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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4507_Библиотеки_им_академика_М_И_Перельмана.pdf
3 Physiology ofthePeripheral andCentral Hearing System
43
Inner Hair Cells
IHCs are a type of hair cell with a goblet-shaped nucleus in its center (Fig.3.6).
They are arranged in a single row along the cochlear duct (Fig.3.7a). Stereocilia are
arranged in a “U” shape. The lateral part is supported by inner columnar cells, and
the other parts are supported by phalangeal cells. There are no connection specializations such as desmosomes and gap junctions in mature IHCs. Unlike OHCs, the
bodies of IHCs are not separated from each other. Direct communication between
IHCs is possible, but specialized connections between cells have not been found;
there are only tight connections with columnar and phalangeal cells. Only the apical
side is isolated from each other by supporting cells [11, 12, 22]. Cell connections
are in the form of tight and adjacent connections with supporting cells. The apical
part of the cell is surrounded by endolymph on the scala media side. The basolateral
part is surrounded by perilymph, supporting cells, and neuronal terminals. The arcuate zone of the BM contains IHCs. The IHC body does not vibrate when the BM
moves because this part of the BM is immobile. The stereocilia arrangement is
U-shaped on the apical side and is not in contact with the lower surface of the tectorial membrane. The stereocilia are embedded in the cuticular layer. Each IHC has
20–30 stereocilia. IHCs are 2–8μm in length. They are in contact with type I spiral
ganglion cells (SGCs), which are large bipolar neurons that constitute the major
population of SGCs (90–95%). IHCs form ribbon synapses with the afferent nerve
bers of type I SGCs. Presynaptically, numerous large round vesicles are arranged
around a dense body. This is called a ribbon synapse. Ribbon synapses are
a
b
c
Fig. 3.7 (a) Stereocilia arrangement of inner and outer hair cells. Scale bars: 10 mm. (b)
Stereocilia of outer hair cells. (c) The tectorial membrane
44
M. Baran et al.
multivesicular and allow sustained release of glutamate-containing synaptic vesicles [11, 22, 25, 37].
Inner Hair Cell Neurotransmission: In Fig.3.6, when the stereocilia are deected
in an IHCs, the (+) deection induces K+ entry into the cell and the cell depolarizes.
K+ entry into the cell leads to the opening of voltage-sensitive Ca2+ channels and
increased intracellular calcium levels. Ca2+ entry triggers the release of the neurotransmitter (glutamate), and an action potential is generated in the neuron. Increased
calcium stimulates Ca2+-sensitive K+ channels. The release of potassium repolarizes
the cell. Increased intracellular calcium is excreted out of the cell by an ion pump. In
stereocilia, the transmission channels are partially open at rest, resulting in the release
of extremely small amounts of the neurotransmitter. This allows spontaneous activity
to occur in the afferent pathway of the auditory nerve even in the absence of sound.
The connections between the inner hair cells and the auditory nerve can be classied
according to the spontaneous activity of the auditory nerve. Each inner hair cell
makes a connection according to this classication. They have a bimodal distribution, with 30–40% of the auditory nerve consisting of bers with low spontaneous
discharge (<18 spikes/s) and 60–70% consisting of bers with high spontaneous
discharge (>18 spikes/s). The excitation thresholds are 80–90dB for low spontaneous wave bers and 30–40dB for high spontaneous wave bers. Compared to the
modiolar (medial) side, which is innervated by low spontaneous discharge bers,
high spontaneous discharge bers are more abundant on the columnar (lateral) side
of IHCs and their terminals are larger and richer in mitochondria [9, 22, 32].
Outer Hair Cells
OHCs have a long cylindrical structure with a basal nucleus. They are arranged in
three to four rows along the cochlear duct (Fig.3.7a, b). The stereocilia arrangement
is in the shape of a “W” [22]. The length of the OHC varies throughout the cochlea.
It is shorter basally than apically. Typically, the length of an outer hair cell is
10–80μm. The number of stereocilia is 100–120. Stereocilia are inserted into the
tectorial membrane (Fig.3.7c). OHCs are supported basally by Deiters cells and
apically (in the reticular lamina) by the outer column, Deiters cells, and Hensen
cells. Direct communication between outer hair cells is achieved by gap junctions
with supporting cell pairs. OHCs can be studied in three parts (Fig.3.8) with respect
to their function [11, 22, 23, 38].
The apical part: This is the part where mechanical energy is converted into electrical energy through transduction channels according to the deection of
stereocilia.
The lateral part: This is the part where electrical energy is converted back into
mechanical energy, biotransformation takes place, and cochlear
amplication—electromotility—occurs.
The basal part: This is the part where mechanical energy is converted into electrical energy by discharge of neurotransmitters from synaptic structures.
In the lateral membrane of OHCs, the connections between the cortical layer and
the plasma membrane are like the “triads” in the muscle structure. They show contractile activity. Proteins or motor proteins localized to the lateral wall of OHCs
3 Physiology ofthePeripheral andCentral Hearing System
45
Fig. 3.8 Morphology of outer hair cells
change the length of the hair cells in response to conformational changes. That is,
OHCs have the ability to change their length in response to changes in transmembrane voltage. This electromotile response results from structural changes in a membrane-bound protein molecule called Prestin. In OHC motility, changes in membrane
potential are accompanied by changes in the axial stiffness of the cell [38–41].
Outer Hair Cell and Electromotile Responses: Prestin functions as an extrinsic
voltage sensor using cytoplasmic anions (generally Cl−) and has recently been recognized as a motor protein related to pendrin and other sulfate/anion transporters. In
response to changes in membrane potential, they change the length of the OHC—
electromotility—in microseconds. After binding with millimolar afnity, anions
create a response in the membrane to transmembrane voltage changes. The movement of anions to the extracellular side is hyperpolarized, while that to the cytoplasmic side is depolarized, where the length of the Prestin motor protein becomes
shorter. If there is no monovalent anion in the cytoplasm, the Prestin molecule is in
46
a short state. The outer hair cell is in maximum contraction [39, 40, 42, 43]. The
afnity of Prestin for monovalent anions is I−>Br−>NO−3>Cl−>HCO−3>F−.
For salicylates, the anion-binding portion of Prestin is in competition with the active
ingredients of aspirin. The binding afnity of salicylates is 300 times higher than
that of chloride ions. High doses of aspirin can signicantly reduce OHC electromotility, resulting in hearing loss [39, 40, 43–45].
M. Baran et al.
3.5.3 The Tectorial Membrane
This is a noncellular mass of connective tissue. It extends from the base of the
cochlea to the tip and covers the organ of Corti. It is connected to the interdental
cells of the spiral limbus, which secrete the medial matrix of the tectorial membrane. On the lateral side of the organ of Corti, the inferior surface of the tectorial
membrane is in contact with the stereocilia of the outer hair cells and Hensen cells.
The mass and dimensions of the tectorial membrane increase inversely with frequency across the cochlear duct. Ultrastructural studies have revealed at least two
types of brils within the tectorial membrane, called brils and non-brils. The two
main types of brils are referred to as type A and type B.Type B brils are associated with the stereocilia of OHCs. The tectorial membrane does not contain IHC
stereocilia. The tectorial membrane also contains collagen and other molecules.
These molecules appear as brils and matrix. Chondroitin-4-sulfate, enriched with
glycosaminoglycans, and the non-collagenous compound α-tectorin, whose chromosomal mutations cause deafness, are different compounds of the tectorial membrane. The protein called otoancorin is located in the region where the tectorial
membrane joins the spiral limbus, and its mutation causes hearing impairment
[22, 34].
3.5.4 The Osseous Spiral Lamina
This is a narrow, spiral-shaped sheet of bone that runs from the modiolus to the
inner edge of the BM.The interior of the spiral lamina is perforated by channels
known as habenula perforata. Nerve bers entering and exiting the organ of Corti
lose their myelination and enter the organ of Corti [12, 23].
3.5.5 Cochlear Mechanics
The cochlea has mechanical properties that are both passive and active. The cochlea,
especially the organ of Corti, is a marvel of biological engineering of intricate,
microscale mechanical systems. The most important point with respect to peripheral auditory functions in mammals is that a simpler, passive resonant system consumes active energy to detect and amplify acoustic energy. This feature of cochlear
mechanics was demonstrated in cadavers by von Bekesy. Because cochlear
3 Physiology ofthePeripheral andCentral Hearing System
47
mechanisms at this level are independent of other functions, they do not require
energy (e.g., ATP). The organ of Corti is considered as passive structure by von
Bekesy, is considered passive [18, 46].
3.5.5.1 Passive Mechanics
The primary component of passive cochlear conduction is hydromechanical in
nature, and it is well-known that the combined contributions of multiple structures
determine the character of the cochlear resonance [18]. Passive features have also
been discovered in the postmortem cochlea, and a tonotopic arrangement of the
cochlea has been proposed. Mechanically, the cochlea can be represented by a
sequence of radial sections extending from the base to the apex. The resonant frequency of each section is determined by the average mass and stiffness of its
BM. The frequency response at any given location is determined by systemic
changes in its physical properties along the length of the cochlea. For example, the
BM has a lower mass and higher stiffness in the basal portion of the cochlea but a
larger mass and lower stiffness in the apical portion. For this reason, the basal portion exhibits maximum vibration at high frequencies, whereas the apical portion
exhibits maximum vibration at low frequencies [32, 39, 43, 46].
As a result, the sound pressure wave is transmitted as mechanical energy through
the base of the stapes to the perilymph in the SV, i.e., to the base of the cochlea. This
pressure wave propagates along the cochlea toward the apex. The vibration of the
BM is greatest in the frequency range produced by sounds that match the characteristic frequency of the BM.Since the cochlea cannot be compressed at this point
because it is bony and hard, the pressure waves pass through the organ of Corti,
enter the ST, and propagate from there to the round window. The physical properties
of the BM determine an individual’s hearing limits and ability to discriminate frequency differences within the hearing range [9, 22, 46].
3.5.5.2 Active Mechanics
Experimental measurements of BM vibrations in the postmortem cochlea have
shown that BM movements increase linearly with sound pressure level without
cochlear amplication [46]. However, passive mechanical properties are not sufcient to explain the frequency selectivity and excellent sensitivity of mammalian
hearing. The active mechanism was rst proposed by T.Gold [47, 48]. The existence of a mechanical energy source was discovered as sounds produced in the inner
ear called otoacoustic emissions. When in vivo mechanical measurements were
made in guinea pigs, it was found that the peak of the emitted wave was quite sharp
at low-level stimuli and exhibited nonlinear growth as the sound level increased
and, at low-level stimuli, the vibration amplitudes of the BM were two to three
times higher than the stapes displacement level [49, 50]. This tells us that cochlear
mechanics has a nonlinear function. The sharpness and sensitivity of sound increase
dramatically in BM vibration measurements in the living cochlea. In other words,
responses to sound are more stable in the living cochlea than in the dead cochlea.
This function is called cochlear amplication. Positive feedback occurs locally
along the length of the cochlea, and amplication of BM vibrations occurs in a cycle
48
M. Baran et al.
[51, 52]. The characteristics of cochlear sound are transmitted by the auditory nerve
bers precisely through the synapses of IHCs. OHCs are key elements that regulate
the frequency selectivity, dynamic range, and sensitivity of the mammalian ear. In
the absence of OHCs, hearing thresholds decrease by 40–50dB and frequency resolution deteriorates. The function of the ear becomes linear. The Prestin molecule is
responsible for the production of OHC somatic motility, and in mice lacking Prestin,
hearing thresholds are reduced by approximately 50dB and frequency selectivity is
lost. The common clinical problem in sensorineural hearing loss is initial OHC
damage. Later, with OHC damage, amplication is lost and sensorineural hearing
loss gradually progresses [40, 48, 53]. In response to changes in membrane potential, OHCs in the mammalian cochlea actively change their cell length. This electromotility, mediated by the recently identied voltage-sensitive motor molecule
Prestin, is believed to underlie cochlear amplication. The response is seen within
microseconds [44]. This is because motor responses are fast, and this speed is not
limited by diffusion. The medial olivocochlear (MOC) bundle can regulate the gain
of cochlear amplication. Medial olivocochlear efferent neurons innervate OHCs in
the mammalian cochlea and are capable of frequency-specic control of peripheral
auditory sensitivity [51, 52].
3.5.6 Frequency Analysis oftheCochlea
Studies of how frequency analysis was conducted in the cochlea can be divided into
three periods. The rst period began in the second half of the 1700s and lasted until
the late 1940s. At the beginning of this period, it was believed that the interior of the
human cochlea was lled with air. When Cotugno rst suggested in 1760 that the
cochlea was lled with uid, many scientists at the time did not believe it. In 1777,
Meckel came up with a clever plan to bury the cadaver of a recently deceased person
in snow and freeze it, perhaps creating the world’s rst cochlear ice cube. In this
way, he proved that Cotugno was right by showing that the cochlea was lled with
uid. The most detailed and impressive studies explaining the structure of the
cochlea came from Alfonse Corti in 1851. Corti’s drawings of the inner ear, based
on his observations at the time, not only led to the naming of the organ of hearing
after him but also contain details that still amaze people today. At the time, however,
it was not known which part of the organ of Corti did what. One of the rst theories
of how sound analysis takes place in the inner ear was proposed by Ohm in 1843,
where the idea was put forward that sound analysis should be done with some kind
of Fourier or spectral analysis. Twenty years later, in 1863, a researcher named
Helmholtz stated that different parts distributed throughout the cochlea resonate
with sound like a tuning fork, depending on the frequency. Helmholtz’s views left
their mark on what we can call the rst period of sound analysis in the inner ear. The
second period began in the late 1940s and lasted until the early 1970s. During this
period, the most important contributions were made by George von Bekesy, who
received the Nobel Prize in 1963. von Bekesy described vibration in the 1960s using
stroboscopic and microscopic studies of cadaver temporal bone samples and various
3 Physiology ofthePeripheral andCentral Hearing System
49
cochlear models. His studies showed that Helmholtz’s views were inconsistent with
observations in two ways. First, vibration was not seen as a simple example of independent mechanical resonators resonating. Different parts of the cochlea appeared
to be mechanically connected. Second, there were observations of broad vibration
patterns that did not support a high degree of frequency separation. These ndings
suggested that the cochlea must contain an additional “ne-tuning” mechanism.
Von Bekesy’s discoveries led to the development of the propagating wave theory.
The third phase of sound analysis began in the early 1970s and is continuing until
today. During this period, von Bekesy’s theory of wave propagation has become
prominent. He demonstrated a local electromechanical amplication process in
which OHCs act as both sensors and feedback elements. This local amplication
process is under the control of the central nervous system (CNS). Through the afferent synapses of IHCs, information is transmitted to the CNS by a mechanoelectrochemical process [11, 24, 32, 39].
3.6 The Central Auditory System: APerspective
Acoustic information from the peripheral auditory system is encoded in the timing
and rate of ring of spiral ganglion neurons projecting to the CNS [54]. Basic auditory features such as frequency spectrum, temporal changes, and sound location are
extracted by progressive analyses in the auditory nuclei [9].
3.6.1 Auditory Nerve Fibers
Information is transmitted from cochlear cells to neurons through the cochlear ganglion (Fig.3.9). Because the ganglion is located in the nucleus (modiolus) of the
cochlear spiral, it is also called the spiral ganglion. Approximately 30,000 ganglion
cells in each inner ear innervate hair cells. It has been shown that this transmission
is chemical and that the transmitter involved in the transmission is glutamate. The
cochlear branch of the vestibulocochlear nerve consists of the axons of the neurons
innervated by the hair cells. They terminate in the dorsal and ventral cochlear nuclei
in the medulla oblongata. Type I primary afferent neurons in the spiral ganglion
constitute 95% of all afferents and each synapse on a single inner hair cell. Type I
spiral ganglia are myelinated bipolar neurons and have glutaminergic synapses. In
immunohistochemical studies, AMPA (α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid) and NMDA (N-methyl-d-aspartate) receptor subtypes
were expressed in these ganglia. GluR 2/3 and GluR4 subunits are located at the
type I inner hair cell synapse of the spiral ganglion. Type I metabotropic glutamate
receptors may contribute to glutamate action by the spiral ganglia. Glutamate alone
may not be a hair cell neurotransmitter. The presence of P2X2 receptors in the auditory nerve may indicate that ATP has an excitatory function and may be one of the
possible neurotransmitters. High glutaminergic synaptic activation causes neurotoxicity in the IHC type I spiral ganglion. Loud noise or other trauma causes
50
Fig. 3.9 Afferent and efferent innervation in the organ of Corti
M. Baran et al.
structural disturbances in the postsynaptic region due to excessive transmitter (glutamate) release. Type II afferent neurons, 5% of all afferents, innervate 5–28 outer
hair cells each. Type II spiral ganglia are unmyelinated pseudomonopolar neurons.
The identity of the neurotransmitter is unknown. It may contribute to the medial
efferent feedback system through central connections [9, 11, 22]. Type 1 spiral gan-
glia differ in terms of spontaneous activity and threshold [9]. The spontaneous spike
rates of the spiral ganglia in the absence of sound stimulation range from near 0 to
more than 100 spikes per second [55]. High spiking rate bers respond at low sound
intensities, but their rate saturates early at higher intensities, whereas low spiking
rate bers activate at higher sound intensities with late or no saturation [55]. High
spiking rate bers originate from the side of the IHC facing the columnar cells and
pass through the modiolus near the ST region. Medium and low spiking rate bers
originate from the modiolar side and the SV side [9, 22, 55]. Type I afferent auditory
nerve bers make only a single synaptic contact with a single IHC.These synapses
are called ribbon synapses. Ribbon synapses allow the IHC to activate each afferent
nerve ber. It maintains the precise timing required for time-based sound localization and frequency time coding, allowing for the continuous generation of action
potentials [9, 55].
3 Physiology ofthePeripheral andCentral Hearing System
51
3.6.2 The Subcortical Auditory Nuclei
3.6.2.1 The Cochlear Nucleus
The auditory nerve bers that enter the cochlear nucleus retain the spatial congurations (tonotopic organization) that originated in the cochlea. There are two main
exits from the cochlear nuclei to other subcortical nuclei, called the dorsal and ventral acoustic streams [9, 11]. Ventral acoustic stream: Fibers emerging from the
projecting cells rst pass through the trapezoid body from the ventral surface of the
brainstem and reach both nuclei of the superior olive complex. Here, the stimulus in
both the ears is compared in terms of intensity and time, and this information is used
for sound localization. This pathway is the binaural sound localization pathway
[13]. Dorsal acoustic stream: This pathway, which includes the dorsal and intermediate acoustic striae, is the pathway formed by bers originating from cells that
project to the contralateral nucleus of the lateral lemniscus and the inferior colliculus. This pathway is the pathway by which complex auditory stimuli are analyzed,
primarily for sound identication. Each ber of the auditory nerve that enters the
cochlear nuclei gives off branches both anteriorly and posteriorly.
– The anterior branch innervates the area known as the anteroventral cochlear
nucleus and carries acoustic information for binaural sound localization in the
ventral stream.
– The posterior branch carries information for both sound identication and sound
localization and innervates the dorsal cochlear nucleus along with the postero-
ventral cochlear nucleus.
In each nucleus, low frequencies are located anteriorly or ventrally, while high
frequencies are located posteriorly or caudally.
3.6.2.2 The Superior Olivary Complex
The olivocochlear efferent system, a cluster of neurons dened in the superior olivary complex in the brainstem, has two anatomically and histologically distinct
parts: lateral and medial efferent [22, 51, 52].
Lateral Efferent Fibers: These are unmyelinated bers that arise from the lateral
nucleus of the olivocochlear system and innervate the inner hair cells ipsilaterally.
They form axoaxonic or axodendritic synapses with the afferent bers of IHCs and
control both the postsynaptic discharge of afferent nerve bers and the input of
acoustic information to the central nervous system. Although they have cholinergic
synapses, they contain neurotransmitters such as acetylcholine, dynorphin, and calcitonin gene-related peptide, which act as excitatory neurotransmitters to increase
postsynaptic discharge of the auditory nerve, and dopamine, enkephalin, and
gamma-aminobutyric acid (GABA), which act as inhibitory neurotransmitters to
decrease postsynaptic discharge of the auditory nerve [16, 20, 49].
Medial Efferent Fibers: These are myelinated bers that arise from the medial
nucleus of the olivocochlear system and innervate OHCs contralaterally [13].
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M. Baran et al.
Medial olivocochlear (MOC) neurons, which cross at the base of the fourth ventricle, receive information from both cochleae. Olivocochlear efferent bers entering the cochlea via the inferior vestibular nerve release the neurotransmitter
acetylcholine, which alters the micromechanical properties of OHCs and thus the
mechanical properties of the BM.The medial olivocochlear system is responsible
for cochlear amplication, frequency selectivity, and auditory sensitivity in the
auditory system. They increase the signal-to-noise ratio in the cochlea, making it
easier to nd signals in background noise. Electrical or acoustic stimulation from
the oor of the fourth ventricle via contralateral stimulation activates the medial
olivocochlear bers. This activity inhibits ipsilateral responses, and these responses
are observed in nerve responses and otoacoustic emission recordings [51, 52, 56].
Sound processing in the cochlea is inuenced by cholinergic efferent axons from
medial olivocochlear neurons in the brainstem [57]. The effect of the MOC system
occurs by suppressing cochlear responses through hyperpolarization of OHCs.
MOC activation on outer hair cells occurs through nicotinic acetylcholine receptors
alpha 9 and alpha 10. Activation of these receptors causes Ca2+ entry into OHCs and
opening of K+ channels, resulting in hyperpolarization of the cell [58, 59]. There are
three subgroups of Ca2+-activated potassium channels according to the speed of
channel conduction: high-speed (BK), medium-speed (IK), and low-speed (SC)
conduction. The BK and SK channels have been shown to exit the auditory system.
Studies show that SC channels in hair cells play an important role in cholinergic
inhibition and that the efferent neurotransmitter is acetylcholine. It is known that K+
channel blockers such as iberiotoxin, apamin, kinin, d-tubocurarine, tetraammonium chloride inhibit acetylcholine responses in OHCs [51, 55–59].
3.6.2.3 The Lateral Lemniscus
Fibers originating from the superior olivary nucleus project through the inferior colliculus and lateral lemniscus. It has two major nuclei: dorsal and ventral. The second site of sound interaction, the Probst commissure, is located here [13].
Ventral Nucleus: This is part of the monaural sound stream. It receives contralateral input from all cell types in the ventral cochlear nucleus. It does not receive input
from the superior olive nuclei and is not involved in binaural sound localization. It
projects ipsilaterally to the inferior colliculus. The cells of the ventral lateral geniculate nucleus are believed to process temporal information, and the pool of neurons
they contain specializes in revealing the temporal characteristics of complex sounds
[13, 60].
Dorsal Nucleus: This is part of the binaural sound localization pathway. It
receives input from the ipsilateral MOC, the contralateral cochlear nucleus, and the
ipsilateral and contralateral efferents. This nucleus is primarily inhibitory and projects to both sides of the inferior colliculus. Most of its neurons excite contralateral
impulses, inhibit ipsilateral impulses, and are sensitive to interaural time differences
[9, 13, 18].
It allows detection of different sound source localizations in the horizontal plane.
It provides inhibition in the lower stages of the auditory system during lateralization
of the sound source. Lateralization occurs rst in the superior olivary complex;