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date: 23 September 2019

Introduction and overview

Abstract and Keywords

This article briefly outlines the structure and function of the auditory periphery. It intends to introduce the fundamental mechanisms that underlie the function of the auditory periphery. The more the inner workings of the ear are probed into, the more wondrous seem to be capacities, and the biological mechanisms underlying them. The article describes these mechanisms in detail. Two tasks that are central to peripheral auditory function are: conversion of the mechanical energy carried by airborne sounds into bioelectrical signals, and coding the information content of those sounds by frequency filtering. Multiple elements combine to meet these challenges, ranging from middle-ear mechanics. The article briefly overviews the structure and function of the external, middle, and inner ear, its development, repair, and genetics, aiming to provide a better understanding of the intricate machinery of the auditory periphery.

Keywords: auditory periphery, ear, auditory function, airborne sounds, bioelectric signals, frequency filtering

1.1 Introduction

This volume of the Oxford University Press Handbook of Auditory Sciences (OUPHAS) has a simple title. The Ear expresses the intention of providing a handbook of fundamental material that can serve both as an introduction and as a reference work for anyone interested in the auditory periphery. Thus, each chapter aims for a mix of tutorial and advanced information. The focus throughout is on mechanistic, functional evidence, and many chapters concentrate on cellular and molecular explanations. Before continuing it is essential to acknowledge the diligent and generous efforts of the authors who contributed to this volume. Obviously, scientific resources such as this exist only through such dedication and every reader should appreciate the thoughtful explanations and insights these authors have provided. As an overview and introduction, this chapter will be only lightly referenced, but rather will, in the main, refer to those chapters that cover each topic in depth.

It seems almost unnecessary to address the motivation for a volume titled The Ear. Even the briefest exposure to the structure and function of this sensory organ causes a sense of wonder in the observer. The more we probe its inner workings, the more wondrous seem to be its capacities, and the biological mechanisms underlying them. This volume is aimed at describing those mechanisms in some detail. Of course the additional motivation for understanding the auditory periphery is to understand central processing of peripherally derived information that becomes our perception of sound. The process of mechanotransduction leads to altered activity of auditory nerve fibers. The responses of auditory nerve fibers and their onward transmission will be covered in the second volume of this Handbook, The Auditory Brain. Still higher levels of analysis are examined in the third volume, Hearing.

Two tasks are central to peripheral auditory function: conversion of the mechanical energy carried by airborne sounds into bioelectrical signals, and coding the information content of those sounds by frequency filtering. We will see that multiple elements combine to meet these challenges, ranging from middle-ear mechanics (Chapter 3) to the specialized ionic environment of the inner ear (Chapter 7). In a remarkable example of biological adaptation, the differentiated mechanics of the cochlea map stimulus frequency onto a neurosensory epithelium. Many aspects of peripheral auditory function have become better understood. For example, we have a clear appreciation of the fact that the mechanosensory hair cells themselves empower the cochlear amplifier (Chapter 6). We now know some of the proteins that contribute to inner ear development and function, raising the hope for repair (Chapter 13) or improved protection of hearing in the clinical setting. This volume describes not only basic physiological mechanisms, but also clinical aspects (Chapters 2 and 15), development (Chapter 12), and genetics of the inner ear (Chapter 14). This opening chapter briefly outlines the structure and function of the auditory periphery to preview and motivate the following chapters.

(p. 2) 1.2 The external and middle ear

The auditory periphery has three anatomical divisions: the external ear, which includes the pinna and concha on the surface and the external auditory canal bounded by the tympanum or eardrum, the middle ear cavity, which contains the ossicular chain that couples airborne vibration to the third part, the inner ear, the cochlea (Fig. 1.1).

The propagation of acoustic energy through the external and middle ears is covered thoroughly in Chapter 3, and earlier reviews (Merchant et al., 1998). Here we provide a brief summary. The visible external ear collects sound and funnels it toward the opening of the auditory canal, thus providing some amplification. Because the human ear canal is a nearly straight tube about 2.5 cm long, it is broadly resonant at 4 kHz. Thus, frequencies near 4 kHz tend to be enhanced by the resonant quality of the external ear, accounting in part for our best sensitivity in that frequency range. More importantly, the external ear (and head) provides important ‘sound shadows’ so that sounds originating from different positions in space can be recognized by their intensity profile and characteristic frequency signatures.

 Introduction and overviewClick to view larger

Fig. 1.1 Coronal view of the external, middle, and inner ear.

Drawing (1939) by M Brödel, assisted by PD Malone, SR Guild, and SJ Crowe. Reproduced with permission from ‘Three Unpublished Drawings of The Anatomy of the Human Ear’, 1946. Original art in the Max Brödel Archives, Walters Collection #980, Department of Art as Applied to Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

 Introduction and overviewClick to view larger

Fig. 1.2 The normal middle ear seen through the eardrum with an otoscope. Visible portions of the ossicular chain are emphasized with a thin white line.

Image courtesy of Dr Howard Francis, Otolaryngology – Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

 Introduction and overviewClick to view larger

Fig. 1.3 Drawing of the middle and inner ear.

Drawing by M Brödel (1941), assisted by PD Malone, SR Guild, and SJ Crowe. Reproduced with permission from ‘Three Unpublished Drawings of The Anatomy of the Human Ear’, 1946. Original art in the Max Brödel Archives, Walters Collection #989, Department of Art as Applied to Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Sound waves traveling down the canal cause motion of the tympanic membrane, lower pressure (rarefaction) causing it to bulge out, higher pressure (compression) to move in. At this point, the airborne pressure wave is transmitted to the attached ossicular chain of the middle ear. The middle ear bones or ossicles, the malleus, incus, and stapes (Figs 1.2 and 1.3) have the essential task of transferring the airborne pressure waves into motion of the fluid of the inner ear. Since the cochlear fluids are incompressible compared with air, there is an impedance mismatch that must be overcome. The middle ear alleviates this problem in two ways. First, the area of the tympanic (p. 3) (p. 4) membrane is about 25 times that of the stapes footplate. Thus, airborne vibrations falling onto the larger tympanic area are concentrated into more energetic motions of the much smaller stapes footplate. In addition, the orientation of the middle ear bones confers a slight mechanical advantage, about 1.3 to 1. These factors together (about 30-fold gain) serve to lessen the otherwise severe acoustic impedance mismatch. The importance of middle ear transmission is emphasized by the fact of efferent feedback in the form of small muscles that control the motion of the stapes (stapedius muscle innervated from the VIIth, facial, nerve) and the eardrum (tensor tympani innervated from the Vth, trigeminal, motor branch). Contraction of these muscles limits motion of the ossicular chain, and can reduce the trauma otherwise caused to the inner ear by excessively loud sound.

Thus, it should be obvious that disruption of the middle ear reduces acoustic sensitivity, producing a ‘conductive’ hearing loss. This can be temporary, as during middle ear infection (otitis media), or permanent when bony scarring (otosclerosis) impedes motion of the ossicles (although this can be corrected surgically). In some cases middle ear loss requires some functional measure. For example, a tuning fork might be inaudible to a person with conductive hearing loss, but can be heard when the stem is pressed to the skull and transmits to the inner ear by bone conduction, bypassing the middle ear. In contrast, damage to the inner ear causes ‘sensorineural’ hearing loss that does not benefit in this test. The origins and assessment of sensorineural hearing loss are described in Chapter 2. An important addition to these methods is the use of distortion product otoacoustic emissions (DPOAEs) to assess cochlear viability and middle ear patency, especially in infants (Chapter 4). These ‘ear sounds’ also occur spontaneously and are thought to result from the active mechanical amplification arising from outer hair cell electromotility (Chapter 6).

1.3 The inner ear

The cochlear duct of mammals consists of a coiled tube formed by three parallel membranous compartments. Movement of the stapes footplate in the oval window sets up waves within the fluid of the scala vestibuli. These deflect the cochlear partition to propagate through the scala tympani to the distensible membrane covering the round window. Static displacements of the stapes are relieved by fluid movement through the helicotrema at the apical end of the cochlea. However, stimulation by sound is not static but periodic, and the pattern of motion of the cochlear partition depends on the stimulation frequency (Fig. 1.4). The basilar membrane is narrower and stiffer near the oval window (the cochlear base) and so vibrates maximally for higher frequency tones. The basilar membrane becomes progressively broader and more flexible toward the cochlear apex, where lower frequency tones cause maximal vibration. Afferent neurons carrying acoustic information to the brain usually innervate a single hair cell at only one point along the cochlear spiral (Ginzberg & Morest, 1984). Thus, as explained in Chapter 5, the frequency-dependent motion of the cochlear partition (the basilar membrane and cellular elements of the organ of Corti) lies at the heart of auditory perception. The inner ear can distinguish the frequency content of sounds because of the selective innervation of a mechanically tuned sensory epithelium, the organ of Corti in the cochlea.

1.3.1 The cochlear partition

 Introduction and overviewClick to view larger

Fig. 1.4 Artist’s conception of cochlear tonotopy. The cochlear duct is drawn as though unrolled from its original spiral. Segments ‘c’, ‘b’, and ‘a’ indicate high, to middle, to low frequency regions.

Reproduced with permission from unpublished illustration by M Brödel for Dr Samuel J Crowe in 1930. Original art in the Max Brödel Archives, Walters collection #879, Department of Art as Applied to Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

 Introduction and overviewClick to view larger

Fig. 1.5 Cross-section of the mouse cochlea, middle turn. Reissner’s membrane separates the perilymph in the scala vestibuli from the endolymph produced in the scala media by the stria vascularis. The organ of Corti is subject to differential motion of the overlying tectorial membrane (retracted during fixation in this image) and the underlying basilar membrane.

Modified from original micrograph, osmium-stained plastic section, courtesy of J Taranda, University of Buenos Aires, Buenos Aires, Argentina.

Viewed in cross-section (Fig. 1.5), the cochlear partition consists of the basilar membrane and the hair cells and supporting cells (the organ of Corti) lying upon it. These all lie beneath the scala media, the central membranous tube that is flanked on top and bottom by the scala vestibuli and the scala tympani, respectively. Within the scala media is the tectorial membrane, an acellular gelatinous sheet that is mechanically coupled to the stereociliary bundles of hair cells (as seen in (p. 5) (p. 6) Fig. 2.5, this often retracts and lifts away from the hair cells during fixation). The scala media is bounded by Reissner’s membrane on the top, and is delimited by the reticular lamina that forms the apical surface of the hair cell epithelium, and not by the basilar membrane. This distinction is important because the scala media is filled with endolymph, a high potassium, low sodium, and low calcium fluid similar in ionic makeup to cytoplasm. The endolymph is produced by a secreting epithelium called the stria vascularis, which lines the outer wall of the scala media. The scala vestibuli and scala tympani contain perilymph, which has the low potassium, high sodium, and millimolar calcium concentrations of normal extracellular fluid. Since the basilar membrane itself does not present a diffusion barrier, the basal surface of the hair cells is bathed by low-potassium perilymph, while their apical, hair-bearing surface faces high-potassium endolymph. At their apical surface, the hair cells and supporting cells are joined by intercellular junctions (zona occludens) that provide a tight seal against fluid exchange across that surface. As we will see, this unique disposition of ionic media is important for hair cell function (Wangemann, 2006). One important result is that a voltage difference exists between endolymph and perilymph, with the endolymph being 80–90 mV positive to perilymph. The endolymphatic potential provides additional driving force for potassium ions to flow into the cochlear hair cells. The topic of inner ear ionic homeostasis is covered in Chapter 7.

Disruption of inner ear fluid balance is often cited as a possible basis for Ménière’s disease that can include sensorineural hearing loss but more notably vestibular dysfunction, including dizziness, nausea, and inappropriate eye movements. In some cases it seems that the normal circulation of endolymphatic fluid is blocked or otherwise altered, leading to distension of the scala media – a condition called endolymphatic hydrops. The pathogenic mechanisms remain unknown but may relate to the complex ionic homeostasis of the cochlea. In this respect it is of some interest that the most common non-syndromic ‘deafness’ genes in some human populations are mutations in connexin proteins that form gap junctions among cochlear supporting cells (Chapter 14). One hypothesis suggests that endolymphatic potassium is recycled through the interconnected supporting cells of the organ of Corti (Chapter 11), perhaps by way of gap junctions.

1.3.2 Hair cell structure and function

The sensory epithelium, the organ of Corti, is made up of exquisitely differentiated supporting cells and mechanosensory hair cells. The non-sensory supporting cells play important roles in cochlear function, from sequestering extracellular glutamate, to forming rigid ‘beams’ that stiffen the cochlear partition. We are only just beginning to appreciate the many capabilities of the supporting cells, including their potential roles during development. The specialized structure and function of the supporting cells is the topic of Chapter 11. The cochlear hair cells in mammals are divided into two types, inner and outer, based on their position relative to the center of the cochlear spiral. Inner hair cell function is detailed in Chapter 9. Chapter 6 examines outer hair cell electromotility, while efferent inhibition of these cells is covered in Chapter 10. In a cochlear cross-section, one can see the single row of flask-shaped inner hair cells and three rows of columnar outer hair cells (Fig. 1.6). The hair bundle of each cell is coupled to the overlying tectorial membrane (either by direct contact (outer hair cells), or through fluid viscosity (inner hair cells)) and is subject to lateral shear by the differential motion of the tectorial and basilar membranes.

 Introduction and overviewClick to view larger

Fig. 1.6 Cross-section from the middle turn of the mouse cochlea. The inner and outer cells (IHCs and OHCs) are outlined in white, and the hair bundles have been drawn exaggerated to emphasize their functional polarity. Blue: type I afferent neuron to an IHC; turquoise: type II afferent to an OHC; red: medial olivocochlear efferent; fuchsia: lateral olivocochlear efferent.

Original micrograph courtesy of J Taranda, University of Buenos Aires, Buenos Aires, Argentina.

 Introduction and overviewClick to view larger

Fig. 1.7 (A) Stereocilia arranged in three tiers on an outer hair cell in the cochlea of an adult rat. (B) Tip links (indicated by arrows) connecting shorter stereocilia to their taller neighbors on a rat outer hair cell.

Images courtesy of Drs D Furness and C Hackney, Keele University, Staffordshire, UK.

How is this motion of the cochlear membranes converted into bioelectrical receptor potentials? The answer begins by noting the structure of the staggered stereociliary array atop each hair cell (Fig. 1.7). This staircase-like arrangement of modified microvilli is oriented similarly in all cochlear hair cells, with the tallest hairs furthest from the center of the cochlear spiral (the modiolus). This specific orientation is essential to mechanotransduction. Deflection toward the tallest hairs depolarizes the cell and opposite motion hyperpolarizes. Thus, the relative motion between the (p. 7) (p. 8) tectorial and basilar membranes produces coordinate changes in membrane potential in the inner and outer hair cells at any one position along the cochlear duct. Deflection along the axis of bilateral symmetry of the hair bundle pulls on molecular tethers that link stereocilia in adjacent rows. Evidence suggests that tension on these so-called ‘tip links’ is transmitted to a spring-like gate of mechanosensitive transducer channels (Ricci et al., 2006). While the molecular identity of the transducer channel remains unknown, biophysical measurements classify it as a very large conductance, non-selective cation channel. Further details of hair bundle structure and function are provided in Chapter 8.

Three additional points bear mentioning here. The first is that, in the absence of stimulation, resting tension in the hair bundle pulls open approximately 10% of the hair cell’s transduction channels. Thus, sinusoidal deflection of the hair bundle results in a sinusoidal change of tension on the transducer channel gates (i.e. open probability) to alternately depolarize and hyperpolarize the hair cell’s membrane potential. The second and third points are related to the first. The resting tension in the hair bundle is calcium sensitive, so that the low level of calcium in endolymph plays an important role in setting the resting level and dynamic range for hair cell stimulation (Farris et al., 2006). Third, the calcium-dependent tensioning results from active molecular motors, composed of non-muscle myosin that pulls against the actin core of the stereocilium (Gillespie, 2004). Since the actin–myosin interaction is calcium dependent, calcium influx through open transduction channels provides a feedback mechanism that helps to set the hair cell’s dynamic range. A second, very rapid feedback of calcium onto channel gating underlies a mechanical resonance that contributes to frequency tuning in some non-mammalian hair cells. Active hair bundle mechanics may combine with outer hair cell electromotility in the overall scheme of cochlear signaling (Fettiplace & Hackney, 2006; Hudspeth, 2008).

1.3.3 Hair cell innervation and functional differentiation

Sound-induced changes in membrane potential trigger subsequent voltage-dependent processes in cochlear hair cells, whose functional significance is related to the differential innervation pattern of inner and outer hair cells (Figs 1.6 and 1.8). As will be detailed later, outer hair cells possess a voltage-driven molecular motor that returns mechanical energy to the cochlear vibration pattern (Chapter 6). This electromotile feedback mechanism is subject to central control through the predominant efferent cholinergic innervation of the outer hair cells (Chapter 10). In contrast, the inner hair cells receive the great majority of afferent contacts from spiral ganglion neurons. Thus their receptor potentials encode transmitter (glutamate-like) release onto afferent dendrites by altering the open probability of voltage-gated calcium channels clustered near to transmitter release sites, or ribbons (Chapter 9). Electromotility, and transmitter release, are strongly modulated by voltage-gated potassium channels that make up the bulk of the membrane conductance in both the outer and inner hair cells. It is worth noting that potassium channels in the basolateral membranes of hair cells face a perilymph-like solution with a low level of potassium. Consequently, potassium flux through these channels is outward and hyperpolarizing. Conveniently then, potassium flux in through apical transducer channels and out across the basolateral membrane of hair cells can be ‘downhill’ in both directions, off-loading the energy demands of ionic pumping to the stria vascularis that generates the potassium-rich endolymph (Chapter 7).

 Introduction and overviewClick to view larger

Fig. 1.8 Surface view of a mouse organ of Corti. Red shows immunolabeling for CTBP2 (‘ribeye’), a protein found in the nucleus and at ribbon synapses. Green is the immunolabel for synapsin 2, a marker of efferent nerve terminals found on outer hair cells, and on afferent dendrites below inner hair cells. Scale bar: 20 μm.

Micrograph courtesy of S Pyott, University of North Carolina, Wilmington, North Carolina, USA.

Cochlear afferent neurons have their cell bodies within the central core, or modiolus of the cochlear spiral (hence ‘spiral ganglion neurons (SGNs)’). Type I afferents make up 95% of SGNs and project a single dendrite radially to contact a single inner hair cell. In fact, in most inner hair cells, a single presynaptic density, or ‘ribbon’, provides the sole synaptic input to a single type I afferent (Nouvian et al., 2006). This uniquely specialized arrangement means that type I afferent (p. 9) signaling reflects the transmission capacities of a single ribbon synapse. This is all the more remarkable when one observes that single ribbons possess a few hundred synaptic vesicles at most, and depend on the gating of a cluster of ∼100 voltage-gated calcium channels. Nonetheless, this limited arsenal can support spontaneous activity up to 100 Hz in some SGNs, and encodes the timing and intensity of acoustic signals throughout the lifetime of the organism. To help overcome these limitations, dozens of type I afferents contact a single inner hair cell, providing multiple parallel channels. Hair cell synaptic function is covered in Chapter 9.

There are many fewer type II afferents and these smaller neurons send a dendrite into the region of the outer hair cells, where it turns basally to extend hundreds of micrometers, appearing to contact large numbers of outer hair cells and supporting cells (Perkins & Morest, 1975; Fechner et al., 2001). The functional consequence of this innervation pattern, and indeed the function of type II afferents overall, remains enigmatic since there is essentially no information about their adequate stimulus. The other neuronal contacts of the outer hair cells are better understood. Efferent cholinergic neurons project from somata in the superior olivary complex to synapse on the basal pole of outer hair cells. These larger medial-olivocochlear neurons (MOCs) are distinct from a population of lateral olivocochlear neurons (LOCs) that synapse onto type I afferent neurons beneath inner hair cells in the mature cochlea (Guinan, 2006). Reminiscent of the situation for type I and type II afferents, the larger MOC efferents have revealed important details of their function, while the smaller LOC efferents remain unresolved with respect to function, pharmacology, and activation pattern. Release of acetylcholine (ACh) from MOC efferents causes outer hair cells to hyperpolarize. This effect has several unusual features, among them that the hair cell’s ACh receptor (composed of α9 and α10 subunits) is a ligand-gated cation channel genetically related to nicotinic receptors of nerve and muscle (Chapter 10). Calcium entry through this receptor activates calcium-dependent potassium channels to hyperpolarize and inhibit the hair cell (Fuchs & Murrow, 1992; Glowatzki & Fuchs, 2000; Oliver et al., 2000).

Electrical activation of the MOC efferent axons reduces the amplitude of the compound cochlear action potential evoked by a brief tone burst (Galambos, 1956). Recordings from single type (p. 10) I SGNs showed that sensitivity is reduced most at the best frequency for that neuron, corresponding to a loss of tuning by the cochlea (Wiederhold & Kiang, 1970). Given that MOC efferents contact outer hair cells, and that type I SGNs innervate inner hair cells, the logical conclusion is that outer hair cells must somehow contribute to the acoustic sensitivity and tuning of inner hair cells and their postsynaptic type I SGNs. We now know that this contribution occurs through the mechanism of electromotility, the ability of outer hair cells to generate mechanical force in response to a change in their membrane potential (Chapter 6). This mechanical contribution from outer hair cells confers high sensitivity, enhanced tuning, and non-linearity to the cochlear vibration pattern (Chapter 5). Although many aspects remain to be detailed, the central core of this hypothesis is well established (Oghalai, 2004). Outer hair cells most definitely can generate movement in response to a voltage signal (the chorus line of ‘dancing hair cell’ videos on the internet attest to this fact). Thus, it is presumed that sound-evoked receptor potentials drive outer hair cell mechanical output, which enhances the cochlear motion stimulating the inner hair cell. During efferent inhibition, receptor potentials are shunted, and the membrane is hyperpolarized, shifting and diminishing the voltage-to-force relation of the outer hair cell and so reducing this positive feedback. Electromotility is produced by a ‘piezoelectric protein’ called prestin, a modified organic anion transporter highly expressed in the basolateral membranes of outer hair cells (Zheng et al., 2000). Charge-coupled conformational changes in thousands of prestin molecules sum to alter cellular shape and stiffness. Targeted disruption of the prestin gene causes hearing loss in mice (Cheatham et al., 2004), and a prestin mutation is associated with a form of inherited deafness in humans (Liu et al., 2003).

Remarkably then, the exquisite sensitivity and tuning of the cochlea result in part from the fact that cochlear hair cells themselves can generate movement. A perhaps even more remarkable consequence is that the resulting motion of the cochlear partition produces fluid motions that can propagate backward through the middle ear to be detected in the external ear canal! Such otoacoustic emissions are, in fact, a normal property of the healthy inner ear, and they have become an important diagnostic tool (Chapter 4). ‘Ear sounds’ can be spontaneous, or evoked by clicks, or as distortion products resulting from the presentation of combination tones. Otoacoustic emissions report on the health of the cochlea (especially the outer hair cells), independent of deficits that may affect signal propagation from inner hair cell to afferent neuron, and further upstream (Kemp, 2002).

1.4 Development and repair

The structural and functional complexity of the inner ear inspires one to ask: how does it get this way? What morphogenetic patterns and molecular cues can produce the intricately coiled and differentiated cochlear duct (Chapter 12)? Beyond a desire to understand this process lies the hope of finding cues to trigger the regeneration of sensory hair cells, whose irretrievable loss deafens the mammalian cochlea. Hair cell regeneration does occur in non-mammalian vertebrates, inspiring studies to find the molecular determinants that distinguish these epithelia from those of mammals (Chapter 13).

The inner ear begins as an ectodermal invagination to form the otocyst adjacent to the hindbrain. With limited exceptions, nearly all the sensory cells, supporting cells, and neurons of the inner ear will develop from this apparently featureless hollow sphere. The requisite sequence of induction/specification, proliferation, and differentiation begins in the second embryonic week in rodents, and can continue into postnatal life for some aspects of functional maturation (Kelley, 2007). A succession of extrinsic growth factors and intrinsic transcription factors concatenate to direct the developmental stages (Chapter 12). For example, fibroblast growth factors released from the hindbrain or periotic mesenchyme direct otocyst induction. Anteroposterior and dorsoventral (p. 11) axes of development are influenced by bone morphogenetic proteins (BMPs), whereas auditory epithelial specification is directed in part by Six1 and sonic hedgehog genes. The coordinated orientation of hair cells within a sensory sheet depends in part on so-called ‘planar-cell-polarity’ factors (Deans et al., 2007). In some ways the most intriguing questions arise when one considers these later steps of hair cell and supporting cell differentiation. It is here that mammalian and non-mammalian inner ears diverge, since supporting cells in birds, for example, are able to re-differentiate into sensory hair cells after loss (Chapter 13). It is thought that specific transcription factors (Hes1, Hes5) act to prevent hair cell formation by presumptive supporting cells in the mammalian inner ear (Chapter 12) (White et al., 2006).

Even after the cochlea is morphologically complete, development continues as hair cells and associated neurons gradually reach functional maturity. Altricial rodents such as mice and rats respond to sound in the second postnatal week. Even at the day of birth, however, cochlear hair cells can mechanotransduce, and excitation of afferent neurons is quickly established. Days before the onset of hearing, afferent SGNs display ‘spontaneous’ action potentials that are driven by hair cell transmitter release. These occur at low frequencies (∼1 Hz) and are patterned into bursts. Evidence now exists that this behavior is driven by slow oscillations in cochlear supporting cells, exciting hair cells by release of adenosine triphosphate (ATP) (Tritsch et al., 2007). Although they are electrically active, cochlear hair cells at this stage are not yet mature. In particular, they generate calcium action potentials that cease to occur about the onset of hearing. This change from excitable to more ‘linear’ behavior results from a reduction in the number of voltage-gated calcium channels, and an increase in voltage-gated potassium conductance through the appearance of novel channel types (Kros, 2007). Afferent synaptic transmitter release also becomes more efficient at this same time. Indeed, these coordinate changes in hair cell functionality within a 24-hour period around the onset of hearing suggest that this late maturational stage is as critical as earlier, more visible phases of morphogenesis.

1.5 The genetics of hearing and deafness

As in all aspects of biology and medicine, the genetic revolution has enhanced our understanding of the inner ear, and emphatically changed the way we study it (Chapter 14) (Steel & Kros, 2001). Linkage analysis of inherited hearing loss in isolated human populations has identified proteins involved in ionic homeostasis, intercellular integrity, hair bundle structure, and synaptic transmission, to name but a few (Petit, 2006). Human ‘deafness genes’ have been incorporated into transgenic mouse models for detailed studies of structure and function (Friedman et al., 2007). Still further insights have arisen from the study of spontaneously arising mutations in mice that affect balance and hearing. At the same time, it is important to recognize that ‘hearing loss’ is an extremely complex and generic concept. The potential causes range from genetic mutation through environmental toxins, to overuse via loud sound exposure. Furthermore, these all can be interacting partners in pathogenesis. It is likely, for example, that genetic variance, as well as the history of sound exposure contributes to age-related hearing loss – ‘presbycusis’. Consequently, presbycusis is being investigated through genome-wide association studies in which a large number of markers (small nucleotide polymorphisms, ‘snips’) are correlated with hearing status to identify multiple genetic loci (Van Laer et al., 2008).

All these methods are generating an ever-growing list of gene products whose mutation leads to inner ear dysfunction. Some of these mutations produce syndromes in which hearing loss is just one symptom. Usher’s syndrome, for example, is characterized by hearing loss and blindness due to retinitis pigmentosa. To date, 11 different genetic loci, including nine identified genes have been associated with variants of Usher’s syndrome (Chapter 14). Remarkably, of the known ‘Usher proteins’ virtually all are involved in some aspect of stereociliary formation or function (p. 12) (El-Amraoui & Petit, 2005). ‘Non-syndromic’ hearing loss, as the name implies, has no other (apparent) associated deficits and accounts for the majority of inherited deafness, including more than 100 genetic loci to date. As mentioned above, the range of involved proteins is wide. A striking number of these involve the gap junction protein connexin, attesting to the fundamental importance of epithelial integrity and signaling for inner ear function (Nickel & Forge, 2008). Likewise, numerous mutations of potassium channels are causal to hearing loss in humans or mouse models (Yan & Liu, 2008), as expected from the unique potassium homeostasis of the inner ear, as well as the predominance of potassium conductances in the hair cell’s basolateral membranes.

1.6 From fundamentals to therapies

This volume intends to introduce the fundamental mechanisms that underlie the function of the auditory periphery. Of course no such effort can remain tutorial, as this volume aims to be, without leaving out interesting and important topics. These omissions become more obvious when considering the array of problems that are presented to the practicing clinician. For example, one would like also to consider blood flow to the inner ear when concerned with pathogenesis. A survey of some of the clinical problems that confront the otolaryngologist is presented in Chapter 2. The challenge lies in determining the underlying pathogenic mechanisms at a molecular level, with the hope of translating that knowledge into effective therapies. Unfortunately, we have a long way to go in treating almost every aspect of inner ear disease, with hair cell regeneration as perhaps the highest peak in that mountain range of challenges. Thus the enormous benefit provided by cochlear implants more than justifies their expanded utilization and further development (Chapter 15). The extraordinary growth of nanotechnology and tissue engineering promises still further progress in implant utility, and may provide methods for enhanced integration with cochlear nerve fibers, or stimulation within the central nervous system.

Of equal importance to repairing hearing is improved prevention of damage. A variety of necessary drugs from antibiotics to cancer therapeutics are ototoxic (Chapter 2). Obviously, exposure to excessively loud sound also is a major source of inner ear damage. The efforts to avoid any such risks will be better motivated with improved understanding of how the damage occurs, that is, through continued investigation of the fundamental mechanisms of inner ear function described in these chapters. Further, this knowledge of molecular mechanisms will combine with the identification of genetic variations that predispose to some types of cochlear damage (Chapter 14). Consequently, the risk–benefit calculations for ototoxic antibiotics can be sharpened if genetic predispositions to that type of damage are known in advance. Likewise for persuasive recommendations to protect against sound damage – when genetic variants that increase risk are understood, and can inform each individual’s choices of occupational and recreational loud sound exposure.

Finally, this volume aims to give every reader a better understanding of the intricate machinery of the auditory periphery. Whether that reader is a student entering the field, a clinical practitioner, or a worker in an allied field of study, the hope is that they will find this volume a resource of basic information, and perhaps a catalyst to make their own contributions to the ongoing challenge, and adventure, of understanding the beautiful mysteries of the ear.


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