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Journal of Vestibular Research, Vol. 6, No. 3, pp. 185-201, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0957-4271196 $15.00 + .00 ELSEVIER 0957-4271 (95)02042-X Original Contribution THE RECOVERY OF STATIC VESTIBULAR FUNCTION FOLLOWING PERIPHERAL VESTIBULAR LESIONS IN MAMMALS: THE INTRINSIC MECHANISM HYPOTHESIS* Cynthia L. Darlington* and Paul F. Smitht *Department of Psychology and the Neuroscience Research Centre, University of Otago and the tDepartment of Pharmacology, School of Medical Sciences, University of Otago Medical School, Dunedin, New Zealand Reprint address: Dr. Cynthia L. Darlington, Dept. of Psychology, University of Otago, Dunedin, New Zealand. Tel: (64) (3) 479 764'1, Fax: (64) (3) 479 8335 D Abstract- This theoretical paper describes the "intrinsic mechanism hypothesis," a new hypothesis of vestibular compensation, the behavioral recovery that follows unilateral deafferentation of the vestibular labyrinth (UVD). The most salient characteristic of vestibular compensation is the decrease in the severity of the static ocular motor and p$ostural symptoms that follow UVD, associated with a recovery of resting activity in the ipsilateral vestibular nucleus complex (VNC). The speed of static compensation in some mammalian species (for example, cat) has suggested that reactive synaptogenesis is an unlikely explanation because it is too slow. Other, more rapid mechanisms, such as denervation supersensitivity, receptor-up-regulation, or increased neurotransmitter release, were reasonable possibilities. However, to date, each study that has addressed these possibilities has failed to find any change that could account for the recovery of VNC resting activity. The search for such "substitutive" mechanisms was based on the hypothesis that something other than the VNC neurons themsefives would activit: that have to "replace'' the the ipsilateral vestibular nerve normaHy provides. However, brainstem slice studies demonstrate that, at least in vitro, VNC neurons do not need the vestHndar nerve in order to generate resting activity. On the basis of these and other considerations, *This paper is dedicated to the memory of Professor John I. Hubbard, our mentor and friend, who died October 1, 1995. RECEIVED 20 June 1995; AccEPTED we suggest that following a brief calcium-induced diaschisis, VN C neurons ipsilateral to the UVD reactivate the intrinsic membrane properties that normally contribute to their resting activity in vivo, and that this recovery of resting activity accounts for static vestibular compensation. D Keywords- vestibular compensation; unilateral labyrinthectomy; vestibular nerve transection; vestibular nucleus. Introduction "Vestibular compensation~' is a process of behavioral recovery that occurs following theremoval of afferent input from the vestibular labyrinth, either by surgical removal of the vestibular receptors or by transsection of the vestibular nerve. Immediately following unilateral peripheral vestibular deafferentation ' o:; ocmar motor and postural symptoms develops; these symptoms are usually divided into static and dynamic symptoms, depending upon whether they persist in the absence of head movement (static) or occur as a result of head movement (dynamic) (see 1-5 for reviews). However, in some mammalian species, within a few days, the static symptoms have undergone a remarkable degree of recovery (compensation), even in 12 October 1995. 185 (' 186 C. L. Darlington and P. F. Smith darkness. The extent of the static compensation is generally greater in light than in darkness, because vision is used to reduce symptoms like spontaneous ocular nystagmus (SN) (Table 1). However, among lower mammalian species (for example, rat, guinea pig, cat), even in darkness, static symptoms such asSN have usually compensated to less than 1007o of their initial values by 3 to 4 days ble For reasons that are not clear, SN compensation in dar!<.ness appears to take sus monkey 0 to 20 days in humans (1 Compensation of the static symptoms is correlated with a recovery of resting activity in the ipsilateral vestibular nucleus complex (VNC), although the extent of the recovery of resting activity is controversial and varies between the different subnuclei (Table 2). Despite the fact that vestibular compensation research began in the 1800s with the work of Flourens and Bechterew (see 1 for a review) and that an enormous volume of research has been published on the subject since, the neurophysiological and neurochemical bases of vestibular compensation are still not completely understood. In this theoretical paper, we propose a new hypothesis, called the "intrinsic mechanism hypothesis," which we believe ac- counts for most of the published data in the area of vestibular compensation of static vestibular function in mammals. The intrinsic mechanism hypothesis proposes that vestibular compensation of the static symptoms of UVD is directly related to the recovery of resting activity in the ipsilateral VNC, which is largely a result of changes in the intrinsic 1nembrane of VNC neurons (22). This ~zddresses static vestibular is not intended to include submammalian species such as frogs: 1) do not exhibit SN, which in lower mammals compensates more quickly than most other static and dynamic symptoms (see 1-5 for reviews); 2) in frogs, compensation of static symptoms such as roll head tilt occurs over a period of months and has not been demonstrated to be tightly correlated with the recovery of resting activity of type I VNC neurons ipsilateral to the UVD (see 1-5 for reviews); 3) in frogs, vestibular compensation is associated with an enhancement of the efficacy of the excitatory brainstem commissural input to the ipsilateral VNC, whereas in mammalian species no such change in efficacy has been demonstrated and these commissural fibres form part of a functionally inhibitory commissural system (see 1-5 for reviews). Table 1. Examples of Studies of Different Mammalian Species That Demonstrate Rapid Compensation of Spontaneous Nystagmus Author(s) Species Sirkin et al. (6) Smith et al. (7) rat guinea pig Newlands and Perachio (8) Yamanaka et al. (9) Haddad et al. ( i 0) gerbil rabbit cat Days to Compensation Min Value Post-UVD 3-4 (light) 2 (light) 2 (red light) 1 -2 (light) 4 (light) 3 (light and dark) 2 b/1 5 s 1 . 6 b/1 5 s 1 b/15 s N/A 2.5 b/i 0 s 2 °/S %Max Value Post-UVD 2 8 5 N/A 7 2 Examples of studies of 4 species in which compensation of spontaneous nystagmus (SN) develops rapidly. "Light" and "dark" refer to the conditions under' which the measurements were made; "b" refers to beats of spontaneous nystagmus; s: second; N/ A: data not available. % max value: %of maximal SN measured at that time post-UVD. 'red light' in (7) refers to measurements made in red light, to which guinea pigs are blind; before this the animals were maintained in total darkness for 50 h post-UVO. All values tor these studies are approximate and are estimated from the authors' graphs. Note that these particular studies have been selected as examples because the majority are systematic studies, that is, measurements made on a regular basis so that "time-to-compensation" can be estimated. The Intrinsic Mechanism Hypothesis 187 Table 2. Examples of Studies of Mammalian Species That Demonstrate Recovery of Resting Activity in the Ipsilateral VNC Author(s) Hamann and Lannou (14) Smith and Curthoys (1 5) Newlands and Perachio (8) Precht et al. (16) Ried et al. (17) Pompeiano et al. (1 8) Lacour et al. (i 9) Zennou-Azogui et al. (20) Waespe et al. (21) Species Preparation Subnucleus rat guinea pig gerbil cat cat cat cat cat monkey anesthetized anesthetized decerebrate decerebrate anesthetized decerebrate alert alert alert MVN MVN MVN MVN MVN LVN LVN LVN MVN MVN medial vestibular nucleus. LVN lateral vestibular nucleus. For the purposes of our hypothesis, which specifically concerns static compensation in mammals, we propose that the dynamic aspects of vestibular compensation are largely dependent on the recovery of resting activity in the ipsilateral VNC and, in addition, the substitution of other sensory inputs for the missing labyrinthine input (see 2-5,23 for reviews). Hence, the intrinsic mechanism hypothesis in not a mono-causal hypothesis of vestibular compensation: it proposes a specific mechanism for one aspect of vestibular compensation, but fully acknowledges that other, more complex mechanisms, involving other parts of the CNS, are responsible for dynamic compensation. We acknowledge that much of our hypothesis is speculative; however, we suggest that whether or not it is entirely correct, it is completely testable. As Robinson (24, p. 519) said in discussing his early models of oculomotor function, "These hypothetical schemes attempt to anticipate what must eventually be discovered by ... experimentation and are offered here the Drovoking debate and further investigation.'' Our hypothesis is based on a number of assumptions regarding vestibular compensation, which we will address in turn. We emphasize that the following is not intended to be an exhaustive review of the literature (for literature reviews on vestibular compensation in mammals, see 1-5, 25-28); we cite papers only according to their direct relevance to the hypothesis we are describing. Assumptions of the "Intrinsic Mechanism Hypothesis" Assumption 1: The stimulus for vestibular compensation is the inactivation of the vestibular afferents, not their degeneration. A comprehensive theory of any form of plasticity must address the question of what, precisely, is the stimulus for the adaptive or maladaptive neural change in question. In the case of vestibular compensation, there is considerable evidence that surgical removal of the vestibular receptor cells (unilateral labyrinthectomy, UL) and surgical transsection of the vestibular nerve result in similar behavioral symptoms, a similar asymmetry in neuronal activity between the bilateral vestibular nucleus complexes (VNC), and similar patterns of vestibular compensation (for example, compare 6,15,29,30). However, it is clear that the vestibular nerve degenerates much more tion than following a UL example 6,30). This suggests that it is the inactivation of the vestibular nerve, or some event associated \vith it, that is the stimulus for vestibular compensation, not the structural degeneration of the vestibular nerve itself. This hypothesis has not been tested directly in mammalian species; however, it has been tested in frogs. Kunkel and Dieringer (31) reported that the electrophysiological changes that occur in the frog 188 VNC following UVD are similar following preor post-ganglionic vestibular nerve transsection (see also 32). In the cochlear nucleus, blockade of VIIIth nerve activity by tetrodotoxin produces a rapid glial reaction in the absence of degeneration, suggesting that the cessation of presynaptic activity may be a sufficient stimulus for the activation of "recovery" processes (33). That inactivation of the vestibular nerve is the stimulus for vestibular compensation is also supported by the observation that celeraceci the vestibular nerve ipsilateral to the labyrinthectomy (34). Assumption 2: Vestibular compensation is not due to any form of recovery in the peripheral vestibular system. Although evidence has been reported recently that demonstrates regeneration of vestibular receptor hair cells following aminoglycoside toxicity (35-38), there is no evidence to suggest that vestibular receptor cells can regenerate following surgical UL or vestibular nerve transsection (for example, 6,39,40). Only a few studies have examined the function of neurons in Scarpa's ganglion following UVD: all of these studies have shown that the number of neurons with remaining resting activity is very small and that the discharge of these few neurons is erratic and of low frequency (6, 15,29). Taken together, these studies suggest that vestibular compensation is not due to any form of recovery in the peripheral vestibular labyrinth. Assumption 3: Static compensation is correlated with a recovery of resting · activity in ipsilateral vestibular nucleus complex (VNC) neurons. There is little question that vestibular compensation of static ocular motor symptoms such as SN is correlated with a recovery of resting activity in type I neurons of the ipsilat- C. L. Darlington and P. F. Smith eral medial vestibular nucleus (MVN). What is debatable is the extent of the recovery, which seems to vary in different studies according to the type of preparation used (see 41, 42 for discussion of this point; Table 2). Recently, Waespe et al. (21) have demonstrated, in the alert monkey, that a substantial degree of resting activity has recovered in type I MVN neurons at 1 month following a bilateral vestibular neurectomy. This result demonstrates quite dearly that the recovery of lYfVN neurons cannot be attributed to the anesthetic used to record them, or to the use of decerebration or spinal transsection. Furthermore, because the neurectomy was bilateral, therecovery of type I resting activity cannot be attributed to the contralateral MVN or to the vestibular commissures (for example, 15,43, 44). Lacour et al. (19) and Zennou-Azogui et al. (20,45) have also reported a significant recovery of resting activity in the ipsilateral lateral vestibular nucleus (LVN) following unilateral vestibular neurectomy in the alert cat; however, Pompeiano and colleagues (eg 18) have reported a limited recovery of resting activity in small LVN neurons with cervical spinal projections. The recovery of resting activity in the LVN may be more limited than in the MVN, which may explain the slower and less complete compensation of some static postural symptoms (for example, roll head tilt in guinea pigs; see 2 for a review). The general consensus that static compensation is correlated with a recovery of resting activity in the ipsilateral VNC is supported by metabolic studies using 2-deoxyglucose (for example, 46,47 ,48) and cytochrome oxidase (49). However, these same studies demonstrate changes in widespread areas of the CNS, which may be related to the compensation of persistent static postural symptoms and dynamic ocular motor and postural symptoms. According to morphological studies, there is little cell loss in the ipsilateral VNC following UVD (18,50-52). In the ipsilateral and contralateral LVN following UVD, the presence of glial fibrillary acidic protein (GFAP) has been reported, which may be related to some form of structural reorganization in the The Intrinsic Mechanism Hypothesis 189 LVN in addition to phagocytosis of primary vestibular terminals (53). Although the electrophysiological and metabolic studies described are correlational, it is not unreasonable to suggest that the partial recovery of resting activity in neurons of the ipsilateral VNC may have a causal role in static compensation, since lesions of the ipsilateral VNC have been shown to prevent compensation or to cause a loss of compensation (decompensation) (54,55). Assun1ption 4: Some aspects of mam1nalian static compensation (for example, compensation of SN) are not dependent on reactive synaptogenesis, denervation supersensitivity, receptor up-regulation, or increased neurotransmitter release within the ipsilateral VNC. Since Spiegel and Demetriades (54), numerous researchers have entertained possible explanations for static compensation in terms of changes within the ipsilateral VNC, for example, reactive synaptogenesis, denervation supersensitivity, receptor up-regulation, or increased neurotransmitter release. To date, none of these explanations can adequately account for static compensation in all mammalian species (Table 3). Reactive synaptogenesis has often been suggested as a possible explanation for vestibular compensation; although there is evidence to support its occurrence in frog (for example, 66,67), the evidence from lower mammalian species (for example, 5 ,68) suggests that these changes develop too slowly to be the primary cause of the compensation of SN, which has been shown to occur within 3 to 4 days, even in darkness, in guinea pig and cat (68; Table 1). It has been demonstrated in many studies that vestibular compensation in frog is associated with an increase in the efficacy of excitatory brainstem commissural input to ipsilateral VNC neurons (for example, 31 ,69, 70; see 2 for a review). However, studies in mammalian species have failed to find any corresponding change in commissural efficacy (for example, 8,15,16,17,71,72) and, in any case, in mammals the vestibular commissures are part of a functionally inhibitory system between horizontal canal-related 2nd-order MVN neurons (for example, 73; see 44 for a discussion). Table 3. Studies That Have Not Demonstrated Changes in the Ipsilateral VNC That Can Account for the Recovery of Resting Activity Following UVD Author(s) Species Cochran et al. (56) frog Knopfel and Dieringer (57) frog de Waele eta!. (58) Raymond et al. (59) Li et ai. (60) Calza et a!. (61) Smith and Curthoys (I 5) de Waele et al. (62) Smith and Darlington (63) Darlington et al. (64) Newlands and Perachio (8) Precht et al. (16) Reid et al. (17) Korte and Friedrich (51) Gacek et al. (52) Thompson et al. (65) rat ral Finding no evidence for increased NMDA receptor mediation of commissural input no evidence for increased NMDA receptor mediation of commissural input no increase in NMDJ\ receptor mRI\I.t, no increase 1r: giuta:1atE receptor~ ~a; rat guinea pig guinea pig guinea pig guinea pig gerbil cat cat cat cat monkey no evidence for up-regulation of acetylcholine or GABA receptors no increase in efficacy of commissural input to ipsilateral VNC no evidence for increased NMD/\ receptor function in ipsilateral VNC no increase in NMDA receptor sensitivity no increase in ACTH-(4-1 0) receptor sensitivity no increase in efficacy of commissural input to ipsilateral VNC no increase in efficacy of commissural input to ipsilateral VNC no increase in efficacy of commissural input to ipsilateral VNC morphological changes slow morphological changes slow increased GABA levels in ipsilateral VNC, presumed to increase inhibition NMDA: N-methyl-o-asparate. "VNC ": vestibular nucleus complex. 'ACTH-( 4-1 0)': adrenocorticotrophic hormone, fragment 4-1 0. 190 We and others have suggested that static compensation might be related to an increase in the affinity, efficacy, or number of Nmethyl-n-aspartate (Nl\IIDA) receptors on the ipsilateral VNC neurons (62, 74-78). However, electrophysiological (57 ,63), pharmacological (59), and biochemical studies (58) do not support an increase in the number or sensitivity of NlVfDA receptors in the ipsilateral VNC. Other studies of inhibitory amino acid and acetylcholine receptors also do not suooort ,,:oanges might be rei a ted w the recovery of resting activity (61). Some studies have examined whether therelease of amino acid neurotransmitters changes during vestibular compensation. Thompson and colleagues (65) reported that GABA levels increase in the ipsilateral LVN and decrease in contralateral LVN at 3 to 6 days post-UVD. Li and colleagues (60) have reported that glutamate concentrations gradually decrease in the ipsilateral VNC following UVD and that they do not recover to normal levels within 7 days post-UVD. However, Henley and Igarashi (79) have reported that at 10 months post-UVD, normal glutamate levels have been re-established in the ipsilateral VNC of the squirrel monkey. These studies suggest that, at least with respect to amino acids, it is unlikely that increased neurotransmitter release can explain the recovery of resting activity in ipsilateral VNC neurons. One possibility that has not been systematically investigated in mammals is that static compensation may be due to a rapid alteration of the intrinsic membrane properties of ipsilateral VNC neurons (22,80,81). Darlington and colleagues, using extracellular recording from 1\!IVN neurons in guinea pig brainstem slices ipsilateral to a previous have reported a trend toward higher resting discharge rates compared to MVN neurons in slices from labyrinthine-intact animals (22,63,64). However, to date, no intracellular studies of the membrane properties of MVN neurons ipsilateral to a chronic UVD, have been conducted (except in frog, where the resting potentials and input resistances of ipsilateral VNC neu- C. L. Darlington and P. F. Smith rons were found to be similar to those in labyrinthine-intact frogs (70)). Although many lesion studies have been conducted in the search for an explanation of vestibular compensation (see 2 for a review), one area of the CNS in which lesions have consistently been shown to disrupt compensation is the inferior olive. Llinas and colleagues (82) reported that inferior olive lesions in rat prevented compensation or caused decompensation of the static oc:1lar '11otor and postural symptoms, a result that has been replicated Azzena and colleagues using guinea pig. Other studies have shown that in labyrinthineintact rats, inactivation of the inferior olive by chemical lesions or reversible cooling causes a decrease (approximately 33 OJo) in the resting activity of contralateral MVN neurons, which recovers over time (84). It is interesting that inferior olivary neurons are themselves endowed with numerous intrinsic membrane properties, some of which allow them to maintain pacemaker activity in vitro (for example, 85). It is possible that, under normal circumstances, the contralateral inferior olive contributes to the resting activity of type I MVN neurons and that, following UVD, synaptic input from inferior olivary neurons, driven by their intrinsic properties, is used to "recalibrate" pacemaker activity in the deafferented MVN. Assumption 5: In the labyrinthineintact animal, the intrinsic properties of VNC neurons contribute to their resting activity_, along with synaptic input. The hypothesis that the recovery of resting activity in the ipsilateral VNC during vestibular compensation is due to a "substitutive" process that provides the missing resting activity (for example, reactive synaptogenesis or denervation supersensitivity) is based on the assumption that resting activity is reduced in the ipsilateral VNC following UVD because the ipsilateral vestibular nerve usually supplies VNC neurons with all of their tonic excitation. The Intrinsic Mechanism Hypothesis However, this assumption is difficult to test because it is difficult to obstruct vestibular nerve input to the ipsilateral VNC without producing a UVD and thereby activating the changes that lead to vestibular compensation. There are several lines of evidence that suggest that the vestibular nerve may not be solely responsible for VNC neuron resting discharge. First, Raymond and colleagues (68) have estimated that approximately 35!1Jo of immunoreactive synaptic in the JvfVI\f are due to vestibular nerve input, suggesting that, for many IVIVN neuronsj another 65% of synaptic inputs derive from other sources. Second, Li and colleagues (60) have reported that following UVD, the loss of glutamate across the various subnuclei of the ipsilateral VNC is variable and, at 2 days postUVD, reaches a maximum of only about 21 OJo in the ipsilateral MVN. Since there is convincing evidence that the transmitter used by the vestibular nerve is glutamate (see 86,87 for reviews), these results are also consistent with the view that the vestibular nerve is only partially responsible for the resting activity of VNC neurons and that a substantial amount of glutamatergic excitation may derive from other sources. Third, many LVN neurons do not show large decreases in resting activity following UVD, suggesting that they do not rely on the vestibular nerve for the majority of their resting activity (for example, 18). Fourth, a large number of in vitro brainstem slice studies have shown that the resting discharge of MVN neurons persists in brainstem slices maintained in vitro, in the absence of from the vestibular nerves and mos1 other Sf; fer· 191 88,124 for reviews). However, at present, there is no evidence that such intrinsic membrane properties contribute to the resting activity of VNC neurons in vivo; this will be an important area of investigation for future studies. It is unlikely that intrinsic properties would account for all, or even most, of the resting activity that is observed in VNC neurons in vivo 0 25, there will be an in1portant contribution made· the: vestibular nerve ex~·L.,_,.,~ . inferior ne:urons; , including other VNC neurons. Hovvever, the in vitro data suggest that intrinsic properties n1ay, nonetheless, make a contribution to VNC neuron resting activity. Assumption 5 may offer a partial solution to a persistent problem that has confronted modellers of oculomotor function. In order to obtain an eye position signal from a head velocity signal, the head velocity signal must be mathematically integrated. If, however, the head velocity signal (that is, vestibular nerve input) is superimposed upon a background signal (that is, resting activity also supplied by the vestibular nerve), then both signals would be integrated, resulting in errors of eye position (see 127, 128). If, however, the resting activity of VNC neurons were provided partially by intrinsic membrane properties that are independent of synaptic input, this problem would be partially overcome because the major function of the vestibular nerve would be to deliver head movement infonnation that modulates this resting 2 or in the presence of 81,1 3, 4;see88fo:·a neurons demonstrate In vitro studies suggest that a persistent conductance may be at least partly responsible for this resting activity (1 02,113, 114; Table 4; see also 122, 123). This evidence strongly suggests that VNC neurons have the capacity, at least in vitro, to generate resting activity as a result of their intrinsic membrane properties (see 22,81, 1\1any vestibular compensation studies have failed to find neurotransmitter, receptor, or other changes within the ipsilateral VNC that account for the recovery of resting activity (see Table 3). We propose that this is because the C. L. Darlington and P. F. Smith 192 Table 4. Studies That Have Demonstrated Resting Activity in the Mammalian VNC In Vitro Species Subnucleus Recording rat rat rat rat rat rat guinea pig rat guinea pig rat explant incl. VNC MVN MVN MVN MVN MVN MVN MVN MVN MVN extracellular extracellular extra/intracellular intracellular extra/intracellular extracellular extracellular intracellular intracellular extracellular 'ntracellular extracellular extracellular intracellular intracellular extracellular intracellular extra/intracellular intracellular extracellular (FP) extracellular extracellular intracellular extracellular extracellular intracellular extra/intracellular extra/intracellular extracellular patch clamp patch clamp intracellular intracellular extracellular extracellular extracellular intracellular extracellular Author(s) Fukuda and Loeschcke (89) Kobayashi and Murakami (90) Gallagher et al. (9 i) Lewis et al. (92) Ujihara et al. (93) Ujihara et al. (94) Darlington et al. (22) Lewis et al. (95) Serafin et al. (96) Doi et al. (97) Phelan et 81. 1·~8\ Smith et al. 199) Darlington et al. ( 1 00) Serafin et al. ( 1 0 1 ) Serafin et al. ( 1 02) Smith et al. (1 03) Phelan and Gallagher (1 04) Carpenter and Hori (1 05) Gallagher et al. (1 06) Capocchi et al. (1 07) Smith and Darlington (63) Dutia et al. (80) Serafin et al. (1 08) Darlington et al. (64) Johnston et al. (1 09) Serafin et al. (11 0) de Waele et al. ( 1 11 ) Lin and Carpenter (81 ) Lin and Carpenter (112) Kinney et al. (113) Takahashi et al. (114) Johnston et al. (115) Vibert et al. (116) Hutchinson et al. (117) Hutchinson et al. ( 11 8) Darlington and Smith (119) Vibert et al. (120) Lapeyre and De Waele ( 1 21 ) ~ ,-.. .!. :;u1nea p1g guinea pig guinea pig guinea pig guinea pig rat rat rat rat guinea pig rat guinea pig guinea pig rat guinea pig guinea pig rat rat rat rat rat guinea pig guinea pig guinea pig guinea pig guinea pig guinea pig ~;iVl\1 MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN MVn MVN MVN MVN MVN MVN MVN MVN MVN MVN MVN Abbreviations as in previous tables. FP: field potential recording. resting activity that reappears during vestibular c01npensation was never completely dependent upon vestibular nerve input in the first place. It was partially due to intrinsic membrane properties that also contribute to VNC neuron resting activity in the labyrinthine-intact animal. At present, the best evidence in support of this assumption is that when the MVN ipsilateral to the UVD is removed from a compensated animal and maintained in vitro, resting activity recovers within a few hours in many MVN neurons, even in the presence of synaptic blockade within the slice (22,63 ,64). A number of in vivo electrophysiological stud- ies have provided evidence that is consistent with these in vitro results: the recovery of resting activity in VNC neurons ipsilateral to a UVD has been found to persist following transsection ofbrainstem and cerebellar commissural inputs (for example, 15,16), decerebration (for example, 8, 16,18, 129) or spinal transsection (42,130), although the amount of resting activity remaining may be reduced in some cases (for example, spinal transsection; 42,130). We do not exclude the possibility that intrinsic membrane properties (for example, persistent Na + conductances) in ipsilateral VNC neurons are in some way up-regulated during 193 The Intrinsic Mechanism Hypothesis vestibular compensation in order to compensate for the loss of the contribution that vestibular nerve input makes to VNC neuron resting activity (for example, 22, 115). However, our hypothesis places the main responsibility for the recovery of resting activity in ipsilateral VNC neurons on intrinsic properties that are already present in the normal VNC. If the resting activity that returns during vestibular compensation is provided by intrinsic properties that are present under normaL. labyrinthine-intact circumstances, why does it disappear immediately following UVD? One very likely possibility is "neural shock" or "diaschisis" (see 131 for a review). It is well known that following deafferentation due to physical trauma or hypoxia/ischemia, neurons at the center of the damage (the so-called "core") die quickly, whereas those that received synaptic input from the neurons in the core (the "penumbral region") undergo secondary pathological changes, sometimes referred to as the "secondary injury" phenomenon (see 131 for a review). In many cases, a reduction in electrical and metabolic activity and, sometimes, cell death in the penumbra is due to excitotoxicity caused by an increased release of glutamate from dying neurons in the core. At first, the increased glutamate release causes injury discharges, but gradually intracellular calcium increases as N-methyl-Daspartate (NMDA) receptor /channels and voltage-dependent calcium channels are opened (for example, 132; see 133 for a review). Recent high-performance liquid chromatography (HPLC) studies by Lj et al. (60) demonstrate that the levels of glutamate within the ipsilateral VNC do not decrease '"'·'·n even the reduction in glutamate concentrations in the ipsilateral I'v1VN is only about 12 to 21 GJo. This means that high glutamate concentrations remain in the ipsilateral VNC following possibly without normally functioning presynaptic mechanisms for metabolising the glutamate once it is released. This may create a situation in which VNC neurons are overstimulated by glutamate released by the dying vestibular nerve; those VNC neurons that do not received direct input from the vestibular nerve i.ULAU._, ........ may receive increased glutamatergic input from other VNC neurons. Since the original brainstem slice studies in mammalian species (91; see 88 for a review), researchers have been surprised by the degree of resting activity present in the deafferented VNC and how quickly this resting activity recovers following a brief incubation period (that is, 1 to 2 h) in vitro. Why is it that the resting activity of MVN neurons in vivo gradually recovers over 2 to 3 days following whereas the resting activity of I'vfVN neurons in brainstem slices n1aintained in vitro can recover following 1 to 2 h of incubation in artificial cerebrospinal fluid (ACSF)? One possible explanation is that, in the latter case, superfusion with ACSF washes out the glutamate released by the vestibular nerve following UVD, thus short-circuiting the diaschisis that normally follows the deafferentation. Assumption 7: Peripheral vestibular deafferentation causes biochemical changes in the ipsilateral VNC that are consistent with diaschisis, especially those relating to calcium. We propose that following UVD, the glutamate concentrations within the ipsilateral VNC, which are sustained during the first 24 hours, result in a form of calcium-induced diaschisis: glutamate overstimulates AMPA/ kainate and NMDA receptors on VNC neurons, resulting in increased calcium influx, leading to increased and perhaps the calcimn chanrurtner nol"\f'rlf"c>Al"li· glutamate into the There is no direct evidence to support this assumption, although there are now a great many findings that are consistent with it. The induction of immediate early genes (lEGs) has been demonstrated to be a marker for cell damage in the penumbral regions of a stroke or a surgical lesion (132; see 134 for a review). 194 The lEG protein, fos, in particular, is induced in many cases of neural damage, and its induction is often correlated with increased intracellular calcium concentrations ( 132; see 134, 135 for reviews). Kaufman and colleagues (136) reported the induction of c fos in the bilateral l\IIVN at 24 h a chemical UVD in rats. Elsewhere t'os induction was transient and and Perachio c fos and zif/268 a lesser are induced by anodal stimulation of the vestibular nerve. At present, there is no direct evidence to support the assun1ption that UVD or anodal stimulation of the vestibular nerve results in an increased calcium influx in the ipsilateral VNC. However, it has recently been reported that depolarization of the vestibular nerve causes an increased calcium influx in ipsilateral MVN neurons, measured using rhod 2 fluorescence (140). This increased calcium influx could be blocked by an NMDA receptor antagonist or reduced by the L-type calcium channel antagonist, nifedipine. If UVD causes injury discharges in the vestibular nerve at the time of the deafferentation, then this might result in increased calcium influx in ipsilateral VNC neurons. One result that is consistent with the possibility of injury discharge is that administration of procaine to the round window prior to UVD results in a reduction in the severity of UVD ) . The VHUJH.,.u.-~.<.A'V•U that the ·;es:ibular disat the time of the UVD and reducing calcium inf1ux 1n ipsilateral VI'IC neurons see also 132). To date, the available protein phosphorylation studies also support calcium-related changes in the VNC following UVD. Flohr and colleagues have found a number of phosphorylation changes in whole brain homogenates from different stages of vestibular C. L. Darlington and P. F. Smith compensation in the frog; some of the protein substrates are phosphorylated by calciumcalmodulin-dependent protein kinases (142), another appeared to be immunologically similar to the GAP-43/B-50 protein, which is phosphorylated the calcium-diacylglycerolactivated see also One is why cell death VNC in the presence of increased intracellular calcium. It has :Jeen demonstrated ~hat some populations aeurons the increase in intracellular calcium is reversible ; see 146 for a review). Ourthe development of hindbrain ischemia, the lVIVN was found to be one of the most resistant brainstem areas to cell death (145). One possible explanation for the survival of VNC neurons is the availability of calcium-binding proteins within the cytoplasm of the neurons, which can bind and therefore inactivate free calcium ions. It has been reported that neurons that are immunoreactive for the calciumbinding protein, calretinin, are resistant to the neurotoxicity induced by $-amyloid protein, w~ich is presumably calcium related (147). A recent study by Sans and colleagues (148) has demonstrated the presence of mRNA for calretinin in the VNC and that following UVD, the concentration of calretinin mRNA does not decrease in the ipsilateral VNC during the first 3 days post-UVD (see also 149). It may be that the return of resting activity to the VNC following UVD is the recovery from calcium-induced diaschisis, not simply a replacement of resting activity previously supplied by the vestibular nerve. If the accumulation of intracellular calcium is the cause of a which accounts for the loss of resting in the ipsilateral VNC immediately following UVD, then it would be expected that drugs that reduce this calcium influx would reduce the extent of the diaschisis and therefore the severity of the UVD symptoms. A number of behavioral studies have demonstrated that a pre-UVD systemic injection of a voltage-sensitive calcium channel antagonist or an NMDA receptor I calcium channel antagonist can reduce the The Intrinsic Mechanism Hypothesis 195 UVD syn1ptoms (see Table 5; see 159 for contrary evidence regarding flunarizine). In the most compelling of these studies, a series of injections of the calcium-dependent enzyme inhibitor, calmidazolium chloride, into the ipsilateral VNC or IVth ventricle resulted in a large reduction in the severity of the UVD symptoms (154). Assumption 8: The contribution of intrinsic properties to the resting activity of V_NC neurons enhances sensitivity to dynan1ic vestibular inputs in both the labyrinthine-intact and compensated states. Mathematical models of the vestibular compensation process have indicated that it is difficult, if not impossible, for the mechanism that is responsible for the recovery of resting activity in ipsilateral VNC neurons to also bring about a recovery of the dynamic response of those neurons to head movement (except insofar as recovery of resting activity contributes to dynamic recovery) (compare 43 and 72,160,161). The "intrinsic mechanism" hypothesis that we propose entails that the recovery of resting activity is partially independent of synaptic modulation of that resting activity by remaining vestibular, visual, proprioceptive, or cutaneous afferent inputs. Since "pacemaker" neurons are very sensitive to synaptic modulation (see 81 for a discussion), the provision of resting activity by intrinsic properties would increase the sensitivity of VNC neurons to synaptic inputs. This would be especially important in the compensated animal where the only remaining vestibular input is that communicated via the commissural fibers from the contralateral VNC. Conclusions The hypothesis described in this paper was inspired both by the rapid progress made by in vitro studies of the mammalian VNC (see 81,88,92 for reviews) and the slow progress made in the attempt to identify the cause of the return of resting activity to the ipsilateral VNC following UVD (see 2, 25 for reviews). We believe that the most salient characteristic of vestibular compensation is the reduction in the severity of the static ocular motor and postural symptoms following UVD, correlated with a recovery of resting activity in the ipsilateral VNC, particularly type I neurons in the MVN. The slower and less complete dynamic compensation depends on this recovery of symmetrical vestibular tone in order to modulate VNC neuron activity during head movement by signals from the remaining labyrinth (via the vestibular commissures) and other sensory inputs (see 2,4 for reviews). The speed of static compensation in lower mammals has al- Table 5. Studies That Support the Hypothesis That Reducing Calcium Influx Facilitates Vestibular Compensation Author(s) Tolu et al. (150) Darlington and Smith (I 51 ) Sansom et al. (I 52) Leinhos and Flohr (1 53) Sansom et al. ( 1 54) Sansom et al. (155) Darlington et al. ( 1 56) Jerram et al. (I 57) Yamanaka et al. (9) Maclennan et al. (158) Specie;: guinea guinea guinea frog guinea guinea guinea guinea rabbit guinea pig pig pig pig pig pig pig pig flunarizine verapamil MK-801 flunarizine calmidazolium chloride CGS 19755 MK-801 methylprednisolone dexamethasone ginkgolide B blocks VSCC blocks VSCC blocks NMDA/CC (noncompetitive) blocks VSCC blocks calcium-dependent enzymes blocks NMDA/CC (competitive) blocks NMDA/CC (noncompetitive) synthetic steroid- may block calcium influx glucocorticoid may block calcium influx platelet-activating factor antagonist that reduces calcium influx VSCC: voltage-sensitive calcium channels. NMDA/CC: N-methyl-o-aspartate receptor-mediated calcium channels. competitive: competitive antagonist. noncompetitive: noncompetitive antagonist. C. L. Darlington and P. F. Smith 196 ways suggested that reactive synaptogenesis is an unlikely explanation with respect to those species, because it is too slow. Other, more rapid mechanisms, such as denervation supersensitivity, receptor-up-regulation or increased neurotransmitter release, were reasonable possibilities. However, to date, each study that has addressed these possibilities has failed to find any change that could account for therecovery of l\IIVN resting activity that correlates with static compensation. The search for such ''substitutive" :nechanisms was based 0n 1.he VNC neurons themselves would have to "replace)) the missing resting activity, which the ipsilateral vestibular nerve normally provides. However, this hypothesis has been challenged by the wealth of in vitro brainstem slice studies that demonstrate that, at least in vitro, MVN neurons do not need the vestibular nerve in order to generate resting activity. On the basis of these considerations, we suggest that the most parsimonious explanation of static compensation in mammals is that, following a brief diaschisis, VNC neurons ipsilateral to the UVD reactivate the intrinsic membrane properties that normally contribute to their resting activity in vivo. His possible that such properties are in some way up-regulated examS ) ; ho\'v ever, this is not a necessary of our Acknowledgment- This research was supported by a Project Grant from the Health Research Council of New Zealand (to CD and PS). REFERENCES l. Schaefer KP, Meyer DL. Compensation of vestibu11. Igarashi M, Ishikawa K. Post-labyrinthectomy ballar lesions. In: Kornhuber HH, ed. Handbook of senance compensation with preplacement of cerebellar sory physiology, vol. 6/2, Berlin: Springer; 1974: vermis lesion. Acta Otolaryngol (Stockh). 1985;99: 463-90. 452-8. 2. Smith PF, Curthoys IS. Mechanisms of recovery fol12. Fetter M, Zee DS, Proctor LR. 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