Associative Learning Contributes to the Persistence of Fatigue-Like Behavior in Male Mice in a Model of Cancer Survivorship

Authors

Elisabeth G Vichaya
Josephine K Darpolor
Phillip S Gross
Jessica M Molkentine
Daniel W Vermeer
Paola D Vermeer
John H Lee
Cullen M Taniguchi
Robert Dantzer

Publication Date

1-1-2023

Journal

Brain, Behavior, and Immunity

Abstract

Persistent fatigue is a debilitating side effect that impacts a significant proportion of cancer survivors for which there is not yet an FDA-approved treatment. While certainly a multi-factorial problem, persistent fatigue could be due, in part, to associations learned during treatment. Therefore, we sought to investigate the role of associative learning in the persistence of fatigue using a preclinical model of cancer survivorship. For this purpose, we used a murine model of human papilloma virus-related head and neck cancer paired with a curative regimen of cisplatin-based chemoradiation in male C57BL/6J mice. Fatigue-like behavior was assessed by measuring variations in voluntary wheel running using a longitudinal design. Treatment robustly decreased voluntary wheel running, and this effect persisted for more than a month posttreatment. However, when wheels were removed during treatment, to minimize treatment-related fatigue, mice showed a more rapid return to baseline running levels. We confirmed that the delayed recovery observed in mice with continual wheel access was not due to increased treatment-related toxicity, in fact running attenuated cisplatin-induced kidney toxicity. Finally, we demonstrated that re-exposure to a treatment-related olfactory cue acutely re-instated fatigue. These data provide the first demonstration that associative processes can modulate the persistence of cancer-related fatigue-like behavior.

Keywords

Humans, Male, Mice, Animals, Mice, Inbred C57BL, Cancer Survivors, Motor Activity, Research, Neoplasms

Comments

Supplementary Materials

PMID: 36323360