Electroacupuncture reprograms microglia to drive BDNF-dependent hippocampal neurogenesis and antidepressant responses in chronic stress model

Background Aberrant microglial activation and impaired adult hippocampal neurogenesis are critically involved in depression pathogenesis. Although electroacupuncture (EA) demonstrates clinical antidepressant efficacy, its mechanisms in modulating microglia and promoting neurogenesis remain unclear. Methods Male C57BL/6J mice were subjected to chronic mild stress (CMS) for 3 weeks, then divided into groups for subsequent intervention. The groups received either EA at the Yintang (GV29) and Baihui (GV20) acupoints, imipramine (IMI) administration as a positive control, or no treatment/vehicle control for an additional 3 weeks. Anxiety- and depression-like behaviors were assessed using a battery of behavioral tests, including the sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM), and open field test (OFT). The status of microglia and neurogenesis were detected with immunofluorescence imaging. Structural changes in synapses were quantified using Golgi staining. The underlying molecular mechanisms were probed by examining brain-derived neurotrophic factor (BDNF)-related signaling pathways via Western blotting and quantitative real-time PCR. Microglia were depleted using colony-stimulating factor-1 receptor (CSF-1R) antagonist PLX5622, and BDNF-TrkB signaling was blocked by ANA-12. Results We found that EA treatment significantly alleviated CMS-induced anxiodepressive behaviors. Crucially, EA induced a shift towards a pro-neurogenic microglial phenotype in the hippocampus. Furthermore, EA enhanced adult hippocampal neurogenesis and synaptic plasticity. Mechanistically, EA augmented BDNF function through promoting BDNF maturation, repressing MeCP2-mediated transcriptional inhibition, and activating PKA expression. Critically, microglial depletion by PLX5622 or TrkB inhibition by ANA-12 abolished EA-induced neurogenesis and behavioral improvements. Conclusions Our findings demonstrate that EA alleviates depression by driving a pro-neurogenic transformation of microglia. These reprogrammed microglia, in turn, enhance BDNF function via the coordinated multiple convergent pathways, ultimately promoting hippocampal neurogenesis and restoring synaptic plasticity.