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EDITORIAL |
1 Institute for Science & Technology in Medicine and School of Life Sciences, Keele University, Keele ST5 5BG, UK
2 School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK
Email: m.g.evans{at}keele.ac.uk and c.j.kros{at}sussex.ac.uk
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Introduction |
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 Top Introduction References |
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The cochlea is essentially a frequency analyser, splitting sound into its component frequencies and signalling them to the next stage of the auditory pathway, the cochlear nucleus, in separate neural channels. Before dealing with the mechanisms of cochlear function highlighted by the reviews, we should first set the scene by considering the basics of structure and function in the cochlea. Cutting the mammalian cochlea from top to bottom (apex to base) reveals the three fluid-filled scalae that together form the cochlear spiral (see Fig. 1 in Wangemann, 2006). The middle one, scala media, contains an unusual and unique extracellular solution, endolymph, that is rich in K+ and low in Ca2+. It also has a large positive voltage, the endocochlear potential. The sensory receptors within the organ of Corti, the hair cells, are immediately beneath yet protected from the endolymph – only the apical surfaces of the cells, with the stereociliary bundle that houses the transduction channels, are in contact with the endolymph. The remainder of the cell, surrounded by the basolateral cell membrane, contacts an extracellular fluid of normal composition – perilymph. This effectively divides the hair cell in two: the apical transduction apparatus and the basolateral membrane, the latter containing an array of ion channels that perform a number of roles, in particular shaping the receptor potential and driving the release of excitatory neurotransmitter onto the afferent nerve terminals. The basilar membrane, which carries the travelling wave induced by sound from base to apex, is beneath the hair cells and connected to them via supporting cells. There is one other crucial division – in mammals there are two types of hair cell arranged in rows within the organ of Corti that spiral up the cochlea, inner hair cells (IHCs) in the inner row surrounded by three rows of outer hair cells (OHCs). IHCs receive many afferent nerve fibres and are the primary sensory receptors. OHCs receive principally efferent fibres and function as cellular amplifiers, under neural control, boosting the vibrations of the basilar membrane and thereby increasing both cochlear sensitivity and frequency discrimination.
This Special Issue of The Journal of Physiology focuses on five aspects of cochlear function: the maintenance of the ionic gradients across the hair cell apical membrane that provide the source of the transduction current; mechanoelectrical transduction; the role of the OHCs and the amplification they provide; the control of this amplification by the olivocochlear efferent nerve fibres; and finally the rapid signalling to the CNS provided by the IHC afferent synapse. It will become apparent that there is considerable interdependence among these roles.
Formation of the endolymph
The role of the cells of the stria vascularis in forming and maintaining the endolymph is described by Wangemann (2006). A number of channels and transporters combine to produce the endolymph, the potassium within forming the major component of the transduction current entering the hair cells and producing the receptor potential. The potassium is then recycled back to the stria vascularis and out again into the endolymph. Clearly, moving potassium from perilymph to endolymph must require energy, but not at the hair cells' expense since the potassium movements in through the transducer and out through the basolateral membrane are downhill. There is a potential problem, however. All components must work together, and the loss of just one may produce deafness or a balance disorder. For example, mutations in genes coding for certain gap junction channels, ion transporters and K+ channels within the cells of the stria vascularis can cause deafness in humans. There are a number of null mutations in mouse models that are now providing important information about the functional roles of the various channels and transporters that work in concert to produce the endolymph and maintain its composition and volume.
Mechanoelectrical transduction – the transducer channel
Much of what we know about hair cell transduction comes from pioneering work by Hudspeth and Corey in frogs and Crawford and Fettiplace in turtles. They stimulated the conical-shaped hair bundles (of about 100 stereocilia arranged in a regular array) using fast piezoelectric devices while recording transducer currents from the hair cells. In his review, Corey (2006) begins by summarizing this work. We know that the transduction channels are located close to the top of the bundle of stereocilia, and that the gating is associated with the extracellular tip links that join stereocilia in adjacent rows within the bundle. There has to be some direct mechanical input to the channel, and in most models this is the tip link or something connected to it. Probably because of this, transduction is direction sensitive, and displacement of the bundle towards the tallest row of stereocilia opens the channels whereas displacement in the opposite direction closes them. The channels are permeable to a wide range of cations (some of which can be quite large), but crucially they are permeable to calcium, and calcium entry through the channels makes them shut, a process called adaptation, which regulates the bundle's operating point. The transducer channels have a large single channel conductance and are blocked by aminoglycoside antibiotics such as dihydrostreptomycin. It is notable that the basic mechanism of transduction appears to be similar in non-mammalian vertebrates and mammals, but mammals clearly have managed to speed up transduction to extend hearing into the range of many tens of kilohertz.
To the uninitiated then, it might come as a surprise to learn that we do not know the molecular identity of the transduction channel (Corey, 2006). Corey describes the difficulty associated with identifying the channel, and gives suggestions for the leading contenders. Top of the list are certain TRP channels, which we know are involved in mechanosensation in a number of animals. The race is on and of course it has been for some time, but often the techniques available can provide false trails. Nonetheless, the use of mouse or rodent mutants with a hearing or balance phenotype is likely to be of immense value in the search for the channel. Furthermore, because of the detailed knowledge we have of the channels' conductance properties, combined with the increasing knowledge of TRP channels and other possible contenders, it should be possible to proceed in an orderly manner through the contenders.
Converting transduction into amplification
A major step forward in our understanding of the cochlea was made about 20 years ago with the demonstration of active motility in hair cells. Physiologists investigating cochlear function since Von Békésy have been aware that the slightest damage to the cochlea increases thresholds and compromises function. The system is vulnerable and easily insulted. There are probably a number of reasons for this, but the major one is that cochlea depends on its cellular components for its sensitive and faithful output. In addition, the sensitivity of the system has to be maximal at low sound pressures, but must be turned down as the sound level increases. Two forms of hair cell motility that could lead to amplification within the cochlea were found in the 1980s, active bundle movements (Crawford & Fettiplace, 1985) and, unique to OHCs, fast longitudinal contractions of the cylindrical cell body termed somatic electromotility (Brownell et al. 1985; Ashmore, 1987). The active bundle movements were found originally in turtle auditory hair cells, driven by the membrane potential change produced by current injection through an intracellular microelectrode, but recently they have been found in OHCs as well (Kennedy et al. 2005). This means that the OHC has potentially two separate mechanisms that can produce amplification. How these mechanisms might interact, or indeed work separately, and how any interaction might vary at different frequency places along the cochlea, is an intriguing and perplexing question.
The recent research on active hair bundle movements is reviewed by Fettiplace (2006). The movements are intimately associated with the gating of the transducer channels that adapt to a maintained stimulus through a mechanism that depends on calcium influx through the channel. Since the channel is mechanically gated, its closing during adaptation can exert forces back onto the bundle producing movement. Because the OHC hair bundle is attached to the overlying tectorial membrane, these forces could be fed back into the cochlear partition, potentially increasing the mechanical input to the IHCs. A notable aspect of this mechanism is its direct linkage to channel gating and therefore its potential to work in a tonotopic manner – speeding up for the higher frequency hair cells towards the cochlear base. In mammals, however, the channel opening is too rapid to be resolvable with conventional stimulation and recording techniques.
The nature of the OHCs fast somatic electromotility is reviewed by Dallos et al. (2006). The motor protein that produces the motility is prestin, expressed in OHCs and packed into the lateral membranes at high density. Prestin is a member of a family of anion transporters and is thought to bind internal Cl– ions at a positively charged site. Prestin is voltage dependent and displaces positive charge across the membrane, possibly with Cl– bound, and in the process is thought to undergo a conformational change producing motility. Thus changes in the OHC membrane potential are converted into changes in cell length, with positive or negative changes in membrane potential producing contraction or elongation, respectively. The importance of prestin is underscored by the raised thresholds and reduced frequency selectivity found in prestin knock-out mice. A question mark relates to the effective frequency dependence of the OHC motility, particularly in view of the low pass filter provided by the cell membrane, and the impressive frequency ranges enjoyed by most mammals.
Regulation of OHC function within the cochlea
In design terms it seems sensible that in their role as cochlear amplifiers, OHCs should be under some sort of adjustable gain control. The OHCs receive direct synaptic connections from neurones in the superior olivary complex of the brainstem, and electrical stimulation of this pathway has the effect of raising the thresholds of both IHCs and their auditory nerve fibres, via a direct inhibitory effect on the OHCs. This pathway, then, does appear to provide the expected gain control. It is commonly referred to as the efferent pathway to distinguish it from the afferent or sensory pathway from the cochlea to the brain. OHCs also have afferent connections, although they only amount to approximately 5% of the total in the auditory nerve. They are difficult to record from and are poorly understood.
OHCs are tightly attached to supporting cells at their apices and bases, but once development is completed they have relatively wide spaces in-between, filled with perilymph. Thus changes in cell length should be able to influence the microgeometry of the organ of Corti. This ability will depend on the stiffness of the reticular lamina (top edge of organ of Corti) and basilar membrane (bottom edge) and on the forces generated by the OHCs. The review by Frolenkov (2006) considers the mechanisms that regulate OHC electromotility, and illustrates the niche occupied by the OHC within the organ of Corti and the relevant structural features of the OHC. Clearly the efferent input to the OHCs must exert a major influence on electromotility, but precisely how it does this is a matter of speculation. In addition to a direct synaptic input to the OHC that might regulate electromotility electrically, there is also the possibility of other indirect modes of regulation provided by the efferents, for example by altering OHC stiffness or by an effect on prestin mediated by Cl– binding or phosphorylation. This concert of potential regulatory mechanisms would also provide for regulation over both fast and slow time scales.
A system that regulates OHC electromotility must also regulate the mechanics of the cochlea. How the efferents manage this is the subject of the review by Cooper & Guinan (2006). They describe the experimental approach of using a laser interferometer to measure the influence of the efferents on the nanometer motion of the basilar membrane produced by sound. With surgical skill in electrode placement it is possible to stimulate the efferents electrically. As expected from the classical work of efferent effects (e.g. Wiederhold & Kiang, 1970), efferent stimulation reduces the basilar membrane motion at its peak (its characteristic frequency), consistent with a reduction in the gain of the cochlear amplifier. This effect builds up over a fraction of a second. Less expected are inhibitory effects that develop over a much slower time scale (1–2 min) and excitatory effects observed at frequencies well above the characteristic frequency. These findings indicate that the controlling input (the efferent synapse) regulates the output (basilar membrane motion stimulating IHCs) via different mechanisms. While clearly complicated, this notion fits in well with the several potential regulatory mechanisms of OHC electromotility outlined by Frolenkov (2006).
Signalling sound to the brain
The OHCs act in concert in amplifying the travelling wave to produce a sharp peak at a characteristic frequency (the position of this peak moving towards the base as the frequency increases). This in turn means that the IHCs positioned at the peak will receive a greater stimulation than their neighbours off-peak. At frequencies below about 3–4 kHz the firing of the nerve fibres is phase-locked to the tone, meaning that the probability of firing cycles at the tone frequency. The synapse must therefore be able to transmit information at these frequencies, and do so without fatigue. As a starting point, one can speculate that this remarkable temporal coding must be provided by a fast synaptic mechanism in IHCs. In the final review, Moser et al. (2006) discuss excitation–secretion coupling at the IHC ribbon (afferent) synapse. Fast BK channels in the IHC membrane serve to shorten the membrane time constant, and at active zones where neurotransmitter (glutamate) is released, Ca2+ channels are packed in to deliver Ca2+ and induce exocytosis of nearby synaptic vesicles docked at the presynaptic ribbon. Knowledge about the relationship between intracellular Ca2+ in the active zone and exocytosis has allowed different models of the active zone to be considered, and the authors suggest that the level of control goes down to a ‘nanodomain’ around a single Ca2+ channel.
Twenty-first century horizons
The last 20 years or so have seen some very exciting developments in our understanding of cochlear function – how sound is resolved into component frequencies for onward processing by the higher centres in the auditory pathway. Genes that are linked to deafness and hearing disorders are being found and their functions are beginning to be understood. From the physiological perspective we have a comprehensible idea of how the cochlea works, but at each stage there are still a number of important gaps in our knowledge – some of these are pointed out by the review authors. For example, how exactly do the OHCs amplify the travelling wave on the basilar membrane, and how do the proposed mechanisms, involving fast changes in OHC cell length and bundle movements, act together to produce this amplification? At the level of the transducer, we do not know the identity of the channel or how it is gated in detail, or how channel opening and adaptation interact to induce force generation by the bundle. As for the afferent synapse, how does it keep releasing vesicles of neurotransmitter so rapidly and without running out of supplies? Furthermore, how do all of these processes extend to high frequencies, particularly in mammals that hear well into the kilohertz range?
What might be discovered in the next 50 or 100 years? It is impossible to tell, but significant advances are likely to be made in our understanding of the genetic causes of deafness and hearing loss, and in our overall understanding of the molecular and cellular basis of hearing, from the mechanics of the cochlea up to perception at cortical level. This in turn will surely revolutionize our ability to intervene successfully in cases of deafness or hearing loss.
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References |
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TopIntroductionReferences |
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Cooper
NP
&
Guinan
JJ
Jr (2006). Efferent-mediated control of basilar membrane motion. J Physiol
576, 49–54.
Corey
DP (2006). What is the hair cell transduction channel?
J Physiol
576, 23–28.
Crawford
AC
&
Fettiplace
R (1985). The mechanical properties of ciliary bundles of turtle cochlear hair cells. J Physiol
364, 359–379.
Dallos
P, Zheng
J
&
Cheatham
MA (2006). Prestin and the cochlear amplifier. J Physiol
576, 37–42.
Fettiplace
R (2006). Active hair bundle movements in auditory hair cells. J Physiol
576, 29–36.
Frolenkov
GI (2006). Regulation of electromotility in the cochlear outer hair cell. J Physiol
576, 43–48.
Kennedy HJ, Crawford AC & Fettiplace R (2005). Force generation by mammalian hair bundles supports a role in cochlear amplification. Nature 433, 880–883.
Moser
T, Neef
A
&
Khimich
D (2006). Mechanisms underlying the temporal precision of sound coding at the inner hair cell ribbon synapse. J Physiol
576, 55–62.
Wangemann
P (2006). Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential. J Physiol
576, 11–21.
Wiederhold ML & Kiang NYS (1970). Effects of electric stimulation of the crossed olivocochlear bundle on single auditory nerve fibres in the cat. JASA 48, 950–965.
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