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Kchip4a: a Biophysical Modulator of Learning from Disappointment

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Kchip4a: a Biophysical Modulator of Learning from Disappointment KChIP4a: a biophysical modulator of learning from disappointment Dissertation for obtaining a doctorate degree in natural sciences presented to the Faculty of Biosciences of Goethe University by Kauê Machado Costa from Belém do Pará, Brazil Frankfurt am Main (2017) (D 30) Accepted by the Faculty of Biosciences of Goethe University as a PhD dissertation Dean: Prof. Dr. Sven Klimpel 1st expert assessor: Prof. Dr. Manfred Kössl 2nd expert assessor: Prof. Dr. Jochen Roeper 3rd expert assessor: Prof. Dr. Amparo Acker-Palmer 4st expert assessor: Prof. Dr. Bernd Grünewald Date of disputation: 19.04.2018 “Exploration is in our nature. We began as wanderers, and we are wanderers still.” ― Carl Sagan, Cosmos Acknowledgements I would like to express my enduring gratitude to: Prof. Dr. Jochen Roeper for providing unwavering, outstanding and continuous support, trust, motivation, funding and fun during my stay in his lab. Prof. Dr. Gilles Laurent for having me in his lab as a rotation student and for providing very instructive comments and support as a member of my thesis committee. Prof. Dr. Manfred Kössl for being my official PhD thesis supervisor at the Biological Sciences Faculty and for providing insightful comments as a member of my thesis committee. Prof. Dr. Gaby Schneider for the highly profitable, illuminating and friendly collaboration over the entire course of my thesis. Prof. Dr. Eleanor Simpson and Prof. Dr. Eric Kandel for, in a short conversation in Columbia, providing me with the crucial yet often forgotten insight that neuroscience always needs a solid grounding in behavior. Dr. Mahalakshmi Subramaniam for teaching me in vivo neuronal recordings. The other institute PIs, Dr. Torfi Sigurdsson and Dr. Sevil Duvarci for comments on my project during lab seminars. Our workshop team, Charly Winter, Thomas Wulf and Hans-Peter Günster for the assistance with setting up crucial hardware and software for my study. Günther Amrhein for the excellent support in caring for our animals, and for helping me practice my (still atrocious) German. Maren Baier and Dr. Arjan Vink for all the help and patience with handling my move to Germany and (many) visa renewals. Regina Giegerich for helping me navigate the treacherous world of German university bureaucracy and making sure we always got what we needed. Carolin Stoffer for assistance with the German summary. Beatrice Fisher for providing incredible technical support to my project, helping me write my German summary and for steering our lab with outstanding competence, discipline and care. Our technicians Jasmine Salmen, Maria Cristina Giardino and Felicia Müller-Braun for their distinguished technical support. My current and former labmates Navid Farassat, Josef Shin, Lora Kovacheva, Somanath Jaganath, Kanako Otomo, Strahinja Stojanovic, Dennis Schneider, Dr. Poonam Thakur, Alois Kreuzer and Sylvie Kutterer for making my time in the lab highly collaborative, fun and productive. My institute colleagues Pascal Voguel, Sebastian Betz and Johannes Hahn for all the fruitful discussions and all the help over the years. Brian Rummel for providing important suggestions when I was setting up the behavior equipment, and the shared conversations and beers over the course of the years. Ivaylo Borislavov Iotchev, for being a good friend and always inspiring wild, challenging discussions about basically everything. Our conversations in front of the building are deeply missed. Raquel de Brito Lima, for the love and companionship over the last two years. I am always learning from and being inspired by you. My parents Jessé Carvalho Costa and Silvia Nadia Lopes Machado, for giving me an amazing childhood, supporting me in everything I always wanted and instilling in me a love for science, knowledge and literature. I am very happy with the opportunities you have provided me and I hope to always make the best use of them. Table of Contents List of figures....................................................................................................................... II List of tables ........................................................................................................................ V List of abbreviations .......................................................................................................... VI English Summary ............................................................................................................... IX Short German Summary .................................................................................................... XI Detailed German Summary .............................................................................................. XIII 1. Introduction ............................................................................................................... 1 1.1. The midbrain dopamine system .................................................................................. 1 1.2. Dopamine and disease .............................................................................................. 21 1.3. Dopamine and learning ............................................................................................. 28 1.4. Kv4 channels and KChIP4a ....................................................................................... 57 1.5. Study question and objectives ................................................................................... 72 2. Methods ....................................................................................................................73 2.1. Ethical standards of animal experimentation ............................................................. 73 2.2. The KChIP4-KO mouse line ...................................................................................... 73 2.3. Anesthesia and general surgical procedures for in vivo recordings .......................... 74 2.4. In vivo extracellular single-unit recordings with juxtacellular labeling ....................... 76 2.5. Conditional exon-deletion mouse lines for assessing KChIP4a function .................. 92 2.6. Procedures for behavioral analysis in transgenic mouse lines ................................. 96 2.7. Fitting behavioral data with a modified Rescorla-Wagner model ............................ 106 2.8. Semi-quantitative IHC of Kv4.3 channels ................................................................ 108 2.9. Statistical analyses .................................................................................................. 110 3. Results.................................................................................................................... 111 3.1. Effects of KChIP4 KO on in vivo dopamine neuron activity..................................... 111 3.2. Behavioral differences between KChIP4-DAT-Ex3d and DAT-cre KI mice ............ 127 3.3. Effects of KChIP4-DAT-Ex3d on Kv4.3 channel expression ................................... 142 3.4. Behavioral differences between DAT-cre KI controls and WT mice ....................... 143 4. Discussion ............................................................................................................. 153 4.1. Full KChIP4 KO reduces spontaneous pausing of VTA DA neuron activity ............ 153 4.2. KChIP4a as a selective modulator of learning from negative feedback .................. 155 4.3. Circuit mechanisms of the behavioral effects of KChIP4 Ex3d ............................... 157 4.4. Physiological effects of KChIP4 KO versus KChIP4 Ex3d on DA neurons ............. 160 4.5. Potential implications for synaptic integration and plasticity ................................... 163 4.6. Neuronal subtype specificity of KChIP4a function ................................................... 171 4.7. Potential implications for disease ............................................................................ 174 4.8. Alternative splicing and behavior ............................................................................. 178 4.9. Behavioral differences between DAT-cre KI and DAT-cre WT mice ....................... 180 4.10. Perspectives ............................................................................................................ 185 4.11. Conclusion ............................................................................................................... 188 References ........................................................................................................................ 189 Curriculum Vitae ................................................................................................................... i Academic production related to this thesis......................................................................vii I List of figures Figure 1.1. Biosynthetic pathway of DA production. ............................................................... 2 Figure 1.2. Major excitatory and inhibitory afferents to midbrain DA neurons. ....................... 5 Figure 1.3. General schematic of midbrain DA neurons within cortico-BG-limbic circuits. ...... 8 Figure 1.4. Major in vivo firing modes of midbrain DA neurons and their postsynaptic effects. .....................................................................................................................................14 Figure 1.5. Atypical VTA DA neurons have long rebound delays. .........................................16 Figure 1.6. DA signal reward prediction error in Pavlovian conditioning. ...............................35
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