Auditory Science Exposing the workings of the inner ear Hearing is fundamental to how we interact with the world around us, yet much remains unknown about our biological response to sound. Paul Fuchs, Professor of Otolaryngology-Head and Neck Surgery and Director of the Center for Hearing and Balance at Johns Hopkins University, has spent over three decades investigating the physiology of tiny cells deep in the ear that relay messages to and from the brain, helping us make sense of our auditory world.

hether listening to music, activating the eardrum, sound waves stimulate deciphering speech, or the movement of tiny cells in the inner ear hearing the wail of an known as hair cells. Hair cells – so-called due emergency siren, sound to the hair-like bundles that sit atop them – are is fundamental to how then moved by motion in the fluid of the inner Wwe experience and respond to the world ear, which changes the electrical properties around us. Our perception of sound is key of the cells. This means that information can to communicating with others, can warn us be sent to the brain in the form of electricity of danger, and is capable of evoking great via nerve cells. emotion, playing a vital role in our social,

mental and emotional lives. All of this activity is orchestrated in the Surface view of the sensory epithelium within the cochlea – the mammalian inner ear – a tiny cochlea. A red label of their nuclei indicates three rows HOW SOUND REACHES THE BRAIN coiled structure whose name derives from of outer hair cells (OHCs) and one row of inner hair cells (IHCs). The large synaptic contacts of efferent neurons In order for the brain to make sense of the the Greek for snail shell due to its spiral shape. on outer hair cells, and a plexus of efferent endings sensory input, it has to receive information in Professor Paul Fuchs and his research team below inner hair cells are labelled green. a currency it understands – electrical signals. are focused on understanding the cochlea Sound waves are converted into electrical and have uncovered the importance of its cells signals in the inner ear through a finely in governing our sound perception, focusing and hair cells that allow for electric-chemical choreographed sequence of activity. After on synapses – crucial gaps between neurons information to flow between the cells.

AFFERENT SIGNALS: EAR TO BRAIN Two classes of afferent neurons innervate the cochlea, referred to as Type I and Type II spiral ganglion neurons. These cells carry information towards the brain. Larger Type I afferents report information about sound including timing, intensity, and frequency with each one having a single dendrite – a spiny branch that carries information to the neuron cell body – that connects to a hair cell. Working together, Type I cells relay the information content of sound up to our brains to be processed.

Type II neurons are less prevalent and much smaller in size, making them altogether more Professor Fuchs and colleagues have shown elusive and difficult for scientists to study. that efferent innervation of inner ear cells CHARACTERISING THE FUNCTION OF TYPE II CELLS changes over time and could be significant Although their existence had been known for 60 years, the function of these rare little to the hearing loss that many people Professor Fuchs in his office at Johns Hopkins University School of Medicine. cells remained a puzzle until 2009 when a experience in later life graduate student in Paul Fuchs’ laboratory, Auditory Science

A cross section of the cochlear epithelium on which inner (IHC) and outer (OHCs) hair cells have been outlined. Multiple type I cochlear afferents (solid green) connect with IHCs and carry auditory Detail information to the brain. Type II afferents (dotted green) are few in number (5% of total) and contact RESEARCH OBJECTIVES dozens of OHCs. The scarce type II afferents may Professor Fuchs investigates the detailed report tissue damage in the cochlea, by analogy to What first made you want trauma and associated pathologies such workings of the inner ear. pain fibres in skin. Two classes of efferent neurons (labelled red) contact OHCs or the dendrites of type I to study hearing? as hyperacusis and tinnitus. Positive afferents to regulate the sensitivity of the cochlea. Since my biology thesis at Reed College modulators of inhibitory synapses could FUNDING with Stephen Arch, I have been interested protect from acoustic trauma. Drugs that NIH, the David M. Rubenstein Fund for in synaptic signalling. My doctoral thesis at silence Type II neurons after damage is done Hearing Research and the John E. Bordley Stanford with Donald Kennedy concerned could reduce hyperacusis. Longer term is Professorship. Catherine Weisz, identified the function of presynaptic inhibition at the crayfish the hope to regenerate cochlear hair cells Type II cells, making a major breakthrough in neuromuscular junction. As a postdoctoral whose loss underlies profound deafness, COLLABORATORS auditory science. First published in Nature, fellow with Robert Fettiplace at Cambridge perhaps through the use of stem cells. Dr Elisabeth Glowatzki, Professor the team accessed the neurons by dissecting University, I learned that the inner ear (in that Nearer-term is the possibility of using gene of Otolaryngology-Head and Neck the cochlea from young rats. By using case, of the turtle!) provides an outstanding therapy to restore synaptic connections of Surgery, JHU School of Medicine; Dr specialist electrophysiological equipment to model for linking synaptic signalling directly afferent neurons that retract after acoustic Hakim Hiel, Senior Research Associate, measure electric currents, Weisz was able to to perception and behaviour. The solitary overexposure, or as a function of age. Otolaryngology-Head and Neck Surgery, show that Type II neurons did react to sound, synaptic contact of each Type I cochlear Finally, cochlear implants, other hearing JHU School of Medicine; Dr Ana Belen but in a rather surprising way. afferent confers its frequency selectivity, prosthetics and their implementation will Elgoyhen, Professor of Pharmacology in timing and intensity coding. Inhibitory continue to improve, providing tremendous the Faculty of Medicine of the University CELLS FOR PAINFUL SOUNDS synapses from a unique class of efferent benefits today. of Buenos Aires; Dr Eleonora Katz, Intriguingly, the study showed that the cholinergic neurons regulate cochlear Associate Professor, Department of neurons were sensitive to a chemical known Type II cells may be responsible for processing sensitivity. So one can assign fundamental What are the best ways to protect Physiology, Molecular and Cellular as ATP, a molecule linked to pain and to tissue extreme noises – sounds which could be aspects of hearing to the function of these our ears from damage? Biology, Faculty of Exact and Natural damage. The cells were already known to synaptic contacts. Avoid prolonged exposure to very loud Sciences, University of Buenos Aires; react only to very loud sounds. This led Chang described as painful, or even traumatic sound (gunfire, many workplaces, many Dr Rai Winslow, Raj and Neera Singh Liu in the Fuchs group to show that Type II Are some people more sensitive to noise music venues). The challenge is that such Professor of Biomedical Engineering, JHU cells are strongly activated when cochlear than others, and could this be mediated damage may be imperceptible at first School of Medicine. hair cells are damaged, as can occur during EFFERENT CONNECTIONS which could be a route of investigation for via Type II cells? but accumulates over time and can hasten extreme noises – sounds which could be Whilst it may be intuitive that the brain future drug studies. Yes. Hearing loss often is accompanied or exacerbate age-related hearing loss. BIO described as painful, or even traumatic. Many receives signals from ear cells, cells in the by a paradoxical ‘gain of function’ Paul Fuchs is a graduate of of us have experienced sounds that made us ear also receive outgoing signals from the Little is known about the implications pathology, hyperacusis, whose most severe Does the cochlea have the ability Reed College (biology, 1974) uncomfortable and could even be described brain. Professor Fuchs and colleagues have of efferent innervation over the lifespan, manifestation results in pain on exposure to repair itself after damage? and Stanford University (PhD as painful, leading us to remove ourselves characterised the function and molecular but recent research suggests that it could to only moderately loud sound. Such In short, no. At least, we mammals neurobiology 1979). After from that situation and it is possible that make up of efferent neurons, including medial be involved in hearing loss associated with morbid hyperacusis (‘noxacusis’) may be have lost the capacity to regenerate postdoctoral work at Cambridge, Type II neurons are fundamental to initiating olivocochlear neurons (MOC). It is known age. Using voltage-clamp recording – an a product of upregulated Type II afferent hair cells that is found in all other he joined the Physiology faculty at this behavioural response. Professor Fuchs that MOC neurons play a role in governing electrophysiological technique to measure sensitivity, analogous to the hyperalgesia vertebrates. The partial denervation of the the University of Colorado in 1983. He hopes to develop an animal model to explore the sensitivity of afferent signalling, reliant ion channel activation – Professor Fuchs’ that contributes to neuropathic pain in the cochlea also appears to be irreversible. moved to Johns Hopkins in 1995 where behaviours related to acoustic pain processing. on unusual nicotinic acetylcholine receptors, student Stephen Zachary was able to measure somatic nervous system. There can be temporary threshold shifts he is the John E. Bordley Professor and the activity of individual inner hair cells in after acoustic overexposure that recover vice-Chair for Research in Otolaryngology- mouse models of age-related hearing loss. What do you hope will be the next big in days. However, this is a warning sign to Head and Neck Surgery. By studying mice at various ages across breakthrough for hearing basic research? avoid repetition of that experience – the the lifespan, they have shown that efferent Our own work is aimed at drug targets underlying damage can accumulate and CONTACT innervation of inner ear cells changes over time that could ameliorate or prevent acoustic become permanent. Professor Paul Fuchs and could be significant to the hearing loss Johns Hopkins University that many people experience in later life. School of Medicine Department of Otolaryngology, LOOKING TO THE FUTURE The best ways to protect our ears from Head and Neck Surgery Whilst much is yet to be discovered about Baltimore, MD 21205, USA how we process auditory stimuli, great strides damage? Avoid prolonged exposure have been made in understanding the function to very loud sound (gunfire, many E: [email protected] of cochlear cells that are at the centre of our T: +1 410 955 6311 ability to hear. Professor Fuchs’ continued workplaces, many music venues) W www.hopkinsmedicine.org/profiles/ commitment to characterising the make-up results/directory/profile/3376185/paul- of cochlear neurons may provide key insights fuchs Schematic operation of the cochlea. Sound waves excite a positive feedback vibration between the frequency- dependent travelling wave (TW) on the basilar membrane and an active electromechanical amplification into therapeutics for hearing disorders such W http://neuroscience.jhu.edu/research/ produced by outer hair cells (OHC). This results in a sensitive, sharply tuned input to inner hair cells that excites as hyperacusis and tinnitus. In the meantime, faculty/30 a pool of type I cochlear afferent nerve fibres (ANF) by the release of the neurotransmitter glutamate. Afferent the next time we hear a piercing alarm, W http://centerforsensorybiology.org/ information to the brain is processed to produce our acoustic percepts, and in addition, excites activity of medial and lateral olivocochlear bundle efferents (MOCB, LOCB) that inhibit cochlear outer hair cells (MOCB) and type I we might want to thank our Type II neurons fuchs-laboratory/ afferent nerve fibres (LOCB). for the warning.

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