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date: 19 November 2019

(p. xvii) Introduction and Overview

(p. xvii) Introduction and Overview

Overview

Sound is created by vibrations that propagate as pressure waves through a medium. The sense of hearing begins with these small pressure changes being detected as tiny, rapid vibrations of the eardrums. Yet when we think about our sense of hearing, our vibrating eardrums are not what come to mind. We assign sounds to specific objects, animals, or people, and are able to place them at specific locations in space. Hearing plays an important role in creating an internal representation of our environment, which is crucial for guiding our movements and actions. For many animals, including humans, another important function of hearing is to share reproductive or emotional states through vocal communication. Humans in particular use speech, language, and music to communicate abstract ideas and emotions. Transforming the vibrations of two eardrums into a detailed representation of the acoustic environment is a challenging task, even for the brain. This task is made even more challenging by the fact that this transformation has to occur very rapidly and accurately, because the fleeting nature of sound excludes the possibility to ‘take a second look’ at a sound stimulus.

This book is a collection of chapters, written by leading experts in the field, summarizing our current knowledge of how neuronal circuits in the auditory brainstem extract and encode the fundamental acoustic features of sound. As briefly outlined in this “Introduction and Overview” and in more detail in the respective chapters, the challenges of processing even basic sound features led to the evolution of some extreme neuronal and synaptic specializations and very precisely organized neuronal circuits in the auditory brainstem. These specializations and the need to process sound rapidly and reliably led the long-held assumption that auditory brainstem circuits have to be very stable, showing little, if any of the plasticity that is typically encountered in higher brain areas. However, over the past 10 to 15 years an increasing number of studies have revealed unexpected levels of plasticity in almost all auditory brainstem circuits. The highest level of plasticity has been observed during development, when young circuits (p. xviii) exhibit use- and activity-dependent plasticity to increase the precision of synaptic connectivity and to fine-tune the intrinsic membrane properties of neurons. Another significant degree of plasticity occurs after cochlear trauma and partial or complete deafness. Peripheral hearing loss can also trigger maladaptive plasticity, which is thought to generate some forms of central hearing impairments such as tinnitus or hyperacusis. A major goal of this book is to illustrate the many forms of plasticity that have been observed in the healthy and pathological auditory brainstem.

The Handbook is aimed at readers who already have a basic background in neuroscience, such as more advanced neuroscience students or postdoctoral fellows, who wish to get an introduction and thorough overview of the current state and challenges of the auditory field, including existing areas of controversy. It also can be a valuable resource for basic and clinical neuroscientists not working in the auditory brainstem who would like to get an update as to the current state of research in the auditory brainstem and on the plasticity mechanisms in lower brain areas. Each chapter is designed to stand on its own, but readers without a strong background in auditory neuroscience or readers who want to gain a more comprehensive picture of the current state of the field will benefit greatly from reading the chapters in sequence. This book does not cover all aspects of research on the auditory brainstem. Rather, the chapters will cover areas that have seen significant progress in the past decade and in which significant advancements have been made in revealing new forms of plasticity and their underlying mechanism.

Before I proceed with providing a brief overview of the auditory brainstem and outlining the sequence and content of chapters, I first want to express my sincere gratitude to all the authors who contributed to make this book happen. This book was only possible thanks to the great effort and time each author dedicated to his or her chapter, along with the generosity, patience, and positive attitude they all showed throughout all stages of editing.

A Brief Introduction to the Auditory Brainstem

Sound-evoked vibrations of the tympanic membrane are conducted to the cochlea by the middle ear bones, which elicit traveling waves that propagate along the cochlear spiral from its base to the apex. These waves deflect the stereocilia bundles of cochlear hair cells, the primary sensory cells in the auditory system, leading to their depolarization. Hair cells are arranged linearly along the cochlear spiral. Each hair cell responds best to a specific sound frequency, which gradually shifts along the length of the cochlea. Hair cells close to the base of the cochlea respond to high sound frequencies while hair cells at the apex of the cochlea respond to low frequencies. Thus, sound frequency is represented systematically along the cochlea, giving rise to a tonotopic organization, (p. xix) which is maintained throughout all auditory areas and represents one of the fundamental organization principles of the auditory system.

Upon depolarization, hair cells release the neurotransmitter glutamate, which excites the postsynaptic dendrites of spiral ganglion neurons and leads to the propagation of action potentials down their axons, which form the auditory nerve, through which all cochlear activity is transmitted on its way to the brain. Most of the spiral ganglion neurons form thick, myelinated axons (type 1 category), which make up 95% of the fibers of the auditory nerve. Type 1 spiral ganglion neurons contact a single hair cell, but each hair cell in turn is contacted by 5 to 10 spiral ganglion neurons, which differ in their physiological properties (see chapter 2). The information that is encoded by the activity of the auditory nerve is quite limited. Each auditory nerve fiber essentially only encodes three aspects of a sound stimulus: (1) the start and end (encoded by the rise and fall of firing activity); (2) the loudness (encoded by the firing rate); and (3) the frequency (defined by the location of the presynaptic hair cell along the cochlea). The brain is now challenged to make wise use of this limited information in order to create the rich perception of the acoustic environment that most of us take for granted.

One of the basic strategy by which the mammalian brain successfully solves this problem is the extensive use of parallel processing pathways. Parallel processing of different aspects of sound allows for increased processing speed, ensuring that the auditory system can keep up with the rapid arrival of different acoustic stimuli, and for the optimal extraction and encoding of sound features. Parallel pathways allow the auditory system to take advantage of highly specialized synaptic, neuronal, and circuit properties to optimize the extraction and encoding of one sound feature while ignoring most others, which are processed by another specialized pathway. For example, so-called octopus cells in the cochlear nucleus are morphologically and biophysically optimized to faithfully preserve the onset of a sound stimulus down to the level of microseconds, but the specialization that allow them to do this makes them largely insensitive to the frequency of the sound (chapter 4). Other pathways are specialized for sound localization. Unlike other sensory systems in which the location of a stimulus is reflected by the location of the receptors being activated in the sensory epithelium, in the auditory system the receptor location in the cochlea encodes the frequency of sound, not the location of a sound source in space. Thus, the location of a sound source has to be computed de novo in the brain by using specialized circuits. Binaural neurons in these circuits faithfully encode very small interaural sound intensity or time differences, which vary according to the incoming direction of sound (see chapters 13 and 14) but provide a relatively poorly representation of the absolute loudness of the sound. As a consequence of this parallel processing strategy, the brainstem contains a vast network of interconnected auditory nuclei and numerous specialized cell types. In fact, the complexity of brainstem pathways in the auditory system exceeds that found in any other sensor system.

The first part of this book (chapters 1–22) is organized such that it follows the ascending auditory pathway, from the cochlea to the inferior colliculus (Figure I.1). Each of the chapters in this part focuses on the anatomy, connectivity, physiology, function, (p. xx) and plasticity (normal and pathological) of one particular nucleus. The remaining chapters (chapters 23–27) review aspects of auditory brainstem function or plasticity that are not restricted to a specific area, such as the descending auditory pathways, the role of glial cells, central changes associated with aging, and higher processing functions carried out by the brainstem.

Introduction and OverviewClick to view larger

Figure I.1. Highly simplified schematic illustration of the mammalian ascending auditory brainstem of mammals, emphasizing the major areas and pathways that are covered in this book. For simplicity, descending and neuromodulatory pathways are not shown here but are described in several chapters of this volume.

Afferent and Efferent Innervation of the Cochlea

The first three chapters review the afferent and efferent innervation of the cochlea and its development. Chapter 1 by Brikha R. Shrestha and Lisa V. Goodrich summarizes our current understanding of how the cochlea is wired up during development. This chapter begins by illustrating the underlying cellular and molecular mechanisms of the key events involved in the generation and maturation of spiral ganglion neurons. This is followed by a summary of how the peripheral processes from SGNs initially connect to their hair cell partners and how these early connections are subsequently reorganized to correct for any initial errors. Finally, the authors provide an overview of the steps (p. xxi) and mechanisms by which the centrally directed axons from SGN connect to the three subdivisions of the cochlear nucleus, the first auditory nucleus in the brainstem.

Parallel ascending auditory pathways begin in the cochlea, where each inner hair cell is innervated by many Type 1 afferent fibers. Type 1 afferent fibers fall into functionally diverse groups, which differ in their spontaneous discharge rates and their sensitivity to sound. In chapter 2, Paul Albert Fuchs summarizes the distinguishing properties of Type 1 afferents and reviews the (still controversial) pre- and postsynaptic mechanisms that give rise to different groups of Type 1 afferents. In addition, he discusses new emerging hypotheses about the function of type 2 afferents, a class of sound-insensitive fibers that contact outer hair cells and whose physiological properties and functional role in hearing has remained enigmatic. Based on recent results, the author proposes a role of Type 2 afferents in signaling the presence of harmful acoustic conditions or in the generation of abnormal gain control after cochlear trauma.

The cochlea not only sends information to the brain but is also directly modulated by the brain via efferent fibers that originate from neurons located in the superior olivary complex in the brainstem. These efferent fibers are part of the lateral or the medial olivocochlear system, depending on their targets in the cochlea and the neuron type from which they originate in the brainstem. In chapter 3, Ana Belén Elgoyhen, Carolina Wedemeyer, and Mariano N. Di Guilmi summarize the differences between these two systems before they go on to review the organization, physiology, and function of the medial olivocochlear system and explain the mechanisms by which cholinergic synapses are used by the medial system to hyperpolarize hair cells. They also summarize the reorganization events that occur during development and the wide-reaching consequences of cholinergic modulation of immature hair cells during the maturation and organization of central pathways.

The Cochlear Nucleus Complex

Upon entering the brain, auditory nerve fibers bifurcate to send collaterals to each of the three subnuclei of the cochlear nucleus complex, the anteroventral cochlear nucleus, the posteroventral cochlear nucleus, and the dorsal cochlear nucleus (Figure I.1). The cochlear nucleus has been investigated extensively and its principle cell types and their responses to sound and biophysical and synaptic properties have been summarized in many excellent reviews and books (listed in chapters 4 and 5). Therefore, the chapters in this book do not focus on these aspects but rather emphasize synaptic and neuronal plasticity in the cochlear nucleus, which is receiving increased attention. This section summarizes how synapses, neurons, and circuits in the cochlear nucleus change with acoustic stimulation, cochlear damage, and aging and will describe how synaptic transmission is influenced by neuromodulatory systems, whose activity levels correlate with different behavioral states.

In chapter 4, Donata Oertel, Xiao-Jie Cao, and Alberto Recio-Spinoso review the forms of short-term plasticity that have been observed at synapses between auditory (p. xxii) nerve fibers and neurons in the ventral cochlear nucleus. Although the classic forms of activity-dependent plasticity such as long-term potentiation or long-term depression have never been observed in ventral cochlear nucleus (VCN) neurons, synapses in the VCN exhibit short-term depression when challenged in acute in vitro slice preparations. The chapter summarizes current knowledge of this short-term depression and discusses its relationship to sound responses in vivo and possible contributions to auditory processing. In contrast to the VCN, where the level of synaptic plasticity is generally weak, perhaps to ensure a stable and reliable processing of acoustic stimuli in this pathway, synapses in the DCN are highly plastic, exhibiting multiple forms of short-term as well as long-term plasticity. In addition, synaptic transmission in the DCN is modulated by a host of neuromodulators, suggesting that processing of auditory information in the DCN is influenced not only by previous acoustic stimulation but also by the animal’s internal state.

In chapter 5, Laurence O. Trussell provides a comprehensive summary of the various types of activity-dependent synaptic plasticity in the DCN and their underlying mechanisms, as have been revealed in in vitro brain slices preparation. The author also reviews the complex influence of the neuromodulators noradrenalin, dopamine, serotonin, endocanninoids, and zinc on synaptic transmission at DCN synapses and it explores the mutual interactions between neuromodulation and activity-dependent plasticity.

Cochlear hair cells and afferent synapses are sensitive to damage by loud noise, pharmacological drugs, and aging. Cochlear damage not only makes it more difficult to detect sound, but it also frequently triggers the emergence of more complex hearing problems such as understanding speech in noisy environments, the perception of phantom sounds (tinnitus), or even an increased sensitivity to certain sounds (hyperacusis). These secondary hearing impairments arise from changes in central auditory areas, including structural and physiological changes in in the cochlear nucleus, which are summarized and discussed in chapters 6–9. In chapter 6, Maria E. Rubio summarizes the anatomical, structural, and molecular changes that are caused by genetic or acute hearing loss. These changes include both presynaptic and postsynaptic modifications and are influenced by the severity (total or partial), the time course (sudden or slow), and the type (sensorineural or conductive) of hearing loss. These synaptic changes are highly variable, with some occurring surprisingly fast, within hours of hearing loss, while others develop slowly; some changes are temporary, reversing with the restoration of normal hearing, while others are permeant.

These structural changes are accompanied by changes in synaptic transmission and intrinsic neuronal properties, which are summarized in chapter 7 by Ruili Xie, Tessa-Jonne F. Ropp, Michael R. Kasten, and Paul B. Manis. In addition, they discuss how these changes may compensate for decreased auditory nerve activity. As is the case with structural changes, physiologic adaptations vary with the type of hearing loss. While a complete picture has yet to emerge, detailed understanding of how cochlear nucleus circuits change with specific forms of hearing loss will provide important information for predicting how the central auditory system will react when auditory nerve activity (p. xxiii) is reintroduced, for example by correcting conductive hearing loss or with cochlear implants.

Paradoxically, one of the most consistent changes observed in in vivo recordings in the cochlear nucleus after peripheral trauma is an increase in spontaneous spiking activity. This increase in sound-independent activity may be misinterpreted by higher auditory centers as being sound-generated, leading to the hypothesis that this increase in spontaneous spiking activity is, in part, responsible for the perception of phantom sounds (tinnitus). In chapter 8, James A. Kaltenbach and Donald A. Godfrey summarize three decades of research aimed at identifying the changes in the cochlear nucleus circuitry and excitability that may lead to the generation of tinnitus and discuss the major controversies and challenges of this type of research.

Although the auditory nerve provides the majority of synaptic inputs to the cochlear nucleus, the activity of cochlear nucleus neurons is also influenced by other sensory modalities, such as the somatosensory system. In chapter 9, Susan E. Shore and David T. Martel describe how somatosensory inputs to the dorsal cochlear nucleus modulate auditory processing. They discuss how somatosensory inputs engage spike timing- dependent plasticity and how this may contribute to the generation of tinnitus. This chapter also summarizes results from recent studies in animal models showing that bimodal auditory-somatosensory stimulation can induce long-term depression in DCN neurons and that application of similar bimodal sensory stimulation in human tinnitus patients successfully reduces subjective tinnitus loudness and discomfort. These studies provide encouraging examples of how the fundamental biological mechanisms of neuronal plasticity can be harnessed to correct central pathologies in humans that may arise from maladaptive plasticity.

The Nuclei of the Superior Olivary Complex

The major projection target of the VCN is the superior olivary complex (SOC), located ventrally in the brainstem (Figure I.1). The SOC is a collection of nuclei whose size and relative arrangement show considerable variations between species, reflecting adaptations to their particular hearing range and auditory specializations. Approximately 6 to 12 distinct nuclei or cell groups have been identified, depending on the species investigated. SOC neurons are involved in a diverse set of tasks. Cell groups involved in sound localization encode the time or intensity differences of sound signals from the two ears. Other cell groups provide descending inputs to the cochlear nucleus and the cochlea via the olivocochlear fibers (see chapter 3). This book contains six chapters on the SOC. Four chapters focus on the SOC nuclei involved in sound localization: the medial nucleus of the trapezoid body (MNTB), the medial superior olive (MSO), and the lateral superior olive (LSO). One chapter is dedicated to the superior paraolivary nucleus (SPON), a prominent nucleus present in all mammals, including humans, which is hypothesized to be involved in the detection of silent gaps or periodic patterns of sound. The final chapter focuses on the role of the perineuronal nets, a form (p. xxiv) of extracellular matrix, in SOC function and plasticity. The nuclei in the SOC that contain olivocochlear neurons are discussed in the chapter about the descending auditory system (chapter 22).

Chapters 10 and 11 describe the function, development, and plasticity of the medial nucleus of the trapezoid body (MNTB), a prominent glycinergic nucleus that provides stimulus-locked inhibition to several nuclei in the SOC and beyond. MNTB neurons are unique in that they receive excitatory input from a single giant terminal, the Calyx of Held, which is the largest and fastest synapse in the mammalian brain. The sheer size of the Calyx of Held has allowed researchers to simultaneously record from both the presynaptic Calyx and the postsynaptic MNTB neuron, thus providing detailed insight into the function of individual synapses and making the Calyx of Held one of the best understood synapses in the mammalian brain. In chapter 10, Shobhana Sivaramakrishnan, Ashley Brandebura, Paul Holcomb, Daniel Heller, Douglas Kolson, Dakota Jackson, Peter H. Mathers, and George A. Spirou summarize the development of the MNTB, including the major steps by which the pre- and postsynaptic elements within the MNTB are assembled and the molecular signaling events involved in these processes. They also describe how competition between immature calyces innervating the same postsynaptic MNTB neuron ultimately results in the characteristic single-calyx innervation of mature MNTB neurons.

Despite often being considered a simple relay nucleus, the MNTB continues to exhibit activity-dependent plasticity after development is completed. As described in detail in chapter 11 by Leonard K. Kaczmarek, mature MNTB neurons express experience-dependent plasticity by ways of modulating the expression and function of their voltage-gated potassium channels. MNTB neurons express a large variety of potassium channel subunits whose relative expression levels vary between individual neurons. As a result, different MNTB neurons respond to sound with slightly different delays and temporal accuracy. This cellular diversity is modulated by sound-driven activity and the production of nitro oxide and cyclic GMP, thus creating a means to dynamically adapt the firing patterns of MNTB neurons according to the ongoing acoustic environment.

The MNTB provides synaptic inhibition to two nuclei whose function is to compare the differences in the arrival times and intensity of sound between the ears (interaural time and sound level differences, respectively). These differences vary systematically with the azimuthal direction of the incoming sound and provide highly reliable cues used to compute the location of the sound source in space. Interaural time differences are most useful for lower sound frequencies, which neurons in the sound localization pathway can still phase-lock to. In contrast, interaural sound level differences comprise the major cue for high-frequency sounds, which are more strongly attenuated by the head than low frequency sounds. Thus, animals with low-frequency hearing primarily rely on time difference cues for sound localization, while animals with high-frequency hearing primarily rely on sound level differences, a fact that is also reflected by the size of the respective nuclei.

(p. xxv) In chapter 12, Benedikt Grothe, Christian Leibold, and Michael Pecka summarize what is currently known about how MSO neurons encode interaural time differences. The authors illustrate the structural and cellular optimizations that enable these neurons to accomplish the astonishing feat of encoding interaural time differences on a microsecond timescale. Several controversial models have been proposed to describe how these minuscule time differences are represented in the MSO. These models are still highly debated, and chapter 12 will discuss the pros and cons of these models considering recent results from both animal models and human psychophysical studies.

While the MSO encodes interaural time differences, neurons the lateral superior olive (LSO), are specialized for encoding interaural intensity differences. In chapter 13, Eckhard Friauf, Elisa G. Krächan, and Nicolas I. C. Müller take a deep look at both in vivo and in vitro data from a host of mammalian species to provide a detailed review of our current knowledge of the organization of the LSO across mammalian species, as well as the development of its synaptic inputs and physiological response properties. Studies in the LSO have revealed a number of novel mechanisms involved in the developmental organization of inhibitory circuits and their activity-dependent short-term plasticity, even at later ages. The chapter discusses these phenomena and their mechanisms, and contemplates their implications on the neuronal encoding of interaural intensity differences.

The third major SOC nucleus that derives its inhibition from the MNTB is the SPON. In contrast to the MSO and LSO, which integrate information from both ears, the SPON is a monaural nucleus, receiving excitatory and inhibitory drive only from the contralateral ear. In chapter 14 Anna K. Magnusson and Marcelo Gómez-Álvarez, explain that SPON neurons preferentially fire action potentials after a sound stimulus ends (OFF-response). As described in more detail in the chapter, this OFF-response is made possible by an exquisite combination of strong MNTB-derived inhibition, present during sound presentation, and rapid depolarization when the sound stops, caused by the activation of low-voltage-activated membrane ion channels. The SPON is a prominent nucleus in all mammalian species, including humans, suggesting an important role in hearing; however, this role is still a matter of debate. Magnusson and Gómez-Álvarez discuss some intriguing hypotheses, such as the participation of SPON neurons in the initial processing of prosodic information, that are based on the tuning of SPON neurons to periodic sound stimuli, or rhythm sensitivity, as well as their interesting projection patterns to auditory and non-auditory areas.

The final chapter in the series on the SOC focuses on the role of the extracellular matrix in SOC function and plasticity, an area that has recently received increased attention. In chapter 15, Markus Morawski and Mandy Sonntag describe the distribution of perineuronal nets, a specialized component of the extracellular matrix, in the superior olivary complex. The chapter summarizes the formation and development of perineuronal nets and discusses current ideas on how perineuronal nets regulate synaptic transmission and neuronal excitability, and thus could be closely linked to their plasticity.

(p. xxvi) The Nuclei of the Lateral Lemniscus

The lateral lemniscus is a thick fiber bundle running dorsoventally on the lateral edge of the brainstem. It contains axons that relay auditory information from the cochlear nucleus and superior olivary complex to the auditory midbrain, the inferior colliculus. Embedded in this fiber bundle are the three nuclei of the lateral lemniscus: ventral, intermediate, and dorsal. Compared to the other areas of the auditory brainstem, many aspects of the nuclei of the lateral lemniscus remain poorly understood. In chapter 16, Felix Felmy summarizes what is currently known about the anatomical connectivity, neuron types, and physiological properties of the neurons in these nuclei and summarizes several recent in vivo studies, which have contributed to current hypotheses on the possible function of these neurons in sound processing.

The Inferior Colliculus

The inferior colliculus (IC), often called the ‘auditory hub’ of the brainstem, is where the auditory information that has already been processed by lower auditory brainstem nuclei converges for further integration and processing (Figure I.1). Subsequently, this information is transmitted to the auditory thalamus and several non-auditory areas, which include neuromodulator centers, limbic areas, and areas involved in behavioral control. In addition, the IC gives rise to descending projections that modulate the activity of lower brainstem nuclei and it receives descending projections from the auditory cortex (see chapter 23). This book includes five chapters (17–21) that focus on the IC. Certain aspects of IC function are also a major component of subsequent chapters on the descending auditory pathway (chapter 22), aging (chapter 23), and higher-level auditory processing in the brainstem (chapters 25 and 26).

In chapter 17 Nell Beatty Cant describes the trajectories different groups of axons take through the brainstem on their way to the IC and discusses the intrinsic organization of the three main fiber bundles that connect the IC to the rest of the brainstem. This chapter also summarizes the course of fibers that directly connect major auditory nuclei in the brainstem, including the commissural pathways. The chapter provides a comprehensive and unprecedented summary of the organization of the white matter in the auditory brainstem, information that will undoubtedly be valuable for interpreting present and especially future high-resolution imaging studies of the normal and pathological auditory system.

Neurons in the IC are tuned to a large variety of sound stimuli and show a diversity of response patterns, reflecting their different their synaptic inputs, membrane properties, and the influence of the vast intrinsic network in the IC. In chapter 18, Tetsufumi Ito, Munenori Ono, and Douglas L. Oliver give a detailed review on the different neuron classes in the IC based on morphology, neurotransmitter types, synaptic organization, membrane properties, and responses to sound. The authors then cover recent progress (p. xxvii) in understanding the organization and function of the intrinsic synaptic network in the IC, which has remained enigmatic for a long time. Reflecting its integrative function and performance of higher auditory processing, which often requires adjustments to changing acoustic environments, the IC shows a high degree of plasticity, some forms of which are discussed in this chapter as well. This plasticity is especially pronounced when auditory nerve activity is severely decreased by noise-induced cochlear trauma or by age-related hearing loss. In chapter 19, Alan R. Palmer and Joel I. Berger review and synthesize the large literature describing the many ways in which the IC reacts to hearing loss, including changes in neurotransmitter systems, spontaneous activity, and sound-evoked responses. The authors also summarize previous attempts, using pharmacological approaches as well as acoustic or electrical stimulation, to modulate or reverse pathologic, hearing-loss induced IC activity in animal models.

As described in chapter 20 by Adrian Rees and Llwyd D. Orton, a unique feature of the auditory system is the presence of subcortical commissural connections connecting homologous nuclei on both sides of the brain (see also chapter 17). The most prominent of these commissural connections is the fiber tract that connects the two inferior colliculi. In their chapter, these authors review what type of neurons contribute to this commissure, what targets they project to, and how commissural connections influence sound-evoked responses in the IC. Based on this information, the authors propose a model of how commissural connections in the IC contribute to sound localization by reducing the ambiguities in the encoding of the azimuthal component of incoming sound that are present in the firing rate of neurons in a single IC.

In addition to receiving inputs from ascending and descending auditory pathways, the IC is also the target of several neuromodulatory systems that influence how the IC processes auditory information. As summarized by Laura Hurley in chapter 21, the IC is under the influence of neuromodulatory centers that release acetylcholine, dopamine, noradrenaline, or serotonin. Although these centers are not considered part of the ascending auditory system, neurons in these areas nevertheless can respond to sound and thus can establish auditory-modulatory feedback loops that change the responses of IC neurons according to internal or reproductive state or the saliency of a sound stimulus. This chapter reviews these modulatory influences and their underlying mechanisms, and provides examples as to how and under what conditions modulatory inputs to the IC can change auditory-evoked behaviors.

Descending Auditory Pathways

A characteristic feature of the auditory system is the presence of an extensive top-down modulatory system that arises from multiple stages along the ascending pathway. These descending projections, in turn, influence auditory processing at almost every stage, including the cochlea (see chapter 3). Descending projections are activated under various acoustic stimulation conditions and have been associated with a variety

(p. xxviii) of hearing impairments. In chapter 22, Brett R. Schofield and Nichole L. Beebe summarize the organization and discuss possible functions of the descending auditory system, focusing on pathways that release the neurotransmitters glutamate, GABA, glycine, dopamine, and acetylcholine. Following an overview of the anatomical organization of these systems, the authors highlight research areas that have progressed significantly in recent years, including the influence of corticofugal projections on sound processing and plasticity in the IC as well as the close interactions between modulatory systems and descending pathways. They conclude with a discussion of circuit loops and chains in the descending system, speculate as to whether the ventral nucleus of the trapezoid body (an area in the superior olivary complex) serves as a central hub of the descending system, and identify key questions in the field that remain open.

Age-Related Changes in the Auditory Brainstem and Thalamus

Age-related hearing loss, or presbycusis, is the most common type of sensorineural hearing loss. It is usually a progressive hearing loss that begins with the inability to hear high-frequency sounds and, as aging continues, progresses to include lower frequencies. Although many consider presbycusis a normal part of the aging process, we now know that its progress is greatly accelerated by frequent exposure to even modest noise levels. Presbycusis has become more prevalent and its onset shifted to younger ages in industrialized societies, where ambient or recreational noise levels are on the rise and life expectancy continues to increase. In addition to peripheral hearing loss due to deterioration of the cochlea, age-related hearing loss is accompanied by changes in the central auditory system that arise independently from peripheral damage with age. These central changes are thought to contribute to subtler hearing impairments, for example difficulty understanding speech in noisy environments. In chapter 23, Donald M. Caspary and Daniel A. Llano review age-related changes in neurotransmission that have been observed in the auditory brainstem and thalamus and try to untangle what aspects of these changes are a consequence of decreased peripheral input and what aspects are due to the aging. They also discuss how these synaptic changes contribute to decreased precision in the temporal processing of sound, one of the hallmarks of central presbycusis.

Glial Cells in the Auditory Brainstem

Most neuroscience research, including that on the auditory brainstem, has largely ignored the contribution of glial cells, which make up about 90% of brain cells. In recent years, however, there has been increasing interest in how glial cells participate in the development and function of auditory brainstem neurons and their synaptic connections. In chapter 24, Giedre Milinkeviciute and Karina S. Cramer provide a comprehensive (p. xxix) review of the role the three major types of glial cells in the brain (astrocytes, micoglia, and oligodendrocytes) have in auditory brainstem development, function, and injury. Our current understanding of the developmental role of glial cells stems primarily from experiments in the chick brainstem. Studies in this system revealed a critical role of astrocyte-secreted factors in the maturation of inhibitory inputs. In addition, astrocytes seem to play a role in regulating dendritic arborization and axonal targeting. In the primary sound localization nuclei of both chicks and mammals, oligodendrocytes contribute to the fine-adjustment of the conduction velocity of axons, which is critical for regulating the exact arrival time of synaptic inputs to binaural coincidence detector neurons. Finally, the chapter reviews how microglial cells react to cochlear trauma or ablation and act as phagocytic scavengers to remove inactive inputs and play a supportive role in the formation of new, compensatory synaptic connections.

Higher Auditory Functions in the Brainstem

While the faithful encoding of fundamental sound features is undoubtedly the major task of the auditory brainstem, research over the past two decades has provided increasing evidence that subcortical auditory areas also perform surprisingly complex functions that were previously attributed to cortical circuits. Two chapters in this book provide examples of such higher functions performed in the IC. In chapter 25, Manuel S. Malmierca, Guillermo V. Carbajal, and Carles Escera summarize experimental results that link stimulus-specific adaptation (SSA) exhibited by neurons in the non-lemniscal divisions of the IC (cortical regions) to true deviance detection. More than simply adapting to a repeated (predictable) stimulus, these neurons enhance their responses when a novel (unexpected) stimulus occurs, thus acting as deviance detectors. The authors discuss the circuit and neuronal mechanisms by which SSA emerges in the IC, taking into consideration and evaluating results from anatomical, cortical reversible inactivation, and pharmacological studies in vivo. They propose that SSA is a neuronal correlate of mismatch negativity, a component of the auditory event-related potential recorded in humans that appears when subjects perceive a change in stimulation. They also discuss SSA in the conceptual framework of predictive coding theory.

In humans, activity in the IC can be recorded non-invasively using scalp electrodes that record the synchronous, sound-evoked activity of populations of auditory neurons. One component of these auditory brainstem responses is the frequency following response (FFR), which reflects the highly temporally precise, phase-locked response of the IC to periodic stimuli. In chapter 26, Nina Kraus and Trent Nicol review studies that use the FFR to investigate representations of speech and music processing in the human IC. The authors give a short tutorial of FFR by describing the general characteristic of FFR and what components of speech are reflected by it. They describe evidence that the encoding of various components of speech is altered by traumatic brain injury and in poor readers, such as those with dyslexia, and is conversely enhanced in subjects who have undergone auditory enrichment or training. Because the FFR to speech and other (p. xxx) complex stimuli is closely connected to the listener’s level of literacy and ability to listen in noise, the authors argue for increased clinical use of brainstem FFR to objectively assess a listener’s ability to encode fast speech signals.

Auditory Brainstem Prosthesis

The cochlear implant is the most successful neuronal prosthesis, providing hearing to hundreds of thousands of otherwise deaf people. Cochlear implants bypass a dysfunctional cochlea by electrically stimulating the spiral ganglion neurons, or their axons, directly; thus their success depends on the presence of a functional auditory nerve. Because patients without an auditory nerve cannot benefit from a cochlear implant, scientists and surgeons have attempted to reestablish hearing in these patients through electrical stimulation of other central auditory structures, such as the cochlear nucleus and inferior colliculus. In chapter 27, Robert V. Shannon reviews the current state of the auditory brainstem implant, which stimulates the cochlear nucleus. After giving an overview of the surgical approach and of the type of hearing experienced by implant users, he discusses possible reasons for the variability in performance observed between patients. Based on data obtained from human and animal studies, he proposes the intriguing hypothesis that the degree of speech perception attained after an auditory brainstem implant critically depends on the surgical preservation of the small cell cap region. This region is especially well developed in humans, compared to other mammals, and is likely to play a critical role in encoding amplitude modulations of sound, a critical cue for speech recognition.

Acknowledgments

My foremost gratitude goes to the authors who contributed to this book by generously sharing their scholarly insight and valuable time. I also want to thank my colleges and laboratory members for many insightful and stimulating discussions, and their patience while my mind was occupied by this book. A special thanks is extended to Ada Brunstein from Oxford University Press for her skillful guidance and encouraging humor throughout the process.