The involvement of 5-HT was necessary for EA-mediated improvement of post-stroke depression.

The prevalence of depression is as high as about 30% within five years after stroke, while there is still no breakthrough in the Western medical treatments for post-stroke depression (PSD) in clinical practice. The traditional acupuncture treatment has been practiced to be effective for the therapy of PSD, but its mechanism still needs to be elucidated. With a combination of methods, including behavioral testing, immunofluorescence, in vivo electrophysiological recording, mRNA sequencing, genetic modulation, and in vivo fiber recording techniques, this study showed that electroacupuncture (EA) at Baihui (GV20) and Shenting (GV24) acupoints improved the depressive-like behaviors and neuronal electrophysiological activities in PSD model mice, which was established by bilateral injection of collagenase IV into the medial prefrontal cortex (mPFC). Moreover, it was found that the EA-mediated improvement was comparable to that of fluoxetine. The mRNA sequence analysis indicated that the 5-hydroxytryptamine (5-HT) system was involved in the pathogenesis of PSD. Meanwhile, the number of 5-HT positive neurons in the dorsal raphe nucleus (DRN) and 5-HT in the mPFC was significantly decreased, and ablation of neurons in the DRN could prevent the efficacy of EA. The neuronal activity of excitatory and inhibitory neurons in mPFC can be modulated by chemogenetic activation or inhibition of the TPH2-positive neurons in the DRN projecting to the mPFC. Together, our results have provided the insight of the biological mechanism underlying acupuncture in the treatment of PSD and revealed the scientific connotation of acupuncture in both clinical and scientific value.