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Journal of Vestibular Research, Vol. 6, No. 3, pp. 185-201, 1996
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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).
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Note added in proof: Since the submission of this manuscript, a number of important papers
have been published which are consistent with the hypothesis which we have advanced. Ris
et al. (1) have reported a complete recovery of ipsilateral type I neuron resting activity in the
alert guinea pig, 1 week following unilateral labyrinthectomy (UL). Several papers have been
published which confirm the induction of c-fos (2-4) in the vestibular nuclei following UL.
In one study, Kitihara et al. (4) reported that decompensation induced by the administration
of an NMDA receptor/channel antagonist, caused a reappearance of c-fos expression in the
vestibular nuclei. Finally, in a recent study by Zirpel et al. (5), it has been reported that unilateral
cochlear removal causes an increased calcium influx in the ipsilateral nucleus magnocellularis
(the avian cochlear nucleus).
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in the embryonic chick. J Neurophysiol. 1995; 74:1355-1357.