Response Properties of Neighboring Neurons in the Auditory Midbrain by Chandran V. Seshagiri B.A. Physics, Rice University, 1997 SUBMITTED TO THE HARVARD-MIT DIVISION OF HEALTH SCIENCES AND TECHNOLOGY IN PARITAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN HEALTH SCIENCES AND TECHNOLOGY AT THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY JUNE 2006 ©2006 Massachusetts Institute of Technology All rights reserved. Signature of Author: ______________________________________________________ Harvard-MIT Division of Health Sciences and Technology 26 May 2006 Certified by: _____________________________________________________________ Bertrand Delgutte Associate Professor of Otology and Laryngology and Health Sciences and Technology, Harvard Medical School Thesis Supervisor Accepted by: ____________________________________________________________ Martha L. Gray Professor of Medical Engineering and Electrical Engineering Director, Harvard-MIT Division of Health Sciences and TechnologyResponse Properties of Neighboring Neurons in the Auditory Midbrain by Chandran V. Seshagiri Submitted to the Harvard-MIT Division of Health Sciences and Technology on 26 May 2006 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Health Sciences and Technology ABSTRACT The inferior colliculus, the primary nucleus in the mammalian auditory midbrain, occupies a central position in the ascending auditory pathway. Nearly all ascending neural pathways converge and synapse in the central nucleus of the inferior colliculus (ICC). Further, the anatomical arrangement of axons and neurons in the ICC suggests the existence of functional regions which may play a role in organizing different types of physiological information. To investigate this organization, we characterized the response properties of neighboring neurons in the ICC. To record reliably from neighboring neurons, we adopted a relatively new electrophysiological technique, tetrode recordings. Tetrodes have four closely spaced recording sites (<20µm) which record multi-unit activity from a small number of neighboring neurons. The recorded signals contain action potentials originating from more than one neuron. Based on action potential wave shape differences across the four channels, we can reconstruct the contributions of individual neurons. Applying tetrode recordings to the ICC of anesthetized cats, we successfully reconstructed individual spike trains for 190 neurons at 52 recording sites. To quantify the advantage of tetrodes, we compared our multi-channel recording results with waveform sorting from single-channel electrode recordings. At best, only 32% of the single-units from tetrode sorting were correctly identified using single-channel recordings. We used tetrode to characterize pure tone responses of neighboring neurons in the ICC in terms of frequency selectivity, level dependence, temporal discharge patterns, and sensitivity to interaural time differences. We find similarities in best frequency and pure-tone threshold among neighboring neurons; however, we find large disparities in bandwidth, level dependence, temporal discharge patterns, and sensitivity to interaural time differences. These results suggest that neighboring neurons in ICC can greatly differ in membrane properties and/or their patterns of synaptic input from different brainstem nuclei and tonotopic regions. Using tetrode recordings, we investigated how well multi-unit responses represent the response properties of the contributing single-unit responses. We find that multi-unit 3responses represent single-unit best frequency, pure-tone threshold and level dependence well, and they represent single-unit bandwidth and interaural phase sensitivity poorly. These results suggest caution must be used not to infer single-unit responses from multi-unit recordings. Thesis Supervisor: Bertrand Delgutte Title: Associate Professor of Otology and Laryngology and Health Sciences and Technology, Harvard Medical School 4ACKNOWLEDGEMENTS Nothing worth doing in this life is ever worth doing alone. This thesis is the culmination of many years of work, but it is also the product of strong relationships and wonderful friendships. I would like to thank everyone who has walked with me, helped me, and supported me in this journey: Bertrand Delgutte, my advisor, for supporting me and this work. I came into his group interested in studying ‘neural populations,’ though, at the time, I didn’t really know what that meant. Through all the years of twisting and winding down the often unclear path of trying to make sense of neural populations, Bertrand was always encouraging and supportive. I am forever grateful to him for allowing me to walk my own path. My thesis committee for giving me their time and interest. Their suggestions have proved invaluable in developing this thesis. Thank you to Doug Oliver for making many trips from Connecticut to attend committee meetings. I would like to especially thank Jennifer Melcher who was always a great source of encouragement. Her interest and enthusiasm in this project has always been appreciated. Matthew Wilson, the brains behind the development of the tetrode, graciously opened up his lab to me. Under the guidance of his student, Linus Sun, I was able to learn the intricate art of making tetrodes. Connie Miller and Leslie Liberman for providing surgical support. Ishmael Stefanov-Wagner for providing engineering support. Special thanks to Dianna Sands who makes the world work. All my colleagues at EPL and in the Speech and Hearing program. This is a great graduate program, largely because of the warm and collegial atmosphere created by the wonderful students. Don H. Johnson, my research advisor at Rice University, for setting me on this path in the first place. I cannot thank him enough for giving me the opportunity to work with him as a senior in college. His expressive enthusiasm and love for his work is infectious, and the experience of working with him changed my life forever. I cannot adequately express my gratitude to him. All my friends both in and out of Boston who stood by me, put up with me, and generally kept me sane all these years: Ray, Radha, Brad, Courtney, Jonno, Domenica, Dave O, Irina, Leo, Zach, Tarun, Arpit, Dave (Spin), Edwin, Sarita, Yogi, Theresa, Jonathan and Caroline. Miles, Trane, Ken, Hamid, Eddie, and Bono for keeping me