Springer Handbook of Auditory Research. Series Editors: Richard R. Fay and Arthur N. Popper

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3 Springer Handbook of Auditory Research Series Editors: Richard R. Fay and Arthur N. Popper

4 Springer Handbook of Auditory Research Volume 1: The Mammalian Auditory Pathway: Neuroanatomy Edited by Douglas B. Webster, Arthur N. Popper, and Richard R. Fay Volume 2: The Mammalian Auditory Pathway: Neurophysiology Edited by Arthur N. Popper and Richard R. Fay Volume 3: Human Psychophysics Edited by William Yost, Arthur N. Popper, and Richard R. Fay Volume 4: Comparative Hearing: Mammals Edited by Richard R. Fay and Arthur N. Popper Volume 5: Hearing by Bats Edited by Arthur N. Popper and Richard R. Fay Volume 6: Auditory Computation Edited by Harold L. Hawkins, Teresa A. McMullen, Arthur N. Popper, and Richard R. Fay Volume 7: Clinical Aspects of Hearing Edited by Thomas R. Van De Water, Arthur N. Popper, and Richard R. Fay Volume 8: The Cochlea Edited by Peter Dallos, Arthur N. Popper, and Richard R. Fay Volume 9: Development of the Auditory System Edited by Edwin W Rubel, Arthur N. Popper, and Richard R. Fay Volume 10: Comparative Hearing: Insects Edited by Ronald Hoy, Arthur N. Popper, and Richard R. Fay Volume 11: Comparative Hearing: Fish and Amphibians Edited by Richard R. Fay and Arthur N. Popper Volume 12: Hearing by Whales and Dolphins Edited by Whitlow W.L. Au, Arthur N. Popper, and Richard R. Fay Volume 13: Comparative Hearing: Birds and Reptiles Edited by Robert Dooling, Arthur N. Popper, and Richard R. Fay Volume 14: Genetics and Auditory Disorders Edited by Bronya J.B. Keats, Arthur N. Popper, and Richard R. Fay Volume 15: Integrative Functions in the Mammalian Auditory Pathway Edited by Donata Oertel, Richard R. Fay, and Arthur N. Popper Volume 16: Acoustic Communication Edited by Andrea Simmons, Arthur N. Popper, and Richard R. Fay Volume 17: Compression: From Cochlea to Cochlear Implants Edited by Sid P. Bacon, Richard R. Fay, and Arthur N. Popper Volume 18: Speech Processing in the Auditory System Edited by Steven Greenberg, William Ainsworth, Arthur N. Popper, and Richard R. Fay Volume 19: The Vestibular System Edited by Stephen M. Highstein, Richard R. Fay, and Arthur N. Popper Volume 20: Cochlear Implants: Auditory Prostheses and Electric Hearing Edited by Fan-Gang Zeng, Arthur N. Popper, and Richard R. Fay Volume 21: Electroreception Edited by Theodore H. Bullock, Carl D. Hopkins, Arthur N. Popper, and Richard R. Fay Continued after index

5 Richard J. Salvi Arthur N. Popper Richard R. Fay Editors Hair Cell Regeneration, Repair, and Protection

6 Richard J. Salvi Arthur N. Popper Center for Hearing and Deafness Department of Biology University of Buffalo University of Maryland Buffalo, NY College Park, MD USA USA Richard R. Fay Parmly Hearing Institute 6525 North Sheridan Road Loyola University Chicago Chicago, IL USA Series Editors: Richard R. Fay Arthur N. Popper Parmly Hearing Institute Department of Biology 6525 North Sheridan Road University of Maryland Loyola University Chicago College Park, MD Chicago, IL USA USA ISBN: e-isbn: Library of Congress Control Number: Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Cover illustration: The image includes parts of Figures 5.2 and 2.5 appearing in the text. Printed on acid-free paper springer.com

7 Contents Contributors... Series Preface... Volume Preface... vii ix xi 1. Overview: Regeneration and Repair... 1 Richard J. Salvi 2. Morphological Correlates of Regeneration and Repair in the Inner Ear Jason R. Meyers and Jeffrey T. Corwin 3. Recovery of Function in the Avian Auditory System After Ototrauma James C. Saunders and Richard J. Salvi 4. Functional Recovery After Hair Cell Regeneration in Birds Robert J. Dooling, Micheal L. Dent, Amanda M. Lauer, and Brenda M. Ryals 5. Hair Cell Regeneration: Mechanisms Guiding Cellular Proliferation and Differentiation Elizabeth C. Oesterle and Jennifer S. Stone 6. Protection and Repair of Inner Ear Sensory Cells Andrew Forge and Thomas R. Van De Water 7. Gene Arrays, Cell Lines, Stem Cells, and Sensory Regeneration in Mammalian Ears Marcelo N. Rivolta and Matthew C. Holley Index v

8 Contributors jeffrey t. corwin Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, USA, micheal l. dent Department of Psychology, University at Buffalo SUNY, Buffalo, NY 14260, USA, robert j. dooling Department of Psychology and Center for the Comparative Evolutionary Biology of Hearing, University of Maryland, College Park, MD 20742, USA, andrew forge Centre for Auditory Research, UCL Ear Institute, University College London, London WC1X 8EE, UK, matthew c. holley Department of Biomedical Science, University of Sheffield, Sheffield, S10 2TN, UK, amanda m. lauer Department of Psychology and Center for the Comparative Evolutionary Biology of Hearing, University of Maryland, College Park, MD 20742, USA, jason r. meyers Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor MI 48109, USA, elizabeth c. oesterle Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology, University of Washington, Seattle, WA , USA, vii

9 viii Contributors marcelo n. rivolta Centre for Stem Cell Biology, University of Sheffield, Sheffield, S10 2TN, UK, brenda m. ryals Department of Communication Sciences and Disorders, James Madison University, Harrisonburg, VA 22807, USA, richard j. salvi University of Buffalo, Center for Hearing and Deafness, Buffalo, NY 14214, USA, james c. saunders University of Pennsylvania, Philadelphia, PA 19104, USA, jennifer s. stone Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology, Seattle, WA , USA, thomas r. van de water Department of Otolaryngology, Cochlear Implant Research Program, University of Miami Ear Institute, University of Miami, Miller School of Medicine, Miami, FL , USA,

10 Series Preface The Springer Handbook of Auditory Research presents a series of comprehensive and synthetic reviews of the fundamental topics in modern auditory research. The volumes are aimed at all individuals with interests in hearing research, including advanced graduate students, postdoctoral researchers, and clinical investigators. The volumes are intended to introduce new investigators to important aspects of hearing science and to help established investigators to better understand the fundamental theories and data in fields of hearing that they may not normally follow closely. Each volume presents a particular topic comprehensively, and each serves as a synthetic overview and guide to the literature. As such, the chapters present neither exhaustive data reviews nor original research that has not yet appeared in peer-reviewed journals. The volumes focus on topics that have developed a solid data and conceptual foundation rather than on those for which a literature is only beginning to develop. New research areas will be covered on a timely basis in the series as they begin to mature. Each volume in the series consists of a few substantial chapters on a particular topic. In some cases, the topics will be ones of traditional interest for which there is a substantial body of data and theory, such as auditory neuroanatomy (Vol. 1) and neurophysiology (Vol. 2). Other volumes in the series deal with topics that have begun to mature more recently, such as development, plasticity, and computational models of neural processing. In many cases, the series editors are joined by a coeditor having special expertise in the topic of the volume. Richard R. Fay, Chicago, IL Arthur N. Popper, College Park, MD ix

11 Volume Preface The human brain s ability to sense and interpret acoustic events taking place in remote or nearby locations in the external environment is mediated by highly specialized and extremely sensitive sensory hair cells located in the inner ear. These cells transduce acoustic information from the environment into a pattern of neural activity that can be interpreted by sophisticated neural networks located at multiple levels of the central nervous system. It has long been known that hair cell loss in mammals due to aging, ototoxic drugs, acoustic trauma, infection, or genetic factors results in permanent hearing loss or balance problems. Over the past 50 years, efforts to find a cure for deafness have focused on hardware and engineering solutions. While much effort has been made to use electronic means to improve hearing, the next giant step toward restoring hearing to the profoundly deaf will involve regenerating the damaged biological structures in the inner ear, in particular the hair cells and spiral ganglion neurons. The major clinical advances in hearing and balance that will occur in the 21st century will involve biologically based medical innovations that were set into motion during the past few decades by the discovery of hair cell regeneration and by the recognition that stem cells exist in many regions of the nervous system, including the inner ear. These discoveries, and the potential for helping people with hearing loss, are the focus of this volume. In Chapter 1, Salvi reviews the history of studies on hair cell regeneration and provides an overview of current knowledge as well as new technologies to promote regeneration and repair. The recognition that hair cell regeneration can occur in nonmammals gave way to ground breaking studies using gene therapy to simulate hair cell regeneration in mammals. The history of the field, as well as what is known about the morphology associated with regeneration and repair of sensory hair cells, are the focus of Chapter 2 by Meyers and Corwin. One of the fundamental issues examined is whether regenerated hairs arise from repair of damaged cells, conversion of support cells to hair cells, or proliferation of support cells that differentiate to either hair cells or replacement support cells. One of the most important areas that stimulated studies of damage, regeneration, and repair has been in the avian auditory system. In Chapter 3, Salvi and Saunders describe the remarkable recovery of function of the avian auditory system following acoustic trauma and ototoxic insult. Physiological studies show significant recovery, with only minor deficits except for cases in which the xi

12 xii Volume Preface supporting cells are destroyed. In Chapter 4, Dooling, Dent, Lauer, and Ryals go into considerable detail about actual recovery of hearing function following loss of hair cells. Behavioral measures of hearing, the gold standard, show almost complete recovery of function on simple measures such as threshold as well as highly sophisticated measures that involve discrimination of complex vocalizations. The mechanisms involved in proliferation, differentiation, and regeneration are discussed in detail by Oesterle and Stone in Chapter 5. The roles that growth factor, intercellular signaling, intracellular signaling and differentiation factors play in proliferation, conversion, and repair are carefully considered. In Chapter 6, Forge and Van De Water consider ways to protect sensory hair cells from damage so that regeneration is not needed. The modes of cell death are reviewed and various strategies for blocking cell death such as antioxidants, inhibition of apoptosis, and small molecules that block genes or enzymes in the cell death pathway are considered. Finally, in Chapter 7, Rivolta and Holley discuss new experimental approaches that may aid in understanding cell death, cell repair, proliferation, and differentiation. The use of gene array technologies and inner ear cell lines may provide more efficient and comprehensive methods for understanding apoptosis, repair, and regeneration. As is often the case, new volumes in the Springer Handbook of Auditory Research amplify and extend materials discussed in earlier volumes in the series. While the current volume concerns regeneration and repair, engineering methods have been quite successful in dealing with deafness. In particular, cochlear implants have been a widely used approach and this was covered in depth in Vol. 20 of the series, Cochlear Implants (edited by Zeng, Popper, and Fay). The genetics of the ear and of hearing loss was discussed in detail in Vol. 14, Genetics and Auditory Disorders (edited by Keats, Popper, and Fay). While the current volume focuses on hair cells, Vol. 23, Plasticity of the Auditory System (edited by Parks, Rubel, Fay, and Popper), includes chapters that consider overall plasticity at many levels of the auditory system. Mechanisms of damage to the auditory system is considered at length in in Vol. 31, Auditory Trauma, Protection, and Repair (edited by Schacht, Popper, and Fay). Finally, the physiology and function of sensory hair cells is discussed in many chapters of Vol. 27, Vertebrate Hair Cells (edited by Eatock, Fay, and Popper). Richard J. Salvi, Buffalo, NY Arthur N. Popper, College Park, MD Richard R. Fay, Chicago, IL

13 1 Overview: Regeneration and Repair Richard J. Salvi 1. Introduction 1.1 Hair Cells and the Acoustic World The human brain s ability to sense and interpret acoustic events taking place in remote or nearby locations in the external environment is mediated by highly specialized and extremely sensitive sensory hair cells located in the inner ear. Although the external ear and middle ear play important roles in collecting, amplifying, and relaying acoustic information from the environment to the inner ear, the resulting mechanical vibrations of the basilar membrane are of little value unless they can be transduced by the sensory hair cells into a pattern of neural activity that can be interpreted by sophisticated neural networks located at multiple levels of the central nervous system. The sensory hair cells in the inner ear represent the obligatory entry point for gaining access to the central auditory or vestibular systems. It has long been known that hair cell loss in mammals due to aging, ototoxic drugs, acoustic trauma, infection, or genetic factors results in permanent hearing loss or balance problems. Humans suffering from profound hearing loss due to massive loss of cochlear hair cells are shut off from the world of music and oral communication. Profoundly deaf individuals who are unable to communicate orally can experience a sense of social isolation when trying to interact with the hearing world. Over the past 50 years, efforts to find a cure for deafness have focused on hardware and engineering solutions. The crowning achievement of this effort has been the multichannel cochlear implant. A microphone at the front end of the cochlear implant converts sound into an electrical signal; this mechanical to electric transduction process is reminiscent of the one that takes place in hair cells to initiate hearing. The electrical output of the microphone is fed to a speech processor that segregates the electrical signal into approximately 16 frequency channels; the electrical output of each channel is relayed to an electrode located near the low-, mid-, or high-frequency region along the length of the cochlea, much like the keys on a piano. While modern cochlear implants have done a remarkable job in enhancing speech comprehension in the profoundly deaf, the perceptual qualities of the electrically evoked sound is inferior to the natural sound of speech and music conveyed to the auditory nerve by the hair cells. 1

14 2 R.J. Salvi The next giant step toward restoring hearing to the profoundly deaf will involve regenerating the damaged biological structures in the inner ear, in particular the hair cells and spiral ganglion neurons. The major clinical advances in hearing and balance that will occur in the 21st century will involve biologically based medical innovations that were set into motion during the past few decades by the discovery of hair cell regeneration and the recognition that stem cells exist in many regions of the nervous system, including the inner ear. 1.2 Zeitgeist, Regeneration, and Repair The history of science is often impeded by roadblocks, intellectual and technical, that hinder the advancement of our thinking and imagination. Our views of the world are often constrained by existing knowledge that is accepted as fact by the majority of scientists: the so-called Zeitgeist or spirit of the times. The collective knowledge and prevailing views of the majority can have a profound impact on how new scientific findings are viewed and interpreted for years or even centuries. New data and theories are often immediately rejected by the majority if the findings go against the prevailing view. Indeed, individual scientists may reject their own findings and consider them artifacts or experimental errors if the data contradict prevailing beliefs, opinions, or knowledge. The ancient theory of sensory processing known as the principle of likeness postulated that sensory stimuli in the environment evoked activity within the sensory organ of the same kind (Gitter 1990; Sente 2004). On the basis of this principle, Empedocles proposed the theory of implanted air in the 4th century b.c. whereby sound in the environment evoked a similar activity within the ear to induce the sensation of hearing. The doctrine provided an intellectual framework, though a distorted one, for interpreting the gross anatomical and microscopic observations that were made over the next 2000 years. In the 1500s, Coiter rejected the theory of implanted air based on careful anatomical observations of the middle ear and Eustachian tube. Nevertheless, the principle of likeness persisted for another 100 years until it was finally put to rest by detailed examination of the inner ear with the compound microscope and advances in neurophysiology. My first encounter with the Zeitgeist blinded my thinking on hair cell regeneration. In the late 1970s, I had been studying the effects of acoustic trauma on the firing patterns of auditory nerve fibers in mammals. The dogma at the time was that hair cell loss was permanent and irreparable. At the 1978 meeting of the Acoustical Society of America, I attended a special session on comparative studies of hearing in vertebrates in which Robert Capranica reviewed his work on anurans. Capranica ended his presentation with a provocative finding showing that when ototoxic aminoglycosides were applied to the frog s inner ear, they completely abolished neurophysiological activity from the ear (Capranica 1978). Surprisingly, the frog s hearing recovered after a few weeks. This was an unexpected finding that defied any conventional explanation. Several thoughts raced through my mind. Were frog hair cells incapable of being destroyed

15 1. Overview 3 by aminoglycosides? Were aminoglycoside antibiotics capable of causing only transient damage to the hair cells or neurons? If frog hair cells could not be destroyed with aminoglycoside antibiotics, maybe they could be destroyed with high-level acoustic stimulation. To test the later hypothesis, we started collaborating with the Capranica lab. Capranica s group drove the frogs from Ithaca, NY to our labs in Syracuse and we exposed the frogs to high-intensity impulse noise in the range of db peak sound pressure level (SPL). Exposures at these levels had caused massive hair cell loss in mammals, and I expected they would do the same in frogs. Afterwards, the frogs were driven back to Cornell University and 1 2 months later their hearing was tested via electrophysiological methods. Surprisingly, the auditory function of the noise-exposed frogs was completely normal. Did the frogs have a potent, long-lasting acoustic reflex that they were using to thwart our acoustic trauma? We tried more vigorous noise exposures several times, but nothing seemed to work. Because normal hearing always returned in the frogs, we eventually dropped the project, considering it a complete failure. Had we examined the frog s inner ear immediately after treatment with aminoglycoside antibiotics or acoustic overstimulation, we most likely would have seen missing sensory hair cells after the traumatic event and if we had waited a few weeks we would have observed a normal sensory epithelium filled with newborn hair cells (Baird et al. 1993). I never imagined that hair cells could regenerate after aminoglycoside treatment or acoustic trauma and we missed the opportunity to discover hair cell regeneration in nonmammals. The frog trauma data did not conform to our view of the world and therefore was ignored. Less than a decade later, Corwin, Cotanche, Rubel, Ryals, and other showed that hair cells regenerated in the avian ear after acoustic overstimulation and ototoxicity (Corwin and Cotanche 1988; Ryals and Rubel 1988). A new chapter in auditory neuroscience had started. The Zeitgeist has shifted 180 degrees, and the possibility that hair cell regeneration could be stimulated to occur in mammals via gene therapy became a realistic and exciting possibility (Zheng and Gao 2000; Izumikawa et al. 2005). Looking backwards through the rear view mirror of time, it is interesting to note that hair cell regeneration in amphibians had already been discovered by Stone in the 1930s, but it was largely overlooked only to be rediscovered and embraced 50 years later (Stone 1933, 1937). 1.3 Regeneration in Fish and Amphibians The first reports of hair cell regeneration date back to the 1930s when it was discovered that after tail amputation or reamputation, the amphibian lateral line organs on the body surface would grow back by forming a regenerative placode that migrated into the regenerating tail where it formed a neuromasts with new hair cells that received afferent innervation (Stone 1933, 1937; Speidel 1947; Wright 1947; Jones and Corwin 1996). These findings indicate that amphibians possess stem cells that self-renew and differentiate into hair cells and support cells.