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Chemotherapy Induced Deficits in Cognition and Affective Behavior

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Chemotherapy Induced Deficits in Cognition and Affective Behavior Chemotherapy Induced Deficits in Cognition and Affective Behavior DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Brant Lee Jarrett Graduate Program in Neuroscience The Ohio State University 2013 Dissertation Committee: Anne Courtney DeVries, Advisor Randy J. Nelson Jonathan P. Godbout Georgia A. Bishop Copyright by Brant Lee Jarrett 2013 Abstract Advances in cancer detection and treatment have substantially increased the survival rate for breast cancer patients. Chemotherapeutic drugs, particularly anthracyclines, have potentially toxic side effects in the brain- impacting memory, processing time and verbal fluency, depression, and anxiety. More than 30% of patients undergoing chemotherapy for breast cancer suffer from cognitive deficits, depression, or anxiety during and after treatment. Furthermore, for some women these symptoms persist for decades after treatment cessation. Therefore, alleviating anxiety, depression, and cognitive deficits among cancer survivors is important for both quality of life (QOL) and long-term physical health. However, despite the high incidence and significant impact on quality of life, little is known about the cause of the chemotherapy related effects on cognition and affective behavior and no effective treatment currently exists. The present body of work examined the effects of chemotherapeutic agents doxorubicin and cyclophosphamide (AC) on behavior in a non-tumor bearing mouse model. The goals of this dissertation are to determine the physiological mechanism through which AC impairs cognition and affective behavior, as well as test the efficacy of minocycline, an antibiotic with anti-inflammatory properties, in amelioration of chemotherapy-induced changes in behavior. Chemotherapy treated mice exhibited greater anxiogenic-like and depressive-like behavior than the vehicle group; however, there was not a difference in overall activity level, suggesting that these differences were not due to chemotherapy- induced lethargy. In addition, microglia in the brains of chemotherapy-treated mice had ii shifted to a proinflammatory state compared to the vehicle group. There was an overall increase in proinflammatory cytokine expression, specifically tumor necrosis alpha (TNF-α) and interleukin 6 (IL-6), in the chemotherapy-treated mice. We also show that administration of minocycline during chemotherapy reduces expression of IL-6 and prevents depression and anxiety behavior in chemotherapy treated mice. Chemotherapy also affected learning and memory; both the chemotherapy- treated and vehicle-treated mice were able to acquire the task by the final day of training. However, the vehicle-treated mice reached asymptotic performance after fewer training sessions than the chemotherapy-treated mice. Furthermore, the chemotherapy- treated mice took significantly longer to find the escape box than the vehicle-treated mice on training days 2-5. In contrast, there were no group differences in overall locomotor activity level. In addition, chemotherapy increased proinflammatory cytokine expression (TNF-α, IL-1β, and IL-6) in the hippocampus, a region of the brain that is critical for spatial learning and memory. Minocycline reversed the chemotherapy- induced cognitive deficits and increase in IL-6. Together, these data suggest that the administration of doxorubicin and cyclophosphamide in doses that are at the lower limit of doses used in women being treated for breast cancer, produce neuroinflammation, including microglia activation, increased proinflammatory cytokine expression and concomitant cognitive deficits and alterations in affective behavior in female mice. Treatment with minocycline reverses the behavioral and inflammatory effects of chemotherapy. These findings suggest a possible mechanism by which chemotherapy alters neuropsychological behavior. More iii importantly administration of minocycline to cancer patients receiving chemotherapy may improve quality of life and overall physical and mental health; currently no treatments exist for chemotherapy-induced cognitive deficits. Furthermore, minocycline is readily administered in hospitals, is well tolerated over long periods of time, and would be an inexpensive treatment as it is also available in generic form. iv Dedication This thesis is dedicated to my wife, Olivia Olsen Jarrett for being next to me and supporting me every step of the way and to Von and Elaine Jarrett, for guiding and encouraging me. v Acknowledgments As a masters student at Brigham Young University studying the effects of stress in humans I became familiar with Courtney DeVries research and wanted to work with animal models in her lab. Over the years Courtney has been influential in instructing and helping me to become a scientist. She was always open to new ideas and new projects and her knowledge of animal behavior was essential in helping me design and carry out successful behavioral studies. I will forever be indebted to her for helping me obtain my PhD. Kate Karelina and Katie Stuller were also influential in helping me transition from clinical research to animal studies. Kate was very patient in answering all of my questions and Katie broadened my horizon by teaching me about immunology and how to apply it to the various projects I was working on. Adam Hinzey assisted me in a number of different projects and was very helpful in designing and carrying out projects. Monica was always willing to help with every aspect of my projects and made the lab a fun environment and Zhang Ning truly is an expert surgeon, without whom I would not have been able to work on a number of projects. I owe a great deal of thanks to the Nelson lab for allowing me to use their equipment and specifically to James Walton who was always willing to show me new techniques and help me modify experimental designs to make them better. Thanks to Chen Shan for performing some of the behavior and other aspects of the experiments and Tracy, Laura, John, and Taryn for all of their insight. vi I have had a lot of help from a number of faculty members and collaborators at OSU. I want to thank Dr. Randy Nelson, Dr. Georgia Bishop, and Dr. Jonathan Godbout for serving on my candidacy and dissertation committees. Your time and input have been invaluable in my success. I want to thank Dr. Maryam Lustberg and Dr. Charles Shapiro for guidance on the drug administration and making possible this amazing project. I also want to thank Eric Wohleb, Ashley Fenn, Dr. Jon Godbout, and Dr. Kevin Foust for all of their help and insight with this chemotherapy project specifically. They have been wonderful to collaborate with. I also want to thank all of the undergraduates that spent many hours assisting with all of the tedious aspects involved in research, specifically Christine Fung, Julie Corbett, Mark Serpico, David Paternite, Allison Butler, Mandy Fritsch, and Andrew Tarr. Finally I have to thank my family for everything. My wife was willing to follow me out here, away from all of our family and friends, to be a single mom for four and a half years while I continued my education. My parents always encouraged me and believed in me and always pushed me to obtain as much education as possible. My father is my hero and was the perfect example of hard work. Many times as a young teenager I would have to work with him instead of playing with my friends. Although I hated it then, it helped me learn the importance of hard work without which, I wouldn’t be where I am today. vii Vita May 1997 ............................................... Mountain View High School 2006………………………………….B.S. Psychology, Brigham Young University 2009………………………………….M.S. Psychology, Brigham Young University 2009 to present ..................................... Graduate Student, Department of Neuroscience, The Ohio State University Publications Stuller, K.A., Jarrett, B., and DeVries, A.C. (2012). Stress and social isolation increase vulnerability to stroke. Experimental Neurology, 233(1):33-9. PMID: 21281636. Karelina K, Stuller KA, Jarrett B, Zhang N, Well J, Norman G, DeVries AC (2011). Oxytocin mediates social neuroprotection after cerebral ischemia. Stroke, 42 (12), 3606-3611. PMID: 21960564. Jarrett B, Bloch GJ, Bennett D, Bleazard B, & Hedges D (2010). The influence of body mass index, age and gender on current illness: a cross-sectional study. International Journal of Obesity, 34, 429-436. PMID: 2001903 Whitney T, Hedges D, Brown B, Jarrett B (2008). A comparison between Asperger's syndrome and autism according to clinical and demographic factors in children, adolescents, and young adults. Journal of Therapeutic Schools & Programs, 3, 1, 98-115. Field of Study viii Major Field: Neuroscience ix Table of Contents Abstract ................................................................................................................. ii Dedication .......................................................................................................... viii Acknowledgments ................................................................................................ vi Vita ................................................................................................................... viiiiii List of Tables ........................................................................................................ xi List of Figures ...................................................................................................... xii Chapter
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