Anxiolytic effects of accelerated continuous theta burst stimulation on mice exposed to chronic restraint stress and the underlying mechanism involving gut microbiota

Background: Accelerated continuous theta burst stimulation (acTBS) is a more intensive and rapid protocol than continuous theta burst stimulation (cTBS). However, it remains uncertain whether acTBS exhibits anxiolytic effects. The aim of this study was to investigate the impact of acTBS on anxiety model mice and elucidate the underlying mechanisms involved, in order to provide a more comprehensive understanding of its effects. Methods: Chronic restraint stress (CRS) model was employed to observe the anxiolytic effects of acTBS. The study focused on evaluating the impact of acTBS on behavior, neuroinflammation, gut and gut microbiota in mice with anxiety induced by CRS. Results: The application of acTBS ameliorated anxiety-like behaviors in CRS-induced mice. Notably, it effectively suppressed the activation of microglia and reduced the level pro-inflammatory cytokines in PFC, hippocampus, and amygdala of anxiety mice. Additionally, acTBS alleviated astrocyte activation specifically in hippocampus. The NF-kappa B signaling pathway involved in the anti-inflammatory effects of acTBS. Furthermore, acTBS ameliorated inflammation and histological damage in colon. 16S rRNA analysis revealed that acTBS significantly enhanced the relative abundance of Lactobacillus, while normalized the dysregulated levels of Coriobacterales, Bacteroides, and Parabacteroides caused by CRS. These changes facilitated chemoheterotrophic and fermentation functions within the microbiota. Importantly, changes in microbiota composition influenced by acTBS was found to be correlated with anxiety-like behaviors and neuroinflammation. Conclusions: acTBS exerted anxiolytic effects on mice exposed to CRS, which was associated with the modulation of gut microbiota.