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Brants Dissertation 11.26.13.pdf (1.59 MB)

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Chemotherapy Induced Deficits in Cognition and Affective Behavior

Jarrett, Brant Lee
http://rave.ohiolink.edu/etdc/view?acc_num=osu1385457601

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
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 shifted to a proinflammatory state compared to the vehicle group. There was an overall increase in proinflammatory cytokine expression, specifically tumor necrosis alpha (TNF-a) 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-a, IL-1B, 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 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.
Courtney DeVries (Advisor)
Randy Nelson (Committee Member)
Georgia Bishop (Committee Member)
Jonathan Godbout (Committee Member)
181 p.
Behavioral Sciences; Neurosciences

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Citations

  • Jarrett, B. L. (2013). Chemotherapy Induced Deficits in Cognition and Affective Behavior [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385457601

    APA Style (7th edition)

  • Jarrett, Brant. Chemotherapy Induced Deficits in Cognition and Affective Behavior. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1385457601.

    MLA Style (8th edition)

  • Jarrett, Brant. "Chemotherapy Induced Deficits in Cognition and Affective Behavior." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385457601

    Chicago Manual of Style (17th edition)

osu1385457601
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This open access ETD is published by The Ohio State University and OhioLINK.