Associative learning contributes to the persistence of fatigue-like behavior in male mice in a model of cancer survivorship

• Published in: Brain, behavior, and immunity behavior, and immunity, 2023-01, Vol.107, p.296-304
• Main Authors: Vichaya, Elisabeth G., Darpolor, Josephine K., Gross, Phillip S., Molkentine, Jessica M., Vermeer, Daniel W., Vermeer, Paola D., Lee, John H., Taniguchi, Cullen M., Dantzer, Robert
• Format: Article
• Language: English
• Subjects: Animals; Associative learning; Cancer; Cancer Survivors; Chemoradiation; Conditioned responses; Fatigue; Humans; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neoplasms; Survivorship
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2022.10.018

•A mouse model of cancer survivorship showed persistent reductions in wheel running.•Removal of wheels during treatment accelerated post-treatment running recovery.•However, running appeared to attenuate cisplatin-induced kidney toxicity.•Treatment related cues were able to acutely re-instated running deficits. 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.