Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, USA.
Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA.
Brain Behav Immun. 2023 Jan;107:296-304. doi: 10.1016/j.bbi.2022.10.018. Epub 2022 Oct 30.
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.
持续疲劳是一种使人虚弱的副作用，影响了相当一部分癌症幸存者，而目前还没有获得 FDA 批准的治疗方法。虽然疲劳的确是一个多因素的问题，但持续疲劳可能部分是由于治疗期间的关联学习所致。因此，我们试图使用癌症幸存者的临床前模型来研究关联学习在疲劳持续中的作用。为此，我们使用了一种与人乳头瘤病毒相关的头颈癌的小鼠模型，并结合顺铂为基础的放化疗进行了治愈性治疗，该模型使用了雄性 C57BL/6J 小鼠。通过使用纵向设计测量自愿轮跑的变化来评估疲劳样行为。治疗强烈地降低了自愿轮跑，并且这种效果在治疗后持续了一个多月。然而，当在治疗期间移除轮子以尽量减少与治疗相关的疲劳时，小鼠表现出更快地恢复到基线跑步水平。我们证实，在持续有轮子可使用的小鼠中观察到的延迟恢复并不是由于增加了与治疗相关的毒性，事实上，跑步减轻了顺铂引起的肾毒性。最后，我们证明了重新接触与治疗相关的嗅觉线索会急性地重新引发疲劳。这些数据首次证明了关联过程可以调节与癌症相关的疲劳样行为的持续时间。
