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Sleep Alterations in Mouse Genetic Models of Human Disease

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Sleep Alterations in Mouse Genetic Models of Human Disease University of Kentucky UKnowledge Theses and Dissertations--Biology Biology 2016 SLEEP ALTERATIONS IN MOUSE GENETIC MODELS OF HUMAN DISEASE Mansi Sethi University of Kentucky, [email protected] Author ORCID Identifier: http://orcid.org/0000-0002-6636-171X Digital Object Identifier: https://doi.org/10.13023/ETD.2016.522 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Sethi, Mansi, "SLEEP ALTERATIONS IN MOUSE GENETIC MODELS OF HUMAN DISEASE" (2016). Theses and Dissertations--Biology. 38. https://uknowledge.uky.edu/biology_etds/38 This Doctoral Dissertation is brought to you for free and open access by the Biology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Biology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Mansi Sethi, Student Dr. Bruce F. O'Hara, Major Professor Dr. David F. Westneat, Director of Graduate Studies SLEEP ALTERATIONS IN MOUSE GENETIC MODELS OF HUMAN DISEASE DISSERTATION A dissertation submitted in partial fulfillment of the Requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky By Mansi Sethi Lexington, Kentucky Director: Dr. Bruce F. O’Hara, Professor of Biology Lexington, Kentucky 2016 Copyright © Mansi Sethi 2016 ABSTRACT OF DISSERTATION SLEEP ALTERATIONS IN MOUSE GENETIC MODELS OF HUMAN DISEASE Sleep is a process essential for the well-being of an animal and in humans as much as one-third of our life is spent in sleep. Yet, the biological need for sleep still remains a conundrum. Our knowledge of the genes influencing sleep and the mechanisms regulating the process can be advanced with the utilization of genetic and genomic approaches which, in turn, may inform us about the functions of sleep as well. With this goal, I have investigated and examined sleep-wake phenotypes for a variety of transgenic and knock out animals. For the first part of my research (Chapter 3), I examined mouse models of Alzheimer’s disease, and a combined model of Alzheimer’s disease (AD) and Diabetes. Sleep disturbances in case of AD are evident long before the onset of cognitive decline. I investigated sleep-wake alterations in 5XFAD, a double transgenic mouse model of AD which displays an early onset of AD pathology and cognitive impairments. We found that these mice have shorter bout lengths under baseline conditions. This was true for both sexes, however, the effect was more prominent in females. Additionally, females also had a shorter duration of sleep compared to control animals. These overall bout length reductions are indicative of increased sleep fragmentation similar to the ones seen in human AD patients. Inadequate sleep is associated with increased risk for metabolic disorders such as diabetes besides neurodegenerative diseases such as AD. There is also growing evidence that type 2 diabetes mellitus (T2DM) poses an increased risk of AD. To understand how the two conditions interact, we studied a combined mouse model of AD and diabetes (db/AD) which was generated by crossing of db/db (diabetic obese mice) and APP-PS1 (knock-in AD mouse model). The resulting mice showed profound cerebrovascular as well as AD pathology. Both females and males, diabetic AD animals had longer sleep duration compared to non-diabetic AD animals. They also exhibited attenuated sleep-wake rhythms. Females were found to have shorter sleep bouts than males. In addition, significant two way interactions were found for the age and db/AD genotype. Our findings suggest that db genotype and not cerebrovascular pathologies affect sleep in our mouse model. For the last part of my research, we analyzed over 300 single gene knock out mouse lines generated on a C57BL6/NJ background, monitored at The Jackson Laboratory. With this unbiased approach where the knockouts were chosen at random, we identified 55 novel genes affecting various sleep traits, utilizing a variety of statistical approaches. Sex differences were found for a number of knockouts as well as controls. Control females were found to have shorter bout lengths and less sleep duration compared to male littermates. Keywords: amyloid beta, sleep fragmentation, diabetes, phenotyping, piezoelectric system, knockout mice Mansi Sethi December 9, 2016 SLEEP ALTERATIONS IN MOUSE GENETIC MODELS OF HUMAN DISEASE By Mansi Sethi Director: Dr. Bruce F. O’Hara, Professor of Biology Lexington, Kentucky 2016 Bruce F. O’Hara Director of Dissertation David F. Westneat Director of Graduate Studies December 9, 2016 To the inspirational women of my life, my mom and my grandmothers ACKNOWLEDGEMENTS "All progress takes place outside the comfort zone." - Michael John Bobak My graduate life has been a journey of a lifetime; with experiences that challenged me to explore paths beyond my comfort zone. I owe gratitude to many people around me without the support and assistance of whom this journey would not have been possible. First and foremost, thanks to my advisor Bruce O’Hara who is an incredible person. His continued support and guidance lead me to where I stand today. He has not just been a mentor who introduced me to the field of sleep and taught me the tricks of the trade, but he is also someone who I look up to as a role model. His approach at training is commendable; it instilled in me the confidence to conduct research independently and equipped me how to think deeply about the problem at hand and how best to address it. I am equally grateful to my family- my dad, my brothers and especially my mom who is just not my pillar of strength but also my lifeline. Her support and faith in my capabilities has been my driving force throughout. Also, I would like to express my gratitude towards my cousin Rajni and a dear friend- Jasmin who were always there for me when I needed them the most. Lexington always felt like home because of the wonderful biology staff- Bev (a motherly figure), Jacquie, Jacqueline Lee and many others who always have been so welcoming and helpful. Special thanks to Seth who came to my rescue every time I was stuck with any technical issue or for last minute poster print outs. Graduate life would have been devoid of fun and excitement had it not been for my second family (in Lexington)- Rupam, Moushumi, Aman, Deepshi, Harpriya, Ishita, Priyanshi, Sampurna, Subu, Payal and Rahul. I have shared many cherishable moments with these guys- impromptu plan of driving all the way to Cincinnati for an Indian movie to visiting Cumberland falls at night to see the moonbow. They held their doors always open for me. And, also thanks to my friends from India- Shweta, Khushboo, Kamiya, Namrata and Saddy for their helpful inputs from time to time. I am also thankful to my friends from the department- Qian Chen, Wenwen, Lakshmi, Deep, Swagatha who helped to adapt to a new environment on my arrival to the States and iii provided me with valuable tips in times of need. Also, I would like to appreciate my labmates- Ren and Chanung, and especially Martin who will hold special place in my heart forever. Martin was a second mentor after Bruce who inspired me with his dedication towards his work, and his intellect and love for the field of sleep and science. I extend my deepest appreciation towards my wonderful thesis committee members- Dr. Robin Cooper, Dr. Craig Sergant and Dr. Duncan for their suggestions and encouragement over the years. I am fortunate to have the opportunity to also attend their classes on campus, and collaborate with Dr. Duncan. She helped me learn the technicalities of writing scientific papers and also how to approach a problem systematically. I am also thankful to Dr. Kevin Donohue and Anuj Agrawal who guided me with the new capabilities of our sleep recording system and helped in trouble shooting when needed, and Statistics faculties- Dr. Stromberg, Dr. Westgate and Dr. Gebert. Their excellent teaching methods made me fall in love with data analysis and statistics. I also owe my appreciation to Dr. Doug Harrison with whom I had the opportunity to work initially besides Dr.
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