Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (8): 3598-3608.doi: 10.4103/NRR.NRR-D-24-01189

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Intermittent theta-burst stimulation promotes neurovascular unit remodeling after ischemic stroke in a mouse model

Jingjun Zhang1, 2, #, Ming Ding1, 3, #, Lu Luo1, Dan Huang1, Siyue Li1, Shuying Chen4, Yunhui Fan1, Li Liu1, Hongyu Xie1, Gang Liu1, Kewei Yu1, Junfa Wu1, Xiao Xiao3, *, Yi Wu1, *   

  1. 1Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China; 
    2Department of Rehabilitation Medicine, The Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; 
    3Behavioral and Cognitive Neuroscience Center, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China; 
    4Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China
  • Online:2026-08-18 Published:2026-04-27
  • Contact: Yi Wu, PhD, wuyi@fudan.edu.cn; Xiao Xiao, PhD, xiaoxiao@fudan.edu.cn.
  • Supported by:
    This study was supported by the National Key R&D Program of China, Nos. 2021ZD0202805 (to XX), 2019YFA0709504 (to XX); the National Natural Science Foundation of China, Nos. 82172544 (to YW), 32471083 (to XX), 81972140 (to JW), 82272604 (to HX), 82102491 (to SC); the Brain Science and Brain- Like Research Project of Shanghai Sixth People’s Hospital, No. ynnkxyb202410 (to JZ); and Shanghai Science and Technology Committee Sailing Program, No. 23YF1403800 (to LL).

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Abstract: The neurovascular unit plays a critical role in maintaining brain structure, function, and homeostasis. Following ischemic stroke, dysfunction and dysregulation of this unit contribute to nerve–blood vessel uncoupling. Intermittent theta-burst stimulation is a repetitive transcranial magnetic stimulation that operates within the theta wave range and can either promote or inhibit cortical excitability. Previous studies have shown that intermittent theta wave stimulation has neuroprotective effects, but the underlying mechanisms remain unclear. In this study, mice subjected to middle cerebral artery occlusion/reperfusion were treated with intermittent theta-burst stimulation. The results showed that intermittent theta-burst stimulation significantly improved neurological function and motor recovery, reduced apoptosis in the peri-infarct region, and activated the PI3K/AKT/GSK3β/β-catenin signaling pathway. Additionally, intermittent theta-burst stimulation suppressed inflammation through the PI3K/AKT/GSK3β and NF-κB pathways. Notably, intermittent theta-burst stimulation strengthened A2 astrocyte–blood vessel coupling, and the effects of intermittent theta-burst stimulation were reversed by the PI3K inhibitor LY294002. These findings demonstrate that intermittent theta-burst stimulation promotes neurovascular unit remodeling and improves neurological outcomes by modulating microglia and astrocytes via the PI3K/AKT/GSK3β and NF-κB signaling pathways. 

Key words: astrocyte, blood–brain barrier, glycogen synthase kinase 3 beta, intermittent theta-burst stimulation, ischemic stroke, microglia, neural protection, neuroinflammation, neurovascular unit, vascular protection