NEUROMODULATION OF INTRINSIC AND SYNAPTIC PLASTICITY IN AUDITORY CORTEX Deepti Rao A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Department of Cell and Molecular Physiology in the School of Medicine Chapel Hill 2011 Approved by Paul B. Manis, Ph.D. Benjamin D. Philpot, Ph.D. Robert Sealock, Ph.D. Serena M. Dudek, Ph.D. Sridhar Ragavachari, Ph.D. © 2011 Deepti Rao ALL RIGHTS RESERVED ii ABSTRACT DEEPTI RAO: Neuromodulation of Intrinsic and Synaptic Plasticity in Auditory Cortex (Under the direction of Paul B. Manis) The study of auditory system development and plasticity is important. Large populations of people suffer from hearing loss throughout their lifetime. To optimize treatment for children with hearing loss, it is crucial to understand how early hearing loss affects the development and processing of the central auditory system. Equally important is the understanding of how changes in neural activity in the auditory pathways can have an effect on its function. In this thesis, I studied 1) how hearing loss affects auditory cortical activity and 2) the mechanisms that could underlie learning and memory of sound information. In the first study, I found that hearing loss enhances auditory cortical activity and alters the manner in which the auditory cortex responds to the neuromodulator serotonin. In the second study, I found that the auditory cortex follows unique cellular learning and memory rules and these rules are altered by the neuromodulator acetylcholine. iii ACKNOWLEDGMENTS I want to express my deep gratitude and thanks to my thesis advisor, Dr. Paul Manis for giving me guidance, advice and furthering my knowledge. I would like to thank the following people for all of their support: my lab mates (past and present), my thesis committee members Drs. Ben Philpot, Serena Dudek, Robert Sealock and Sridhar Ragavachari and the department of cell and molecular physiology for their constant support and advice. iv TABLE OF CONTENTS LIST OF TABLES .............................................................................................................................. vii LIST OF FIGURES ........................................................................................................................... viii CHAPTER 1 .......................................................................................................................................... 1 INTRODUCTION ................................................................................................................................. 1 1. Functional architecture of A1 ..................................................................................................... 3 1.1 Recurrent synapses of Layer 2/3 pyramidal neurons ...................................................... 4 2. Developmental plasticity in auditory cortex ............................................................................. 7 2.1 Cellular mechanisms of plasticity in auditory cortex ........................................................ 9 2.1.1 Spike timing-dependent plasticity (STDP) ................................................................... 10 2.1.2. Intrinsic Plasticity ............................................................................................................ 13 2.2 Hearing loss in A1 ............................................................................................................... 15 3. Neuromodulation in A1 ............................................................................................................. 16 3.1 Serotonergic regulation of developmental plasticity ...................................................... 17 3.1.1 Role of serotonin in developmental plasticity .............................................................. 17 3.1.2 Role of serotonin in auditory cortical function .............................................................. 18 3.2 Cholinergic regulation of developmental plasticity ......................................................... 19 3.2.1 Role of acetylcholine in developmental plasticity ........................................................ 19 3.2.2 Role of acetylcholine in auditory cortical function ....................................................... 20 4. Mechanisms of neuromodulation in A1 .................................................................................. 21 4.1 Serotonergic modulation of plasticity ............................................................................... 22 4.2 Cholinergic modulation of plasticity .................................................................................. 24 Conclusion ...................................................................................................................................... 26 CHAPTER 2 ........................................................................................................................................ 30 v HEARING LOSS ALTERS SEROTONERGIC MODULATION OF INTRINSIC EXCITABILITY IN AUDITORY CORTEX (Rao et al. 2010) .................................................................................... 30 1. Abstract ....................................................................................................................................... 31 2. Introduction ................................................................................................................................. 32 3. Materials and Methods ............................................................................................................. 35 4. Results ........................................................................................................................................ 42 5. Discussion .................................................................................................................................. 50 CHAPTER 3 ........................................................................................................................................ 72 MUSCARINIC MODULATION OF STDP AT RECURRENT SYNAPSES IN AUDITORY CORTEX ............................................................................................................................................. 72 1. Abstract ....................................................................................................................................... 73 2. Introduction ................................................................................................................................. 74 3. Materials and Methods ............................................................................................................. 76 4. Results ........................................................................................................................................ 81 5. Discussion .................................................................................................................................. 89 CHAPTER 4 ...................................................................................................................................... 109 DISCUSSION ................................................................................................................................... 109 1. Auditory development and plasticity ..................................................................................... 111 2. SNHL and A1 plasticity ........................................................................................................... 112 3. STDP in the human brain ....................................................................................................... 115 4. Functional relevance of STDP rules in A1 ........................................................................... 117 5. Closing remarks ....................................................................................................................... 119 REFERENCES ................................................................................................................................. 122 vi LIST OF TABLES CHAPTER 2 1. Membrane and action potential measurements…………………………………………………………………………68 vii LIST OF FIGURES CHAPTER 1 1. Learning induced changes in synaptic strength in auditory cortex..……………..27 2. Muscarinic receptor signaling………………......……………………......................28 CHAPTER 2 1. Experimental protocol for measuring neuronal excitability and the actions of 5HT………………………………………………………………..56 2. Serotonin decreases excitability of A1 neurons in normal rats………………………………………………………………………………………57 3. Sham surgery decreases, while cochlear ablation increases, excitability in P12-21…………………...………………….……………..59 4. Cochlear ablation does not affect 5HT modulation of excitability in P12-21 rat A1………………………………..…….………………..61 5. Summary of changes in resting potential, input resistance and adaptation ratios for each experimental group………………….........……….63 6. Activation of 5-HT 2 receptors does not affect the firing rate to current pulses……………………………….……………………..……..…………65 7. Cochlear ablation decreases the ability of 5HT to modulate excitability in P30-35 rat A1……………………….………………..………………...66 8. Comparison of firing rate as a function of current injection...……………………..70 CHAPTER 3 1. Synaptic modification of L2/3 auditory cortical synapses induced by repetitive pre-postsynaptic pairing……..………...………………….....98 2. Muscarinic receptor activation induces