Mechanisms of High Sensitivity and Active Amplification in Sensory Hair Cells A dissertation presented to the faculty of the College of Art and Sciences of Ohio University In partial fulfillment of the requirements for the degree Doctor of Philosophy Mahvand Khamesian August 2018 © 2018 Mahvand Khamesian. All Rights Reserved. 2 This dissertation titled Mechanisms of High Sensitivity and Active Amplification in Sensory Hair Cells by MAHVAND KHAMESIAN has been approved for the Department of Physics and Astronomy and the College of Art and Sciences by Alexander B. Neiman Professor of Physics and Astronomy Joseph Shields Dean of College of Arts and Sciences 3 Abstract KHAMESIAN, MAHVAND, Ph.D., August 2018, Physics Mechanisms of High Sensitivity and Active Amplification in Sensory Hair Cells (118 pp.) Director of Dissertation: Alexander B. Neiman Hair cells mediating the senses of hearing and balance rely on active mechanisms for amplification of mechanical signals. In amphibians, hair cells exhibit spontaneous self-sustained mechanical oscillations of their hair bundles. In addition to mechanical oscillations, it is known that the electrical resonance is responsible for frequency selectivity in some inner ear organs. Furthermore, hair cells may show spontaneous electrical oscillations of their membrane potentials. In this dissertation, we study these mechanisms using a computational modeling of the bullfrog sacculus, a well-studied preparation in sensory neuroscience. In vivo, hair bundles of the bullfrog sacculus are coupled by an overlying otolithic membrane across a significant fraction of epithelium. We develop a model for coupled hair bundles in which non-identical hair cells are distributed on a regular grid and coupled mechanically via elastic springs connected to the hair bundles. We first refine a model of a single hair bundle and study the effect of membrane potential on mechanical oscillations and sensitivity of sensory hair cells. In particular, we show that the fast adaptation is necessary to account for the experimentally observed responses to variations of the membrane potential. We then study the collective dynamics of coupled hair bundles and their response to mechanical and electrical stimuli. Our simulations of coupled hair bundles identify two distinct regimes of collective spontaneous dynamics: oscillation quenching and synchronization. The former regime is experimentally observed in bullfrog sacculus. We characterize stimulus-detection properties of the coupled hair bundles and show that coupling-induced suppression of spontaneous oscillations enhances stimulus discrimination. We further analyze the collective response of coupled hair bundles to variations of the membrane potential. We 4 show that these variations may alter mechanical response significantly and thus may yield an effective mechanism of sensitivity enhancement and gain control. 5 To my parents, with love. To my sisters, Maryam and Marjan. To my best friend and beloved, Pooya. 6 Acknowledgments I would like to express my deepest appreciation and thanks to my advisor, Prof. Alexander Neiman, for giving me the opportunity to work with him. Without his encouragement, guidance, and scientific wisdom over the past three years, this dissertation would not have been possible. I greatly appreciate his kindness and belief in me. I would like to thank my committee members: Prof. Horacio Castillo, Prof. David Tees, and Prof. Tatiana Savin for their time, interest, and helpful feedbacks. Also, special thanks to Prof. Lutz Schimansky-Geier for taking the time to discuss my proposal. I appreciate Prof. Kourosh Nozari, my graduate advisor in Iran, for all his support that gave me the courage to come to the U.S. and pursue my Ph.D. Special thanks to my parents for all their endless love, encouragement, and believing in me throughout my life. I cannot thank you enough for what you have done for me. I am sorry for being miles away from you! My heartfelt thanks to my sister Maryam for being patient with me in my long absence and offering words of encouragements. To my twin sister Marjan for her invaluable support and affection. I wish we could have spent our Ph.D. life together like we have been during our Bachelor and Master. Thank to all my true friends and family for their understanding and encouragement in many moments. And, thank to Pooya, for his loving support and continuous encouragement during these years of Ph.D. Words cannot describe how lucky I am to have you in my life. 7 Table of Contents Page Abstract.........................................3 Dedication........................................5 Acknowledgments....................................6 List of Tables......................................9 List of Figures...................................... 10 List of Abbreviations.................................. 18 1 Introduction..................................... 20 1.1 Hearing in mammals............................. 21 1.2 Bullfrog saccular hair cells.......................... 27 1.3 Adaptation by hair bundles.......................... 30 1.4 Spontaneous oscillations of the hair bundle................. 32 1.5 Spontaneous oscillations of the membrane potential............. 36 1.6 Research goals................................ 39 2 Effect of membrane potential on mechanical oscillations of a single hair bundle. 41 2.1 Introduction.................................. 41 2.2 Models and methods............................. 42 2.3 Deterministic dynamics............................ 47 2.4 Stochastic dynamics.............................. 51 2.4.1 Static electrical sensitivity...................... 55 2.4.2 Dynamic electrical sensitivity.................... 56 2.4.3 Mechanical sensitivity........................ 58 2.5 Conclusion.................................. 59 3 Coupled hair bundles................................ 61 3.1 Introduction.................................. 61 3.2 Models and methods............................. 62 3.3 Deterministic dynamics of coupled hair bundles............... 67 3.3.1 Effects of system size and membrane’s mass on coupled hair bundles 71 3.3.2 Effect of membrane potential on coupled hair bundles........ 72 3.3.3 Conclusion.............................. 74 3.4 Stochastic dynamics of coupled hair bundles................. 75 8 3.4.1 Effects of system size, membrane’s mass, and membrane potential on stochastic coupled hair bundles.................. 78 3.4.2 Conclusion.............................. 80 4 Localized Mechanical Stimulations......................... 82 4.1 Introduction.................................. 82 4.2 Effects of coupling on localized stimulation................. 84 4.3 Conclusion.................................. 88 5 Sensitivity and signal detection in coupled hair bundles.............. 89 5.1 Introduction.................................. 89 5.2 Stimulus and collective response measures.................. 89 5.3 Sensitivity of coupled hair bundles to mechanical stimuli.......... 91 5.4 Effect of membrane potential on collective response to mechanical stimuli. 94 5.5 Collective response and background activity: signal encoding and discrim- ination..................................... 95 5.6 Collective response to time-varying electrical stimuli............ 99 5.7 Conclusion.................................. 101 6 Conclusion and Outlook.............................. 104 References........................................ 108 9 List of Tables Table Page 2.1 Description and values of model parameters from Ref. [1]............ 45 10 List of Figures Figure Page 1.1 The ear is divided into three major parts: the outer ear, middle ear and inner ear. The outer ear is external part of the ear, which consists of the pinna and external auditory meatus (ear canal). The pinna collects the vibrations in the air and focuses it on the eardrum (tympanic membrane). The outer ear is separated from the middle ear by the tympanic membrane. The middle ear contains three minuscule bones called malleus, incus, and stapes; The inner ear has three parts: the vestibule and the semicircular canals, which are concerned with equilibrium, and the cochlea, which is involved with hearing. Modified from Ref. [2].................................... 22 1.2 Cross sectional view of the organ of Corti. The organ of Corti contains two types of sensory hair cells and number of supporting cells. The hair cells arranged on the basilar membrane are organized as one row of inner hair cells and three rows of outer hair cells. Outer hair cells are directly connected to the tectorial membrane through their tips of tallest stereocilia. Inner and outer hair cells are innervated by afferent and efferent nerve endings, respectively. Hair bundles of inner hair cells and outer hair cells are bathed in endolymph, whereas the basolateral sides of the hair cells are bathed in perilymph. Modified from Ref. [3]......................... 23 1.3 Schematic diagram of hair bundle. (left): Transduction channel is located at the top of the stereocilium, including a tip link which connect adjunct stereocilia. (right): Mechano-electrical transduction begins with the hair bundle deflection. The increased tension upon positive deflection of the hair bundle compels the transduction channels to open. Stereocilia, composed of parallel actin filaments, move as rigid rods, pivoting at their bases. Modified from Ref. [5].. 25 1.4 (a) A scanning electron micrograph depicts roughly a dozen hair bundles protruding from the apical epithelial surface of the sacculus, a receptor for seismic vibration and airborne