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Rat Model of Pre-Motor Parkinson's Disease Rat Model of Pre-Motor Parkinson‘s Disease: Behavioral and MRI Characterization. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Engineering by Pallavi Satish Rane 3/28/2011 Christopher H. Sotak, Ph.D. Jean A. King, Ph. D. Academic Advisor Research Advisor Professor Professor Department of Biomedical Engineering Department of Psychiatry Worcester Polytechnic Institute University of Massachusetts Medical School, Worcester George D. Pins, Ph.D. Nanyin Zhang, Ph. D. Associate Professor Assistant Professor Department of Biomedical Engineering Department of Psychiatry Worcester Polytechnic Institute University of Massachusetts Medical School, Worcester Gregory J. DiGirolamo, Ph. D. Associate Professor Department of Psychology College of Holy Cross ii Acknowledgements As the ―graduate student‖ part of my life draws to a close, I cannot help but look back and be grateful for the support of numerous friends, family members and members of the WPI and UMass community. First and foremost, I have to mention my mentors Dr. Chris Sotak and Dr. Jean King. Dr. Sotak gave me a chance to start this journey and allowed me to start working in his lab even when I was just a first yea r student. Dr. Sotak, I cannot thank you enough for your support, encouragement, guidance, and most of all, for your patience with my ―200 questions‖ attitude. You have always made me feel immensely welcome in this foreign country. You will always have a s pecial place in my heart. Dr. Jean King has guided me through. Jean, CCNI has been a second family to me and I could not have made it through some really tough times without your support and kindness. You have been a role model to me, as one of the strongest women I have ever met in my life. I really admire your incessant working attitude. I am grateful to Dr. George Pins from WPI, Dr. Nanyin Zhang from UMass, Worcester and Dr. Gregory DiGiro lamo from Holy Cross for being on my committee and guiding me thro ugh the process. Dr. Pins, I appreciate you allowing me to use the microscope at the last minute to help me finish my work. Nanyin, I could not have finished my imaging studies and imaging analysis without your guidance. I really appreciate all the time you gave me to help me interpret my results. Gregg, I would really like to thank you for your guidance during the aversion behavior. iii You really helped me nail that study and figure out the appropriate behavior. Thank you all for taking the time and effort to read my thesis. I really appreciate my lab mates Wei Huang, Meghan Heffernan and Zhifeng Liang . Wei‘s support, Meg‘s wisdom and Zhifeng‘s immense knowledge regarding almost everything and most of all of your friendship, has made these years something I ca n remember as one of the most pleasant times in my life. I am really glad that I can call you all not just my lab mates but also my friends. I thank Yvette Gonzales from CCNI and Jean Siequist from WPI for helping me through some crazy paperwork. I do not know how you guys deal with these things with the efficiency that you do. I appreciate Amanda Blackwood, Yin Guo and Dr. Schahram Akbarian who helped me during my immunohistochemistry studies. I would like to take this opportunity to thank my friends Hemis h, Jitish, Abhijit, Parul, Sarang, Kunal, Saurabh, Padmaja, Amit and Akanksha at WPI, my cousins Nirmala and Abhijeet Dalvi and my niece Natasha. You guys have been like a rock in my life and anchored me. Your love has helped me keep on going when everythi ng seemed to fail. Finally, I would like to thank my parents, Sheela and Satish Rane, my brother Charudatta and sister Poonam for being patient with my ‗this is the year I am going to graduate‘ statement for the past 4 years. Aai and Baba, you are the best parents any one can have. I love you. iv Table of Contents ACKNOWLEDGEMENTS II TABLE OF FIGURES VIII LIST OF ABBREVIATIONS XV ABSTRACT 1 CHAPTER 1. INTRODUCTION 4 Motivation ................................................................................................................................................................................... 4 Thesis outline ............................................................................................................................................................................. 6 CHAPTER 2. PARKINSON’S DISEASE 8 History .......................................................................................................................................................................................... 8 Demographics ............................................................................................................................................................................ 9 Etiology of Parkinson’s disease ........................................................................................................................................... 9 Genetics of PD 10 Environmental causes of PD 14 PD neuropathology ................................................................................................................................................................ 16 Diagnosis and clinical symptoms...................................................................................................................................... 18 Motor symptoms 18 Non-motor symptoms of Parkinson’s disease 20 Pre-motor stages of Parkinson’s disease ....................................................................................................................... 21 Treatment .................................................................................................................................................................................. 24 Summary .................................................................................................................................................................................... 26 CHAPTER 3. MAGNETIC RESONANCE IMAGING 27 Nuclear Magnetic Resonance to Magnetic Resonance Imaging ............................................................................. 27 Nuclear spin and magnetic dipole moment .................................................................................................................. 27 Longitudinal and Transverse relaxations ..................................................................................................................... 31 v Signal acquisition ................................................................................................................................................................... 38 Echo 38 Spin Echo RF pulse sequence 39 Gradient Echo RF pulse sequence 40 Spatial encoding ...................................................................................................................................................................... 43 Slice selection 44 Phase encoding 45 Frequency encoding 45 K-space 46 Fourier transform and MRI ................................................................................................................................................. 47 Functional MRI ........................................................................................................................................................................ 49 Hemodynamic response, deoxyhemoglobin and MRI signal 49 Blood oxygenation level dependent fMRI 52 Resting state MRI 53 CHAPTER 4. MODEL DEVELOPMENT 58 Animal Models of Parkinson’s disease ........................................................................................................................... 58 6-Hydroxy dopamine............................................................................................................................................................. 59 Experimental procedures .................................................................................................................................................... 63 Animals 63 Surgery 63 Spontaneous locomotion test 64 Elevated beam test 64 Gait Analysis 66 Immunohistochemistry 66 Data Analysis ............................................................................................................................................................................ 67 Results ........................................................................................................................................................................................ 69 Conclusion ................................................................................................................................................................................. 70 CHAPTER 5. AVERSION CHANGES IN PD 73 Rational ...................................................................................................................................................................................... 73 Experimental Procedures .................................................................................................................................................... 76 Animals 76 Arousal Behavior Test 76 Avoidance Behavior Test 77 Functional MRI 78 vi Data Analysis ............................................................................................................................................................................ 80 Results ........................................................................................................................................................................................ 81 Discussion
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