Yuan Linran, Wang Yunlei, Hu Xueyan, Zuo Yao, Jin Tianyu, Li Xudong, Li Xingzhu, Cheng Lingna, Zhang Haojie, Zhang Tong
Department of Neurology, Qilu Hospital of Shandong University, Jinan, China (L.Y., T.Z.).
Department of Neurorehabilitation, China Rehabilitation Research Center, Beijing Bo'ai Hospital (L.Y., Y.W., X.H., Xudong Li, Xingzhu Li, L.C., H.Z., T.Z.).
Stroke. 2025 Aug;56(8):2277-2290. doi: 10.1161/STROKEAHA.125.050084. Epub 2025 Apr 25.
Rehabilitation is an efficacious method to improve poststroke motor dysfunction. Various rehabilitative techniques have become popular in this field of research. However, it has not been reported whether better outcomes can be achieved if rehabilitation training is conducted at the optimal time of the day.
A model of photothrombotic ischemic stroke was used in C57BL/6 mice, and poststroke 24-hour activity cycles were evaluated. We found an activity peak around Zeitgeber time (ZT)13 (21:00) and a trough around ZT20 (04:00) during the dark phase. In addition, we selected ZT6 (14:00) as the daytime training group (corresponding to the ZT13 training group, ZT20 training group, and ZT6 training group, respectively). The 3 groups underwent treadmill training for 4 weeks. Functional and histological recovery levels were compared. In addition, bulk RNA sequencing analysis was used to explore the possible molecular mechanisms.
The results showed that stroke-induced mice maintained a regular nocturnal locomotor rhythm with reduced amplitude. Motor recovery was greater in the ZT13 training group than in the ZT6 group, with a trend toward better outcomes at ZT13 than ZT20. The ZT13 group also showed superior neuronal survival and neurogenesis compared with ZT6, while improvements between ZT13 and ZT20 were less pronounced. Bulk RNA sequencing suggested that synaptic plasticity, calcium signaling, cAMP signaling, and MAPK (mitogen-activated protein kinase) signaling pathways contributed to neural repair differences between ZT13 and ZT6. In addition, the results showed a similar pattern of motor recovery in female and aged mice trained at ZT13 compared with ZT6, reinforcing the benefits of time-of-day training.
In conclusion, rehabilitative training during the most active phase is beneficial for enhanced recovery outcomes. Our study suggests that rehabilitation should be conducted when the body is in an optimal physiological state-that is, a time-of-day-dependent rehabilitation strategy.
康复是改善中风后运动功能障碍的有效方法。各种康复技术在该研究领域已变得流行。然而，尚未有报道称如果在一天中的最佳时间进行康复训练是否能取得更好的效果。
在C57BL/6小鼠中建立光血栓性缺血性中风模型，并评估中风后24小时的活动周期。我们发现在黑暗阶段，大约在时间geber时间（ZT）13（21:00）出现活动高峰，在ZT20（04:00）左右出现低谷。此外，我们选择ZT6（14:00）作为白天训练组（分别对应ZT13训练组、ZT20训练组和ZT6训练组）。这3组小鼠进行了4周的跑步机训练。比较了功能和组织学恢复水平。此外，使用批量RNA测序分析来探索可能的分子机制。
结果表明，中风诱导的小鼠保持规律的夜间运动节律，但幅度减小。ZT13训练组的运动恢复比ZT6组更大，ZT13组的效果有优于ZT20组的趋势。与ZT6组相比，ZT13组还显示出更好的神经元存活和神经发生，而ZT13组和ZT20组之间的改善不太明显。批量RNA测序表明，突触可塑性、钙信号、cAMP信号和MAPK（丝裂原活化蛋白激酶）信号通路导致了ZT13组和ZT6组之间神经修复的差异。此外，结果表明，与ZT6组相比，在ZT13组训练的雌性和老年小鼠的运动恢复模式相似，这进一步证明了按时间训练的益处。
总之，在最活跃阶段进行康复训练有利于提高恢复效果。我们的研究表明，康复应在身体处于最佳生理状态时进行，即一种依赖时间的康复策略。
