Graduation Year

2024

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Rex M. Philpot, Ph.D.

Co-Major Professor

Paula Bickford, Ph.D.

Committee Member

Mark Kindy, Ph.D.

Committee Member

Javier Cuevas, Ph.D.

Committee Member

Danielle Gulick, Ph.D.

Committee Member

Brendan Walker, Ph.D.

Keywords

Chemotherapy, Cognition, CRCI, High-Affinity Choline Uptake, Sex Differences, Spatial Memory

Abstract

Chemotherapy-Related Cognitive Impairments (CRCIs) are significant consequences of chemotherapy that affect a substantial portion of breast cancer survivors, potentially persisting long after treatment cessation. This series of studies investigated the neuroprotective roles of estradiol and choline against CRCIs induced by cyclophosphamide and doxorubicin (CYP/DOX), commonly known as Adriamycin/Cytoxan (AC) chemotherapy. Utilizing the MMTV-PyVT mouse model of breast cancer, this body of work spans several experimental studies, the first of which evaluates the impact of dietary choline supplementation on spatial memory and cholinergic function in tumor-bearing mice undergoing chemotherapy. The subsequent study tests whether impaired ovarian function and resulting reductions in circulating estradiol (E2) mediates the manifestation of CRCIs, demonstrating the contributions of estradiol depletion to CRCIs and to examine potential protective mechanisms at the molecular level. The final studies explored the effects of AC chemotherapy on cholinergic neurons and choline acetyltransferase activity and assessed whether discrimination learning, a striatal learning task, was impaired by chemotherapy.

The findings from these experiments indicate that not only are spatial memory and High-Affinity Choline Uptake (HACU) impaired by CYP+DOX injection, but that a 2% choline diet can protect against these deficits. In addition, chemotherapy-induced spatial memory deficits can be protected against via the maintenance of physiological E2 concentrations during chemotherapy, suggesting the estrogens provide a protective effect that can be undermined by chemotherapy-induced disruption of ovarian function. Finally, these studies demonstrate that discrimination learning is impaired following repeated CYP+DOX administration, and Choline Acetyltransferase (ChAT) activity is attenuated, but changes in cholinergic neuron density are absent.

These studies highlight the critical role of cholinergic pathways in maintaining cognitive integrity during and after cancer treatment, demonstrating that strategic dietary interventions may offer effective means to reduce or prevent CRCIs during times of ovarian depletion, thereby improving the quality of life for cancer survivors and contributing to the broader understanding of CRCIs, providing a comprehensive examination of the cholinergic mechanisms driving cognitive impairments in breast cancer chemotherapy and laying the groundwork for translational approaches to combat these effects in clinical settings.

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