Department of Cell and Chemical Biology, Laboratory for Neurophysiology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
Department of Cell and Chemical Biology, Laboratory for Neurophysiology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands; Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
Brain Behav Immun. 2024 Jan;115:588-599. doi: 10.1016/j.bbi.2023.11.020. Epub 2023 Nov 19.
Cancer survivors can experience long lasting fatigue resulting in a lower quality of life. How chemotherapy treatment contributes to this fatigue is poorly understood. Previously we have shown in a mouse model of cancer related fatigue that doxorubicin treatment induces fatigue-like symptoms related to disturbed circadian rhythms. However, the specific components of the circadian regulatory circuitry affected by doxorubicin treatment remained unclear. Therefore we investigated the role of the central circadian clock, the suprachiasmatic nucleus (SCN), in chemotherapy-induced fatigue.
We measured circadian controlled behavior and multiunit neuronal activity in the SCN in freely moving mice exhibiting fatigue-like behavior after doxorubicin treatment under both light-dark (LD) and constant dark (DD) conditions. Additionally, we assessed the expression of inflammation related genes in spleen and kidney as potential inducers of CRF.
Doxorubicin treatment significantly reduced both the running wheel activity and time spent using the running wheel for over five weeks after treatment. In contrast to the pronounced effects on behavior and neuronal activity of doxorubicin on circadian rhythms, peripheral inflammation markers only showed minor differences, five weeks after the last treatment. Surprisingly, the circadian SCN neuronal activity under both LD and DD conditions was not affected. However, the circadian timing of neuronal activity in peri-SCN areas (the brain areas surrounding SCN) and circadian rest-activity behavior was strongly affected by doxorubicin, suggesting that the output of the SCN was altered. The reduced correlation between the SCN neuronal activity and behavioral activity after doxorubicin treatment, suggests that the information flow from the SCN to the periphery was disturbed.
Our preclinical study suggests that chemotherapy-induced fatigue disrupts the circadian rhythms in peripheral brain areas and behavior downstream from the SCN, potentially leading to fatigue like symptoms. Our data suggest that peripheral inflammation responses are less important for the maintenance of fatigue. Chronotherapy that realigns circadian rhythms could represent a non-invasive way to improve patient outcomes following chemotherapy.
癌症幸存者会经历持久的疲劳，从而导致生活质量下降。化疗治疗如何导致这种疲劳尚不清楚。我们之前在癌症相关疲劳的小鼠模型中表明，阿霉素治疗会引起与昼夜节律紊乱相关的疲劳样症状。然而，阿霉素治疗影响的昼夜节律调节回路的具体组成部分仍不清楚。因此，我们研究了中央生物钟，即视交叉上核（SCN）在化疗引起的疲劳中的作用。
我们在表现出阿霉素治疗后疲劳样行为的自由活动小鼠中测量了昼夜节律控制行为和 SCN 的多单位神经元活动，在明暗（LD）和持续黑暗（DD）条件下进行。此外，我们评估了脾脏和肾脏中炎症相关基因的表达，作为 CRF 的潜在诱导剂。
阿霉素治疗后，超过五周的时间内，跑步轮活动和使用跑步轮的时间明显减少。与阿霉素对昼夜节律的行为和神经元活动的明显影响相比，外周炎症标志物仅在最后一次治疗后五周时显示出较小的差异。令人惊讶的是，LD 和 DD 条件下的 SCN 神经元活动昼夜节律并未受到影响。然而，SCN 周围区域（SCN 周围的大脑区域）的神经元活动和昼夜节律休息-活动行为的昼夜节律定时受到阿霉素的强烈影响，表明 SCN 的输出发生了改变。阿霉素治疗后 SCN 神经元活动与行为活动之间的相关性降低，表明 SCN 向周围传递信息的过程受到干扰。
我们的临床前研究表明，化疗引起的疲劳会破坏 SCN 下游外周大脑区域和行为的昼夜节律，可能导致疲劳样症状。我们的数据表明，外周炎症反应对维持疲劳的重要性较小。调整昼夜节律的时间疗法可能是改善化疗后患者结局的非侵入性方法。
