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PreprintCited by 5Acupuncture Treatment Research StudiesNeurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration Mechanisms

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

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Zhang, Lijuan, Wei, Ting, Liu, Xuan, Zhang, Lifan, Wang, Dan, Luo, Yucai, He, Yanyan, He, Zhaoxuan, Zeng, Fang·2025·Chinese Medicine
DOI 10.21203/rs.3.rs-7545312/v1PMC PMC12866076

Preprint — published as 10.1186/s13020-026-01334-y · Paper page

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Abstract

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.

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Metadata

Authors
Zhang, L., Wei, T., Liu, X., Zhang, L., Wang, D., Luo, Y., He, Y., He, Z., & Zeng, F.
Affiliations
  • Chengdu University (CN)
  • Chengdu University of Traditional Chinese Medicine (CN)
Corresponding author
Zeng, Fang
ORCID
Venue
Chinese Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-09-26
Volume
21
Issue
1
Pages
62-62
ISSN
1749-8546 (ISSN-L)
DOI
10.21203/rs.3.rs-7545312/v1
PMC
PMC12866076
OpenAlex
W7127353409
Cited by
5
References
1
Citations by year
2026: 5
FWCI
52.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Chinese Medicine (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Sichuan Youth Science and Technology Foundation (23NSFSC6282)
  • National Natural Science Foundation of China (82225050)
  • China Postdoctoral Science Foundation (GZB20240088)
  • Chengdu University of Traditional Chinese Medicine
  • Chengdu University
  • Sichuan Province Science and Technology Support Program (2024YFFK0161)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Acupuncture Treatment Research Studies
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
electroacupuncture, microglial reprogramming, adult hippocampal neurogenesis, BDNF signaling, chronic unpredictable mild stress, depression, anxiety, PLX5622, ANA-12, TrkB, MeCP2, pKa, antidepressant effects, Baihui (GV20)

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