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Anat Rec A Discov Mol Cell Evol Biol. 2006 April ; 288(4): 326–330. doi:10.1002/ar.a.20293.

Structure and Function in the Auditory System:


From Cochlear to Cortex

David R. Friedland
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin,
Milwaukee, WI

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
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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.

Keywords
auditory; cochlea; brain stem; cortex

In this issue, we explore the relationship between structure and function in the auditory
system. Early anatomical studies entailed understanding the relationship between structures
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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 non-organic 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.

Correspondence: David R. Friedland, MD, PhD, Medical College of Wisconsin, Dept of Otolaryngology and Communication
Sciences, 9200 W Wisconsin Ave, Milwaukee, WI 53226, 414-805-5626 (office), 414-805-7936 (fax), dfriedla@mcw.edu.
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Modern auditory science has so many tools at its disposal to study and describe the auditory
system that the field has developed numerous sub-specialties and sub-Societies. This special
issue strives to address this matter in several ways. First, this issue is a celebration of the
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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 inter-connected 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 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 dialog 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


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The manuscripts 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 and colleague (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 upon musical experience. In non-musicians, 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
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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 manuscript (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

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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
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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 if the manuscript and demonstrates how asymmetries in human
and non-human brains are seen in many different auditory tasks. This manuscript also
provides an excellent overview of four state-of-the-art functional imaging methods currently
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in use to study regional activity in the human brain in response to auditory stimuli.

This issue also looks closer 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 non-auditory 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
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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 and colleagues (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

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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
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cochlear nucleus. The use of two anatomic techniques allowed them to further define
potential neuron populations that may sub-serve this reflex. They were able to rule-out
octopus cells based upon 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
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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 produces 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 oto-protection in cochlear implant recipients. Their manuscript also
presents results on similar inhibition for the prevention of noise induced trauma and the
interesting use of hypothermia as an oto- protective strategy.
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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 re-innervate 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 manuscript 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 re-
innervation of regenerated hair cells and better interaction between cochlear implants and
residual ganglion cell fibers..

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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 manuscript highlights the relationship between
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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 multi-system 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 non-progressive 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
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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 which 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 manuscript by
Nothwang and colleagues (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
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demand which 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 non-auditory 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
non-auditory 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 manuscript
by Friedland and colleagues (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

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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
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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, 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,
however, 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
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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
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GABAergic synapses or afferent terminals in the neuroepithelium. This manuscript is a


unique example of directly testing the relationship between structure and function and, even
more illuminating, finding that that 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

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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.
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Acknowledgments
I would like to thank the contributors to this issue for their hard work and continued dedication to auditory research.
I also would like to acknowledge Previous Editor Roger R. Markwald and Current Editor Kurt Albertine for
supporting this issue. I would also like to thank Managing Editor David Bernanke for ensuring the highest quality
publication. A particularly special thank you goes to Associate Editor Jeffrey Laitman for his continued support,
guidance and assistance in the production of this issue and my personal scientific development.

Grant Source: National Institute on Deafness and Other Communication Disorders (NIH/NIDCD)

Grant Number: K08 DC006227

Grant Source: Triological Society Career Development Award

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Friedland DR, Venick HS, Niparko JK. Choice of ear for cochlear implantation: the effect of history
and residual hearing on predicted postoperative performance. Otol Neurotol. 2003; 24:582–589.
[PubMed: 12851549]
Gannon PJ, Holloway RL, Broadfield DC, Braun AR. Asymmetry of chimpanzee planum temporale:
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[PubMed: 9422693]
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Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, et al. Auditory hair cell replacement and
hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med. 2005; 11:271–276.
[PubMed: 15711559]
Minor LB, Solomon D, Zinreich JS, Zee DS. Sound- and/or pressure-induced vertigo due to bone
dehiscence of the superior semicircular canal. Arch Otolaryngol Head Neck Surg. 1998; 124:249–
258. [PubMed: 9525507]
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