Structure and function in the auditory system: From cochlea to cortex

Authors

  • David R. Friedland

    Corresponding author
    1. Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
    • Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226
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Abstract

This special issue of the Anatomical Record examines the relationship between structure and function in the auditory system. Early anatomical studies defined this relationship on a macroscopic level and described the roles of structures such as the tympanic membrane, ossicular chain, Eustachian tube, and cochlea. As new tools emerged, the microscopic structure of the organ of Corti was described and later the brain stem regions involved in auditory processing were identified. Further technical advances allowed the description of cells within these central auditory regions in both morphological and physiological terms. More recently, studies of the auditory system have employed molecular biological techniques and novel imaging protocols. All these techniques continue to provide important insights into the structure and function of the auditory system on gross, cellular, and molecular levels. This issue expounds on this theme by demonstrating the importance of anatomy, whether the shape of the otic capsule or the sequence of a gene, in determining the function of the system and even the phenotype of the organism. The articles in this issue represent the cutting edge of today's auditory science and look back at the evolution of hearing and balance, as well as forward toward improving cochlear implant outcomes and gene therapies for treating sensorineural hearing loss. Anat Rec Part A, 2006. © 2006 Wiley-Liss, Inc.

In this issue, we explore the relationship between structure and function in the auditory system. Early anatomical studies entailed understanding the relationship between structures such as the tympanic membrane or ossicles and their role in transmitting sound to the inner ear. On this gross level, the structure-function paradigm is intuitive as vibrating membranes and lever systems have similar transduction roles in many nonorganic facets of modern society. As we examine the finer structure of the auditory system, however, the structure-function relationship becomes less clear. How, for example, does structure play a role in the activation of the cochlear nerve when a hair cell is stimulated? In describing the biological and molecular components involved in this event, however, we naturally begin to see the microscopic structures critical to this physiological process. For example, the stereocilia and their tip links, the channels allowing ion flux, the neurotransmitter molecules and their physical interaction with receptor molecules. While studies of these phenomena may academically be labeled as cell biology or molecular biology, they ultimately detail an anatomic scaffold without which the system could not function. This issue presents that scaffold in many different forms and scales.

Modern auditory science has so many tools at its disposal to study and describe the auditory system that the field has developed numerous subspecialties and subsocieties. This special issue strives to address this matter in several ways. First, this issue is a celebration of the diversity of the field by demonstrating the questions that differing approaches can raise and answer. For example, this issue presents neuronal tract tracing methods to answer basic anatomical questions of which neurons are interconnected as well as functional MRI studies to probe the seemingly intangible question of how we perceive music. A second goal of this issue is to serve as a primer, for both the novice and the established auditory scientist, to understand the methods others in the field are employing. As the field diversifies, there is a danger of scientists retreating into studies that are comfortable and easy to understand and this limits the exchange of information and scientific dialogue that is critical to advancement. This brings in a third goal of this issue: to foster collaboration and critical thinking among different specialists in the field. There is a tremendous opportunity for new understanding when a molecular biologist sees an additional way of exploring the questions of the anatomist, or the functional radiologist raises questions to be further probed by the neuroscientist. Hopefully, this issue will indeed be seen as a celebration and inspire continued investigations, educate scientists and reverse the trend toward specialization and isolation, and foster unique collaborations and studies to probe the seemingly endless questions regarding auditory system structure and function.

STRUCTURE AND FUNCTION RELATIONSHIPS

The articles in this issue represent state-of-the-art investigations into the relationship between structure and function in the auditory system. The major theme that arises is that structure is everywhere, whether representing the morphology of the otic capsule or the distribution of proteins critical for synaptic transmission. One should not believe that because a system is microscopic, it does not rely on a physical relationship between components in order to function properly. Similarly, it is premature to assume that we have fully characterized the visible and tangible components of the auditory system and their roles in normal behavior. Exemplifying the latter concept, Limb et al. (this issue) investigated the brain regions important in the perception of rhythm, one of the basic foundations of music regardless of culture. Unique to their study was a comparison between trained musicians and those with no musical training. They found rhythm to be processed in all subjects in the right frontal opercular region, thus supporting previous observations. Interestingly, however, there were other brain regions showing differential activation dependent on musical experience. In nonmusicians, right hemispheric activity in motor regions was quite robust, although motor activity such as foot tapping was not observed. Musicians, in contrast, were able to dissociate rhythm from the motor regions and instead showed left hemispheric activation in perisylvian regions traditionally felt to be important in language comprehension. This cutting edge study rattles the foundations of linguistic neuroscience by demonstrating that well-studied language structures in the brain may have secondary roles in individuals trained for other modes of sound interpretation. These regions, therefore, may not be as attuned to language per se as they are to organized sequences of sounds with an underlying syntax and structure.

Limb explores the concepts of syntax and auditory processing in an up-to-date review of functional neuroimaging and the use of music as a tool to understanding cortical processing of sound. His article (this issue) expands on the concept that structures of the brain previously felt to be exclusively used for language in fact have roles in complex sound interpretation. For example, he presents the notion of perfect pitch and dimorphism in the planum temporale. The studies highlighted by Limb suggest that relative reduction in the right planum temporale is correlated with better pitch perception. This is interesting in light of current beliefs that left planum temporale hypertrophy has been an important factor in the evolution of receptive language ability (Gannon et al.,1998). Limb also describes other musical concepts and the brain regions involved in their perception. For example, he shows that the perception of melody, which involves identifying multiple tones and the relative pitch changes between them, is predominantly an auditory cortex process with less interpretation being performed by accessory language regions. This suggests that music is a complex stimulus, the interpretation of which involves purely auditory functions as well as interpretative processes commonly utilized in understanding language.

Firszt (this issue) elaborates on the theme of human cortical asymmetry and the relationship to sound processing. Specifically, she presents some of her recent functional MRI work comparing the processing of speech sounds between normal hearing subjects and those with unilateral hearing loss. In response to speech sounds, normal hearing subjects demonstrate a robust activation of the contralateral cortex as observed by fMRI. Subjects with unilateral hearing loss, however, lose this asymmetry by a combination of decreased activity in the contralateral cortex and increased activity in the ipsilateral cortex. This demonstrates plasticity in cortical auditory and language centers that can adjust to unilateral hearing deficits. Such central plasticity may play an important role in the performance of individuals after cochlear implantation (Friedland et al.,2003). Firszt expounds on the topic of brain asymmetry in the remainder of the article and demonstrates how asymmetries in human and nonhuman brains are seen in many different auditory tasks. This article also provides an excellent overview of four state-of-the-art functional imaging methods currently in use to study regional activity in the human brain in response to auditory stimuli.

This issue also looks closely at the neuronal projections and interconnections between anatomical regions of the brain such as cortex and brain stem. Complementing the functional studies of the cortex noted above is a study by Meltzer and Ryugo (this issue) examining projections from the auditory cortex to the brain stem cochlear nuclei in rodent models. They identified bilateral projections in the mouse to granule cells in the cochlear nucleus. Granule cells receive a wide range of auditory and nonauditory input and likely play a role in modulating auditory signals and responses to them. As such, cortical inputs to these cells may play a role in selective listening. Such selective tasks may include distinguishing predator sounds from environmental noise or recognizing vocalizations from kin versus those of outsiders. Evolutionary development of the cortex may thus be associated with increasing modulation of auditory processes and consequently survival advantages in navigating complex environments or development of social communities.

Continuing the theme regarding structural organization of the cochlear nucleus and neuronal projections is a study by Doucet (this issue) examining a specific class of neuron in the cochlear nucleus, the multipolar cell. This study addresses discrepancies in multipolar cell classification between morphological and physiological studies. Traditionally, multipolar cells have been divided into two anatomic subclasses while physiologically there appear to be several more distinct populations. Doucet performed elegant double labeling and tract tracing experiments to find that within the two classes of multipolar cells, there are subsets of neurons with unique projection patterns. He proposes a subcategory of commissural multipolar cells that project between the cochlear nuclei in contrast to similar-appearing cells with no such interconnection. This study reformulates the morphological descriptions of cochlear nucleus neurons to better correlate with physiological studies and helps to unify the various structural and functional models of the multipolar cells.

Auditory neurons in the central nervous system also participate in pathways out of the brain that innervate structures of the inner and middle ear. Lee et al. (this issue) examined neurons of the central auditory system to identify those that may serve as interneurons in the middle ear muscle reflex. These reflexes are important in protecting the inner ear from loud noise but also appear to play a role in improving the signal-to-noise ratio in certain environments. Through selective sectioning of axonal pathways and focused lesioning of auditory neurons, they have localized a limb of this reflex pathway to the ventral cochlear nucleus. The use of two anatomic techniques allowed them to further define potential neuron populations that may subserve this reflex. They were able to rule out octopus cells based on projection of axons and have begun to focus more attention on the globular bushy cells. This beautifully illustrated and well-crafted study demonstrates the association of structure and function in the auditory system on the gross level (i.e., middle ear musculature and ossicular chain attenuation) as well as the cellular level (i.e., neuronal projections and reflex pathways).

In addition to functional and anatomical methods of investigating the auditory system, advances in molecular biology have led to studies probing genetic contributions to auditory system structure and function. Lustig (this issue) looks at nicotinic acetylcholine receptors and their role in the auditory system. Specifically, he examines one of the phylogenetically oldest classes of receptors, α9 and α10 nicotinic acetylcholine receptors, and their relationship to efferent innervation of hair cells in the organ of Corti. Experimentally, he finds that this receptor complex likely requires interaction with other proteins and he has identified prosaposin as a potential candidate. This interaction may lead to G-protein-mediated effects that account for the inhibition of hair cell activity in noisy environments. This study reinforces the notion that structure and function may be related on many different levels and scales. Specifically, whereas Lee explored a noise protective process on the gross and cellular level, Lustig presented a similar phenomenon but on the molecular level. Both these systems serve to protect the inner ear from noise-induced damage by reducing the effects of sound at the target organ.

Molecular mechanisms protecting the inner ear from damage are also investigated by Eshraghi and Van De Water (this issue), who present a forward-looking review of the processes by which physical trauma and noise produce cell death in the organ of Corti. Their work has shown that insertion of a cochlear implant electrode into the scala tympani leads to a two-phase process of hearing loss. Initially, there is mechanical disruption followed by a progressive hearing loss over the following week. Even in cases with an atraumatic insertion, there is a secondary progressive sensorineural hearing loss. This led to the hypothesis that electrode insertion leads to trauma on the molecular level and they subsequently tested a molecular inhibitor of the apoptosis pathway in their insertion model. This apoptotic inhibitor prevented the progressive hearing loss seen with insertion and may present a strategy for otoprotection in cochlear implant recipients. Their article also presents results on similar inhibition for the prevention of noise-induced trauma and the interesting use of hypothermia as an otoprotective strategy.

Recognizing that protection of the inner ear from damage may not be applicable to all individuals, recent studies have focused on the regeneration of hair cells in the organ of Corti (Izumikawa et al.,2005). An issue with this strategy is how to reinnervate new hair cells with the appropriate auditory nerve fibers and restore the full structural framework of the inner ear. At the cutting edge of genetic therapy, Webber and Raz (this issue) review the genetics of axonal guidance and how genes and their proteins coordinate to lead the auditory nerve to the peripheral cochlea and hair cells. This article demonstrates the complex interactions among signaling molecules that is necessary to establish normal innervation patterns. Exploitation of these guidance cues may lead to therapeutic strategies allowing reinnervation of regenerated hair cells and better interaction between cochlear implants and residual ganglion cell fibers.

Expounding on the concept of structure on a molecular level, McHugh and Friedman (this issue) present two genes and the implications of mutations in their sequence on function of the cochlea and the whole organism. This article highlights the relationship between genotype and phenotype, which is in many ways analogous to the structure-function relationship: the genotype representing the structure of the gene (i.e., its sequence) and the phenotype a reflection of the function of that gene. This thorough review shows how varying the genetic structure leads to differing phenotypes and expression patterns, which may cause isolated organ dysfunction or multisystem abnormalities. For example, they use the cadherin 23 gene to demonstrate that missense mutations can lead to isolated hearing loss of varying degrees while null mutations (i.e., no production of a functional protein) affect the hearing, visual, and vestibular systems. Similarly, wolframin mutations can cause mild isolated nonprogressive hearing loss, or severe hearing loss associated with diabetes insipidus, diabetes mellitus, and optic atrophy.

McHugh and Friedman also discuss these genes in the context of modifier genes, which involve the complex interactions between multiple genes and their alleles. Modifier genes are only recently receiving significant attention and may be evolutionarily significant by imposing selective pressures on sets of genes rather than individual ones. Modifiers also permit varying responses to environmental stimuli. For example, a missense mutation in cadherin 23 may lead to little more than age-related hearing loss. In the context of a loud environment, however, the same mutation may predispose the individual to significant noise-induced hearing loss through modifier gene interactions. This is a phenotype that is not apparent unless the organism is subject to specific environmental conditions. The example given is a negative response (i.e., loss of hearing), yet one can see how variability in modifier genes and associated environmentally responsive phenotypes may exert beneficial evolutionary pressures on a population.

While molecular biological methods have become increasingly prevalent in studies of the peripheral cochlea, applications of such techniques to the central auditory system are relatively rare. However, the completion of the human, mouse, and rat genomes has provided powerful tools for the investigation of complex neuronal systems (Cravchik et al.,2001; Gibbs et al.,2004). Such techniques include high-throughput methodologies that can screen for thousands of genes at a time and define expression patterns of entire functionally related classes of genes. Demonstrating the power of such techniques is the article by Nothwang et al. (this issue), who investigated the superior olivary complex (SOC) for the expression of genes important in auditory neuronal function. They identified genes involved in energy metabolism, receptors, ion channels, and molecular transporters. By characterizing the array of genes expressed in these categories, they were able to infer functional properties on the SOC neurons. Among these properties is a very high energy demand that they argue is related to synaptic transmission and the importance of high-fidelity transmission and timing in the SOC. They also compared the expression of genes in the SOC to nonauditory regions and were able to develop a specific profile of auditory neurons. They identified 33 genes with significantly higher expression in the SOC than in nonauditory brain centers, which included structural genes such as tubulin, myelin-associated glycoporotein, and neurofilament type 3.

The role of cytoskeletal genes in auditory neurons is further investigated in the article by Friedland et al. (this issue). They used high-throughput methods to characterize the expression of cytoskeletal genes in the cochlear nucleus of the rat. In particular, they demonstrate that there is differential expression of the intermediate neurofilament genes between regions of the cochlear nucleus. Through in situ hybridization, they show that such differential expression is associated with morphologically distinct classes of auditory neurons. This study argues that neurofilament proteins provide an intracellular scaffold for neuronal projections and determines axonal caliber. Axonal caliber in turn is correlated with conduction velocity and thus many of the functional properties of auditory neurons. Their results and discussion indicate that cytoskeletal genes are important for normal neuronal function and that mutations are associated with physiologic abnormalities. Indeed, auditory deficits are found in many disorders of the neuronal cytoskeleton, including Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's Disease) (ALS), and Charcot-Marie tooth disease.

Thus far, we have reviewed the relationship between structure and function in the auditory system at the regional brain level, the neuronal level, and the molecular level. There still remains a role for examining the correlation between gross anatomy and the function of the system. This relationship is apparent in comparative anatomical approaches that assess differences in function between morphologically distinct species or in clinical studies that show functional abnormalities that occur with disruption of normal anatomy. Utilizing the latter approach, Carey and Amin (this issue) make use of a rare clinical entity that disrupts the integrity of the otic capsule and causes abnormal vestibular responses to sound. Superior semicircular canal dehiscence in an opening in the roof of the vestibular labyrinth that was first clinically identified less than a decade ago (Minor et al.,1998). Patients with this entity exhibit abnormal responses to sound that suggest a transmission of energy away from the cochlea and stimulation of the saccule and semicircular canals. Carey et al. explain this phenomenon by tracing the evolution of the inner ear and the changing role of the saccule from a low-frequency sound detector to an organ of balance. They also demonstrate how minor disruptions of an evolutionarily old and highly developed structure can cause significant functional changes.

The comparative anatomical approach for demonstrating a structure-function relationship is taken by Hullar (this issue), who correlates the physiological response properties of vestibular nerves with semicircular canal morphology. While not technically a component of the auditory system, the vestibular labyrinth is developmentally and evolutionarily intimately associated with the cochlea. Further, as demonstrated by Carey et al. (this issue), the cochlear and vestibular systems have a common structural and functional ancestry and a retained dependence on otic capsule structure for normal function. Hullar tested three mathematical models correlating semicircular canal curvature and afferent nerve sensitivity in the cat, squirrel monkey, and pigeon. He found that all the models held for the cat and two of the models were valid for the pigeon. In contrast, none of the models were able to correlate structure with function in the squirrel monkey. In discussing this discrepancy, Hullar hits on many of the themes elucidated throughout this issue, namely, that structure-function relationships may be on many different levels. Specifically, his model tested the relationship on the gross anatomical level. However, he notes that the true functional correlates may be at the neuronal or even molecular level, such as the distribution of GABAergic synapses or afferent terminals in the neuroepithelium. This article is a unique example of directly testing the relationship between structure and function and, even more illuminating, finding that the relationship may be deeper than once thought.

CONCLUSIONS

Borrowing an analogy from the physicists and their search for the grand unified theory, the ultimate goal of auditory science is to understand completely how we hear and process everything. The articles in this issue show that this goal will necessarily be a group effort as audition occurs on many levels and requires the interactions of brain regions, neuronal populations, cellular proteins, and genes. Investigating these interactions requires a variety of tools and methods and it is a principal goal of this issue to highlight the investigators and state-of-the-art techniques making inroads on all levels of audition. This issue shows that although we take different approaches, speak seemingly different languages, and study the tangible to unseen, the basic premise is the same: that structure affects function and by understanding all the elements of the scaffold we can one day put the pieces together and solve the puzzle of auditory processing.

Acknowledgements

The author thanks the contributors to this issue for their hard work and continued dedication to auditory research, previous editor Roger R. Markwald and current editor Kurt Albertine for supporting this issue, managing editor David Bernanke for ensuring the highest-quality publication, and especially associate editor Jeffrey Laitman for continued support, guidance, and assistance in the production of this issue as well as the author's personal scientific development.

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