vestibular efferents modulate primary afferent activity depending on whether the acceleration stimulation is passively received (e.g., during an unexpected fall) or is generated actively (e.g., during a somersault). The evidence from studies of peripheral afferents is that there is no difference, passive versus active, for either angular or linear acceleration afferent responses—with one intriguing exception (Sadeghi et al., 2006; Jamali et al., 2009). Blocking of a semicircular duct minimizes afferent response to passive angular acceleration, but the response to the same acceleration actively generated is greater than that for passive stimulation (Sadeghi et al., 2009). The effect of vestibular efferents on the physiological response of primary afferents remains unclear. While in physiological studies electrical stimulation of efferents can increase or decrease spontaneous discharge in different individual afferents, it is unclear how this relates to afferent activity in natural situations.

ANATOMY OF THE VESTIBULAR NUCLEI P.P. Vidal, A. Sans Vestibular primary afferents, which connect the vestibular receptors at the periphery, arrive in the central nervous system in the vestibular nuclear complex. In fact, this description is partially incorrect since: (1) the greater part of these nuclei are totally free of direct vestibular terminal fibers; (2) they receive other sensory

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modalities, especially proprioceptive influx; and (3) the main tract projecting to the vestibular nuclei originates in the cerebellum (Brodal, 1974). Hence, the vestibular complex must be understood as an important junction, which receives various information (visual, proprioceptive and vestibular) leading the nuclei to assume a major role in the maintenance of balance and equilibrium. The vestibular complex is classically divided into superior, lateral, medial and spinal vestibular nuclei and smaller cell groups, the interstitial nucleus of the vestibular nerve, and groups F, L, X, Y and Z. These small groups of cells are topographically associated with the four main vestibular nuclei. The central trunk of the vestibular nerve leaves the inner auditory meatus and orthogonally penetrates the brain stem in front of the external cochlear nucleus. It then splits, in the lateral vestibular nucleus, into ascending and descending branches. The ascending branches project into the superior, medial and lateral nuclei; the descending branches into the lateral

and descending nuclei. Each vestibular fiber provides numerous collaterals, which project into the four vestibular nuclei (Fig. 6). They form a pattern on the second order vestibular neurons: some of these cells are specifically connected to the periphery and receive fibers of only one kind of receptor (vertical or horizontal cristae, maculae), others are multiconvergent and receive fibers from different receptors (Graf and Ezure, 1986 in the cat; Kubo et al., 1977 in the rat; Lannou et al., 1980; Angelaki et al., 1993). Brodal and Pompeiano (1957) have extensively studied the anatomy and the afferent and efferent connections of the vestibular nuclei in the cat (see Brodal, 1972, 1974, for reviews). In the rat, the intranuclear organization of the vestibular nuclei and their relationship with other structures has been investigated by Rubertone and colleagues (Rubertone and Mehler, 1981; Rubertone and Haroian, 1982; Rubertone et al., 1983, 1995). In this section, we will only summarize the anatomy of the main vestibular nuclei to the extent that they are useful for

FIGURE 6  Transversal brain stem section through the medial portion of a postnatal 3-day mouse vestibular complex. Parvalbuminimmunocytochemical labeling (green) shows the distribution of vestibular nerve fibers (arrow) and their branching in vestibular nuclei. MVe, medial vestibular nucleus; LVeD, dorsal part of the lateral vestibular nucleus; 4V, fourth ventricle; Co, cochlear nucleus; 8vn, vestibular nerve; PrH, prepositus hypoglossi nucleus. Courtesy of J. Puyal.

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understanding some important morpho-functional correlations. The vestibular nuclei are limited rostrally by the brachium conjunctivum, laterally by the inferior cerebellar peduncle (restiform body), ventrolaterally by the nucleus and spinal tract of the trigeminal nerve, and medially by the fourth ventricle and the reticular formation. The

location and boundaries of the four main nuclei of the vestibular complex can be found in Paxinos and Watson (2014). TABLE 1 is a summary of the cytoarchitecture, main afferents, efferents and role of these four nuclei. For more detailed information, please refer to Vidal and Sans (2004).

TABLE 1  Summary of the Cytoarchitecture, Main Afferents, Efferents and Role of these Four Nuclei Name (Abbreviation)

Superior Vestibular Nucleus (SuVe)

Lateral Vestibular Nucleus (LVe)

Medial Vestibular Nucleus (MVe)

Descending Vestibular Nucleus (Spinal Nucleus, SpVe)

Cytoarchitecture

Medium-sized cells and small cells

Medium-sized cells

Small (more rostrally) and medium cells homogeneous & densely packed together

Small and medium size cells mostly

Thin fibers cross the nucleus in all directions

Larger cells in the more anterior part

The medium-sized cells Giant cells typical of the LVe predominate in the central (60 μm), are mostly located part of the nucleus in the caudo-dorsal part

Longitudinally oriented fibers coming from the descending vestibular root and from the cerebellum interlace the cells throughout the nucleus Afferents

Cristae & flocculus→central

Utricle & saccule→rostroventral

Cristae→dorso-rostral

Cristae→central

Utricle, saccule, nodulus, uvula and the fastigial nucleus→periphery

Vermis & fastigial nucleus→caudo-dorsal

Otolith organs→ventromedial

Utricle & saccule→periphery

Cervical & lumbar cord→rostro-dorsal

Flocculus, caudal vermis & fastigial nucleus

Flocculus, nodulus, uvula, medial cerebelar nuclei

Cervical & upper thoracic cord→ventral

Cervical cord & cerebral cortex→caudal

Cervical and lumbar cord (via the dorsalspinocerebellar tract) Contralateral MVe

Efferents

Ipsilateral (mostly) & contralateral medial longitudinal fascicles→oculomotor nucleus & trochlear nucleus

Rostro-ventral part→ cervical cord

Oculomotor nuclei (via ascending medial longitudinal fascicles)

Cerebellar cortex & deep cerebellar nuclei (fastigial nucleus)

Thalamus (lateral part of Caudal SuVe & LVe the parafascicular nucleus and the dorsal part of the caudal ventrolateral nucleus)

Cervical anterior cord (via the medial vestibulospinal tract)

Thalamus (lateral part of the parafascicular nucleus, transitional zone between ventrolateral and ventral posterolateral nuclei, & caudal part of the ventrobasal complex)

Oral pontine reticular

Intermediate part→thoracic cord

Ventral→Thalamus (similar to LVe)

Cervical spine

Flocculus

Caudo-dorsal part→lumbosacral cord

Caudal vermis, fastigial nucleus

Reticular formation Contralateral vestibular nuclei

Role

Control of eye movements Control of posture

Stabilization of gaze and posture in the horizontal plane

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Integration of vestibular spinal and cerebellar messages implicated in the control of posture

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FIGURE 7  Multimodal integration within the vestibular nuclei. The vestibular nuclei receive direct input from multiple brain areas including: (i) the vestibular afferents, (ii) areas of the brainstem that carry oculomotor and proprioceptive signals, (iii) the vestibular cerebellum, and (iv) several areas of cortex (e.g. parietoinsular vestibular cortex, PIVC), premotor areas 6, 6pa, somatosensory area 3a, and superior temporal cortex.

VESTIBULAR PROCESSING IN ALERT ANIMALS K. Cullen

Vestibular Pathways and Multimodal Integration Investigations using in vitro, reduced, and anesthetized approaches have provided key insights into the functional circuitries that underlie vestibular processing. This body of work has revealed two distinctive aspects of the vestibular system that make it unique relative to other sensory systems. First, many 2°VN in the vestibular nuclei are also premotor neurons. For instance, in the pathway that generates the vestibulo-ocular reflex (VOR), the same neurons that receive vestibular nerve inputs send direct projections to extraocular motoneurons. Second, the vestibular nuclei receive projections from a wide range of cortical, cerebellar, and other brainstem structures in addition their afferent nerve input. Thus, neurons at the first stage of central vestibular processing combine vestibular nerve input from multiple modalities. Accordingly, the multimodal interactions that occur at the first stage of central processing play an essential role in shaping reflex responses as well as the computations required for higher order vestibular functions, such as self-motion perception and spatial orientation (reviewed in Cullen, 2012). Figure 7 shows the convergence of information that occurs within the vestibular

nuclei, as well as three of the main output pathways that ensure: (1) accurate gaze control (i.e., the VOR pathway); (2) postural control (i.e., vestibulospinal pathways); and (3) the sense of spatial orientation and self-motion (i.e., ascending thalamocortical pathways). Below, each of these three output pathways are considered, with an emphasis on understanding the strategies by which extra-vestibular signals are combined with vestibular information to ensure accurate motor responses and perception during natural behaviors.

VOR Pathways: General Organization The VOR uses information from both the semicircular canals and otolith organs to generate compensatory eye movements in response to head motion in six dimensions. The rotational VOR is produced in response to three dimensions of head rotation that, in turn, activate hair cells in the semicircular canals. The translational VOR is produced in response to three dimensions of head translations that, in turn, activate hair cells in the saccule and utricle. As noted above, the most direct pathway mediating the VOR is a three-neuron-arc consisting of vestibular afferents, projecting to neurons in the ipsilateral vestibular nuclei, which in turn project to the extraocular motoneurons (Fig. 8A). The rotational VOR is one of the fastest reflexes observed in vertebrates, with a response latency of 5–6

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Vestibular Processing in Alert Animals

817 FIGURE 8  (A) A three-neuron arc comprises the most direct pathways controlling the vestibulo-ocular reflex (VOR), which stabilizes gaze by producing an eye movement in the opposite direction to head movement. In addition to their input from the vestibular nerve, VOR interneurons neurons receive a strong inhibitory input from the premotor saccadic pathway, which effectively suppresses their activity during gaze shifts. In this way, VOR suppression is mediated by behaviorally-dependent gating of an inhibitory gaze command signal. (B) In addition to their input from the vestibular nerve, eye movement insensitive neurons in the vestibular nuclei receive proprioceptive and motorrelated inputs which alter their processing in a behaviorally-dependent manner during self-motion. These neurons contribute to the control of posture and balance, as well as the perception of spatial orientation and self-motion.

ms (e.g., Huterer and Cullen, 2002; Minor et al., 1999). In primates, the responses of vestibular nuclei neurons, which comprise most of the intermediate leg of the rotational VOR pathway, are sensitive to both head motion and eye movements (reviewed in Cullen and Roy, 2004). For example, neurons that mediate the rotational VOR response to horizontal rotations, are activated by ipsilaterally directed head velocity and are also sensitive to contralaterally directed eye movements and quick phases of vestibular nystagmus. Furthermore, electrophysiological studies have shown that VN neurons with oppositely directed head and eye movement sensitivities support inhibitory commissural pathways between vestibular nuclei. These commissural pathways are vital for VOR compensation, as well as for the weaker threeneuron-arc that, in part, mediates the translational VOR. Single unit recording experiments have characterized the responses of single neurons in the vestibular nuclei of alert rats during rotation (Kubo et al., 1975; Bush et al., 1993; Lai and Chan, 1995) and linear motion (Lannou et al., 1980; Bush et al., 1993). In rat as well as other rodents (Beraneck and Cullen, 2007 in mice; Kaufman et al., 2000 in gerbil; Ris et al., 1995 in the

guinea pig), a significant percentage of vestibular nuclei neurons are sensitive to eye as well as head motion (see discussion in Beraneck and Cullen, 2007). Accordingly, these neurons likely mediate the intermediate link of the three-neuron-arc that produces the VOR in rodents, as well as complementary circuits that mediate VOR compensation and the translational VOR. Interestingly, these neurons, in the rat and other rodent species such as mice, do show relatively low sensitivities to both head velocity and eye position, as compared with more advanced species such as monkey (Cullen and McCrea, 1993). This leads to the question: What are the functional implications of the relatively lower neuronal sensitivities? One possibility is that neuronal sensitivities are matched to the mechanical constraints of the oculomotor plant; motor control could have a “lower neural cost” in these rodents because the oculomotor plant has a lower inertia load in these rodents than in larger species. However, this idea is not supported by the report that the sensitivities of mouse extraocular motoneurons lie intermediate between those of the monkey and rabbit (Stahl and Thumser, 2012). A second possible explanation for the relatively lower response sensitivities of rodent

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vestibular nuclei neurons is that the gaze stabilization reflexes in these species are less developed in other species such as the cat or monkey. Indeed, rats are afoveate animals with relatively poor visual acuity (Prusky et al., 2000). However, this proposal is not consistent with report showing that the gain of the rat VOR in light is nearly optimal and is in fact comparable to that in the primate (Quinn et al., 1998). One additional possibility is that reduced response reflects a limited need for eye-movement accuracy compared with foveate animals such as the monkey. For example, compared with the rhesus monkey (e.g., Roy and Cullen, 2002), mouse VN neurons generally show lower and more irregular discharges as well as lower eye- and head-movement sensitivities (Beraneck and Cullen, 2007). Thus, the lower information rates of VN neurons in rodents versus monkey may be the result of evolutionary pressure that reduces performance to the minimum required for adequate function.

Multimodal Integration in VOR Pathways: Gaze Dependent Processing As an animal moves through the world, vestibular information is combined with cues from other sources to provide information about self-motion. To ensure stable gaze, retinal-image motion (optic flow) cues command compensatory optokinetic eye movements (OKR) that minimize image motion across the retina. Thus, in everyday life, the VOR and OKR work in tandem to command the eye movements that stabilize gaze during self-motion. Notably, the vestibular nuclei are an important site for this synergistic integration of the vestibular and visual driven sensory-motor transformations that underlie gaze stabilization. In alert rats (Cazin et al., 1980; Lannou et al., 1982), as in other species, simulation of the visual system that mimics self-motion (i.e., optokinetic stimulation) evokes both responses in a majority of the eye sensitive vestibular nuclei neurons and OKR eye movements. Thus, it appears that the same neurons that generate the VOR also contribute to visually driven OKR to ensure gaze stabilization. Rodents, including rats and mice, are afoveate, lateral-eyed animals that produce a relatively limited repertoire of gaze behaviors—largely limited to gaze stabilizing reflexes (i.e., the VOR and OKR responses). Interestingly, in mice, OKR gains are optimal in response to relatively low velocities of stimulation (<10°/s) (Stahl, 2004). While extensive testing remains to be done in the rat, it seems likely that behavioral performance would be optimal in a similar range. Further experiments are needed to fully understand how the complementary VOR and OKN pathways work together in everyday life to produce the eye movements required to stabilize gaze (Fig. 8A).

Finally, recent studies in primates suggest that efference copies of oculomotor/gaze motor commands suppress the modulation of VOR neurons in the VN during gaze redirection (Roy and Cullen, 1998, 2002). Rats, like primates, use rapid coordinated movements of the eyes and head (gaze shifts) to redirect the visual axis from one target of interest to another (Fuller, 1985). Thus, it is likely that the efficacy of the VOR pathways is similarly suppressed in rats during these self-generated head movements since it would otherwise be ­counterproductive—a fully functional VOR would generate an eye-movement command in the direction opposite to that of the intended shift in gaze. Multimodal Integration in Vestibular Pathways: Posture and Perception The integration of vestibular and extravestibular information also plays an essential role in shaping the information carried by output pathways that ensure postural control (i.e., vestibulospinal pathways) and compute spatial orientation and self-motion (i.e., ascending thalamocortical pathways). Notably, during everyday activities, proprioceptive as well as motor-related signals and vestibular inputs provide feedback about an animal’s movement through the world. The vestibular nuclei receive proprioceptive inputs by means of direct projections from the contralateral central cervical nucleus and several regions of the cerebellum (reviewed in Cullen, 2004). Indeed, recent experiments in rats and mice (Medrea and Cullen, 2013; Barresi et al., 2012) suggest that the majority of neurons in the VN are sensitive to passive stimulation of proprioceptive as well as vestibular receptors. Similar reports of vestibular-­ proprioceptive integration in the VN have been made from studies in other species, including cats, squirrel monkeys and cynomolgus monkeys (Macaca fasicularis) (reviewed in Cullen, 2011). Finally, anatomical evidence (Neuhuber and Zenker, 1989; Arvidsson and Pfaller, 1990; Bankoul and Neuhuber, 1992; M ­ atsushita et al., 1995) also strongly suggests that rat central vestibular neurons process proprioceptive afferents, as is the case in other vertebrate species. In response to passively applied combined neck proprioceptive and vestibular stimulation, responses across species can be predicted based on the sum of their vestibular sensitivity and proprioceptive sensitivity when each stimulus is delivered alone. In contrast, when comparable dynamic stimulation is the result of voluntary movement, neuronal responses are attenuated relative to that predicted by a linear model (reviewed in ­Cullen, 2011). Notably, it has been proposed that a copy of the motor efferent command signal is used to cancel vestibular input during active head rotations in rhesus and cynomolgus monkeys (Fig. 8B; e.g., Roy and Cullen, 2004; Sadeghi et al., 2011) and in mice. A similar

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Vestibular Pharmacology

mechanism likely also cancels self-generated vestibular input during active head movements in lower mammalian species, including rats. Implications for the Observed Integration of Signals The multimodal integration observed in early vestibular processing is important for accurate postural control and perceptual stability. First, by combining proprioceptive and vestibular inputs, neurons can create a representation of body movement and/or convert vestibular information from a head-centered into a body-centered reference frame (reviewed in Angelaki and Cullen, 2008). Such computations are required in vestibulospinal pathways to ensure the maintenance of posture and balance during daily activities. Moreover, the suppression of modulation in vestibulospinal pathways during voluntary motion suggests behaviorally-dependent suppression of vestibulospinal pathways when the animal’s goal is to generate self-motion. In addition, such multimodal interactions are likely to play an essential role in higher-level functions such as self-motion perception and spatial orientation. One obvious implication relates to the head direction network. The vestibular nuclei are commonly considered to provide input to this network during active locomotion (reviewed in Taube, 2007). A preliminary report in mice of a persistent static neck signal in VN that is robust during both active and passive motion (Medrea and Cullen, 2013) suggests that the VN provide the required directional heading signal to drive the head direction cell network. As discussed below, current studies are now aimed at understanding how vestibular inputs are integrated with multimodal signals (proprioceptive, motor efferent copy, etc.) to create the internal representation of head direction throughout the Papez circuit.

Postnatal Maturation Semicircular Canals-Related Vestibular Neurons As is the case for vestibular afferents, the 2°VN resting discharge is low and irregular during the first postnatal days. Then their resting discharge increases gradually and becomes more regular to reach adult values by the end of the first month. The first low threshold units appear at P4 at a time when regular firing begins in firstand second-order vestibular neurons. Their threshold continues to decrease to become five times smaller at P14, when it reaches adult values. The sensitivity of the central vestibular neurons is low at birth and increases steadily to reach adult values by P30. Their time constants and phase leads tend to diminish slightly during that period. Despite the fact that the eyes open around P13, central

vestibular neurons only encode the visual signal at P20 (Lannou et al., 1979, 1980; Reber-Pelle, 1984), at a time when spike generation becomes mature in MVe 2°VN (see below, in vitro studies). Otolith-Related Vestibular Neurons Lai and Chan (2001) recorded the spontaneous activities and response dynamics of otolith-related vestibular neurons in decerebrated rats at P7, P14, P21 and P84 (adult). Cells were recorded extracellularly in the LVe and SpVe during constant velocity off-vertical axis rotation, which selectively stimulates the otolith sensors. They displayed sinusoidal position-dependent modulation and could either be modulated during the full-cycle or silenced (“clipped”) during parts of each rotary cycle. From P7 to P84, the proportion of clipped cells progressively decreased from about 75% to less than 25%. The sensitivity of the otolith-related vestibular neurons increased with age to reach a plateau at P21 for clipped cells and P14 for non-clipped cells. At P7, both types of cells had irregular spontaneous activity, which became more regular as the rats matured. Beyond P14, while spontaneous activity increased in all cells, clipped neurons tended to have significantly lower resting rates and higher gains than the non-clipped ones. Irregular neurons could display phase-stable and phase-shift responses, while regular ones always displayed a phasestable response.

VESTIBULAR PHARMACOLOGY G. Holstein, K. Peusner, P.P. Vidal

Classic Vestibular Pharmacology The classic pharmacological properties of vestibular neurons have been the topic of various reviews (Raymond et al., 1988; Smith and Darlington, 1994a, 1994b; Vibert et al., 1994, 2000; Darlington et al., 1995, 1996; de Waele et al., 1995; Vidal et al., 1996a, 1996, 1998, 1999; Takahashi and Kubo, 1997) and of a book (Beitz and Anderson, 2000), which can be consulted to complement the present chapter. Accordingly, this section has been shortened to avoid redundancy. The neurotransmitters involved in the neurotransmission and neuromodulation of the central vestibular neurons are conveniently classified in three groups. First, the excitatory and inhibitory amino acids, aspartate, glutamate, GABA and glycine mediate fast synaptic events through their actions on pre- and postsynaptic ionotropic receptors. The five monoamines (histamine, dopamine, serotonin, noradrenaline, and adrenaline) and acetylcholine modulate, with a slower time constant, the discharge of vestibular neurons by activating metabotropic receptors linked to second messenger

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FIGURE 9  Double GFAP and GluR2 immunofluorescence fluorescence staining of the lateral vestibular nucleus. Neuron of the adult rat lateral vestibular nucleus exhibiting a GluR2 immuno-positive labeling (soma coloured in red). Notice that this neuron is surrounded by numerous astrocytic processes (colored in yellow). Zoom: ×1000.

systems (Hille, 1992). A third group encompasses several neuroactive peptides. At the onset of this section it should be stressed that in vivo microiontophoretic applications, in vivo perfusion through a chronically implanted cannula and in vitro bath-application on a slice all test the effect of a drug at a population level. The changes in neural activity are the summation of its effect both on the recorded neurons and on the neighboring excitatory and inhibitory cells, which project to them. The results must therefore be interpreted with caution. One way of solving this problem in in vitro preparations is to reversibly block synaptic transmission with a high Mg2+/low Ca2+ solution or tetrodotoxin (TTX). Under these conditions, the postsynaptic effect of a given compound can be studied on recorded neurons, independently of interneurons synapsing with the cell. The vast majority of the studies quoted in this chapter were performed in the rat. Nevertheless, studies performed in the cat and the guinea pig are included to present a comprehensive view of the neuropharmacology of the vestibular neurons. Finally, it should be mentioned that, apart from subtle differences, type A and B MVe 2°VN (see Membrane and Firing Properties of Central Vestibular Neurons below) cannot be differentiated through their sensitivity to any of the drugs tested so far.

A. The Excitatory Amino Acids Amino acid neurotransmitters can be subdivided into the excitatory amino acids aspartate and glutamate, and the inhibitory amino acids GABA and glycine. The ionotropic and metabotropic receptors of the amino acids are

known under the name of their main specific agonists (Nakanishi, 1992; Pin and Duvoisin, 1995). Excitatory Amino Acid Receptors All types of excitatory amino acid receptors are expressed by vestibular nuclei neurons including the mGluR1, mGluR2 (Fig. 9), mGluR5 and mGluR7 subtypes of the metabotropic receptors (see Shigemoto et al., 1992; Ohishi et al., 1995; Neki et al., 1996 in the rat). In situ hybridization studies have been used to investigate various subunits of the ionotropic receptors. Rat vestibular nuclei displayed a high density of GluR1, GluR2/3, and GluR4 subunits of the AMPA receptor (Fig. 10a,b), a high density of the R1 and R2C subunits and a lower density of the R2B and R2D subunits of the NMDA r­ eceptors (Petralia and Wenthold, 1992; de Waele et al., 1994; ­Watanabe et al., 1994). The NMDA receptors are co-localized with AMPA receptors in most rat vestibular neurons (Chen et al., 2000), hence cross-modulation between NMDA and AMPA receptors is likely to occur during glutamatemediated excitatory synaptic transmission and could play a role in synaptic plasticity (see below). In agreement with these immunohistochemical and in situ hybridization data, several in vitro electrophysiological studies reported that vestibular neurons were responsive to the various agonists and antagonists of the AMPA/kainate, NMDA and trans-ACPD receptors (for reviews, see Gallagher et al., 1992; de Waele et al., 1995; Vidal et al., 1996a). The effects of AMPA, kainate, NMDA and trans-ACPD agonists and antagonists are largely mediated by postsynaptic receptors, as shown by their persistence during bath-application of TTX and in a high Mg2+/low Ca2+ solution (see also, Darlington et al., 1995, in the guinea pig).

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Vestibular Pharmacology

821 FIGURE 10  (A, B) Confocal images showing immunolabeling with GluR2/3 (A) and GluR4 (B) receptor subunit antibodies (red) in TN principal cell bodies labeled with microtubuleasociated2 (MAP2) (green) at H9. Scale bar in B refers to A and B. Adapted from Popratiloff et al., 2004. (C) Confocal image showing GABA (red) and glycine (green) double-immunolabeled section from the chicken TN, revealed with Alexa Fluor 488 (green) and 647 (red) at H7. GABA labeled most terminals in the TN, which were found mainly on dendrites. A distinct pool of glycine-positive terminals was found consistently around the principal cell bodies. Most horizontal fibers were labeled with glycine (white arrow), with occasional double-labeled GABA and glycine fibers (white arrowhead). PC, principal cell body. Adapted from Popratiloff and Peusner, 2011.

Pharmacological Analysis of Excitatory Amino Acid Mediated Synaptic Transmission in the MVe An excitatory amino acid (glutamate and/or aspartate) mediates synaptic transmission between: (a) the 1°VN and 2°VN (for reviews, see Raymond et al., 1988; Gallagher et al., 1992; Yamanaka et al., 1997); (b) the 2°VN and the contralateral abducens motor neurons; and (c) the excitatory 2°VN and some of the spinal motor neurons (Dieringer, 1995). As demonstrated in the frog (Cochran et al., 1987; Dieringer, 1995), it is also likely that several afferents of the vestibular nuclei neurons, including spinal and excitatory commissural fibers use ­glutamate- and/or aspartate-mediated transmission. The contribution of NMDA receptors to synaptic transmission between first- and second- order vestibular

neurons is still under scrutiny (Lewis et al., 1989; Doi et al., 1990; Kinney et al., 1994; Takahashi et al., 1994 in the rat; Cochran et al., 1987; Straka et al., 1995a in the frog). In this regard, the isolated in vitro whole guinea pig brain preparation (Babalian et al., 1997) is useful, as it allows stimulation of the 1°VN without the problem of current spread to adjacent groups of cells. In this preparation, CNQX (a selective antagonist of AMPA/kainate receptors) suppressed most of the field potentials and EPSPs evoked following stimulation of the eighth nerve. In contrast, APV (an antagonist of NMDA receptors) abolished a small, variable portion of field potentials or EPSPs in about half of the recorded cells, which persisted following CNQX perfusion. In addition, a previous study by Straka et al. (1995a) in isolated frog brainstem indicates

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that the large vestibular afferents (presumably the phasic, irregular ones) activate NMDA receptors in 2°VN. Thus, NMDA receptors are involved at the synapse between 1°VN and 2°VN. However, their exact contribution remains to be determined. Indeed, NMDA receptors are subjected to voltage-dependent block by extracellular Mg2+ (Ascher and Nowak, 1988). Hence, the minor contribution of NMDA receptors recorded in in vitro preparations could become a major one in vivo when MVe 2°VN are more depolarized. Finally, NMDA and trans-ACPD receptors are present at the presynaptic level in the vestibular nucleus (Gallagher et al., 1992 in the rat; Darlington and Smith, 1995 in the guinea pig). They could be expressed at the terminal arborization of the 1°VN, since several NMDA and trans-ACPD receptor subunits are expressed by rat vestibular ganglion cells (Doi et al., 1995; Safieddine and Wenthold, 1997). The functional contributions of these receptors remain to be determined. Functional Roles of NMDA Receptors in the Vestibular Nuclei: Correlation with In Vivo Data In vivo, NMDA receptors on central vestibular neurons play a major role in the maintenance of their resting discharge. Indeed, unilateral perfusion of APV in the vestibular nuclei in alert, unrestrained guinea pigs induces a massive postural and oculomotor syndrome, mimicking unilateral labyrinthectomy (de Waele et al., 1990). It also disables the neural integrator, which processes the velocity signal encoded by the 1°VN into a position signal necessary for stabilizing the eyes. Finally, NMDA antagonists impair the cat VOR triggered by low frequency head rotations (Priesol et al., 2000). These data show that the voltage-dependent block of NMDA receptors in central vestibular neurons by Mg2+ is compensated for in the alert behaving preparation. Different factors could be at play. First, the high resting discharge of the 1°VN could sufficiently depolarize central vestibular neurons to prevent the Mg2+ block. Second, glycine, a co-agonist of the strychnine-­ insensitive site of the NMDA receptors (for review, see Wood, 1995) is co-localized with glutamate in the frog and rat in the largest afferent fibers (Reichenberger and Dieringer, 1994; Reichenberger et al., 1997). As seen above, these fibers underlie the NMDA-mediated response in vestibular neurons in the frog (Straka et al., 1995a, 1995b), the guinea pig (Babalian et al., 1997), and most likely in the rat (Doi et al., 1990; Kinney et al., 1994). Hence, co-release of glutamate and glycine by large irregular fibers could potentiate postsynaptic NMDA receptors. This is a plausible scenario as the strychnine-insensitive site is probably not saturated in vivo (Wood, 1995). In addition, specific agonist (D-serine) and antagonist (7-­chlorokynurenate) of the strychnineinsensitive binding site of NMDA receptors, when

chronically perfused in a vestibular complex of alert, unrestrained guinea pigs (Bénazet et al., 1993), induced opposite asymmetries of the VOR and a reversible postural syndrome.

The Inhibitory Amino Acids Anatomical Studies GABA and glycine are the most prevalent inhibitory transmitters in the CNS (Sivilotti and Nistri, 1991; Sato and Kawasaki, 1991 in the rat). GABA receptors are subdivided into two groups: ionotropic GABAA receptors include chloride ion channels and metabotropic GABAB receptors are associated with second messenger systems (for review, see Misgeld et al., 1995). Glycine receptors are ionotropic receptors quite similar to the GABAA ones (for review, see Betz et al., 1994). The vestibular nuclei are densely innervated by GABA­ ergic and glycinergic afferent fibers (Rampon et al., 1996, in the rat). Not surprisingly, vestibular neurons are also endowed with GABAA (Fig. 10), pre- and postsynaptic GABAB (Holstein et al., 1992, in the rat) and glycinergic receptors. Furthermore, about a third of the rat MVe 2°VN are GABAergic neurons (de Waele et al., 1994). These inhibitory cells encompass the type II interneurons (Shimazu and Precht, 1966) involved in commissural inhibition and second-order vestibulo-ocular and vestibulospinal neurons (Graf et al., 1997). Electrophysiological Studies In vitro studies in slices confirm these morphological findings. Extracellular recordings in MVe 2°VN reveal inhibition through GABAB and GABAB receptors (Dutia et al., 1992). As expected, intracellular recordings in the guinea pig (Vibert et al., 1995a, 1995c) in a high Mg2+/ low Ca2+ solution, or in the presence of TTX, reveal that both type A and B MVe 2°VN are inhibited by GABA, muscimol (a specific GABAA agonist), and baclofen (a specific GABAB agonist). On the other hand, in normal saline, while GABA hyperpolarizes several MVe 2°VN, others are depolarized. Once TTX is added to the bath, these depolarized cells become hyperpolarized. These results in normal saline can be explained as follows: (a) inhibitory interneurons are tonically active in the slice and inhibit some of the recorded MVe 2°VN; (b) GABA and muscimol perfusion interrupt their spontaneous discharge and consequently depress the inhibition they exert on the recorded cell - this leads to a disinhibition of the MVe 2°VN; (c) the disinhibition is large enough in some of the MVe 2°VN to overcome the direct inhibitory effect of GABA and muscimol. Consequently, GABA application results in a net depolarizing effect. Once TTX is added to the bath, the disinhibition is suppressed and the direct inhibition is revealed. Altogether, these results

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show that both MVe 2°VN and the local type II inhibitory interneurons express postsynaptic GABAA receptors. Bath-application of glycine also inhibits MVe 2°VN (Lapeyre and de Waele, 1995 in the guinea pig). This inhibition is suppressed by strychnine but persists in a high Mg2+/low Ca2+ solution. This implies that MVe 2°VN carry postsynaptic, strychnine-sensitive glycinergic receptors. Glycine therefore has two opposite effects in MVe 2°VN: first, it augments the depolarizing effect of glutamate through the glycinergic, strychnineinsensitive modulatory site of the NMDA receptors (see preceding paragraph). Second, glycine hyperpolarizes these cells through their strychnine-sensitive receptors. Functional Considerations Glycine and GABA mediate the effect of at least three inhibitory afferents of the vestibular neurons: (a) the cerebellar Purkinje cells use GABA as their main neuromediator (Sato and Kawasaki, 1991, de Zeeuw and Berrebi, 1996); (b) a commissural pathway links the two medial vestibular nuclei in mammals, through local inhibitory interneurons (the type II neurons). The type II interneurons are activated by contralateral excitatory MVe 2°VN (Shimazu and Precht, 1966). Type II interneurons are both GABAergic and glycinergic (Precht et al., 1973; Furuya et al., 1991); and (c) some GABAergic inferior olive neurons project to the contralateral vestibular complex (Matsuoka et al., 1983). In addition, as seen above, glycine could be colocalized with glutamate and/or aspartate in some of the large-diameter 1°VN (Straka et al., 1995a, 1995b in frog). The GABAA and GABAB receptors of the vestibular neurons play a key role in the control of gaze in the rat (Reber et al., 1996). For instance, commissural i­nhibition mediated by GABAergic interneurons is a key component of the velocity storage integrator included in vestibulo-oculomotor pathways and is a determinant ­ in the regulation of the HVOR gain (Galiana and Outerbridge, 1984; Katz et al., 1991). Perfusions of the ­vestibular nuclei with agonists or antagonists of the GABAA or GABAB receptors provoke a postural and oculomotor syndrome and alter the gain of the horizontal VOR. Systemic injections of baclofen, a GABAB agonist, disable the velocity storage integrator (Cohen et al., 1987; Niklasson et al., 1994 in the rat). Finally, the GABAergic cerebellar Purkinje cells are known to be instrumental in the adaptation and habituation of the horizontal VOR.

Cholinergic Neurotransmission Two types of cholinergic receptors have been described in the central nervous system: nicotinic and muscarinic receptors. The nicotinic receptors are ionotropic receptors, which include a cation channel. The metabotropic, muscarinic receptors act through G proteins and second messenger systems.

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Anatomical Evidence Only a few vestibular neurons appear to be cholinergic in rats (Zanni et al., 1995; Fukushima et al., 2001 and de Waele et al., 1995 for a review). In rabbits, cholinergic 2°VN project to the flocculus, the nodulus and the dorsal cap of the inferior olive. Cholinergic vestibulo-spinal neurons have been detected in the rat, mainly in the lateral vestibular nuclei (Jones et al., 1986). In contrast, nicotinic and muscarinic receptors are abundant in all vestibular nuclei and particularly in the medial vestibular nucleus (Zanni et al., 1995 Dominguez del Toro, 1994 in the rat). Moreover, vestibular nuclei display choline acetyltransferase (ChAT) activity, especially in the rat medial vestibular nucleus (Burke and Fahn, 1985). The origin of the cholinergic innervation of the vestibular nuclei remains to be determined. The afferent cholinergic neurons may be located within the vestibular nuclei or in the pedunculopontine formation, the tegmental dorsal nuclei neurons and/or the contralateral inferior olive. Electrophysiological Evidence Nicotinic and muscarinic agonists depolarize MVe 2°VN. Nicotinic or muscarinic antagonists reversibly suppress this depolarization. These effects are mediated by postsynaptic receptors, since they persist in the presence of tetrodotoxin, or during perfusion of a low Ca2+/ high Mg2+-containing solution. Both muscarinic and nicotinic receptors regulate the rat MVe 2°VN spontaneous activity on brain slices (Ujihara et al., 1989; Phelan and Gallagher, 1992 in the rat). In vivo, systemic and microiontophoretic injections of acetylcholine, physostigmine (an inhibitor of acetylcholine-esterase) and muscarinic agonists result in an excitation of the lateral and medial vestibular neurons. In addition, synaptic transmission between the firstorder and 2°VN was facilitated by cholinergic agonists and not facilitated by muscarinic antagonists. Finally, an excitatory pathway linking the inferior olive to the lateral vestibular nucleus, is depressed following systemic injection of atropine, a muscarinic antagonist (Matsuoka et al., 1985). Behavioral Evidence Unilateral perfusion of the vestibular complex with muscarinic agonists in alert rodents induces a postural and oculomotor syndrome, which is the mirror image of the syndrome induced by unilateral labyrinthectomy (i.e., it results in a net excitatory effect on the vestibular neurons). Several studies also suggest that acetylcholine plays a key role in the compensation of the vestibular deficits. Belladonna alkaloids, which are known to have anticholinergic properties, are the oldest agents used for the prophylaxis of motion sickness (de Waele et al., 1995). Muscarinic receptors are also involved in the cerebellar

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control of the cat vestibulo-spinal reflex gain (Andre et al., 1995). In summary, several lines of evidence suggest that the cholinergic innervation of the vestibular nuclei has important behavioral consequences for the stabilization of gaze and posture. Why some 2°VN are glutamatergic while others are cholinergic remains to be determined.

Modulation of Central Vestibular Neurons by Monoamines The three catecholamines (dopamine, noradrenaline, and adrenaline), serotonin, and histamine are key modulators of large assemblies of neurons, particularly in relation to the different states of vigilance. Furthermore, dysfunctions of the aminergic systems are involved in major neurological disorders, such as schizophrenia or Parkinson’s disease. Monoaminergic modulation of the central vestibular system is likely to be important from a functional point of view. Two arguments support this hypothesis: first, the turnover rates of monoaminergic metabolites in the rat vestibular nuclei are important (Cransac et al., 1996) and second, several agonists and antagonists of the monoaminergic receptors are successfully used in clinical medicine to treat vertigo and motion sickness (for review, see Rascol et al., 1995) and to improve recovery following vestibular deficits (for review, see Smith and Darlington, 1994b). Histaminergic Modulation of the Vestibular System Morphological studies show that histaminergic neurons provide input to all rat vestibular nuclei (Takeda et al., 1987) with the largest projection in the medial and superior nuclei (Tighilet and Lacour, 1996 in cat). Guinea pig vestibular neurons also express H1 and H2 binding sites (Vizuete et al., 1997). In vitro recordings on brain slices demonstrate that histamine mainly depolarizes MVe 2°VN (Phelan et al., 1990; Wang and Dutia, 1995 in the rat; Serafin et al., 1993 in the guinea pig). In the rat, depolarization is mediated by H1 and H2 receptors, while it is only mediated by H2 receptors in the guinea pig (Serafin et al., 1993). In vivo studies indicate that the medial and lateral vestibular nuclei neurons are both inhibited or excited by histamine or histaminergic agonists. In particular, the oculomotor and postural syndromes induced in the guinea pig by unilateral perfusion of the H3 agonist, strongly suggest that: (a) histaminergic fibers projecting to the vestibular nuclei carry presynaptic H3 receptors (Yabe et al., 1993); and (b) the vestibular nuclei neurons are tonically excited in the awake state by histaminergic input. In the rat, histaminergic modulation appears to play an important role during compensation for a unilateral labyrinthectomy (Horii et al., 1993) or in response to multisensory conflicts inducing motion sickness (Takeda

et al., 1993). It is therefore not surprising that histaminergic ligands are widely used in patients for the symptomatic treatment of vertigo and motion sickness (Rascol et al., 1995). In this regard, H3 antagonists are particularly promising. In contrast to standard histaminergic agents, they do not induce drowsiness, an unwanted side effect of histaminergic drugs (Lin et al., 1990). Serotoninergic Modulation of the Vestibular System All vestibular nuclei are richly innervated by serotoninergic fibers, which probably originate in the dorsal raphe nucleus (Giuffrida et al., 1991). 5-HT1A, 5-HT1B and 5-HT2 receptors are expressed by vestibular neurons in the rat (Pazos and Palacios, 1985; Wright et al., 1995; Kia et al., 1996). Serotonin can both accelerate and decrease the MVe 2°VN spontaneous activity in rat brainstem slices (Johnston et al., 1993), with a predominance of excitatory effects. Intracellular recordings in guinea pig brainstem slices (Vibert et al., 1994) show that 80% of the MVe 2°VN are depolarized by serotonin. Interestingly, serotonin directly activates postsynaptic receptors in type B MVe 2°VN, whereas excitation of type A MVe 2°VN is mostly indirect. The depolarizing effect of serotonin can be reproduced (Johnston et al., 1993) by α-methyl-serotonin (a specific agonist of 5-HT2 receptors). However, it is only partly blocked by ketanserin (an antagonist of 5-HT2 receptors). Moreover, the depolarization is accompanied by a decrease of membrane resistance, as previously reported in the rat CNS (Andrade and Chaput, 1991). The serotoninergic binding site remains to be determined. In 15% of type A and type B MVe 2°VN, bath-application of serotonin induces a hyperpolarization, which is likely mediated through 5-HT1A receptors. In vivo, a microiontophoretic injection of 5-HT induces a short hyperpolarization, followed by a large depolarization, in rat lateral vestibular nucleus neurons. Medial and superior vestibular nuclei neurons exhibit: (a) excitatory responses likely mediated through 5-HT2 receptors; (b) inhibitory responses probably mediated through 5-HT1A receptors; and (c) biphasic responses. Finally, intra-cerebroventricular injection of serotonin increases the gain of the rat HVOR (Ternaux and Gambarelli, 1987). The functional raison d’être of the serotoninergic modulation remains to be determined. In vivo studies suggest that serotonin is more likely involved in setting the dynamic properties of the vestibular system rather than in controlling the resting discharge of the vestibular neurons (that is, the static reflexes). Dopaminergic Modulation of the Vestibular System Dopaminergic innervation of the vestibular nuclei was not observed with anatomical methods (Kohl and Lewis, 1987). On the other hand, morphological

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studies detected D2 receptors in the rat vestibular complex, mostly in the MVe (Yokoyama et al., 1994). This discrepancy remains to be clarified. Dopamine depolarizes MVe 2°VN in the rat (Gallagher et al., 1992) and the guinea pig, (Vibert et al., 1995b) whatever the type (type A, B or B+LTS MVe 2°VN). In the guinea pig, depolarization is accompanied by an increase in membrane resistance and is mediated through “D2-like” receptors (D2, D3 and D4). This atypical depolarization is the result of an indirect effect on the inhibitory interneurons contacting the recorded cells (as for the depolarization induced by GABA described above). Indeed, once synaptic transmission is blocked, dopamine has a weak postsynaptic, hyperpolarizing action on all types of MVe 2°VN. The interpretation is that dopaminergic agonists, by acting on presynaptic “D2-like” receptors, inhibit a spontaneous, tetrodotoxin-resistant, release of GABA in normal medium. In support of this hypothesis, following continuous perfusion of bicuculline in the bath, the depolarizing effects of dopamine are replaced by hyperpolarizing effects, as in synaptic uncoupling conditions. In vivo, systemic injections of L-DOPA increase the resting activity of vestibular neurons and microiontophoretic application of dopamine modulates the discharge of these cells. Dihydroergocristine, a non-specific dopaminergic agonist, reduces the nystagmus induced by unilateral labyrinthectomy in the guinea pig. This could explain why vestibular compensation is shortened by systemic injections of “D2-like” dopaminergic agonists (for review, see Vibert et al., 1995b). Noradrenergic Modulation of the Vestibular System Immunohistochemical tracing studies have revealed that noradrenergic neurons of the locus coeruleus project over all the vestibular complex, with a predominance in the rat SVe and LVe (Schuerger and Balaban, 1993 and 1999). Morphological studies have also revealed that vestibular neurons were endowed with β and α2 receptors. β receptors are abundant in the lateral and superior subnuclei and α2 receptors in the MVe (Rosin et al., 1996; Talley et al., 1996). In situ hybridization methods have also demonstrated the presence of α1, α2A and α2C receptor subtypes in all vestibular nuclei (for review, see de Waele et al., 1995). In vitro recordings in guinea pig brainstem slices confirm these anatomical data (Vibert et al., 1994). Noradrenaline depolarizes half of MVe 2°VN and decreases their membrane resistance. Type A MVe 2°VN are less sensitive than type B or B+LTS MVe 2°VN. On the other hand, noradrenaline hyperpolarizes one-fifth of the MVe 2°VN. Isoproterenol (β receptor agonist) depolarizes about 60% of MVe 2°VN, decreasing their membrane resistance. L-phenylephrine (an α1 receptor agonist) also depolarizes about 60% of MVe 2°VN but increases their membrane resistance. Finally, clonidine (α2 receptor

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agonist) hyperpolarizes most MVe 2°VN and decreases their membrane resistance. While the clonidine effect is direct (it persisted in conditions of synaptic uncoupling), most of the depolarizing responses are indirect (they are modified when synaptic transmission is blocked). For instance, α1-mediated effects could not be shown in synaptic uncoupling conditions indicating that these receptor are probably presynaptic in the vestibular nuclei. In vivo, rat LVe and SVe neurons are inhibited by noradrenaline through the activation of α2 receptors (Licata et al., 1993). On the other hand, microiontophoretic injections of noradrenaline in the vestibular nuclei of cerebellectomized cat increases LVe neuron firing rate (de Waele et al., 1995). It is also interesting that vestibular and cervical proprioceptive stimulations modulate locus coeruleus neuron activity (Pompeiano et al., 1990). Furthermore, noradrenergic agonists and antagonists have been shown to modify the dynamic properties of the vestibulo-spinal and vestibulo-ocular reflexes (for review, see Pompeiano, 1989; Pompeiano et al., 1994). The noradrenergic system is therefore likely to regulate the adaptive capabilities of these reflexes (McElligott and Freedman, 1988). Functional Speculations Histamine and dopamine modulate the excitability of both type A and B MVe 2°VN neurons. Histamine is likely to modulate the activity of vestibular neurons according to vigilance state. Dopamine could control the tonic inhibition, which controls vestibular nuclei activity. In particular, dopamine could be crucial to regulate the commissural pathways linking the two vestibular nuclei and in turn the processing of vestibular information and the resting discharge of the vestibular neurons (static reflexes). Serotonin and noradrenaline are more potent on type B and B+LTS neurons. Hence, they possibly modulate the dynamic properties of the vestibular system. Serotonin may increase the responsiveness of the vestibular system to external stimulations and could be linked to arousal. Finally, noradrenaline would be fitted to tune the VOR and vestibulo-spinal reflexes according to various task requirements.

Neuropeptides in the Central Vestibular Network Somatostatin (or SRIF), the opioid peptides, adrenocorticotropin (ACTH) and substance P modulate the activity of central vestibular neurons through specific, metabotropic receptors (for reviews, see Balaban et al., 2000; de Waele et al., 1995). Vestibular neurons have also been shown to be sensitive to specific growth factors, even in adult animals. However, large species differences are observed among mammals concerning the neuropeptides, their receptors and their effect (Gehlert and Gackenheimer, 1997).

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Somatostatin Somatostatin acts as a neurotransmitter in the central nervous system. Five types of somatostatin receptors, SST1–5, have been identified. They modulate neuronal activity through cAMP, G protein, Ca2+ and/or K+ channels (for review, see Reisine and Bell, 1995). Somatostatin immunoreactive cell bodies and fibers are present in all the vestibular nuclei, with a predominance in the periventricular MVe. High affinity somatostatin SST3 (Thoss et al., 1995) and SST4 (Selmer et al., 2000) receptors have also been detected in the vestibular nuclei of the rat. Intraventricular injection of somatostatin induces body rotations around the longitudinal axis (barrel rotations) that are blocked by intrasystemic injection of anti-muscarinic drugs (a suggestion of its indirect effect). In vivo microiontophoretic injection of somatostatin depresses the resting discharge of rabbit LVe neurons. In addition, Purkinje cells, which inhibit vestibular neurons, are somatostatin-immunoreactive and may release somatostatin together with GABA (for review, see Balaban et al., 2000). Finally, somatostatinimmunoreactive neurons can be found in the vestibular ganglion cells of rabbits (Won et al., 1996), which suggests that somatostatin might regulate transmission between the first- and 2°VN. Opioid Peptides Three classes of endogenous opioid peptides have been recognized: the enkephalins, the β-endorphins and the dynorphins. The δ (OP1), κ (OP2) and μ (OP3) receptors are preferentially activated by the enkephalins, the dynorphins and β-endorphins, respectively. In the brain, opiate receptors often activate inwardly-rectifying potassium channels, through adenylate-cyclase inhibition, or block voltage-dependent calcium channels. As a rule they are mostly inhibitory (for review, see Dhawan et al., 1997). Enkephalin-immunoreactive cell bodies and enkephalin terminal endings have been described in the vestibular nuclei (Zanni et al., 1995 in the rat). Preproenkephalin (the precursor of Met- and Leu-Enkephalin) mRNA positive cells were also reported in the medial and lateral vestibular nuclei. Interestingly, the MVe contains the highest density of enkephalinergic neurons of all the central nervous system. Dynorphin immunoreactive sites have also been reported in the LVe and MVe. Finally, rat 2°VN expressed both μ and δ receptors, but only a few κ receptors (Mansour et al., 1994; Zastawny et al., 1994). The endogenous opioid peptide orphanin FQ (or nociceptin) has also been detected in the central vestibular nuclei (Neal et al., 1999). In vitro, morphine (a selective agonist of μ receptors), met-enkephaline and [D-Ala2]leu-enkephalin (a selective agonist of δ receptors) increase the activity of about a third of the medial vestibular neurons (Carpenter and

Hori, 1992; Lin and Carpenter, 1994) by activation of postsynaptic receptors. Naloxone (a specific antagonist of μ and δ receptors) suppresses these excitatory effects and the activity increase resulting from bath-application of acetylcholine. It was therefore hypothesized that cholinergic and opioid receptors could interact in vestibular neurons. A study by Sulaiman et al. (1999) has finally demonstrated that orphanin FQ (nociceptin) was able to modulate vestibular function both on in vitro and in vivo preparations. In vivo, microiontophoretic injections of morphine and enkephalins mainly increase the discharge of medial vestibular neurons (Iasnetsov and ­Pravdivtsev, 1986), while leu- and met-enkephalin decrease the resting discharge of lateral vestibular nuclei neurons. ­Met-enkephalin is believed to be a neurotransmitter in the cerebello-vestibular pathways, like somatostatin. In contrast, leu-enkephalin is usually considered a neuromodulator of vestibular function. The very high density of enkephalinergic neurons in the vestibular nuclei could be explained by the existence of a built-in defense system against motion sickness and vertigo: naloxone (an opiate antagonist) enhances the incidence of motion sickness (for review, see de Waele et al., 1995). Substance P and the Tachykinins Three types of endogenous tachykinins have been identified in the central nervous system: Substance P, Neurokinin A and Neurokinin B, which preferentially activate the NK1, NK2 and NK3 receptors, respectively. Substance P immunoreactive fibers and terminal endings (as well as a few immunoreactive neurons) have been detected within the vestibular nuclei, predominantly in the caudal medial and inferior vestibular nuclei (Vibert et al., 1996, in the guinea pig). These fibers could originate from the brainstem reticular formation and from the vestibular nerve itself. Numerous 1°VN are substance P-immunoreactive in the frog, rabbit, guinea pig, cat, squirrel monkey and in man (Felix et al., 1996). These neurons innervate the utricular and saccular maculae in rabbits and the base of the cristae and the peripheral part of the otolithic maculae in guinea pigs. Therefore, substance P is probably co-localized with glutamate in the thinnest (tonic, regular) vestibular afferents (Usami et al., 1995). In this context, it is curious that in situ hybridization studies have demonstrated only a few, NK-1 receptors in the MVe of rats (Maeno et al., 1993). However, unidentified “substance P receptors” were detected in all rat vestibular nuclei (Nakaya et al., 1994). In guinea pig brainstem slices, substance P depolarized about two thirds of MVe neurons by activating atypical postsynaptic substance P receptors (Vibert et al., 1996). In vivo, intra-systemic injection of substance P accelerates the recovery from postural deficits following unilateral labyrinthectomy.

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Adrenocorticotropin (ACTH), Growth Factors and Other Neuropeptides An in vitro slice study has shown that ACTH depresses the resting discharge of MVe neurons. In vivo, intrasystemic injections of ACTH improve the compensation of the postural and oculomotor syndromes following unilateral labyrinthectomy (for review, see ­Darlington et al., 1996). The ACTH fragment 4–9 appears to be crucial for this effect (Gilchrist et al., 1996). NGF receptors have been detected in the MVe and SpVe, mostly at the borders with the prepositus hypoglossi nucleus (Sukhov et al., 1997). This is interesting because there is increasing evidence that neurotrophic peptides are involved in neuronal plasticity (for review, see Thoenen, 1995). Finally, other types of neuropeptides and neuropeptide receptors have been detected in neurons and/ or terminals within the vestibular nuclei. Fibers positive for neuropeptide Y, neurotensin, vasoactive intestinal peptide (VIP) and cholecystokinin likely innervate vestibular nuclei. Thyrotropin releasing hormone (TRH) and neurotensin receptors have also been described in the vestibular nuclei (Zanni et al., 1995).

Presence of Purine Receptors in the Vestibular Nuclei Adenosine-5′-triphosphate (ATP) is a provider of energy to neurons. ATP also interacts with several membrane receptors and modulates neuronal activity. Seven types of ionotropic receptors (the P2X receptors) and six types of metabotropic receptors (the P2Y receptors) activated by ATP have been described. In addition, several subtypes of P1 receptors sensitive to adenosine have been identified. ATP usually has an excitatory effect on rat neurons (Gu and MacDermott, 1997). Rat MVe 2°VN are sensitive to ATP and are endowed with P2X and P2Y purine receptors (for review, see Chessell et al., 1997). P2 receptor agonists increase, in a dose-dependant manner, the spontaneous discharge of one third of the MVe 2°VN tested in rat brainstem slices and P2 antagonists suppressed this effect.

Vestibular Pharmacology Update Overview A comprehensive review of the pharmacology of the central vestibular system was presented in 2004 (Vidal and Sans, 2004). It has been summarized above so we now focus on more recent studies. While the older literature established neurotransmitter phenotype or pharmacology of groups of vestibular neurons, recent studies are concerned with pinpointing the pharmacological interactions between identified central vestibular neurons and their inputs in defined circuits. This

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approach is hampered by the lack of sharp boundaries and spatial intermingling of different vestibular neuron classes, although some vestibular neuron classes show regional segregation (Malinvaud et al., 2010). Identifying or marking vestibular neuron classes is achieved with a variety of experimental approaches, including the study of: (1) morphologically distinctive vestibular neurons—the principal cells of the chick tangential nucleus (TN), a homolog of the vestibular nuclei, which are characterized by distinctive oval somata, and aligned in rows between parallel bundles of primary vestibular fibers near the lateral surface of the medulla oblongata (Peusner et al., 2012); (2) neurons retrogradely-labeled by delivery of fluorescent dyes into their target nucleus (Bagnall et al., 2007; M ­ alinvaud et al., 2010; GottesmanDavis et al., 2011; Kolkman et al., 2011; Shin et al., 2011); (3) neurotransmitter phenotyping of patch-clamped neurons by performing a single-cell reverse transcription–polymerase chain reaction (RT-PCR, Takazawa et al., 2004); and (4) t­ransgenic mice with genes marked according to neurotransmitter phenotype (Bagnall et al., 2007; Shin et al., 2011; Kodama et al., 2012). Excitatory Amino Acid Neurotransmitters The following account focuses on the important role of AMPA receptors in generating fast synaptic transmission and synaptic plasticity in vestibular nucleus neurons. Immunolabeling Studies Mature functional glutamatergic synapses are characterized by the presence of AMPA receptors concentrated at their postsynaptic densities. AMPA receptors are expressed ubiquitously in the brain. Native AMPA receptors are composed of GluR1, GluR2, GluR3, and GluR4 receptor subunits, each of which contributes to the pharmacological properties and kinetics of the AMPA channel. There is a general pattern of AMPA receptor expression on 2°VN which does not change in different species (Popratiloff et al., 2004), with GluR2/3 and GluR4 predominating, and GluR1 and GluR2 playing minor roles). Using confocal microscopy, AMPA receptor immunolabeling was quantified for each subunit in TN principal cell bodies in 9-day-old hatchling chickens (H9). High levels of GluR4 are associated with rapid AMPA channel kinetics and fast desensitization (Gardner et al., 1999). In adult rat vestibular nuclei, more neurons are labeled with GluR2 than GluR4 (Rabbath et al., 2002). However, a cellular level of analysis was not performed, so the results are not directly comparable to the TN study. Finally, expression of AMPA receptors in the somatic cytoplasm does not invariably confer surface expression (Shao et al. 2012a). Thus, AMPA receptor surface expression remains to be characterized on vestibular nuclei neurons.

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Electrophysiological Studies In most sensory systems, evoked synaptic transmission is known to play a key role in establishing and maintaining functional circuits, but the significance of small amplitude, spontaneous synaptic events has been more elusive. In mature neurons, spontaneous synaptic events have been found to provide sufficient excitatory synaptic drive to generate spike activity, or inhibitory drive to modulate vestibular nucleus neuron output (Shao et al., 2006a). Besides their important function in the neural circuitry, spontaneous synaptic events offer a valuable experimental tool to study the excitatory and inhibitory nature of inputs contacting recorded neurons in brain slice preparations. For example, in voltage-clamp recordings at −60 mV, excitatory events are inward currents, whereas at +10 mV, inhibitory events are outward currents, allowing the events to be distinguished and quantified. Concerns have been raised that, since some axons contacting the recorded neurons are transected during slice preparation, the frequencies measured are lower than in vivo. To deal with this, tetrodotoxin (TTX) is added to the brain slice to block activity-dependent events, so that miniature excitatory (mEPSCs) and inhibitory synaptic events (mIPSCs) are recorded, and the frequency of these events provide a good estimate of the number of inputs contacting the recorded neuron. Finally, neurotransmitter blocking agents are added to the brain slices to determine the glutamatergic, GABAergic, or glycinergic nature of the activity. Thus, key features of the vestibular neural circuitry can be established from recording spontaneous synaptic events, and changes in the circuitry can be identified after peripheral vestibular lesions, known as “vestibular compensation.” Normal brain function depends on CNS neurons establishing and maintaining a balance between excitatory and inhibitory inputs, with imbalance resulting in a major neurological disorder (e.g., Naylor, 2010; Gajcy et al., 2010). At post-hatch day 7 (H7), chick TN principal cells display a 1:4 ratio between excitatory (EPSC) and inhibitory (IPSC) postsynaptic currents, which is established gradually during development (Shao et al., 2003, 2004, 2006b). Unilateral vestibular deafferentation destroys the balance by removing the major excitatory input to vestibular nucleus neurons. Vestibular compensation is thought to involve synaptic plasticity of non-primary vestibular inputs. For example, after unilateral vestibular ganglionectomy (UVG) performed at H4, chickens display severe symptoms at rest immediately after surgery, which start to recover in 52% of the chickens after 3 days (Aldrich and Peusner, 2002; Shao et al., 2009, 2012a, 2012b). Both excitatory and inhibitory events undergo changes in frequency and kinetics in principal cells during the first 3 days post-lesion (Shao et al., 2009, 2012b). EPSC frequency increases in principal cells on

the lesion side 1 day after UVG and remains elevated at 3 days post-lesion in the uncompensated chickens only. The increased EPSC frequency could be related to decreased expression of the voltage-dependent potassium channel, Kv1.2, in terminals contacting the principal cells (Shao et al., 2009). In rat auditory brainstem nuclei, decreased Kv1.2 increases excitatory neurotransmitter release (Dodson et al., 2003). Also, the kinetics of the events change after lesions, with slower mEPSC decay time on the lesion side 3 days after UVG in all operated chickens. Higher levels of GluR2 (Geiger et al., 1995) or lower levels of GluR4 (Zhou et al., 2009) could produce slower mEPSC decay time. Since simultaneous changes in the frequency and kinetics of spontaneous synaptic events can occur within the same neuron and appear to cancel each other, the overall effect on neuron excitability may be uncertain. Synaptic charge transfer offers a valuable tool to evaluate the overall effect of changes in spontaneous synaptic events by integrating all the deviations from baseline generated in one neuron within a set period. For example, excitatory synaptic charge transfer is significantly higher in principal cells on the lesion side compared to the intact side of uncompensated chickens 3 days after UVG, and tends to be higher in principal cells on the lesion side 1 day after the lesion. However, excitatory synaptic charge transfer is balanced bilaterally in principal cells of compensating chickens 3 days after UVG. Thus, increased frequency of excitatory spontaneous synaptic events on the lesion side may be the first step to counter the loss of excitatory input from the primary vestibular fibers, with the second step directed toward achieving balanced excitatory synaptic drive bilaterally for recovery to proceed. Inhibitory Amino Acid Neurotransmitters Gamma-amino-butyric acid (GABA) is the main inhibitory neurotransmitter in the adult brain with multiple important and diverse functions during development (Ben-Ari, 2002) and after lesions in sensory systems (for review, see Caspary et al., 2008). The importance of inhibitory synaptic transmission in the vestibular nuclei has been known since the concept of the vestibular reflex circuitry first emerged, with inhibitory vestibular nucleus neurons forming fundamental components of commissural inhibition, the reciprocal inhibitory connection between neurons participating in the vestibular reflex pathways (Szentagothai, 1950; Furuya et al., 1992). While GABA prevails as the main inhibitory neurotransmitter in rostral brain regions, glycine plays an important role in more caudal brain regions and the spinal cord. However, GABA and glycine may be found in the same brain region, and even in the same neuron (e.g., Ottersen et al., 1988).

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IMMUNOLABELING STUDIES

Neurons positive for GABA and its synthesizing enzyme, glutamic acid decarboxylase (GAD), are scattered throughout the rat vestibular nuclei (Nomura et al., 1984; de Waele et al., 1994; Zanni et al., 1995), guinea pig (Dupont et al., 1990), rabbit (Blessing et al., 1987), cat (Walberg et al., 1990; Tighilet and Lacour, 2001), frog (Reichenberger et al., 1997), mouse (Bagnall et al., 2007), and monkey (Holstein et al., 1996; Holstein et al., 1999a, 1999b). Altogether, GABAergic vestibular nuclei neurons may be classified into five categories based on their axonal output: (1) neurons contributing to commissural inhibition; (2) neurons projecting to the oculomotor and trochlear nuclei; (3) neurons in MVe and SpVe that project to the inferior olivary nucleus; (4) neurons in the rostral MVe and LVe projecting to spinal cord in the medial vestibulospinal tract; and (5) local interneurons with axons ipsilateral to their cell bodies (Gliddon et al., 2005). Less is known about the distribution and function of glycinergic neurons in the vestibular nuclei, with the exception of the well-established glycinergic MVe neurons projecting to the ipsilateral abducens nucleus (Spencer et al., 1989). Nonetheless, a considerable number of glycinergic neuron cell bodies are present in all the vestibular nuclei (Walberg et al., 1990). GABA and glycine immunolabeling has been performed on the chick TN at H5-H7 using fluorescence detection and confocal imaging (Popratiloff and Peusner, 2011). GABA is the predominant inhibitory neurotransmitter, labeling most longitudinally-coursing fibers in transverse sections and >50% of all synaptic terminals. A few horizontal GABAergic fibers were detected. GABA synapses terminated mainly on dendrites in the TN. In contrast, glycine labeling represents about a third of all synaptic terminals, and originates from horizontallycoursing fibers in the tangential nucleus. A distinct pool of glycine-positive terminals usually surrounds the principal cell bodies. While no GABA or glycine-positive neuron cell bodies are observed in the TN, several pools of immunopositive neurons are found in the neighboring vestibular nuclei, mainly in the SuVe and SpVe. Altogether, GABA and glycine have distinct and separate origins and display contrasting subcellular termination patterns which underscore their discrete roles in vestibular signal processing in the TN. In transgenic mouse lines, MVe neurons labeled by their neurotransmitter phenotype, and labeled with α-calbindin, were visualized using confocal microscopy to determine whether they receive GABAergic inputs from floccular Purkinje cells (Shin et al., 2011). Glutamatergic neurons projecting to the ipsilateral oculomotor nucleus and glycinergic neurons projecting to the ipsilateral abducens nucleus received dense somatic inputs from Purkinje cells; whereas glutamatergic neurons

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projecting to the contralateral abducens nucleus, glycinergic neurons projecting to the ipsilateral abducens nucleus, and GABAergic neurons projecting to the contralateral vestibular nuclei, received sparse inputs from Purkinje cells. Altogether, MVe neurons involved in different vestibular neural circuitries received variable numbers of GABAergic inputs from Purkinje cells, or none at all, emphasizing the importance of defining the detailed neural circuitry in which specific vestibular neurons participate. To identify the vestibular nuclei neurons contributing to the inhibitory vestibular commissural pathway, fluorescent tracers were placed on the midline or in the vestibular nuclei at different rostral-caudal levels of the isolated frog brainstem (Malinvaud et al., 2010). Commissural neurons were organized into two main clusters, a large rostral group in the SuVe and MVe, and a smaller caudal group in the MVe and SpVe. Axons crossed the midline in broad bundles at the level of the cell bodies of origin, which are small- to medium-sized and oval to round in shape. There were few or no commissural neurons between the two LVe, although the LVe received substantial numbers of commissural inputs from all other vestibular nuclei. Finally, the commissural neurons in the rostral SuVe/MVe were GABA-positive and resided among other GABAergic vestibular nucleus neurons. No glycinergic commissural neurons were detected in these preparations. ELECTROPHYSIOLOGICAL STUDIES

In many species, GABA-mediated inhibition plays a crucial role in regulating vestibular signal processing, with vestibular nuclei neurons receiving massive GABA­ ergic input from the cerebellum, contralateral vestibular nuclei, inferior olivary nucleus and local interneurons (de Waele et al., 1995; Highstein and Holstein, 2006). Both GABAA and presynaptic and postsynaptic GABAB receptors are expressed in mammalian vestibular nuclei (Holstein et al., 1992; Gallagher et al., 1992; Vibert et al., 1995b,c; Eleore et al., 2005; Gliddon et al., 2005; HeskinSweezie et al., 2010). Inhibitory spontaneous synaptic events undergo major changes during vestibular compensation, but they follow a delayed time course compared to the excitatory events (Shao et al., 2012b). IPSC frequency increases significantly in TN principal cells on the lesion side 3 days after UVG in both compensating and uncompensated chicken. Increased IPSC frequency is primarily due to increased GABAergic events, while the frequency of glycinergic events remains unchanged. Increased GABAergic frequency is accompanied by faster decay time on the lesion side, so that inhibitory synaptic charge transfer remains balanced bilaterally in compensating and uncompensated chickens 3 days after UVG. Thus, balanced inhibitory

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synaptic drive bilaterally is insufficient to promote vestibular compensation in uncompensated chickens. Both excitatory and inhibitory synaptic drive must be balanced bilaterally for vestibular compensation to proceed. The factors responsible for increased GABAergic IPSC frequency and faster decay time in TN principal cells on the lesion side have not been identified, and the role of the changes in recovery of function is uncertain. In the cat, an increased number of GABApositive neurons and terminals were found throughout the vestibular nuclear complex on the lesion side 3 days after UVG (Tighilet et al., 2007), which could be responsible for generating increased GABAergic IPSC frequency. In the rat, GABA neurotransmitter release from commissural inputs onto MVe neurons increased on the lesion side shortly after unilateral labyrinthectectomy (UL) (Bergquist et al., 2008). A faster decay time of IPSCs in principal cells is consistent with finding decreased sensitivity to GABAA receptor agonists in rat and guinea pig MVe neurons on the lesion side after UL (Yamanaka et al., 2000; Vibert et al., 2000). Finally, there is no evidence for changes in glycinergic mIPSC frequency in chick TN principal cells from any experimental group after UVG, although significant fluctuations in amplitude and decay time of the events were recorded (Shao et al., 2012b). Behavioral studies support an important role for GABAB receptors in vestibular compensation, since systemic injection of baclofen, a specific GABAB agonist, decreases spontaneous nystagmus in rats after UL (Magnusson et al., 2000, 2002) and accelerates recovery of postural reflexes in mice (Heskin-Sweezie et al., 2010). However, baclofen generates no postsynaptic currents in TN principal cells from controls, with weak GABABR2 immunolabeling detected on principal cell surfaces (Shao et al., 2012a). In contrast, baclofen decreased mEPSCs and GABAergic mIPSC frequencies in TN principal cells from controls, compensating any uncompensated chickens 3 days after UVG, indicating the presence of functional GABAB receptors on presynaptic terminals. Baclofen decreased GABAergic mIPSC frequency to the greatest extent in principal cells on the intact side of compensating chickens. In uncompensated chickens, baclofen decreased mEPSC frequency to the greatest extent in principal cells on the intact side. Altogether, these results reveal that presynaptic GABAB receptor function is different in compensated and uncompensated chickens. The study supports an important role for GABAB autoreceptormediated inhibition in vestibular nucleus neurons on the intact side during early stages of compensation, while GABAB heteroreceptor-mediated inhibition of glutamatergic terminals plays an important role on the intact side in the failure to recover in uncompensated animals.

Monoaminergic and Neuropeptidergic Neurotransmitters Monaminergic neurotransmitters play a critical role in modulating central vestibular networks, since many agonists and antagonists of these receptors form the mainstay for clinical treatment of vertigo, motion sickness and symptoms of vestibular lesions (for review, see Soto and Vega, 2010). For example, antihistamines are prescribed for motion sickness, methylprednisolone, a glucocorticoid receptor agonist, is the standard treatment for vestibular neurititis, and betahistine, a histamine H1 agonist and H3 receptor antagonist, is prescribed to treat symptoms resulting from peripheral vestibular lesions (Hain and Yacovino, 2005). Despite long-term use, the role of monoaminergic neurotransmitters in modulating central vestibular circuitries is uncertain. To date, studies on the action of monoaminergic neurotransmitters are focused on characterizing their effects on groups of vestibular neurons. HISTAMINE

H3 receptors act as autoreceptors on histaminergic terminals and heteroreceptors inhibiting neurotransmitter release on other types of terminals (Bergquist et al., 2006). Betahistine and the H3 receptor antagonist, thioperamide, decrease the initial symptom of barrel-rolling in rats after UL. Using HPLC to measure neurotransmitter release from the rat MVe in brain slices after exposure to high potassium solution to stimulate the neurons, histamine agonists selectively decrease GABA release through presynaptic H3 receptors acting on GABAergic terminals and presynaptic H1/H2 receptors acting on glycinergic terminals (Bergquist et al., 2006). HPLC shows neurotransmitter release from the entire MVe, leaving open the question of which vestibular neurons are involved in the activity. NORADRENALINE

Locus coeruleus contains noradrenergic neurons, which project to all rat vestibular nuclei, but predominantly to SuVe and LVe. Vestibular nucleus neurons contain α2 or β noradrenergic receptors. Noradrenaline modulates glutamatergic synaptic transmission in diverse CNS regions. When noradrenaline, or its agonists or antagonists, is microiontophoresed onto rat vestibular nucleus neurons, single unit recordings show increased or decreased firing rates when glutamate is added (Barresi et al., 2009). Typically, glutamatergic responses were decreased when recorded from the SuVe, MVe or LVe, which likely involve β receptors, whereas firing rates were increased when recorded from the SpVe where noradrenaline likely operates through α2 receptors. Microiontophoresis does not allow identification of the neurons involved, the relative contribution of different receptors, or the presynaptic or postsynaptic actions of the receptors.

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Vestibular Pharmacology

NEUROSTEROIDS

In the brain, neurosteroids can modulate synaptic transmission and neuronal activity by acting on neurotransmitter receptors or ion channels. Neurosteroids can be produced locally from circulating corticosteroids and progesterone. Their production is increased under stress conditions (for review, see Saman et al., 2012). In addition, vestibular nuclei neurons contain enzymes to synthesize steroids. After vestibular nerve stimulation, extracellular field potentials and spontaneous spike firing rates in rat MVe neurons were studied from brain slices on exposure to neurosteroids (Grassi et al., 2007b, 2010b). Neurosteroids influence MVe neurons by two separate mechanisms, acting through AMPA receptors to increase activity in a few minutes, or acting through GABAA receptors to decrease activity after 20–30 mins. OREXIN (HYPOCRETIN) NEUROPEPTIDE

In the late 1990s, neurons producing orexin were identified in the lateral hypothalamus and shown to form widespread axonal projections throughout the brain. Since orexin deficiency produces cataplexy, a motor disorder resulting from loss of muscle tone, the effect of orexin on rat LVe neurons was studied using RTPCR (Zhang et al., 2011). Orexin receptor mRNAs were found in the LVe, and immunofluorescence revealed that orexin receptors were present in large LVe neurons. In whole-cell patch-clamp recordings, orexin generated an inward current in rat LVe neurons in brain slices. Finally, when orexin is injected into the LVe in living rats, the animals showed postural deficits, including head tilt to the contralateral side and extension of the ipsilateral extremities, related to the excitatory action of orexin on LVe neurons. NEUROTROPHINS

Neurotrophins are a family of growth factors related to nerve growth factor, NGF, and found within the central and peripheral nervous system. Neurotrophins can be produced by muscle cells and retrogradely transported to motor neuron cell bodies with neurotrophin receptors. During development, neurotrophins, including brain-derived neurotrophic factor, BDNF, and neurotrophin-3, NT-3, are essential for neuron survival. In the mature cat, BDNF and NT-3 are involved in recovery of spike firing and synaptic plasticity in abducens motor neurons after transection of the abducens nerve (DavisLopez de Carrizosa et al., 2009). When the abducens nerve stump is exposed to BDNF and NT-3 shortly after transection, synaptic remodeling on the motor neurons is prevented. On exposure to neurotrophins, after loss of presynaptic inputs has occurred, abducens motor neurons recover their synaptic inputs and tonic spike firing upon exposure to BDNF, while phasic firing is generated upon exposure to NT-3. Thus, BDNF and NT-3 together

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play critical roles in retaining presynaptic inputs and recovery of spike firing in abducens motor neurons after axotomy.

Vestibular Pharmacology Summary Vestibular pharmacology is summarized in Fig. 11. The cell bodies of primary vestibular afferent fibers are located in Scarpa’s ganglion. Chemoanatomical, physiological and pharmacological data in a variety of vertebrate species including the rat indicate that the principal neurotransmitter utilized by these cells is glutamate (Yamamoto et al., 1978; Raymond et al., 1984; R ­ eichenberger and Dieringer, 1994; Takahashi et al., 1994; Straka et al., 1995a; Grassi et al., 2001; Nagy et al., 2013). Glycine has also been detected immunocytochemically in 10–20% of the primary afferent neurons in the rat (Reichenberger and Dieringer, 1994; Straka et al., 1996). These latter cells have larger diameters than those containing glutamate alone, whereas the largest diameter ganglion cells and afferent fibers co-localize glutamate and glycine. However, the exact role of glycine in rodent afferent neurotransmission has yet to be clarified, and is likely to be modulatory, since vestibular nerve input to vestibular nuclear neurons has consistently been shown to be excitatory. Several other neuromodulators and marker proteins have been observed in vestibular ganglion cells and afferent fibers including peripherin, substance P, and the calcium binding proteins parvalbumin, calbindin-D28k, and calretinin (Desmadryl and Dechesne, 1992; Kevetter, 1996; Kevetter and Leonard, 1997; Lysakowski et al., 1999; Desai et al., 2005a, 2005b), as have various voltage-gated ion channels (Lysakowski et al., 2011). Vestibular ganglion cell heterogeneity is also reflected in the intrinsic membrane properties of these cells recorded in vitro (for review, see Eatock and Songer, 2011). In the vestibular nuclear complex, the most prevalent excitatory neurotransmitter is glutamate or a closely related amino acid. Neurons containing transmitter levels of glutamate or aspartate have been identified immunocytochemically in all four main vestibular nuclei of the rat, including the large Deiters’ neurons (for reviews, see Holstein, 2012). The inhibitory amino acids γ-aminobutyric acid (GABA) and glycine are also present in these nuclear groups, where they co-exist and may even co-localize (Lu et al., 2008). Immunolabeling using antibodies against GABA or its synthetic enzyme glutamic acid decarboxylase (GAD) as well as in situ hybridization studies have revealed GABA-synthesizing neurons throughout the vestibular nuclei of many species, including rodents. While estimates of the number or density of these cells vary, most studies (e.g., de Waele et al., 1994; Holstein et al., 1999c) report more widespread labeling in SuVe and MVe, where GABAergic cells may constitute 33–43% of the total cell population. The GABAergic

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FIGURE 11  Abbreviations used in the schematic: III: oculomotor complex; IV: trochlear nucleus; VI: abducens nucleus; ACh: acetylcholine; EAAs: excitatory aminoacids; GABA: gamma aminobutyric acid; H-VOR: horizontal vestibulo-ocular reflex pathway; IAA-RP: imidazoleacetic acid ribotide; LVST: lateral vestibulospinal tract; MVST: medial vestibulospinal tract; V-Comm: vestibular commissural pathways; VSR: vestibulosympathetic reflex pathway; V-VOR: vertical vestibulo-ocular reflex pathways.

neurons of the vestibular nuclear complex (VNC) participate in several different functional pathways, including vestibular projections to oculomotor neuron pools, neurons mediating commissural inhibition, vestibuloolivary and vestibulo-spinal projection neurons, and local circuit neurons (for review, see Holstein, 2000). This widespread role is supported by electrophysiological and biochemical studies in mouse brainstem, which have

provided more direct evidence for GABAergic (Bagnall et al., 2007) as well as glutamatergic (Broussard, 2009) signal processing in the VNC. In contrast, some VNC neurons that receive a substantial input from the flocculus, the so-called “flocculus target neurons,” co-express both glutamate and glycine (Shin et al., 2011). This heterogeneity of VNC transmitter phenotypes was recently explored using single-cell expression profiling of mouse

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Vestibular Pharmacology

MVe neurons (Kodama et al., 2012). Three excitatory (designated E1-3) and three inhibitory (I1-3) cell types were distinguished in this study. The E1 group comprises large glutamatergic cells, functionally described as position-vestibular-pause (PVP) neurons, with projections to contralateral oculomotor nuclei critical for mediating the VOR. The E2 cells are also glutamatergic, but project primarily to the cerebellar cortex. The role(s) of E3 glutamatergic cells are not yet known, but they may participate in vestibulo-sympathetic projections. As suggested by prior immunolabeling studies in rats (Tanaka and Ezure, 2004; Lu et al., 2008), many of the inhibitory neurons identified by expression profiling in the mouse co-expressed markers for GABA and glycine. Nevertheless, the I1 cell group is predominantly glycinergic, receiving dense axo-somatic Purkinje cell input from the flocculus and projecting to ipsilateral abducens neurons. Most I2 cells receive axo-dendritic cerebellar input and project to the ipsilateral abducens nucleus, whereas the majority of I3 neurons are likely to be GABA­ergic, and to participate in the inhibitory component of the large vestibular commissural system. There are two major glutamatergic inputs to the vestibular nuclei: primary vestibular afferents and excitatory commissural fibers (for review, see Highstein and Holstein, 2006). The precise roles and distributions of ionotropic and metabotropic glutamate receptor subtypes in mediating these inputs remain to be characterized fully. The earliest research on this topic was conducted in the frog, and suggested that non-NMDA ionotropic receptors mediate the monosynaptic excitatory transmission from the VIIIth nerve to vestibular nuclear neurons (Cochran et al., 1987), while NMDA receptors participate in the excitatory portion of the vestibular commissural system (Knopfel, 1987). Subsequent whole cell voltage clamp recordings from the MVe in rat brainstem slices (Kinney et al., 1994) demonstrated that the excitatory postsynaptic potentials evoked by VIIIth nerve stimulation include an AMPA receptorsensitive, NMDA receptor-insensitive fast component and an NMDA receptor-sensitive slower component. However, the latencies of both components are consistent with monosynaptic transmission. These results, together with numerous subsequent investigations in the rat and other species, have led to the current view that primary afferent input to VNC neurons activates both AMPA and NMDA receptors (Straka et al., 2000). In fact, all known subtypes of excitatory amino acid receptors appear to be present in the VNC (Raymond et al., 1984; Reichenberger and ­Dieringer, 1994; Vidal et al., 1996a; Popper et al., 1997; Lai et al., 2008). Kainate receptor subunits (KA1 and GluR6-7), AMPA subunits (GluR1,2/3,4), and NMDA subunits (NR1, NR2A, NR2B) have been localized by immunocytochemistry in VNC neurons (Chen et al., 2003). These findings were supported and extended by in situ hybridization studies showing high densities of the AMPA receptor subunits

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GluR2/3 and GluR4, the R1 and R2C subunits of the NMDA receptor, and the mGluR1,2,5&7 metabotropic subunits and a lower density of GluR1 AMPA subunit mRNA (de Waele et al., 1995). It appears that postsynaptic AMPA/kainate receptors are largely responsible for mediating the excitatory effects of glutamate-like amino acids on central vestibular neurons (Straka and Dieringer, 1993; Petralia et al., 1994), whereas NMDA receptors are important for shaping the normal resting discharge properties of these cells (de Waele et al., 1990; Straka et al., 1997). The NMDA receptors, together with Group I mGluRs (mGluR1, mGluR5), may also be critical for longer-term modulation of synaptic transmission (Grassi et al., 1995) and, in particular, the plasticity associated with vestibular compensation (Smith et al., 1991 and the section on Vestibular Plasticity below). In contrast, Groups II (mGluR2, mGluR3) and III (mGluR7) metabotropic glutamate receptors appear to inhibit basal glutamate release in the VNC. Evidence for presynaptic NMDA and metabotropic glutamate receptors in the VNC has also been presented in the rat (Gallagher et al., 1992). GABA or GAD-immunolabeled fibers and terminals have been visualized in all VNC regions of the rat. However, these processes are derived from multiple sources, including Purkinje cell afferents, inhibitory commissural fibers, and other intra-VNC connections such as putative GABAergic interneurons, and do not therefore comprise a homogeneous functional innervation of the VNC. The first clear evidence for GABA receptor localization in the rat VNC derived from in situ hybridization studies and showed evidence for mRNA encoding the a1 subunit of the GABAA receptor (Hironaka et al., 1990). Heavy labeling was reported on giant Deiters’ neurons, with moderate grain densities in MVe and SpVe. However, GABAA receptor-related immunostaining has been observed in neurons throughout the VNC, including SuVe, in other mammalian species (Highstein and Holstein, 2006). GABAB receptor localization studies of the vestibular nuclei initially derived from observations of L-baclofensensitive binding sites utilizing an agonist-specific antibody (Martinelli et al., 1992). This indirect approach suggested that both pre-and post-synaptic GABAB receptors were present in the VNC of several mammalians species, including rats. Subsequently, functional pre- and post-synaptic GABAB receptors have been demonstrated in several experimental systems, including rat MVe slices (Dutia et al., 1992) and chick TN (Shao et al., 2003). Together with the amino acid transmitters, VNC neurons may contain a panoply of additional classic transmitters such as acetylcholine, serotonin, histamine, the monoamines, opioid and non-opioid peptides, tachykinins, various growth factors, as well as imidazoleacetic acid-ribotide (Martinelli et al., 2007; for a review see Highstein and Holstein, 2006). Further neurochemical heterogeneity in the rat VNC derives from the presence of neurons that produce the gaseous free radical nitric

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oxide (NO). Since the gas cannot be localized directly in tissue, the capacity of a neuron to produce NO is typically inferred from the localization of the synthetic enzyme neuronal nitric oxide synthase (nNOS), or the histochemical stain NADPH-diaphorase. Using these markers, putative NO-producing cells were reported in adult (Saxon and Beitz, 2000) and developing (Shaer et al., 1996) rat VNC, as well as in rat vestibular ganglion cells, processes, efferents and some type I hair cells (Harper et al., 1994; Chen and Eatock, 2000; Lysakowski and Singer, 2000). An antibody against L-citrulline was utilized to further characterize the NO-containing vestibular neurons, since this amino acid is produced in equimolar amounts with NO and accumulates in the NO-producing cells (Martinelli et al., 2002). Using this approach, NO-producing neurons were identified as small clusters of medium and large diameter multipolar and fusiform cells in each of the four main vestibular nuclei, as well as the e-group of the adult rat VNC. Functionally, several studies suggest that NO participates in vestibular neuronal plasticity as well as in more reflexive motor control mechanisms. Based on the available data in rats, supplemented by information derived from other mammalian species, the following summary can be constructed of the chemoanatomy of the major vestibular projection pathways.   

1. T  he angular VOR stabilizes gaze during head movements. The direct pathway of the horizontal VOR receives input from the horizontal semicircular canal nerves, which are glutamatergic. Recipient regions of the VNC send excitatory glutamatergic projections to the contralateral abducens motor and internuclear neurons and corresponding inhibitory glycinergic projections to the ipsilateral abducens nucleus. The direct pathway of the vertical VOR receives input from the vertical (anterior and posterior) semicircular canal nerves, which are also glutamatergic. Recipient regions of the VNC send glutamatergic projections to the contralateral oculomotor and trochlear motor neurons, as well as GABAergic projections to the corresponding ipsilateral cell groups. The indirect (velocity storage) pathway also utilizes glutamatergic semicircular canal input to the vestibular nuclei, but involves a more complex central neural network to influence oculomotor activity. Although both pathways involve vestibular commissural fibers, the direct pathway decussates at the level of the abducens nuclei and is primarily excitatory and glutamatergic, whereas the indirect pathway crosses more caudally (Katz et al., 1991). At least some of the velocity storage VNC commissural neurons are small and medium sized GABAergic neurons located in the rostral MVe (Holstein et al., 1999a, 1999b) that exert inhibitory action through GABAB receptors (Holstein et al., 1992).

2. T  he lateral vestibulospinal tract (LVST) is the principal pathway through which otolith signals directly influence the extensor musculature of the body. While some data suggest that the LVST utilizes an excitatory amino acid, putatively glutamate, for neurotransmission (Kevetter and Coffey, 1991), almost half of the retrogradely-labeled vestibulospinal neurons present in MVe and SpVe are GADimmunostained (Blessing et al., 1987). In contrast, since labyrinthine-evoked inhibition of neck motor neurons is strychnine-sensitive, but bicuculline and picrotoxin-insensitive, glycine may serve an important role in the vestibulo-colic pathway. No specific information concerning the chemical anatomy of the medial vestibulo-spinal tract is currently available. 3. The vestibulo-sympathetic pathways carry primarily otolith-related vestibular information through the vestibular nuclei to pre-sympathetic cell groups in the caudal medulla. The vestibular neurons of this pathway are rich in glutamate (Holstein et al., 2012) and imidazoleacetic acid-ribotide (Martinelli et al., 2007), a putative neurotransmitter/modulator that participates in the central control of blood pressure (Prell et al., 2004). 4. Vestibulocerebellar projections are glutamatergic from the VIIIth nerve, glutamatergic VNC cells and also via climbing fiber pathways originating in the beta-nucleus and the dorsomedial cell column of the inferior olivary complex (for review, see Barmack, 2003). Vestibular information is conveyed to these two olivary nuclei from the contralateral dorsal y-group (Blazquez et al., 2000) and the ipsilateral parasolitary nucleus, a cluster of GABAergic cells on the lateral margin of the extreme caudal MVe that receive direct vestibular nerve input (Barmack et al., 1998). 5. A formidable vestibular commissural system interconnects all subregions of MVe, SuVe and SpVe bilaterally. This pathway supports push–pull reactions in the VOR from reciprocal semicircular canal pairs, thereby increasing the sensitivity of second order vestibular neurons during head movements. In addition to this important integrative function, the commissural system is critical for velocity storage, as noted above. The excitatory fibers of the commissural system appear to be primarily, if not exclusively, glutamatergic, while the inhibitory fibers contain both GABAergic and glycinergic components.

MEMBRANE AND FIRING PROPERTIES OF CENTRAL VESTIBULAR NEURONS S. du Lac Vestibular nucleus neurons are endowed with membrane and synaptic properties, which are tuned for wide bandwidth, linear signaling. Differences in intrinsic

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Membrane and Firing Properties of Central Vestibular Neurons

membrane properties and ionic currents across different classes of vestibular nucleus neurons reflect specializations of each cell type for functionally distinct roles in self-motion circuits.

Firing Properties The membrane and firing properties of vestibular nucleus neurons differ substantially from canonically studied pyramidal cells in the hippocampus and cerebral cortex, reflecting fundamental differences in operating modes of these functionally distinct cell classes (Eugène et al., 2011). As opposed to pyramidal cells, which are not essential for either sensing or moving and are specialized to detect and signal transient events, vestibular nucleus neurons are critical for both the continuous, integrated sense of self motion and for the frequent generation of compensatory movements. In vivo, vestibular nucleus neurons fire tonically at rates between about 10 and 100 Hz, and they respond to motion signals with increases and/or decreases in this ongoing firing. In vitro, vestibular nucleus neurons also fire spontaneously, but at lower rates. Lin and Carpenter (1993) were the first to show that vestibular nucleus neurons act as endogenous pacemakers, firing in the absence of spontaneous inputs. Several subsequent reports confirmed spontaneous firing of vestibular nucleus (VN) neurons in the rat (Johnston et al., 1994), guinea pig (Serafin et al., 1991a), chick (du Lac and Lisberger, 1995b), and mouse (Murphy and du Lac, 2001). The endogenous pacemaking capabilities are even present in isolated neurons that have been acutely dissociated from brainstem slices (Gittis and du Lac, 2007). In response to synaptic drive or intracellular current injections, VN neurons rapidly modulate their firing. Steady depolarization elicits increases in firing rate, and they adapt modestly relative to cortical or hippocampal pyramidal cells. Evoked firing rates tend to be linear or bilinear as a function of input amplitude over a wide range of inputs and firing rates, as is appropriate for neurons that convey a wide range of rate-coded self-motion signals. The firing capacity varies considerably across neurons, with large premotor neurons capable of sustaining firing rates of several hundred Hz (­Sekirnjak and du Lac, 2006) and small inhibitory interneurons restricted to maintained firing rates below 100 Hz (­Bagnall et al., 2007). Variations in Na+ and Kv3 type potassium currents are major determinants of VN neuronal firing range (Gittis and du Lac, 2007), as discussed below. The spontaneous firing and wide range linear firing properties of VN neurons are shared by other neurons in sensorimotor and cerebellar circuits, including neurons in the neighboring nucleus prepositus hypoglossi (Idoux et al., 2006; Shino et al., 2008; Kolkman et al., 2011b) precerebellar mossy fiber neurons throughout the brainstem (Kolkman et al., 2011a) and cerebellar nucleus neurons (Uusisaari et al., 2007; Bagnall et al., 2009).

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The dynamics of spike generation vary considerably across VN neurons. In response to sinusoidal modulation of inputs, most vestibular nucleus neurons modulate their firing rates sinusoidally (du Lac and Lisberger, 1995a; Ris et al., 2001), but the patterns of response gain and phase vary across cell types. Consistent with a predominantly linear system, neurons that exhibit little or no adaptation in response to steady depolarization behave as broadband or low pass filters when assessed with dynamic stimuli, while neurons that exhibit pronounced adaptation exhibit high pass dynamics (Ris et al., 2001; Sekirnjak and du Lac, 2002; Sekirnjak et al., 2003). Intrinsic currents responsible for the dynamic properties of VN neurons are engaged both by depolarizing (Ris et al., 2001) and hyperpolarizing stimuli (Sekirnjak and du Lac, 2002). Following the cessation of an inhibitory or hyperpolarizing input, many VN neurons exhibit transient post-inhibitory rebound depolarization. Rebound firing correlates with the strength of spike frequency adaptation across VN neurons (Sekirnjak and du Lac, 2002) and is particularly pronounced in neurons that receive extensively somatic innervation by inhibitory synapses from cerebellar P ­ urkinje cells (Sekirnjak et al., 2003; Shin et al., 2011). Several types of VN neurons can be distinguished on the basis of their synaptic connectivity, neurotransmitter expression, and firing properties during behavior. Relating known cell types in vivo to neurons recorded in vitro has been challenging, because functionally distinct cell types have relatively subtle differences in membrane properties. Action potential waveforms have been used to classify VN neurons into two predominant types (A and B), which are distinguished on the basis of the absence or presence, respectively, of a delayed afterhyperpolarization (Serafin et al., 1991c; Johnston et al., 1994) and divergent fates during post-lesional plasticity (Beraneck and Idoux 2012). While excitatory neurons are always type B neurons, inhibitory neurons can exhibit either type A or type B action potentials (Shin et al., 2011; Takazawa et al., 2004; Bagnall et al., 2007). However, firing properties and action potential shape can been considered to vary continuously across VN neurons (du Lac and Lisberger, 1995b; Sekirnjak and du Lac, 2002; Sekirnjak et al., 2003). Recordings from acutely dissociated VN neurons reveal that similar Na+ currents and K+ currents are expressed across MVe neurons (Gittis and du Lac, 2007, 2008), but faster firing (type B) neurons express Kv3.3 channels that are absent in slower firing (type A) neurons (Gittis et al., 2010; see also Brooke et al., 2010). Molecular biological analyses of gene expression profiles in individual VN neurons confirm both continuous variations in ion channel genes across neurons and the presence of two main cell types distinguished primarily on the basis of genes related to action potentials, including Kv3.3 (Kodama et al.,

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2012). Excitatory premotor and precerebellar neurons and inhibitory premotor neurons express higher levels of Na+ and repolarizing K+ genes and lower levels of interspike K+ channel genes than do local inhibitory and slow excitatory neurons.

Ion Channels The ionic currents that underlie the generation of action potentials have been studied in brainstem slices and in acutely dissociated VN neurons, and molecular biological analyses have identified the corresponding ion channels. As with all central neurons, the upstroke of the action potential is generated by the influx of Na+ through voltage gated channels, and the downstroke is generated by the joint efflux of K+ through voltagegated channels and inactivation of Na+ channels. The interspike membrane potential trajectory is dictated by a balance of inward and outward currents that depend on calcium influx during the action potential and on membrane potential trajectory. Thus, the firing properties depend on several ion channels, which themselves vary as a function of firing rate and/or membrane potential via their dependence on voltage or calcium. The ability to sustain high firing rates depends on the availablity of sodium channels. As with other fast-firing neurons, the predominant sodium channel responsible for the action potential is Nav1.6, with additional contributions of Nav1.1 (Kodama et al., 2012). Specializations in sodium channel kinetics, including persistent currents (Serafin et al., 1991d; Gittis and du Lac, 2008), rapid recovery from inactivation, and a resurgent blocking mechanism (Gittis and du Lac, 2008) promote sodium channel availability in VN neurons. Rapid action repolarization in VN neurons is mediated by the Kv3 family of potassium channels, which additionally promote Na+ channel availability (Gittis and du Lac, 2007). Kv3.1 is expressed in all VN neurons, while Kv3.3 is expressed only in the fastest firing neurons (Gittis et al., 2010). In the absence of Kv3 currents, delayed rectifier potassium currents are capable of repolarizing the action potential, but their delay in activation contributes to accumulating Na+ channel inactivation. Variations in both Na+ and Kv3 currents underlie some of the functional differences across VN cell types. Calcium influx during the action potential (Gittis et al., 2010) triggers two predominant K+ currents; the large (big) conductance BK current, and the small conductance SK current. T and R type Ca2+ channels supply the Ca2+ responsible for the gating of BK channels, while N-type and R-type provide the requisite Ca2+ to SK channels (Smith et al., 2002). BK currents contribute to action potential repolarization and to the early component of the afterhyperpolarization following the action potential. In neurons with low expression of Kv3 currents, BK

currents play a critical role in action potential repolarization at the high end of the neuronal firing range (­Gittis et al., 2010). BK currents are thus dispensable for the normal operation of VN neurons but appear to serve as mechanisms for adjusting neuronal gain or firing range (Kolkman et al., 2011a). In contrast, SK currents are critical for the normal operation of VN neurons. Complete blockade of SK currents produces dramatic increases in firing which can lead to unstable membrane potential oscillations (de Waele et al., 1993). Partial blockade of SK currents produces dramatic increases in firing response gain at the expense of a wide input range (Kolkman et al., 2011a); SK currents thus promote broadband linearity via a tight clamp on excitability. Several additional currents engaged during the interspike interval play critical roles in shaping the dynamics of VN neuronal firing. Hyperpolarization activates an outward current with the hallmarks of IA (Serafin et al., 1991b; Johnston et al., 1994; Gittis and du Lac, 2007), which is activated at membrane potentials between about −60 and −40 mV (Hille, 2001). Several ion channel genes in VN neurons are candidates for mediating IA, including Kv3.4 channels, Kv1.4, and Kv4 family channel genes (Kodama et al., 2012). An A-like current predominates at the low end of the firing range of local inhibitory neurons (Serafin et al., 1991a; McElvain et al., 2010), consistent with the observation that A currents and Ca2+dependent K+ currents underlie a larger fraction of total K+ current in slowly firing, local inhibitory neurons than in fast firing projection neurons (Gittis and du Lac, 2007). Inward currents active during the interspike interval or upon the offset of membrane hyperpolarization include persistent Na+ current (Serafin et al., 1991d; Gittis and du Lac, 2008), low threshold calcium currents (Serafin et al., 1990; Sekirnjak and du Lac, 2002), and the hyperpolarization activated current IH (Sekirnjak and du Lac, 2002). Neuromodulators may dynamically shift the balance between opposing outward currents (IA) and inward currents (IH, IT), thereby influencing the firing and filtering characteristics of VN neurons (Beraneck and Idoux, 2012). VN neurons also express cyclic nucleotide channels (Podda et al., 2008), which are themselves likely to be regulated by activity and neuromodulation.

VESTIBULO-AUTONOMIC INTERACTIONS G. Holstein In addition to the vestibulo-ocular, -spinal, and -colic pathways, the central vestibular system influences brainstem regions involved in homeostatic regulation, particularly of blood pressure, heart rate and respiration, and in limbic activity associated with stress, anxiety, and panic. Although a link between the vestibular system and the

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autonomic nervous system was initially described almost a century ago in rabbits (Spiegel and Démétriades, 1922), the participant cell groups, connectivity, chemical anatomy, synaptology and functional significance of these pathways have only recently been addressed systematically. By analogy to the better-characterized vestibulo-ocular and -­spinal reflexes, these projections are often referred to as the ­vestibulo-sympathetic reflex (VSR) pathways. The maintenance of resting blood pressure is chiefly controlled by the baroreflex. Activation of cardiac and arterial baroreceptors by increased blood pressure is conveyed through the brainstem and spinal cord, inhibiting sympathetic nerve activity (SNA) and producing vasodilation of particular vascular beds. This vasodilation decreases blood pressure, thereby inactivating the baroreceptors. Thus, the baroreflex is a relatively long latency, regulatory feedback mechanism that maintains stable blood pressure. The vestibular system, instead, participates in a faster feedforward pathway that commands rapid alterations in blood pressure in response to changes in head position with regard to gravity. This pathway maintains adequate blood flow to the brain during movements and postural adjustments, such as those that occur in climbing, rearing and burrowing behaviors in rodents. The first study in experimental animals correlating changes in blood pressure with alterations in head position was conducted in anesthetized and paralyzed cats, and demonstrated orthostatic intolerance during noseup pitch following bilateral vestibular nerve transection (Doba and Reis, 1974). This breakthrough study was subsequently replicated in unanesthetized cats, rabbits and rats (Jian et al., 1999; Etard et al., 2004; Abe et al., 2008; Nakamura et al., 2009), confirming the existence of a vestibulo-autonomic connection. Evidence for this pathway was also derived from research demonstrating that SNA increases as a result of electrical stimulation of vestibular nerve fibers (Cobbold et al., 1968; for a review, see Yates and Bronstein, 2005). While the semicircular canals, particularly the vertical canals, may contribute to the VSR, evidence to date indicates that the primary sources of vestibular nerve afferents to the VSR are derived from the utricle and saccule. For example, otolith-specific stimulation achieved through linear acceleration or head-up tilt increases SNA and elevates blood pressure while nose-down stimulation decreases such activity in rats, as well as in other experimental animals (Uchino et al., 1970; Yates and Miller, 1994; Woodring et al., 1997; Kerman et al., 2000; Zhu et al., 2007; Abe et al., 2009; Nakamura et al., 2009). Moreover, data from rats has shown that the VSR can be upregulated by exposure to hypergravity (Gotoh et al., 2004; Abe et al., 2007; Tanaka et al., 2009). Based on these studies, it appears that in the rat, as in other species, activity in the VSR pathway is initiated primarily in the otolith organs.

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The VSR can be activated by galvanic vestibular stimulation (GVS) as well as by changes in posture in rats (Abe et al., 2009). GVS entails the application of low level DC current to the region of the mastoid processes (Fitzpatrick and Day, 2004), which activates the vestibular nerve fibers. In humans, GVS induces muscle SNA in the legs (Voustianiouk et al., 2006), similar to that evoked by transition from a supine to a standing position. This SNA, in turn, causes constriction of the peripheral arteries in the legs to prevent pooling of blood in the lower body (Miller et al., 2009; Sugiyama et al., 2011). Sinusoidal GVS (sGVS), in which current passes sinusoidally between the two ears, is highly effective in producing muscle SNA in humans (Bent et al., 2006) and both transient and longer latency changes in blood pressure and heart rate in anesthetized rats (Cohen et al., 2011a). Although sGVS activates the entire vestibular nerve, central modulation of sympathetic activity by sGVS appears to be mediated primarily by otolith-specific neuronal circuits (Carter and Ray, 2008; Cohen et al., 2011b, 2012). Thus, data from the rat as well as other species, including humans, clearly indicate that vestibular nerve activity, particularly from the otolith organs, contributes to the control of blood pressure. Although the regions of the rat vestibular nuclear complex (VNC) that receive VSR-related signals from the vestibular nerve have yet to be identified definitively, evidence originally gathered in other species suggested two general vestibulo-autonomic areas (for review, see Balaban and Yates, 2004). The more caudal region is comprised of the spinal and parvocellular medial vestibular nuclei (SpVe and MVepc, respectively). Early research in several mammalian species showed that ablation of this region abolishes the depressor response (decrease in blood pressure) that is normally observed during caloric irrigation and increases the threshold level of excitation required for eliciting sympathetic responses to electrical stimulation of the vestibular nerve (Spiegel and ­Démétriades, 1922, 1924; Uchino et al., 1970). Similarly, lidocaine injections into this region, which suppress local neural activity, attenuate sympathetic nerve responses to labyrinthine stimulation (Kerman and Yates, 1998). The particular importance of the vestibular nuclei for conveying VSR activity is highlighted by research showing that the effects of bilateral labyrinthectomy on blood pressure are transient (Yates and Miller, 2009), whereas ablation of the caudal VNC causes permanent VSR deficits. Such work suggests that the VNC is a key site for integrating proprioceptive, visual and other sensory inputs with vestibular signals in order to activate the VSR. Functional anatomical studies using c-Fos immunolocalization have been conducted in order to identify the subpopulations of VNC neurons that are activated by vestibular stimuli in the rat. c-Fos is the protein product

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FIGURE 12  Vestibulo-autonomic cells and pathways. (A) C-Fos-­immunolabeled neuronal nuclei (arrows) visualized with diaminobenzi-

dine in the MVNpc of a rat sacrificed 90 minutes following sGVS stimulation. Scale bar: 20 μm. (B) Schematic diagram of the major cell groups mediating vestibulo-autonomic (blue) and baroreflex (red) pathways, and convergent presympathetic activity (purple). Although there are vestibular projections to NTS and to CVLM, little convergence with baroreflex signals occurs prior to processing in the RVLM. Abbreviations: CVLM: caudal ventrolateral medullary region; IML: intermediolateral cell column; NTS: solitary nucleus; RVLM: rostral ventrolateral medulla; VNC: vestibular nuclear complex. Modified from (Holstein et al., 2011b). (C) Immunofluorescence visualization of PhaL-labeled vestibular axons in relation to catecholaminergic (tyrosine hydroxylase positive) processes (red) in the rat RVLM ipsilateral to the injection of PhaL(green) in MVNpc. The vestibular fibers are highly varicose and of fine caliber. Scale bar: 40 μm.

resulting from activation of the immediate early gene c-fos. Following the pioneering studies by Kaufman and colleagues (Kaufman et al., 1992), c-fos expression and/ or c-Fos protein localization have been employed to identify neurons activated by semicircular canal, otolith or combined canal/otolith stimulation achieved through horizontal and vertical linear acceleration, Ferris wheel rotation, off-vertical-axis rotation, centrifugation, spaceflight, and steps of galvanic stimulation (see Holstein et al., 2012). For the most part, these investigations focused on neuronal populations involved in vestibulo-ocular and vestibulo-spinal pathways (Kaufman and Perachio, 2000; Chen et al., 2003). Recently, however, c-Fos immunolabeling was used to visualize neurons activated by sGVS in the rat (Holstein et al., 2012). Following the sGVS stimulation, c-Fos-positive neurons were observed in the caudal half of

SpVe and the entire rostro-caudal extent of MVepc in the rat (Fig. 12). Because the stimulus primarily activated the central otolith system and caused significant changes in blood pressure in these animals (Cohen et al., 2011a, 2012), c-Fos-positive vestibular cells were interpreted as putative vestibulo-sympathetic pathway neurons. This suggests that the caudal vestibulo-autonomic area described in other species as comprising caudal SpVe and MVe (Balaban and Porter, 1998) may not entirely coincide with the VSR regulatory region of the rat VNC, which extends through the entire rostro-caudal extent of MVepc. The baroreflex pathway conveys signals to the nucleus of the solitary tract (NTS), which in turn sends projections to cell groups in the rostral and caudal ventrolateral medullary regions (RVLM and CVLM, respectively) that regulate cardiovascular activity (Fig. 12). VNC

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neurons also send projections to these regions. However, the terminations of VNC and baroreceptor afferent fibers in NTS are apparently distinct in these species, with no functionally meaningful convergence of the two inputs on individual NTS neurons (Balaban and Beryozkin, 1994; Yates et al., 1994). Similarly, despite the presence of VNC terminals in both NTS and CVLM, neither cell group appears to be highly responsive to vestibular nerve stimulation, and NTS lesions do not significantly alter the sympathetic activity resulting from electrical stimulation of the vestibular nerve (Yates and Miller, 1994; Steinbacher and Yates, 1996) in rabbit and cat. In contrast, RVLM neurons receive significant convergent baroreceptor and vestibular input (Yates and Bronstein, 2005) and chemical ablation of the RVLM abolishes the effects of vestibular nerve stimulation on sympathetic nerve activity in cats (Yates et al., 1995). Since baroreflex activation profoundly inhibits RVLM neuronal activity, and the RVLM is an obligatory relay in the descending VSR pathway, the RVLM is the most likely site for convergence of baroreflex and VSR activity. Early anatomical and electrophysiological studies in rabbits and cats emphasized the polysynaptic nature of the pathways from the vestibular nuclei to RVLM, CVLM and NTS (Balaban and Porter, 1998; Yates and Bronstein, 2005). Recently, however, direct projections from SpVe and MVepc to RVLM and CVLM have been demonstrated in the rat (Holstein et al., 2011a). Following unilateral injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PhaL) in MVepc or caudal SpVe, PhaL-labeled axons are observed bilaterally throughout the R/CVLM (Fig. 12). The density of labeled vestibular axon terminals is greatest on the ipsilateral side and at rostral levels, and diminishes more caudally and contralaterally. The direct projections from VNC neurons were confirmed using small injections of FluoroGold in RVLM or CVLM to retrogradely label neurons in the same regions of SpVe and MVepc. These fibers may well serve as the structural basis for both direct (VN to RVLM) and indirect (VN to CVLM, CVLM to RVLM) vestibulo-sympathetic pathways modulating blood pressure in the rat. The chemical mediators of this pathway include imidazoleacetic acid-ribotide (IAA-RP), a putative neurotransmitter/modulator that participates in the central control of blood pressure (Prell et al., 2004). IAA-RP has been demonstrated in vestibular neurons (Martinelli et al., 2007), and co-localizes with both glutamate and GABA in c-Fos-positive vestibular neurons following sGVS stimulation. In addition to the descending VSR tracts that modulate blood pressure and heart rate, there is some evidence that changes in posture and movement can also alter respiration (Yates et al., 2002). However, little of this work has been conducted in the rat, so the generality of the findings remains to be established. In cat, head rotation or electrical stimulation of vestibular afferents

inhibits activity in all of the nerves innervating the respiratory muscles, while such stimuli elicit both excitation and inhibition in some of the nerves innervating upper airway muscles. While inactivation of SpVe and caudal MVe abolishes these responses (Rossiter et al., 1996), functional lesions of the dorsal and ventral respiratory group neurons do not, suggesting that vestibulo-respiratory control is mediated through different cell groups. One such group, the gigantocellular nucleus in the medial medullary reticular formation, has been shown in the rat to receive direct input from the VNC (Xu et al., 2002). Several regions of cerebellar cortex, including a border zone between the nodulus and ventral uvula and a region in the caudal posterior lobe, receive vestibular input and participate in cardiovascular control (­Bradley et al., 1987; Henry et al., 1989). Stimulation of these regions modulates the responses of RVLM neurons (Paton and Spyer, 1990) and alters blood pressure. While ablation of the nodulus and uvula does not affect resting blood pressure and heart rate, cardiovascular responses to changes in posture are impacted (Holmes et al., 2002). Of particular note, Purkinje cells located in the regions of the nodulus and uvula that participate in cardiovascular control project to the SpVe and MVepc (Paton et al., 1991), and bicuculline injections into the SVe attenuate the depressor response resulting from nodulus-uvular stimulation (Henry et al., 1989). Portions of the cerebellum also appear to be involved in influencing respiratory activity. While stimulation of the nodulus and uvula inhibits respiration, stimulation of the anterior lobe, as well as the fastigial nucleus, elicit excitatory as well as inhibitory effects. This has led to a hypothesis that the anterior lobe and fastigial nucleus exert a tonic influence on respiration whereas the nodulus and uvula participate in the adaptive plasticity of vestibulo-respiratory responses (Yates et al., 2002). This hypothesis remains to be tested directly. Lastly, ascending pathways from more rostral areas of the VNC to portions of the parabrachial complex (Balaban, 1996; Cai et al., 2008) and the paraventricular hypothalamic nucleus (Markia et al., 2008) have been described in the rat. These projections are thought to be involved in more affective and emotional behaviors such as stress, anxiety and fear. However, the precise functional role(s) of particular projections and pathways of this system remain to be elucidated.

VESTIBULAR PLASTICITY E. Idoux The functions of the vestibular system go well beyond the stabilization of gaze and posture discussed earlier (McCall and Yates, 2011; Goldberg et al., 2012). Furthermore, as the animal grows, ages and experiences sensory conflicts or lesions, its vestibular inputs mature, change

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and decay. On top of their effect on gaze and posture, vestibular lesions have neurovegetative consequences (e.g., trouble in regulating blood pressure during movements, cf. Vestibulo-autonomic interactions above) as well as cognitive consequences (e.g., impaired navigation, spatial cognition and memory, cf., The Vestibular System and Spatial Navigation below). During a life without lesion, or after a healing period when injured, the stabilization reflexes remain remarkably accurate: such functional homeostasis is made possible only through the continuous plasticity of the vestibular system. Vestibular compensation, evoked earlier, will be used to illustrate the diversity of the mechanisms and the different sites of plasticity within the vestibular system (Dutia, 2010). Damages to the vestibular organs or nerve trigger static and dynamic symptoms, which progressively disappear, a recovery process called “vestibular compensation” (Smith and Curthoys, 1989; de Waele et al., 1989; Gittis and du Lac, 2006; Olabi et al., 2009). While other paradigms (habituation and adaptation) have been used to study plasticity in the vestibular responses, post-lesional vestibular compensation is one of the best documented, especially for the horizontal VOR. This reflexive threeneuron-arc goes from the horizontal semicircular canals to the ipsilateral MVe in the brainstem via the VIIIth nerve, and the MVe 2°VN, then project to the oculomotor nuclei (Baker et al., 1981). In the following paragraphs, it will be explained how during vestibular compensation, plasticity can impact all of these elements (1°VN, 2°VN and the synapse between them, as well as the glia in the MVe). An illustration of plasticity in a pathological case will show, for each of the elements above, whether similar mechanisms are at play under physiological conditions. Finally, we will focus on the main modulators of these plastic events, mostly the influence of cerebellum, stress and hormones.

Vestibular Compensation: An Example of Plastic Recovery The symmetrical organization of the vestibular system is informative in understanding the physiology of the system and the symptoms triggered by a unilateral lesion of the vestibular periphery. The peripheral vestibular organs (semicircular canals and the otoliths organs), as well as the central brainstem nuclei on the left side, are mirrored by those of the right side. Essential to the balance between both sides, commissural inhibition enhances signal detection via a push-pull mechanism: when the animal rotates to the left, the left semicircular canal’s activity increases from the baseline which provides more excitation to the 2°VN. At the same time, activity of the right-side canal decreases, which disfacilitates the 2°VN of the right MVe. This concomitant increase in activity of the left side and decrease on the

right side is further magnified by commissural inhibition: the weight of the inhibition provided by the left side onto the right one increase, and this further decreases the activity on the right side. The decreased activity on the right side lessens the commissural inhibition onto the left side, which increases its activity. Unlike the resting condition, where the average activities of both nuclei are similar, during a rotation, the net activity of the ipsiversive nucleus increases and the activity of the contraversive nucleus decreases: this imbalance signs the rotation (Straka et al., 2005).

Lesions: Symptoms and Recovery Lesions of the peripheral organs or sections of the VIIIth nerve can be either symmetrical (bi-neurectomy or bi-labyrinthectomy) or asymmetrical (unilateral neurectomy, or UL). Right after a UL, the animal shows an abundance of symptoms (Darlington and Smith, 2000), whether at rest (static symptoms) or when stimulated (dynamic symptoms). Static symptoms consist of nystagmus toward the lesioned side (slow phase toward the lesion, fast phase away from the lesion) and postural deficits (de Waele et al., 1989)—the animal’s head is tilted forward and toward the lesioned side, its contralesional limbs are hyperextended, while ipsilesional limbs are flexed (Kasri et al., 2004). When rotated, the animal cannot stabilize its gaze properly, especially toward the lesioned side, as the gain and phase of the VOR are initially impaired. Both the static and dynamic symptoms disappear progressively, yet with different time courses. The static symptoms recover within 7 to 10 days, while it can take a few months for the dynamic symptoms to improve, and they never fully recover. It is noteworthy that the recovery of the dynamic symptoms, albeit slower, is independent of the recovery for the static symptoms (Newlands et al., 2005). If an animal is lesioned on the left side and has undergone sufficient vestibular compensation, a lesion of the right, intact side will trigger similar static and dynamic symptoms, as if the left side was still intact. It is called the Bechterew phenomenon. The Bechterew phenomenon, which is strong evidence that plasticity that occurs during vestibular compensation, has a precise time course. This situation occurs only if the initial static deficits (i.e., caused by the left side lesion) have been compensated. In addition, the more time between the left (first) and right (second) lesions, the more severe the right-sided symptoms (Vibert et al., 1999a). While these experiments show that plasticity exists in the system, they do not demonstrate which neural elements can be modified to achieve recovery. Although the afferent fibers on the non-lesioned side might show more irregular fibers than in control animals (Sadeghi et al., 2007; for review, see Cullen et al., 2009), the main focus will be on the changes occurring at the central

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level—whether they impact on the vestibular nuclei as a whole, the synapse between the vestibular afferent and the 2°VN (1°–2°VN synapse), or the 2°VN themselves.

The Whole Nucleus The silent partners of information processing in the vestibular system, the glia, are modified following UL. Indeed, a microglial response in the vestibular nuclei is apparent as early as 1 day after a lesion and persists for several weeks (Campos Torres et al., 1999). It correlates with increased levels of TNFα, a marker of inflammation, and of neuroprotective factors such as NFkappB or MnSOD (Liberge et al., 2010). Astroglia also show an initial intense activation (within the first 3 days after a lesion) which progressively fades. Before this glial activation, the immediate early genes (IEGs) c-fos and zif-268 are upregulated within a few hours and a few days, respectively, after the lesion (Lacour and Tighilet, 2010). During the first hours of vestibular compensation, both ipsilesional and contralesional transcriptomes are modified (Horii et al., 2004a; Masumura et al., 2007), which reflects intense cellular activity. It is therefore not surprising to find an upregulation of proteins involved in metabolism in the ipsilesional nuclei, even a week after the lesion (Paterson et al., 2006). A set of proteins involved in axonal growth and guidance are also upregulated indicating a potential structural reorganization of the networks during compensation. Such reorganization would benefit from the upregulation of the neurotrophin pathways, which follow a spatio-temporal pattern similar to that of IEGs. These post-lesional changes point towards an increase in neuroprotection after the lesion, as well as a reorganization of the network within the nuclei. Since the network itself is exposed to changes, one can wonder about plasticity occurring at the level of the synapses.

The Synapses Within a week of a UL, the sensitivity of ipsilesional 2°VN to inhibitory neurotransmitters (GABA and glycine) is decreased, which reduces the strength of commissural inhibition from the contralesional side (Vibert et al., 2000; for a review, see Olabi et al., 2009). The actual mechanism seems to be different between GABA and glycine. Despite an overall decrease in GABAA sensitivity of the neurons, the properties of GABAA receptors do not seem to be altered, while glycine mini-IPSCs are more frequent on both sides after the lesion and of larger amplitude on the contralesional side. Potentially then, GABAA decrease could be explained by modification of extrasynaptic receptors (Lim et al., 2010). Unlike GABAB receptors, which remain downregulated GABAA sensitivity is recovered within a few days after the initial decrease (Johnston et al., 2001). How excitatory amino

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acid receptors are involved in vestibular compensation is less clear (Darlington and Smith, 2000). See also Vestibular Pharmacology Update, above. Under physiological conditions, excitatory aminoacid receptors are instrumental in the development and maintenance of plasticity at the 1°–2°VN synapse. In control animals, this synapse is remarkably plastic, at least when the post-synaptic neuron is a type B neuron (cf., Membrane and Firing Properties of Central Vestibular Neurons, above); it can be modulated both upward (long-term potentiation, LTP) and downward (longterm depression, LTD), depending on the firing pattern of the presynaptic fiber and the polarization level of the 2°VN. Initially, it was shown that stimulation of the afferent fibers with a short burst of stimulation (550 ms epochs at 100 Hz repeated 30 times) could result in either LTP or LTD depending on whether the 2°VN was, respectively, hyperpolarized or spontaneously firing during the first half of the epoch (McElvain et al., 2010). Both LTP and LTD relied on an increase of intracellular Ca2+, yet through different glutamate channels; LTP, under hyperpolarization, required calcium-permeable AMPA receptors, while LTD, at rest, involved NMDA channels (star 1 in Fig. 13). It was recently shown that, besides LTD, LTP could be induced at rest, with short burst stimulations (Scarduzio et al., 2012). This study actually showed that, at rest, both LTP and LTD could be induced, both by short or long burst stimulations (2000 ms epochs at 100Hz, repeated four times). At rest, the interval between the bursts is the key parameter to gate which kind of plasticity is triggered; below a certain threshold for that interval, LTP will occur, above it, LTD will be triggered. With these protocols, at rest, NMDA receptors were involved in both LTP and LTD (star 2 in Fig. 13). These results demonstrate that the key factor for 1°–2°VN synapse plasticity is not so much Ca2+ per se, but the fine patterns of intracellular Ca2+ variations. While most studies have focused on the plasticity of type B neurons, the long-burst protocol was shown to be less effective on type A (Pettorossi et al., 2011), as it potentiates the synaptic events of 80% of type B and only 50% of type A. Interestingly, LTD was more often found in the dorsal, parvocellular part of the MVe while LTP was more often found in the ventral, magnocellular part (Grassi and Pettorossi, 2001). Similarly, type A-like neurons, were more frequent in the dorsal part and type B-like neurons, more frequent in the ventral part (Bagnall et al., 2007). Hence, the neurons located in different parts of the VN might present a different plastic repertoire, although these results come from two different studies and the correlation has not been directly tested. Finally, the long burst stimulation had an interesting side effect; in most type A and about half the type B, it promoted a long term potentiation of intrinsic excitability via the activation of mGluR1 (Pettorossi et al., 2011).

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FIGURE 13  This figure summarizes various mechanisms for plasticity in the vestibular system. The central element here is the 2°VN, which receives excitatory synaptic inputs from the afferent fibers (1°VN, black, on the left), and inhibitory synaptic inputs from Purkinje cells and contralateral 2°VN (via the commissural inhibition), both in gray. The various types of plasticity are listed here: (1) LTP is induced by concomitant input from 1°VN and hyperpolarization. Hyperpolarization was experimentally induced but could result from inhibitory synaptic activation. This mechanism involves Ca2+-permeable AMPA receptors (CP-AMPA). (2) LTP or LTD could be induced at rest, depending on the interval between the bursts. The shorter the intervals, the more likely it is to induce LTP (in mauve) instead of LTD (in green) and conversely. NMDA receptors are used in that case. (3) BK channels as a plasticity effector: BK can be modulated by several pathways balancing each other, including activation of mGluR receptors, protein kinase C (PKC) or calmodulin kinase II (CAMKII). (4) Plasticity can occur at both synapses, yet it is more likely to be retained at the parallel fiber-Purkinje cell synapse when short time scale are at play (within a day) while the 1°-2°VN is more likely the plastic site used for long term storage of the changes (between days). (5) potential modulation of BK channels by 17β-estradiol. The actual mechanism is not known in the vestibular nucleus.

Thus, plasticity can not only occur bidirectionally at the 1°–2°VN synapse, but can also induce intrinsic plastic properties in the 2°VN. Changes in intrinsic properties are particularly important in pathological situations, and will be discussed below.

Secondary Vestibular Neurons (2°VN) Soon after the lesion (4 h), the intrinsic excitability of rostral ipsilesional 2°VN increases and lasts for at least a week (Guilding and Dutia, 2005), although probably via two different mechanisms, as the increased excitability depends on modifications in synaptic and intrinsic membrane properties. This combination of intrinsic and synaptic modifications could explain the fast recovery of static symptoms, since the increase excitability and decreased sensitivity to inhibitory neurotransmitters would help the ipsilesional MVe restore its basal discharge. Except for the transitory increase within the first

hours of the lesion, the changes in intrinsic properties slowly develop. They do not appear to be significant in vitro, 2 weeks after the lesion, but become evident after a month, their time course being on par with the recovery from dynamic symptoms (Vibert et al., 1999b; Beraneck and Idoux, 2012). A month after the lesion, the number of neurons is basically the same as in the control, probably due to neuroprotection set up in the early moments of vestibular compensation (Campos Torres et al., 1999). However, on the contralesional side, silent neurons (no resting discharge) are thrice as common as they were in control animals (Beraneck et al., 2004). Furthermore, type B neurons now represent 75% of the recorded contralesional 2°VN while there is a slight increase of type A neurons at the expense of the type B on the ipsilesional side. Quantitatively, the type B 2°VN electrophysiological signature is modified, with reinforcement of the “B-like” properties on the contralesional side (AHP

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even shallower, double AHP more pronounced), with a similar observation for the type A neurons on the ipsilesional side, i.e., a reinforcement of the “A-like” properties. When stimulated, ipsilesional type B and contralesional type A neurons are also more sensitive than their control counterparts (Beraneck et al., 2003, 2004). All of these changes might contribute to the recovery of static and dynamic symptoms. Right after the lesion, the ipsilesional side is deprived of its main excitatory drive from the missing vestibule, which makes this nucleus less active (Ris et al., 1995, 2001). This loss of excitation is exacerbated by commissural inhibition and the end result is that the ipsilesional nucleus is silenced after the lesion. However, after a month of compensation, when the aforementioned changes in intrinsic properties have occurred, and both nuclei are active again, the system has switched from a symmetrical push-pull to a conformation where the tonic activity of the ipsilesional side is modulated by information coming from the contralesional side. As we have seen, right after the lesion, commissural inhibition shuts the ipsilesional nucleus down via a heavy hyperpolarization that prevents 2°VN from firing. Interestingly, when injected with 1-sec-long hyperpolarizing pulses of current in control animals, type B 2°VN increased their spontaneous and current-stimulated firing frequency, a phenomenon called “firing rate potentiation” (FRP) (Nelson et al., 2003). While FRP has been demonstrated outside the context of vestibular compensation, it could well contribute to the transient surge in excitability demonstrated right after the lesion, which helps restore the overall activity of the ipsilesional nucleus during the first week (Ris et al., 1995, 2001; Ris and Godaux, 1998). What are the underlying cellular mechanisms? Obvious candidates are Ca2+-dependent potassium channels such as SK and BK channels, which are both found in 2°VN. Dissection of the molecular mechanisms involved in FRP excluded SK channels, but pointed out the role of BK channel (Nelson et al., 2003). Interestingly, the BK channel seems to be a key feature in the plastic control of intrinsic excitability, since its activity can be modulated both upward and downward from its basal state via different phosphorylation sites (Van Welie and Du Lac, 2011). On one hand, this conductance is increased by the activated calmodulin-kinase II; on the other hand, it is decreased by protein kinase C-mediated phosphorylations. The PKC phosphorylation site on BK channels is also the target of intracellular phosphatases that balance the PKC influence on BK channels. It was proposed that hyperpolarization, like that mediated by commissural inhibition, would decrease the intracellular Ca2+ concentration, thus reducing the endogenous activity of CAMKII. This would lessen the BK hyperpolarizing effect and therefore lead to a net increase of the firing rate (star 3 in Fig.

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13). Unlike CAMKII, PKC activation requires intracellular Ca2+ but also diacylglycerol (DAG), which is typically produced by the activation of protein Gq. Proteins Gq can be activated by metabotropic glutamate receptors like mGluR1 and it has been shown that synaptic stimulation could cause long term enhancement of the firing rate via mGluR (Pettorossi et al., 2011).

Modulation of Plasticity The cerebellum is required when the VOR needs to be adjusted (for review, see Boyden et al., 2004), as well as during vestibular compensation (Beraneck et al., 2008). The cerebellum acts as a comparator between the vestibular inputs (via the parallel fibers) and the error signal coming from the retina (via the climbing fibers). Both signals converge onto the Purkinje cell, which sends inhibitory projections directly onto 2°VN. When short-term learning is involved, the synapses between the parallel fibers and the Purkinje cell store information, but when the changes have been consolidated, the retention site has become the 1°–2°VN synapse and/or the 2°VN themselves (Shutoh et al., 2006). Furthermore, feed-forward inhibition within the cerebellum is instrumental in computing the proper output signal, as shown by the learning deficits of mutant mice lacking GABAA ­receptors in Purkinje cells (Wulff et al., 2009) (star 4 in ­Fig. 13). The main output of the cerebellum to the MVe is the GABAergic Purkinje cells and their activation induces hyperpolarization of their target 2°VN. Given the various effects of bouts of hyperpolarization with or without concurrent activity on the afferent fiber (FRP and LTP, respectively), ad hoc activation of Purkinje cells can be one of the mechanisms to regulate plasticity in the MVe (Menzies et al., 2010). However, direct stimulation of Purkinje cell targeting 2°VN has not lead to conclusive results in the isolated in vitro whole brain of guinea pig (Babalian and Vidal, 2000).

Visual Inputs Visual inputs provide the error signal to drive the Purkinje cells and adjust the adult VOR. They also orient plasticity during postnatal development. During the first postnatal weeks, LTD is the only form of plasticity that long-bursts can trigger in the ventral MVe. It is progressively replaced by LTP, which is the only form of plasticity found in the ventral MVe after the eyes open (and therefore in adults) with that type of stimulation. However, when animals are developing in the dark, LTD can be elicited long after the eyes open. Normal development (i.e., progressive shift from LTD to LTP) can still occur if the light is switched back on (Grassi et al., 2004). This shows not only that similar stimuli in different contexts

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can elicit different plastic events at the same synapse in the vestibular system, but also hints again towards the involvement of Ca2+ in plasticity, since Ca2+ buffer regulation is important during the early moments of the animal’s life (Eugène et al., 2007). Other factors can weigh in to modulate the type of plasticity occurring in the MVe, such as sex steroids or various neuromodulators.

Hormones and Other Chemical Modulators 17β-estradiol (E2) induces LTP while 5α-dihydro­ testosterone (DHT) can cause LTP or LTD (Grassi et al., 2010a, b). Since both E2 and DHT are derived from testosterone by different enzymes, the relative balance of these enzymes can be a mechanism through which the 1°–2°VN synapse could be regulated. The exact molecular mechanism is unknown, but once again, BK could be involved in this mechanism, as E2 potentiates BK channels, albeit very slowly (Nishimura et al., 2008, star 5 in Fig. 13). Other steroids, involved in stress responses, can modulate glutamatergic and GABAergic neurotransmission (Olabi et al., 2009), and might have an optimal range of concentration; a small concentration of glucocorticoids speeds up behavioral recovery while excessive stress will delay it (Grassi et al., 2007; Saman et al., 2012). Stress responses are complex events, which rely as well on neuromodulators like adrenaline and noradrenaline. Neuromodulation has been pointed out as a crucial factor for proper tuning of the vestibular responses and plasticity (for review, see Beraneck and Idoux, 2012). However, in most cases, they elicit elastic changes (i.e., changes that stop when the constraint stops) more than plastic changes (changes that remain when the constraint stops). Histamine seems to be involved in the modulation of plasticity (for review, see Bergquist and Dutia, 2006), although in normal conditions, histamine directly inhibits GABA release (via the presynaptic H3 receptor) or indirect release of glycine via H1/H2 receptors. H3 receptors appear to be bilaterally downregulated for at least 3 weeks, starting within a day after UL. Indirect inhibition via H1/H2 is however very efficient on the contralesional side and is responsible for the imbalance in GABA release after lesion (Bergquist et al., 2006). This could be one of the modulatory mechanisms through which the burden of commissural inhibition is lifted during the first week after lesion (Tighilet et al., 2006).

Conclusions on Plasticity Plasticity in the vestibular system is a typical case of homeostatic functional plasticity. The afferent fiber, the 1°–2°VN synapse, the intrinsic properties of the 2°VN, and even the surrounding glia, can be modulated to ensure proper function. The case of the vestibular compensation shows that each of these mechanisms have

their own time course, as the switch in behavioral strategies can be observed within minutes after the lesion, synaptic and network changes in a matter of days, while deep modifications of intrinsic properties of the neurons can take weeks to months. However, while these changes have been demonstrated, it is not known whether each of them is improving the animal’s condition. Furthermore, it must be remembered that the compensation of static and dynamic deficits seems independent. Commissural inhibition has a pivotal role in the vestibular system. Physiologically, it improves the sensitivity of the reflex by magnifying activity differences between the left and right MVe. Because of that, it is both a burden immediately after the lesion, and after healing, the sole purveyor of the information detected by the remaining contralesional vestibular organs. It could explain how transient changes can be measured in inhibitory neurotransmitters, while the 2°VN modifies their intrinsic properties to cope with the commissural inhibition—a now highly dissymmetrical system. The ebb and flow of the sensitivity of plasticity to inhibitory neurotransmitters illustrates how much the different levers of plasticity can be pushed or pulled individually, depending on the state of the others. Therefore, it is not surprising that plastic events are themselves under the control of so many different systems (cerebellum, stress and sex hormones, neuromodulators, the activity patterns of the afferent fibers, etc.). At the cellular and synaptic levels, evidence is accumulating as to the central role of Ca2+ in plasticity, mostly via subtraction experiments where Ca2+ entry, buffering or effectors are blocked. However, Ca2+ does not work in an “all-or-nothing” fashion. Its concentration and concentration variations are likely to be one of the keystones of plasticity in 2°VN physiology. The role of patterns in Ca2+-modulation, as well as the existence of dendritic Ca2+ micro-domains, have yet to be tested using newly available methods (Idoux and Mertz, 2011).

THE VESTIBULAR SYSTEM AND SPATIAL NAVIGATION P.F. Smith Numerous animal studies dating back to the 1970s and 1980s suggested that the vestibular system contributes to navigation through the spatial environment (“spatial navigation,” e.g., Potegal et al., 1977; Horn et al., 1981; Miller et al., 1983; Mathews et al., 1988, 1989; Semenov and Bures, 1989; Chapuis et al., 1992; Ossenkopp and Hargreaves, 1993; see Smith et al., 2010 for a review). In many of these early studies, any effects of vestibular stimulation or vestibular lesions on spatial navigation were confounded by acute changes in vestibulo-ocular

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or vestibulo-spinal reflex function, and therefore it was unclear as to what extent the deficits might be attributable to changes in spatial memory. In the last decade, animal studies of spatial navigation have been conducted that controlled for the acute effects of vestibular lesions on vestibular reflexes, at least to some extent, by evaluating performance in spatial navigation tasks at different time-points following the lesions (in some cases at long time points after some vestibular compensation had developed). These studies also employed sophisticated methods of assessing spatial navigation and memory, such as foraging tasks and radial arm maze tasks. The first of these studies was published by Wallace et al. (2002) and Stackman and Herbert (2002), closely followed by Russell et al. (2003a). Since this time, many animal studies have been published that have replicated the original findings and shown that unilateral and bilateral vestibular lesions result in profound spatial memory deficits that are long lasting (Baek et al., 2010; Besnard et al., 2012; Machado et al., 2012; Neo et al., 2012; Zheng et al., 2006, 2007, 2009b, 2012a). Zheng et al. (2006) showed, using the foraging task used by Wallace et al. (2002), that the spatial memory deficits caused by unilateral vestibular deafferentation (UVD) were not permanent, but resolved in approximately 6 months. UVD is equivalent to unilateral labyrinthectomy (UL). On the other hand, bilateral vestibular deafferentation (BVD) seemed to cause deficits (Fig. 14) in this task that persisted even after 14 months and were probably permanent (Zheng et al., 2009b; Baek et al., 2010). Similar results were obtained using radial arm maze and T maze tasks (Besnard et al., 2012; Machado et al., 2012; Neo et al., 2012; Zheng et al., 2012a), although some partial recovery over time has been observed (Zheng et al., 2007). The impairment of spatial memory has been demonstrated using both chemical lesions of the vestibular labyrinth (Besnard et al., 2012; Machado et al., 2012; Stackman et al., 2002; Wallace et al., 2002) as well as surgical lesions (Neo et al., 2012; Zheng et al., 2006, 2007, 2009b, 2012a). Animals with BVD usually exhibit a striking locomotor hyperactivity (e.g., Goddard et al., 2008a; Machado et al., 2012; Stiles et al., 2012), and therefore consideration has been given to whether this might explain the poor performance in spatial memory tasks. However, the studies that have analyzed the relationship between spatial memory performance and locomotor hyperactivity following BVD, have failed to find any statistical relationship between the two (Baek et al., 2010). Rats, at least, can exhibit spatial memory deficits without hyperactivity (e.g., Zheng et al., 2012a). Likewise, recent studies show that, although it is conceivable that the spatial memory deficits associated with BVD were linked to changes in anxiety, anxiolytic drugs in fact have no effect on the poor spatial memory performance of BVD rats (Machado et al., 2012; Zheng et al., 2012a). Other

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studies, using tasks such as the five choice serial reaction time task (5-CSRTT), have shown that BVD rats can exhibit clear deficits in spatial tasks even when their rate of response omission is no different from sham control animals. In this task, BVD rats have been demonstrated to generate fewer correct responses and more incorrect responses, with no significant difference in omissions, indicating that their problem performing such tasks is not the inability to respond, but the inability to respond correctly (Zheng et al., 2009a). A further concern about the specificity of the apparent spatial memory deficits is the damage to the auditory system incurred by chemical or surgical vestibular lesions, and the possibility that loss of normal auditory function might be responsible for the spatial memory deficits. However, many of the recent studies have employed tympanic membrane removal in the sham surgical controls, in order to reduce auditory function in the control animals, and have still demonstrated that the BVD animals perform worse in spatial memory tasks than the control groups (e.g., Baek et al., 2010; Zheng et al., 2006, 2007, 2009a, 2009b, 2012a). Studies using different aminoglycoside antibiotics have also shown that it is the vestibulotoxic agents that impair spatial memory (Schaeppi et al., 1991). Taken together, these studies suggest that, in addition to deficits in VOR and vestibulo-spinal reflex function, animals with vestibular lesions, especially bilateral vestibular lesions, exhibit profound spatial memory deficits as a result of the loss of vestibular information to higher centres of the brain.

Relationship to Human Studies The first systematic report of spatial navigation and spatial memory problems in patients with vestibular disorders, was published by Grimm et al. (1989). They described a group of patients (n = 102) with a perilymph fistular syndrome, who experienced not only vestibular symptoms such as positional vertigo but also cognitive and emotional symptoms, such as memory and attention deficits, anxiety and depression. More than 85% reported memory loss; despite a normal level of intellectual function, performance on digit symbol, block design, paired associate learning and picture arrangement tasks, was impaired. Since this study, many further studies have been published which document spatial navigation and spatial memory deficits in patients with various kinds of vestibular disorders (e.g., Peruch et al., 1999; Cohen, 2000; Cohen and ­Kimball, 2002; Borel et al., 2004; for review, see Smith et al., 2005). Brandt et al. (2005) reported that patients with BVD exhibited spatial memory deficits even using a virtual Morris water maze task, where they had only to move a cursor to different remembered points on a computer screen. In these patients the spatial memory

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FIGURE 14  A Rose diagram demonstrating the initial heading angles for sham-lesioned and bilateral vestibular deafferentation (BVD) animals in the dark at 14 months post-op. The plots show the animals’ directions in navigating home in a foraging task where they had to remember the location of a home in darkness. Zero degrees represents the correct heading angle. The mean vector is shown by the black line and 95% confidence interval (C.I.) for the mean is shown by the line extending on either side. The inner circles (dotted lines) indicate the number of observations for the given vectors (blue triangles). Note that the BVD animals’ heading angles were distributed equally around 360 degrees. Reproduced from Baek et al., (2010) with permission.

deficits were correlated with a bilateral atrophy of the hippocampus of approximately 17%. However, in UVD patients, spatial memory deficits were observed only in the case of right vestibular dysfunction and no hippocampal atrophy was observed for left or right vestibular loss (Hüfner et al., 2007). Given the severity of the vestibular symptoms in disorders such as Meniere’s disease, it is conceivable that spatial memory impairment is an indirect consequence of symptoms such as vertigo. However, studies of patients with chronic vestibular loss, and without vertigo, have still

demonstrated spatial memory impairment (Guidetti et al., 2008).

Non-Spatial Cognitive Effects of Vestibular Damage One interesting question is whether the cognitive deficits associated with vestibular lesions are limited to spatial memory impairment. Few studies have addressed this question in animals. Zheng et al. (2004) observed deficits in an object recognition memory task

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in BVD rats, where spatial location was controlled for in the experimental design; however, Besnard et al. (2012) did not observe such deficits. Substantial attention deficits have been reported in the 5-CSRTT following BVD (Zheng et al., 2009a), however, since this task has a spatial component, it is difficult to separate the spatial and nonspatial components. Most human studies have reported that other aspects of memory and general intelligence are normal in patients with vestibular disorders (Brandt et al., 2005). However, there is a substantial literature indicating that the same patients can experience depersonalization/derealization syndromes, which include symptoms such as feeling “spaced out,” “body feeling strange” and even déjà vu (Jauregui-Renaud et al., 2008a, 2008b). There is also a small literature linking vestibular dysfunction with dyscalculia (the inability to manipulate numbers) (Risey and Briner, 1990; Yardley et al., 2002). Whether this might be related to the apparent link between numerosity and spatial memory, is unclear (for review, see Smith, 2012).

Relationship to Hippocampal Function Neurophysiological studies aimed at investigating the neural basis of the spatial navigation and memory deficits that occur following vestibular lesions, focused on the hippocampus and related structures that are known to subserve these functions. Stackman et al. (2002) were the first to demonstrate, using reversible chemical lesions of the vestibular labyrinth in rats, that loss of vestibular function resulted in the abnormal responses of “place cells” (neurons that normally respond selectively to particular locations in the spatial environment) in the hippocampus. They showed that place cell firing patterns lost their spatial selectivity following intra-tympanic injections of tetrodotoxin (TTX), but then recovered as the drug’s effects wore off. In a later study, Russell et al. (2003b) showed that complete and permanent surgical BVD resulted in a similar loss of place cell spatial selectivity. Thalamic head direction cells also appear to rely on vestibular input for their directional firing since their responses are abnormal in rats with vestibular lesions (Stackman and Taube, 1997) or semicircular canal occlusion (Muir et al., 2009), and in otoconia-deficient mice (Yoder and Taube, 2009). Both hippocampal place cells (e.g., O’Mara et al., 1994) and thalamic head directions cells (Stackman and Taube, 1998) have been demonstrated to respond to vestibular stimulation, and caloric and electrical activation of the vestibular system has been shown to evoke long-latency responses in the hippocampus (Horii et al., 1994, 2004b; Cuthbert et al., 2000). Nonetheless, the specific pathways through which vestibular information reaches the hippocampus and precisely how the response of hippocampal neurons to vestibular stimulation is generated, remain to

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be elucidated (for review, see Smith et al., 2010). While Stackman et al. (2002) did not observe any effects of intra-tympanic injections of TTX on hippocampal theta rhythm, more recent studies have reported that BVD causes a severe disruption of this EEG pattern (Russell et al., 2006; Neo et al., 2012; Tai et al., 2012). Since theta rhythm is believed to coordinate the response of hippocampal place cells, this may at least partly explain the disruption of their responses following BVD. Interestingly, however, Neo et al. (2012) reported that the spatial memory deficits caused by BVD persisted even after hippocampal theta rhythm was partially restored through electrical stimulation of the septum. Despite the finding that humans with BVD exhibit atrophy of the hippocampus (Brandt et al., 2005), two studies in rats, one using chemical lesions (Besnard et al., 2012) and another using surgical lesions (Zheng et al., 2012b), showed that similar atrophy does not occur in this species, at least not up to 16 months post-operatively. Stereological cell counting showed that there was no loss of neurons in any subregion of the hippocampus following BVD. Nonetheless, a number of neurochemical changes have been reported in the hippocampus following vestibular lesions, including changes in the expression of: (a) NMDA receptors (Liu et al., 2003a; affinity: Besnard et al., 2012); (b) different isoforms of nitric oxide synthase (Liu et al., 2003b; Zheng et al., 2001); (c) the serotonin transporter, which transports serotonin from the synaptic cleft (Goddard et al., 2008b); (d) tryptophan hydroxylase, which is involved in the metabolism of serotonin (Goddard et al., 2008b); (e) synaptosomeassociated protein of 25 kDa (SNAP-25), a presynaptic nerve terminal protein involved in vesicle exocytosis (Goddard et al., 2008c); and (f) cannabinoid CB1 receptors (Baek et al., 2011). The functional significance of these changes remains to be determined. Zheng et al. (2003) removed hippocampal slices from rats that had previously received a UVD, 4–6 weeks or 5–6 months earlier, and found that the amplitude of field potentials (population spike amplitude, somal field excitatory post-synaptic potential [EPSP] slope, and the field EPSP slope) evoked in CA1 neurons by electrical stimulation of the Schaffer collateral pathway, were reduced bilaterally compared to controls (Zheng et al., 2003). Paired-pulse inhibition was also greater at shorter inter-stimulus intervals (ISIs) and paired-pulse facilitation greater at longer ISIs, in the BVD slices compared to controls, suggesting changes in recurrent and feed-forward inhibition mediated by GABA, as well as changes in facilitation mediated by glutamate, in the CA1 region of BVD rats. Nonetheless, a more recent study, using field potential recording in both anesthetized (up to 7 months post-operatively) and alert rats (up to 6 weeks postoperatively), observed no significant difference in baseline field potentials or in the induction or maintenance

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of long-term potentiation (LTP) in the hippocampus of BVD rats compared to controls.

Spatial Navigation and Memory Beyond the Hippocampus Despite the fact that many studies on the effects of vestibular damage on spatial navigation and memory have focused on the hippocampus, it is obvious that any changes that occur there are part of a very complex network of changes that involve not only structures like the thalamus that relay vestibular information from the vestibular nucleus, but also multiple areas of the limbic system and neocortex. For example, neurochemical changes following BVD have been found in the entorhinal, perirhinal and frontal cortices as well as the hippocampus (Liu et al., 2004; Goddard et al., 2008b, 2008c). Studies in rhesus monkeys have shown that BVD results in an acute inability to update memory-guided saccades during head movement, which gradually recovers over 4 months (Wei et al., 2006). By contrast, deficits related to changes in the relative depth, as opposed to the relative direction, of memorized visual targets, did not recover. Such deficits are likely to be related to changes in the firing of neurons in areas of the brain such as the medial superior temporal area (e.g. Gu et al., 2007). Thus, the neural network that underlies the vestibular contribution to spatial navigation and memory involves many different levels of the limbic and neocortical systems that are engaged in the generation, control and interpretation of heading and spatial perception (for review, see Shinder and Taube, 2010).

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Further Readings Baek, J. H., Zheng, Y., Darlington, C. L., & Smith, P. F. (2009). The CB1 receptor agonist, WIN 55,212–2, dose-dependently disrupts object recognition memory in adult rats. Neuroscience Letters, 464, 71–73. Baloh, R. W., & Honrubia, V. (1990). Clinical Neurophysiology of the ­Vestibular System (2nd ed.). California: FA Davis Co. Bankoul, S., & Neuhuber, W. L. (1990). A cervical primary afferent input to vestibular nuclei as demonstrated by retrograde transport of wheat germ agglutinin-horseradish peroxidase in the rat. Experimental Brain Research, 79, 405–411. Barmack, N. H., Baughman, R. W., Eckenstein, F. P., & Shojaku, H. (1992). Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers. Journal of Comparative Neurology, 317, 250–270. Bettler, B., & Tiao, J. Y. (2006). Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacology & Therapeutics, 110, 533–543. Delfini, C., Diagne, M., Angaut, P., Buisseret, P., & Buisseret-Delmas, C. (2000). Dentatovestibular projections in the rat. Experimental Brain Research, 135, 285–292. Devau, G., Lehouelleur, J., & Sans, A. (1993). Glutamate receptors on type I vestibular hair cells of guinea pig. European Journal of Neuroscience, 5, 1210–1217. Diagne, M., Delfini, C., Angaut, P., Buisseret, P., & Buisseret-Delmas, C. (2001). Fastigiovestibular projections in the rat: retrograde tracing coupled with gammaamino-butyric acid and glutamate immunohistochemistry. Neuroscience Letters, 308, 49–53. Goldberg, J. M., & Cullen, K. E. (2011). Vestibular control of the head: possible functions of the vestibulocollic reflex. Experimental Brain Research, 210, 331–345.

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Graybiel, A. M., & Hartwieg, E. A. (1974). Some afferent connections of the oculomotor complex in the cat: an experimental study with tracer techniques. Brain Research, 81, 543–551. Haroian, A. J. (1984). Fastigial afferent projections in rat: an HRP study. The Anatomical Record, 208, 71A. Ketterer, T. J., Lyon, M. J., & Gacek, R. R. (1990). Commissural projections of the superior vestibular nucleus in the rat. Acta Otolaryngologica, 110, 31–36. Kharazia, V. N., Wenthold, R. J., & Weinberg, R. J. (1996). GluR1immunopositive interneurons in rat neocortex. Journal of Comparative Neurology, 368, 399–412. Korte, G. E., & Friedrich, V. L. (1979). The fine structure of the feline superior vestibular nucleus: Identification and synaptology of the primary vestibular afferents. Brain Research, 176, 3–32. Kukushima, K. (1997). Cortico-vestibular interactions: Anatomy, electrophysiology, and functional considerations. Experimental Brain Research, 117, 1–16. Mouginot, D., & Gahwiler, B. H. (1995). Characterization of synaptic connections between cortex and deep nuclei of the rat cerebellum in vitro. Neuroscience, 64, 699–712. Newlands, S. D., Kevetter, G. A., & Perachio, A. A. (1989). A quantitative study of the vestibular commissures in the gerbil. Brain Research, 487, 152–157. Nishiike, S., Guldin, W. O., & Baurle, J. (2000). Corticofugal connections between the cerebral cortex and the vestibular nuclei in the rat. Journal of Comparative Neurology, 420, 363–372. Petralia, R. S., Wang, Y. X., Mayat, E., & Wenthold, R. J. (1997). Glutamate receptor subunit 2-selective antibody shows a differential distribution of calcium-impermeable AMPA receptors among populations of neurons. Journal of Comparative Neurology, 385, 456–476. Petralia, R. S., Wang, Y. X., Zhao, H. M., & Wenthold, R. J. (1996). Ionotropic and metabotropic glutamate receptors show unique postsynaptic, presynaptic, and glial localizations in the dorsal cochlear nucleus. Journal of Comparative Neurology, 372, 356–383. Peusner, K. D., & Giaume, C. (1994). The first developing “mixed” synapses between vestibular sensory neurons mediate glutamate chemical transmission. Neuroscience, 58, 99–113. Sadjadpour, K., & Brodal, A. (1968). The vestibular nuclei in man: a morphological study in the light of experimental findings in the cat. Journal für Hirnforschung, 10, 299–323. Sato, K., Kiyama, H., & Tohyama, M. (1993). The differential expression patterns of messenger RNAs encoding non-N-methyl-D-aspartate glutamate receptor subunits (GluR1–4) in the rat brain. Neuroscience, 52, 515–539. Shamboul, K. M. (1980). Lumbosacual predominance of vestibulospinal fiber projection in the rat. Journal of Comparative Neurology, 192, 519–530. Shiroyama, T., Kayahara, T., Yasui, Y., Nomura, J., & Nakano, K. (1999). Projections of the vestibular nuclei to the thalamus in the rat: Phaseolus vulgaris leucoagglutinin study. Journal of Comparative Neurology, 407, 318–332. Takahashi, Y., & Kubo, T. (2007). Excitatory synaptic transmission in the rat medical vestibular nucleus. Acta Otolaryngology, Supplement, 528, 56–58. Umetani, T., & Tabuchi, T. (1988). Topographic organization of the corticonuclear and corticovestibular projections from the pyramus and copula pyramidus in the albino rat: an autoradiographic orthograde tracing study. Brain, Behavior and Evolution, 32, 160–168. Umetani, T., Tabuchi, T., & Ichimura, R. (1986). Cerebellar corticonuclear and corticovestibular projections from the posterior lobe of the albino rat, with comments on zones. Brain, Behavior and Evolution, 29, 54–67. Voogd, J., Gerrits, N. M., & Ruigrok, T. J. (1996). Organization of the vestibulocerebellum. Annals of the New York Academy of Sciences, 781, 553–579.

VI.   SYSTEMS

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28.  THE VESTIBULAR SYSTEM

Wang, Y. X., Wenthold, R. J., Ottersen, O. P., & Petralia, R. S. (1998). Endbulb synapses in the anteroventral cochlear nucleus express a specific subset of AMPA-type glutamate receptor subunits. Journal of Neuroscience, 18, 1148–1160. Xiong, G., & Matsushita, M. (2000). Connections of Purkinje cell axons of lobule X with vestibulospinal neurons projecting to the cervical cord in the rat. Experimental Brain Research, 131, 491–499.

Zhang, S., & Trussell, L. O. (1994). A characterization of excitatory postsynaptic potentials in the avian nucleus magnocellularis. Journal of Neurophysiology, 72, 705–718. Zheng, Y., Mason-Parker, S. E., Logan, B., Darlington, C. L., Smith, P. F., & Abraham, W. C. (2010). Hippocampal synaptic transmission and LTP in vivo are intact following bilateral vestibular deafferentation in the rat. Hippocampus, 20, 461–468.

VI.   SYSTEMS