Stress-induced brain extracellular vesicles ameliorate anxiety behavior.

Extracellular vesicles (EVs), nanovesicles secreted by all types of cells, serve as a communication network, carrying information through the bloodstream to distant cells [1, 2]. Notably, brain cells secrete EVs that play a crucial role in regulating neurological functions [3-5]. Meanwhile, the brain detects acute stress and activates mechanisms to enhance stress resistance and maintain homeostasis [6, 7]. However, the specific contribution of brain-derived extracellular vesicles (BDEVs) in modulating the stress response remains elusive. Here we found that administration of the acute stress-induced BDEVs to mice reduced anxiety-related behaviors, and this reduction was also induced by the administration of only three microRNAs (miRNAs) (miR-199a-3p, miR-99b-3p and miR-140-5p) included in the acute stress-induced BDEVs. Furthermore, our findings suggest that miR-199a-3p may contribute to the observed anxiolytic effects, potentially through the suppression of Mecp2 in neurons. These results support a possible role for BDEVs in modulating mental activity under acute stress conditions and provide preliminary insight into the underlying molecular mechanisms. Our study offers a foundation for future exploration of EV- or miRNA-based therapeutic strategies for anxiety-related disorders.