Date of Award

Spring 5-13-2017

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

Advisor

Thane E. Fremouw

Second Committee Member

Shawn W. Ell

Third Committee Member

Marie J. Hayes

Additional Committee Members

Emily A.P. Haigh

Alan M. Rosenwasser

Abstract

Cancer patients treated with adjuvant chemotherapy often experience cognitive decline following treatment. This phenomenon, often dubbed “chemo brain” or “chemo fog” is usually temporary, but for a subset of survivors, these cognitive impairments can be long-lasting (>10 years) and negatively affect patients’ quality of life, career performance, and social fulfillment. While it is unclear what neurobiological mechanisms underlie chemotherapy related cognitive impairment, the majority of the animal literature has focused on adult neurogenesis. One process important for neurogenesis is the proliferation of new neurons within the dentate gyrus of the hippocampus. It is evident that many chemotherapy agents can negatively impact levels of neurogenesis shortly after treatment. However, only a few studies have investigated the long-term impact of chemotherapy on neurogenesis. The present studies explore the long-term impact of three commonly used chemotherapy agents on neurogenesis utilizing immunohistochemistry in a male C57BL/6J mouse model. EXP 1: The effects of cyclophosphamide or doxorubicin on neuronal proliferation were evaluated at 1 day, 56 days and 6 months post-treatment. Results indicated that neither cyclophosphamide nor doxorubicin treatment altered proliferation rates across either short-term or long-term intervals. EXP 2: The effects of 5-FU (alone or in combination with either the antioxidant melatonin or the antidepressant fluoxetine) on neuronal proliferation were evaluated at 1 day, 56 days and 6 months post-treatment. The results indicated that there was no effect of 5-FU or neuroprotectant treatment at any time point. The current studies suggest that neither cyclophosphamide, doxorubicin, nor 5-FU affect neurogenic proliferation in C57BL/6J mice directly after injection or up to 6 months post injection. As such, impaired neurogenic proliferation is an unlikely cellular mechanism for chemotherapy related cognitive impairment detected within this strain.

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