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polarization begins almost immediately with a movement of the kinocilium toward the lateral edge of the cell,
thus taking an eccentric position in each hair cell. The
direction of the movement reflects the emergence of the
preferred direction of stimulation for each hair cell and
hence the incipient morphological polarization vector
(MPV). Preventing the formation of the primary cilium
(kinocilium) prevents proper planar orientation of outer
hair cells (OHCs; Jones, Roper, et al., 2008). Disruption of
PCP signaling pathways has similar effects. In Looptail
mouse mutants, auditory and vestibular hair cells are
disoriented, indicating a role for PCP signaling in establishing vestibular hair cell orientation (Jones & Chen,
2007; Montcouquiol et al., 2003, 2006; Rida & Chen, 2009).
There are also a number of important structures
that serve to mechanically couple individual stereocilia
together as well as link the stereocilia to the kinocilium
mechanically. There is of course the protein linkage
to hair cell transduction channels called “tip links”
that are critical to sensory transduction. Cadherin 23
(Cdh23) and protocadherin 15 (Pcdh15) make up the
tip links (Kazmierczak et al., 2007). Given the complex
architecture of the stereociliary bundle (see Chapter 4),
much more remains to be learned about its molecular
and functional development.
Like the cochlea, each vestibular hair cell is surrounded by supporting cells. However, there is an
additional layer of organization in the vestibular system. In the cochlea, the direction of polarization for the
hair bundle is the same for all hair cells with respect
to the axis of the cochlea (all point laterally from the
central axis). In vestibular maculae, hair bundle orientation is a function of the particular sensory organ
examined. Intrinsic vestibular hair cell polarization is
marked by the cells’ MPV. In each crista, MPVs of hair
cells are oriented in the same direction. However, in
the maculae, MPV orientation depends on the position
of the hair cell on the epithelial surface. As noted in
Chapter 4 that MPVs of hair cells are arranged systematically over the surface of the macular epithelium, and
in the adult both maculae show a line coursing through
the middle regions of the epithelium (striolar regions),
where MPV directions abruptly reverse. Across this
line of polarity reversal, MPVs point in opposite directions. These MPV patterns arise during development
and are thought to depend critically both on PCP signaling pathways and on intrinsic cell polarity.
Stereociliary bundles are not readily identified in
vestibular hair cells before week 7, but as noted above
they do begin to appear earlier than auditory hair cells
(Bryant et al., 2005; Dechesne, 1992; Denman-Johnson
& Forge, 1999; Forge et al., 1997; Mbiene, Favre, & Sans,
1984; Mbiene & Sans, 1986). Similar to the cochlea, the
hair bundle is generally not polarized with its first
appearance on a newly formed vestibular hair cell.
The kinocilium is centrally located and surrounded by
emerging stereocilia (see Figure 2–5). Although outward signs of polarization may not be apparent at this
time, intracellular changes have already begun that
clearly indicate proteins are being organized asymmetrically in the cell. The progressive development of
selected features of vestibular hair cell bundles over
the period of 7 to 15 weeks is illustrated in Figure 2–5.
Morphological polarization occurs rapidly as the kinocilium assumes an eccentric position on the apical surface of hair cells. By week 8, signs of morphological
polarization are seen in large numbers of cells (see Figure 2–5). Moreover, already at this stage there is evidence of a planar organization of MPVs. MPV angles
shift systematically as a function of position over the
macular surface. A clear line of MPV reversal, however,
is not seen. Thus, like auditory hair cells, planar organization of vestibular MPVs does not precisely match the
mature organization initially. Reorientation of incipient MPVs is required. This happens early in rodents.
The striolar line of MPV reversal is sharp and clearly
established several days before birth in the mouse
(Denman-Johnson & Forge, 1999) and likely by weeks
10 to 12 in the human. The cuticular plate is first apparent in some macular hair cells using electron microscopy at about this time (week 10), although traces of
the cuticular plate are seen earlier using specific immunological markers (Nishida et al., 1998). Once bundles
appear in vestibular hair cells, development of the
normal staircase form and maturation occurs rapidly
(see Figure 2–5). By weeks 11 to 12, typical staircase
shapes and numerous lateral and tip stereocilia links
can be found (Anniko, 1983a; Forge et al., 1997; Mbiene
& Sans, 1986). Bundle height increases progressively in
the mouse embryo, reaching mature heights only after
birth (Denman-Johnson & Forge, 1999). In the human,
bundle height increases dramatically between weeks
10 and 11, and the bundles have achieved adult size by
approximately week 15 (Dechesne, 1992). Functional
transduction channels make their appearance in the
tips of stereocilia (in mice) several days before birth
(Géléoc & Holt, 2003) and are estimated to appear by
approximately week 12 for the human. Nascent hair
cells continue to appear at the vestibular epithelial
surface. Discrete samples in time give the impression
of successive waves of new immature bundles. Hair
bundles at various stages of development continue to
mature, and the overlying otoconial membrane continues to elaborate until relatively mature hair bundles
dominate the surface during weeks 11 to 12 (Dechesne,
1992; Denman-Johnson & Forge, 1999).
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INNERVATION OF THE
VESTIBULAR
There are three types of innervation to the inner ear.
First, vestibular receptors communicate information
about head motion to the brain via primary sensory
afferent neurons having cell bodies in the peripheral
statoacoustic ganglion. The statoacoustic ganglion
neurons arise from within the otocyst during development as noted above. Second, the brain can also modify
peripheral sensory receptors by adjusting activity in
efferent neurons that have cell bodies in the brainstem
and axon terminals on the inner ear hair cell sensors or
on primary afferent terminals. Efferent neurons arise
from rhombomere 4 during development (see below).
Third, blood vessels of the inner ear are under the control of sympathetic neurons. These autonomic neurons
originate from neural crest cells during development.
END ORGANS
Development of Afferent Innervation
The statoacoustic ganglion and its neural projections
form over the period from weeks 4 to 9 as progenitor
cells delaminate from the anteroventral wall of the otocyst. By week 7, vestibular and cochlear anlagen can
be distinguished histologically as pars superior and
pars inferior of the statoacoustic ganglion, respectively.
Although distinguishable, these two portions remain
as a contiguous collection of cells until about week 9,
when they actually separate physically into the spiral
and vestibular ganglia (Sher, 1971; Sulik & Cotanche,
2004). The geniculate ganglion (seventh or facial cranial
nerve) separates completely from the vestibular ganglion finally on P1 in mouse.
Most sensory neurons are born between weeks
4 and 8. During week 6, fibers from the statoacoustic
ganglion can be seen entering the rostrolateral wall
and projecting well into the epithelium near the luminal surface of the otocyst (Dechesne, 1992; Sher, 1971;
Van de Water, 1984). Efferent neurites arrive at about
the same time (Bruce, Kingsley, Nichols, & Fritzsch,
1997). The presence of auditory and vestibular afferents
in epithelia is thought to slightly precede the arrival of
efferent terminals, and efferent neurites appear to follow
afferent tracts during their growth (Bruce et al., 1997).
Neurotrophins regulate primary afferent innervation density. Neurotrophins are proteins secreted
by target tissues that serve to prevent the natural cell
death of path-finding neurons (Davies, 1996; LeviMontalcini, 1987; Levi-Montalcini & Angeletti, 1968;
Lewin & Barde, 1996). Hypothetically, the amount of
neurotrophin present ultimately determines the number of neural cells that survive to innervate target cells.
This ability to determine whether developing neurons
survive is known as a neurotrophic effect. Elevated
amounts of neurotrophin can cause excessive growth
of neurites, whereas reduced levels of neurotrophin
decrease neurite outgrowth and decrease survival of
cells. The absence of neurotrophins can result in the
loss of innervation entirely. Neurotrophins also have
neurotropic effects, that is, they may serve to guide
neurites along their growth paths (Fekete & Camparo,
2007; Fritzsch, Silas-Santiago, Bianchi, & Farinas, 1997;
Levi-Montalcini, 1987).
The elaboration of afferent neurites appears to
occur simultaneously with the delamination process
in the otocyst. Two processes underlying afferent
innervation of sensors have been emphasized (Fekete
& Camparo, 2007; Fritzsch et al., 1997). In one model,
neuroblasts send neurites back into sensory epithelia
after delaminating and migrating out of the otocyst.
This model requires a major guidance signal to aid neurites in their pathfinding. In the second model, the dendritic terminal endings of afferent neurites remain in
the region of the original site of delamination, whereas
the cell bodies migrate (translocate) to the mesenchyme
rostromedial to the otocyst. This leaves a ready-made
dendritic path to target sensory regions. In this case,
even though neurites are initially in the proximity of
target sensory regions, they must still grow extensively
and find their specific final sensory destinations. This
second model provides an early-formed path for arriving efferent neurites to follow on their way to the vestibular epithelium. There is evidence for both models,
and it is conceivable that both models operate to some
extent depending on the sensory organ involved. The
importance of each model may depend on the class in
question (e.g., aves versus mammalia). The molecular
cues operating to guide neurite growth are not clear in
the inner ear, although several candidates have been
entertained (Fekete & Camparo, 2007; Fritzsch et al.,
1997; Pauley, Matei, Beisel, & Fritzsch, 2005). The candidates include neurotrophins that may be involved in
both guidance and survival of primary afferent dendrites. The neurotrophins’ brain-derived neurotrophic
factor (BDNF) and neurotrophin-3 (NT-3) are required
for proper innervation patterns and maintenance of all
inner ear ganglion cells. In the absence of BDNF and
NT-3, all ganglion cells die before birth (Ernfors, Van de
Water, Loring, & Jaenisch, 1995; Liebl, Tessarollo, Palko,
& Parada, 1997; Silos-Santiago, Fagan, Garber, Fritzsch,
& Barbacid, 1997).
Statoacoustic ganglion neurons must also form
central projections. Neurites of the central axon must
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grow and terminate on cells within the vestibular
nuclei of the brainstem and cerebellum. Guidance
mechanisms for axons projecting to the central nervous
system (CNS) are independent of those responsible for
peripheral afferent terminations (Pauley et al., 2005).
The signals guiding central afferent projections are
unknown.
By week 7, peripheral afferent projections extend
to all presumptive vestibular sensory epithelia (cristae
and maculae) as well as to the wall of the cochlear duct
(Dechesne, 1992; Sher, 1971). Terminals for vestibular
afferent neurons at this stage are immature, and the
final differentiation and refinement of these projections take place over a prolonged period. In the mouse,
final refinements in vestibular dendrites are made during postnatal periods. In the human, final refinements
occur during the last trimester.
Vestibular afferent neurite terminals are present
in the undifferentiated prosensory epithelium of the
otocyst (see above). Specialized synaptic contacts have
been reported for the mouse vestibular epithelium
as early as five days before birth (e.g., E15; Mbiene,
Favre, & Sans, 1988). The earliest vestibular synaptic
contacts form on postmitotic prosensory cells before,
or coincident with, the onset of hair cell differentiation.
Development of primary afferents in the human parallels events characterized in other mammals. Unmyelinated vestibular primary afferents in humans arrive
in the undifferentiated epithelium during weeks 6 to 7
(Dechesne, 1992; Desmadryl, Dechesne, & Raymond,
1992). Apical tight junctions are present in nascent hair
cells and prosensory epithelia in the human during this
early period. Afferent neurites form numerous synaptic contacts on hair cells, displaying emerging kinocilia
by week 8. By 14 to 15 weeks, most hair bundles are
relatively mature, with only a few immature bundles
appearing on the surface (Dechesne, 1992). Thus, given
an early presence, it is likely that the earliest primary
afferent contacts are made with immature “nonpolarized” hair cells. Through collateralization, contacts may
be made with a mixture of nonpolarized and polarized
hair cells. Descriptions of the surface of the vestibular
epithelium at 8 to 10 weeks suggest that, at any given
time, despite a clearly established striolar boundary,
there are typically several hair cell developmental
stages coexisting in the same vicinity. Moreover, this
developmental mosaic is generalized across the macula (Denman-Johnson & Forge, 1999). Hair cells with
immature bundles appear between relatively more
mature hair cells, forming a complex mosaic of hair
cell stages. It is reasonable to imagine that a sensory
unit, defined as one primary afferent and all hair cells
it innervates, also incorporates a mosaic of hair cell
polarization stages and directions at this stage. Thus,
nascent sensory units are likely composed of hair cells
that do not have a uniform hair bundle polarization
status. Indeed, it would appear that hair cells at this
stage may take on a wide range of immature features,
including hair cells with varying and just-emerging
polarization vectors, particularly those innervating
regions of the line of polarity reversal.
It is important to note that by week 10 in the
human (Dechesne, 1992) and during the period from
E14 to E16 in the mouse, otoconial growth begins and
calcification rates are at their highest levels (Lim, 1984;
Nakahara & Bevelander, 1979; Salamat, Ross, & Peacor,
1980; Veenhof, 1969). Presumably, stimulus-dependent
developmental processes in macular organs could only
become effective during and after this period of otoconial formation. Although initial contacts may form early
(weeks 6 to 7), they may not be functional synaptic contacts, as most of the differentiation of vestibular neural
dendrites occurs relatively late, from week 11 to week
23 (Dechesne et al., 1994; Rüsch, Lysakowski, & Eatock,
1998; Van de Water, Anniko, & Wersall, 1977). Similarly,
the final maturation of vestibular hair cells (particularly
membrane conductances), especially type I hair cells,
occurs during the first and second postnatal weeks for
mice (weeks 23+ for humans) (Dechesne, 1992).
By week 8, primary afferent dendrites penetrate
the basal lamina of the sensory epithelium and send
a single process passing through lower layers to the
superficial apical layer, where they branch to produce
several undifferentiated collaterals (Desmadryl et al.,
1992). The terminals are initially restricted in their
extent and density, but by week 12 they begin to ramify
considerably, covering distances of 30 to 50 microns.
At week 8, clear evidence of synaptic contacts between
afferents and hair cells is present. Synaptic bodies and
coated vesicles can be recognized in hair cell synaptic regions at 8 to 10 weeks (Dechesne, 1992). At these
early stages the afferent terminals are still immature.
Soon thereafter (week 12), the first evidence of incomplete calyces as well as bouton terminals can be seen
(Dechesne, 1992; Dechesne et al., 1994; Rüsch, Lysakowski et al., 1998; Van De Water et al., 1977). During weeks 12 to 13, some maturation is observed, and
incomplete calyces, boutons, and type I and type II hair
cells can be distinguished but are not mature. Numerous tethered dense core vesicles associated with wellformed synaptic ribbons can be identified between
weeks 13 and 15 in the human (Dechesne, 1992). By
approximately week 20, all three dendritic types are
present (calyx only, bouton only, dimorphs) and are
distributed in their normal proportions over the crista.
Although most features of the mature cristae are pres-
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ent, fine structure and function of the vestibular system
in general continues to mature over several weeks after
birth in the mouse. Development of these late features
is discussed in more detail below.
Development of Efferent Innervation
The first efferent axons arrive in the prosensory regions
of the otocyst at about week 6 (E12 in mouse; Fritzsch
& Nichols, 1993; Pujol et al., 1998). These neural processes have origins (cell bodies) in rhombomere 4 of
the hindbrain (future brainstem; see Simmons, Duncan,
Craponde Caprona, & Fritzsch, 2011 for review) and
appear in the otocyst before hair cell differentiation
(Bruce, Kingsley, Nichols, & Fritzsch, 1997). Initially,
vestibular efferent cell bodies form a single nucleus on
each side of the brainstem (medial to vestibular nuclei,
lateral to cranial nerve motor nucleus VI). Both ipsilateral and contralateral cell bodies give rise to early
projections to each end organ. On either side of the
cochlear and vestibular ganglia, efferent fibers tend to
grow along the afferent tracts, and their appearance in
time follows that of afferent projections (Bruce et al.,
1997; Bruce, Christensen, & Warr, 2000). In the absence
of afferent projections, efferent neurites do not reach
the end organs (Ma, Anderson, & Fritzsch, 2000). Efferents travel in the vestibular nerve until they reach the
vestibulocochlear anastomosis, at which point cochlear
efferents segregate from vestibular efferents and enter
the spiral ganglion, initiating the intraganglionic spiral
bundle (IGSB) by weeks 8 to 9. The IGSB follows the
spiral ganglion through the course of the cochlear coil.
There is some evidence that the earliest arrivals in the
cochlea are medial olivocochlear fibers with cell body
origins distinct from vestibular efferents (reviewed by
Simmons, 2002).
As noted, vestibular efferents reach prosensory
regions of the otocyst by weeks 6 to 7, presumably having followed projections of postmitotic delaminating
vestibular ganglion cells. Ultimately, efferent neurites
follow afferent projections in the inferior and superior
vestibular nerves to reach their respective end organs.
Little is known about the nature of terminal contacts
made by efferents during these very early embryonic
periods. It is likely that early efferent arrivals contact
precursors to both type I and type II hair cells directly.
Ultimately, efferents undergo extensive branching in all
end organs and form bouton type axosomatic endings
on type II hair cells and at later stages form axodendritic endings on calyx dendrites innervating type I vestibular hair cells. Axodendritic efferent contacts appear
relatively late, since calyces begin forming late (week
>12). It is likely that efferent contacts are made on the
progenitors of type I hair cells prior to calyx formation
(Favre & Sans, 1978). However, what role, if any, these
terminals play in the differentiation and maturation of
the type I hair cell is unknown. In his pioneering work,
Van De Water (1976) concluded that there was no influence of innervation on cytodifferentiation in explanted
otocysts. Inasmuch as there was no ultrastructural
evaluation of the explants, it may be worth re-examining this issue.
LATE DEVELOPMENT AND MATURATION
OF VESTIBULAR
Although still immature, the human can hear and
respond to head movement at birth. Therefore, a functional inner ear emerges in the human fetus and, for
this reason, the human is considered to be precocial. In
contrast, many nonhuman mammals (e.g., mice, rats,
cats, dogs, ferrets; Curthoys, 1983; Heywood et al., 1976;
Rüsch, Lysakowski et al., 1998; Van Cleave & Shall, 2006)
are relatively unresponsive to head movement and are
deaf at birth and thus are considered altricial (or altricous). Vestibular function in these neonatal, non human
mammals matures during subsequent weeks.
In order to perceive head motion, the forces
associated with head movement must reach the vestibular sensory apparatus, hair cells must transduce
the mechanical stimulus into membrane currents and
release neurotransmitter, and postsynaptic vestibular
ganglion neurons must respond to the neurotransmitter and transmit discharges to the CNS. Once in the
CNS, the signals must be processed and relayed via the
brainstem nuclei and thalamus to vestibular sensory
regions of the cortex (e.g., Lopez & Blanke, 2011; Shiroyama et al., 1999), where perception can take place.
We focus here on the emergence of peripheral vestibular function, which covers adequate stimulation, stimulus transduction, and encoding of information in the
primary afferents of the vestibular nerve. More details
about the mature central vestibular system are briefly
summarized in Chapter 4.
SENSORS
Adequate Stimulation
The vestibular system is an example of a special sense
that relies on elaborate ancillary structures to preferentially select, from among numerous potential environmental stimuli, only a few particular mechanical
events that serve as adequate stimuli. For example,
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Development of Vestibular Function
Transduction Channels and
Associated Membrane Currents
2. ontogEny oF tHE vEstiBulAr systEm And BAlAnCE 29
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apparatus for the ampullae noted above. Thus in the
mammalian fetus, natural mechanical stimuli likely do
reach vestibular hair cell receptors as they acquire the
ability to transduce them into receptor potentials.
Hair Cell Response to
Transduction Currents
The appropriate hair cell response to an adequate stimulus requires more than just transduction channels.
The vestibular hair cell response to transduction currents (i.e., the sensory receptor potential) depends on
the nature of ionic channels located within basolateral
portions of the hair cell membrane. When gated open,
these basolateral ion channels permit the movement of
particular ions across the membrane, thus contributing
to current flow. Collectively, the ability to conduct currents (i.e., the property of conductance, symbolized as
“g”) depends on the number of channels open for each
type of channel. Each channel type is named according to the dominant ion species it conducts. Currents
associated with particular channels are often designated with an “I” and a subscript indicating the specific
ion channel (e.g., potassium current, IK). Conductance
associated with the current IK for example is designated
as gK. There are a variety of voltage-gated channels that
are important in shaping the receptor potential. These
include K+, Na+, and Ca2+ channels (Eatock & Hurley,
2003). These currents determine the resultant hair cell
receptor potential and in turn the characteristics of neurotransmitter release and transmission from hair cell to
primary afferent. Thus, they determine the very nature
of the transfer of information about head motion and
ambient sound to the primary afferent and ultimately
to the brain.
The mature hair cell receptor potential reproduces
the shape of an applied depolarizing current. Thus, the
mature receptor potential normally follows the input
signal reliably so that the gating of channels at the
basolateral surface and the release of neurotransmitter
is synchronized to the stimulus input. Based on work
in animals, we know that the first hair cells born are
not equipped with the adult complement of basolateral membrane ion channels. Undifferentiated otocyst
cells and new hair cells (weeks 7 to 8) have few if any
voltage-gated K+ membrane channels (Correia, Rennie, & Koo, 2001; Eatock & Hurley, 2003; Sokolowski,
Stahl, & Fuchs, 1993). Specific channels appear at different developmental stages in hair cells and each
channel can impart different characteristics to the hair
cells’ response to transduction currents. Early hair cell
responses to simulated transduction currents at the
earliest stages are slow and follow stimulus current
profiles poorly. With the upregulation of particular
genes and the acquisition of new membrane conductances, the hair cell’s ability to follow stimuli improves.
In the bird, mature-like vestibular hair cell membrane
responses and a full complement of ion channels are
present just before hatching (Masetto et al., 2000),
whereas in the altricial mammal the mature configurations of channels and more mature responses emerge in
the late embryo and neonate (E18 to P4; Géléoc, Risner,
& Holt, 2004; Masetto et al., 2000; Rüsch & Eatock, 1996;
Rüsch, Lysakowski, & Eatock, 1998). Figure 2–6 illustrates how a vestibular hair cell receptor response to a
depolarizing current step changes with the acquisition
of new basolateral hair cell channels during development. The imposed depolarizing current is used to simulate depolarizing transduction currents. A relatively
mature response (bottom trace) does not appear until
the g
channels are present. The voltage response of
K,L
the hair cell is the resulting receptor potential, which
modulates transmitter release from the hair cell. Note
the changes in the shape of the receptor potential as
new ion channels are added at different ages of development. Although it is not known, one would anticipate (based on studies in animals) that mature hair
cell responses to stimulation would be present prior to
birth after 20 weeks in the human.
A number of studies have examined the temporal sequence of channel acquisition in animals
(Eatock & Rüsch, 1997; Géléoc et al., 2004; Géléoc &
Holt 2003; Hurley et al., 2006; Li, Meredith, & Rennie, 2010; Masetto et al., 2003; Rüsch, Lysakowski, et
al., 1998; Sokolowski et al., 1993). We have tabulated
the sequence of acquisition of several membrane ion
channels for the chick and mouse (Table 2–1) based on
the work of several laboratories (i.e., Géléoc et al., 2004;
Masetto et al., 2000; Rüsch, Lysakowski, et al., 1998).
One striking difference to be noted regarding the acquisition sequence in vestibular hair cells versus that for
auditory hair cells is the fact that there are no descrip-
2+
tions of Ca
-based hair cell action potentials (spikes)
during vestibular development. Although the reason
for this has not been explored, one might speculate that
the early appearance of the fast IKA and I
(BK) chan-
K(Ca)
nels in vestibular hair cells may prevent the development of hair cell spiking. In the cochlea, BK channels
appear late in the maturation of inner hair cells (IHCs),
and prior to their appearance, the IHCs generate spontaneous Ca
2+
-based action potentials. This spontaneous
action potential activity is thought to be critical for the
refinement of peripheral and central auditory neural
30 BALANCE FUNCTION ASSESSMENT AND MANAGEMENT
+g
at E18
Stimulus:
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pA
Depolarizing
Current
Responses:
Early
mV
mV
mV
Late
Figure 2–6. The effects of acquiring selected K+ channels on the hair
cell receptor response.
larizing current applied.
currents (levels reflected in picoamps, pA).
stimulus, (traces 1–4), are schematic representations of the receptor potential response. During development, the shape of the receptor potential changes with the addition or removal of each channel.
The first response tracing represents a young age where the hair
cell has acquired only the early delayed rectifier, g
tional channels appear successively over time (e.g., g
g
traces 2 and 4) . Traces 2 and 3 illustrate the kind of change in
K,L
membrane response produced by electrically inactivating g
before presenting the stimulus (trace 3). Corresponding ages in the
chick embryo are shown to the right of traces. Note how ultimately
the response follows the step depolarizing currents closely as the
cell acquires g
responses (m
Masetto et al. (2000) and Chen and Eatock (2000) with permission.
From Genetics, Embryology, and Development of Auditory and Vestibu-
lar Systems (2011) (p. 216) by
mV
Top tracing shows the hypothetical step depo-
(trace 4) and matures. Hair cell membrane voltage
K,L
V) are schematic representations of data reported by
1.
g
at E10–E12
Kv
2.
at E14
+g
KA
3.
-g
at E14
KA
4.
K,L
This depolarization simulates transduction
The four traces below the
(trace 1). Addi-
Kv
, g
K(Ca)
KA
and
(-gKA)
KA
Sherri M. Jones and Timothy A. Jones.
circuits during development (e.g., Jones & Jones, 2011).
Cochlear IHC spiking disappears as BK channels are
upregulated during development just before the onset
of hearing (Brandt et al., 2007; Fuchs & Sokolowski,
1990; Kros et al., 1998; Marcotti et al., 2003a; Schweizer
et al., 2009).
BEHAVIORAL RESPONSE TO HEAD MOTION
In the precocial chicken, there is no question that the
vestibular system is virtually mature at hatch inasmuch
as hatchlings quickly learn to walk bipedally within
minutes to hours. In the human, it also is likely that
the peripheral vestibular system is mature at birth.
However, it will be at least a year before any walking
is done. Considerable maturation is required in central
motor control circuitry as well as in the skeletomotor
system itself. To evaluate the development of vestibular responses to head motion, it is useful to study the
behavior of altricial mammals (rats, cats, mice, gerbils,
etc.). In such animals, during a span of 2 or 3 weeks,
the vestibular apparatus goes from nonfunctional to
functionally mature and this occurs with observable
behaviors. When a mature animal lying face up is
2. ONTOGENY OF THE VESTIBULAR SYSTEM AND BALANCE 31
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Table 2–1. Age of Appearance for Various Currents
Recorded from Vestibular Hair Cells or Primary Afferent
Neurons in the Chick and Mouse*
Current Chick Mouse
I
Kv
I
Ca
I
KA
I
K(Ca)
I
h
I
K,L
I
Kir
* The appearance and distribution of different ion channels
throughout development contribute to the developing hair
cell’s response to stimulation, release of neurotransmitter,
and developing neural discharge patterns. Information
from Masetto et al. (2000) and Géléoc et al. (2004) unless
otherwise noted.
Chicken: equivalent days of incubation (E) are given
based on Hamburger and Hamilton (1951) staging. Mouse:
embryonic (E) days of gestation are equivalent to days
post conception (dpc, Kaufman, 1992). Days postnatal are
designated with a “P” where P0 is the day of birth or hatch.
“?” = not reported.
** Expression in vestibular primary afferents beginning at E15
and decreasing by birth. Changes in the density of the different ICa types (L, P/Q, N, R, T) also occurred from E15 to
birth (Chambard, Chabbert, Sans, & Desmadryl, 1999).
*** Based on expression of BK channels in the rat (Schweizer,
Savin, Luu, Sultemeier, & Hoffman, 2009), which first appear
at P12 and diminish by P23.
E10 E14
E10 E15–birth**
E12 ?
E14 P12–P23***
E16 P3
E17 E18
E19 E15
dropped from a reasonable height onto a soft sponge
base, it will turn quickly to right itself and land on its
feet. This is the air-righting reflex and it can be used
to assess the combined maturity of the vestibular and
motor control systems. This reflex is absent at birth in
rats when the vestibular system is still immature. It
appears first between 9 and 14 days after birth (e.g.,
Hard & Larsson, 1975; Laouris, Kalli-Laouri, & Schwartze, 1990). In contrast, reflex compensation to maintain
gaze during rotation on a turntable appears as early as
3 days after birth in the rat (Parrad & Cottereau, 1977).
Thus, despite immature peripheral receptors (noted
above), it is clear that some behavioral responses can
be elicited in the neonatal rodent. Of course behavioral
testing alone leaves open the question of whether the
behavioral immaturities reflect the functional status
of peripheral or central components or both. Human
studies evaluating eye movements in response to rotational stimuli suggest that some aspects of compensa-
tory eye movements are mature at 6 to 10 months of
age (e.g., Cioni, Favilla, Ghelarducci, & La Noce, 1984;
Cyr, Brookhouser, Valente, & Grossman, 1985; VienerWacher, Toupet, & Narcy, 1996), although other aspects
continue to mature up to late childhood or adolescence
(e.g., Cyr et al., 1985; Herman, Maulucci, & Stuyck,
1982; Valente, 2007; Viener-Wacher et al., 1996). Studies of standing balance function generally demonstrate
continued maturation of balance into late childhood
and adolescence (e.g., Casselbrant et al., 2010; Charpiot,
Tringali, Ionescu, Vital-Durand, & Ferber-Viart, 2010;
Hirabayashi & Iwasaki 1995; Valente, 2007). It is likely
that behavioral maturation in the human is due to central myelination and circuit refinements after birth.
Recent work in this area is summarized at the end of
this section.
PRIMARY AFFERENT FUNCTION
When recording normal mature individual vestibular
primary afferent neurons in the absence of head movement, the neurons are not silent but rather discharge
spontaneously and continuously (Figure 2–7). This is
true for afferent neurons innervating both ampullar
(semicircular canal) and macular (otoconial gravity
receptors) epithelia. Discharge rate (action potentials/
sec, also called spikes/sec) remains relatively constant
unless the head is moved thus stimulating or inhibiting hair cells and neurons innervating them. At first
thought, in the absence of head movement one might
suppose that such tonic activity is due to the constant
stimulation of gravity receptors (utricle and saccule)
by the ever-present gravitation field of Earth. However, tonic spontaneous vestibular afferent discharge
is present in animals that have no otoconia and thus
animals that cannot sense gravity (Jones, Jones, et al.,
2008). Continuous (tonic) activity arising from the vestibular sensors normally provides a profound influence on CNS circuitry throughout most of the neuraxis
including brainstem, hypothalamic, and limbic systems (e.g., Balaban, 2002; Porter & Balaban, 1997; Balaban & Porter, 1998; Yates, 1996; Yates & Miller, 1998).
These afferent signals assert a powerful influence on
descending skeletomotor and autonomic systems and
provide input for compensatory eye movements, perceptual tracking of position, and orientation in space.
Tonic vestibular activity constantly adjusts alpha and
gamma motor neuron outflow, thus controlling background antigravity muscle tone and posture under an
imposing gravitational force field. Therefore, spontaneous as well as sensory-induced tonic activity arising
32 BALANCE FUNCTION ASSESSMENT AND MANAGEMENT
02
A.
Adult
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Irregular
Discharge
Adult
CVm*: 0.462
82.0spikes/s
Regular
Discharge
Adult
CVm*: 0.033
75.5spikes/s
0.2s
B.
04812162
P7 Neonate
4
Time (s)
figure 2–7. Spontaneous discharge activity of vestibular primary afferent neurons in mice.
A . Adult mice: Each voltage spike represents an individual action potential.
presented.
rates.
acterized by irregular spacing between spikes, and a high C
pattern tends to show regular spacing between spikes and a low C
Jones, et al. (2008). B.
the superior vestibular nerve in the neonatal mouse at P7 (corresponding human age:
10 to 12 weeks). Note the time scale difference in B. This record was made over a period
of approximately 24seconds. Each vertical “spike” represents the onset time of the neural
spike discharge during this portion of the recording. Discharge rate is slow and an irregular
firing pattern (with high CV) typical for neonatal vestibular neurons is apparent. Unpublished data. CVm* = indicates that CV values were normalized for spontaneous rate based
on mouse data. From Genetics, Embryology, and Development of Auditory and Vestibular
Systems (2011) (p. 219) by Sherri M. Jones and Timothy A. Jones.
These cells were chosen for illustration because they have similar high discharge
Two types of activity patterns are recognized. Irregular discharge (top tracing) is char-
Spontaneous spike train of primary afferent neuron recorded from
V. A regular spike discharge
V. Modified from Jones,
No stimulus is
from vestibular sensors plays an important role in nervous system function.
Spontaneous vestibular discharge patterns are of
two types in mammals and birds: regular and irregular. Just how regular or irregular the neural discharge
is depends in part on the nature of the dendritic synaptic termination and on the nature of the membrane
channels resident in the neuron (Eatock, Xue, & Kalluri, 2008; Iwasaki, Chihara, Komuta, Ito, & Sahara,
2008; Kalluri, Xue, & Eatock, 2010). The regularity can
vary widely and this variety can be quantified using a
single number called the coefficient of variation (CV
= standard deviation/mean spike interval). The value
of the CV normally varies between 0 and 1. The CV
approaches 1.0 as the discharge pattern becomes more
irregular (more stochastic, to be precise), whereas the
CV approaches 0.0 as the discharge becomes more regular. Figure 2–7 illustrates the discharge patterns of reg-
2. ontogEny oF tHE vEstiBulAr systEm And BAlAnCE 33
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ular and irregular vestibular afferents in mature (Figure
2–7A) and developing (Figure 2–7B, P7 neonate) mice.
Discharge rates in mature mice range from less than 10
to over 140 spikes/sec, with most between 55 and 110
spikes/sec (e.g., Jones, Jones, et al., 2008). The recordings of Figure 2–7B were made in vivo from primary
afferent neurons of the superior vestibular nerve (Jones
& Jones, 2011). The discharge pattern of the neonate
reflects a relatively low discharge rate (~8 spikes/sec)
with irregular discharge timing (CV = 0.66).
Recording the activity patterns of individual vestibular primary afferent neurons in intact animals (i.e.,
in vivo) is challenging. Some investigators have instead
explored the use of vestibular explant preparations. In
this case, the labyrinth with the ganglia are removed
and maintained in a physiological solution. Vestibular
primary afferents recorded in a mouse inner ear explant
preparation are also spontaneously active (Desmadryl,
Raymond, & Sans, 1986). Afferent discharge patterns
in explants have been measured on different postnatal days. Mean spontaneous discharge rates were low
initially (day of birth, P0: 5 to 10 spikes/sec) and all
neurons displayed irregular activity. Remarkably, regular discharge patterns were found at P1 and older.
Beginning between P6 and P8, discharge rates increase
dramatically (>80 spikes/sec), and the proportion of
regular fibers increase as well. In a similar preparation in the chicken, Galicia, Cotes, and Galindo (2010)
reported irregular spontaneous discharge rates on the
order of 40 spikes/sec and CVs above 1.0 in recordings
as early as five days before birth (E15). Many of the
patterns found in the in vitro preparation were similar
to those reported for in vivo studies (discussed below).
In vitro studies provide many practical advantages
while at the same time raising the question of whether
neurons behave the same when studied in their natural
environment, that is, in vivo.
Spontaneous discharge patterns of horizontal
canal neurons have also been recorded in vivo in the
neonatal rat from age P1 to P20 (Curthoys, 1983). Discharge rates were low at the youngest ages (<10 spikes/
sec, P1 to P3) and all neurons exhibited irregular spontaneous discharge patterns. The first regular fibers
were seen on P4. Discharge rates and the proportion
of regular fibers increased substantially after P10 (30 to
40 spikes/sec). Nonetheless, rates for regular cells were
still somewhat below the adult values at P20. Romand
and Dauzat (1982) reported similar findings in the cat
except that regular spontaneous discharge patterns
were seen as early as P1. An example of an irregularly
discharging macular primary afferent at P7 is shown in
Figure 2–7B (mouse in vivo recording). In vivo recordings in the chick embryo at E19 showed that regular
discharge patterns were present, and on average the
rate for embryos was 22 spikes/sec versus 60 spikes/
sec for post-hatch animals (Jones & Jones, 2000b). Note
that discharge rates were somewhat lower in the in vivo
recordings compared with explants. This may reflect
the effects of anesthesia used in in vivo preparations
or conditions associated with in vivo preparations. In
summary, in the rodent at birth, spontaneous activity
is immature, showing low discharge rates and being
dominated by irregular firing patterns. Maturation of
discharge patterns progresses over a period of weeks.
One role of the horizontal canal is to detect head
turning and to activate vestibular neurons to send a
signal to the brainstem that produces eye movements
that compensate for head motion and maintain gaze
on a stationary visual target. This is known as the
vestibulo-ocular reflex (VOR). One question to ask is:
When are primary afferents capable of delivering a
compensatory signal comparable to that of the mature
system? Curthoys (1983) evaluated this question by
measuring the response of horizontal canal primary
afferent neurons to head rotation in rats at ages from
P1 to P20. At P1 neural responses were sluggish and
highly variable. By P6 to P8, the neural response gain
approached that of the adult. This suggests that, for
some stimuli, the neuroepithelium at P8 is capable of
generating signals comparable to those of an adult.
These findings are consistent with results noted above
showing that morphological and electrophysiological
features of hair cell function (e.g., calyx, membrane
channels, vestibular efferents) emerge during the first
two to three postnatal weeks in rodents (weeks 13 to 23
in humans). Indeed, VOR gains in juvenile mice (P21
to P26) are slightly, but significantly, lower than those
in mature animals at 3 to 4 months old (Faulstich et al.,
2004). Central improvements likely mediate the final
maturation changes. Similar maturational changes are
reported for children (Casselbrant et al., 2010).
The basic structural elements of the macula are
in place in the chick before hatch (by E16). The question is, when does macular function emerge? Little
information is available regarding macular functional
development in any species. Recordings of macular
vestibular evoked potentials (VsEPs) have been made
in embryos and hatchling chicks (E18 to P22; Jones &
Jones, 2000a). Responses were obtained as early as E19
(1 to 2 days before hatch). Therefore, the onset of macular function occurs at least by E19 in the chick and
likely earlier. Macular response thresholds decreased
rapidly to approach adult values within days of hatch.
Other response characteristics also matured systematically over similar periods (response latencies shortened
and amplitudes increased). These findings, and the fact
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