Advances in the Antidepressant Effects of Electroacupuncture Through Regulation of Microglia-Mediated BDNF Signaling and Hippocampal Neurogenesis

Abstract

Objective

To summarize the regulatory network linking microglia, brain-derived neurotrophic factor (BDNF) signaling, and hippocampal neurogenesis, and to clarify the potential antidepressant mechanisms of electroacupuncture.

Methods

We systematically reviewed and integrated recent findings from preclinical and clinical studies regarding microglial activation, BDNF/tropomyosin receptor kinase B (TrkB) signaling, hippocampal neurogenesis, and electroacupuncture intervention in depressive disorders, retrieved from PubMed, Web of Science, and CNKI databases up to June 2026.

Results

Depression is closely associated with neuroinflammation, impaired neuroplasticity, and disrupted hippocampal neurogenesis. Aberrant microglial activation may inhibit hippocampal neurogenesis by releasing pro-inflammatory cytokines, excessively engulfing synapses, and disturbing the neural microenvironment. These pathological changes interact with dysregulated BDNF/TrkB signaling and jointly contribute to depressive phenotypes. Electroacupuncture may exert antidepressant effects by modulating microglial phenotypic transformation, suppressing pro-inflammatory mediator release, and upregulating BDNF/TrkB signaling and its downstream pathways.

Conclusion

Electroacupuncture may improve depression through coordinated regulation of microglia-mediated neuroinflammation and BDNF-related neuroplasticity. This mechanism provides a scientific basis for further mechanistic research and clinical application of acupuncture in depression.

Introduction

Depression is one of the most common psychiatric disorders worldwide and has long ranked among the leading contributors to disability-adjusted life years and years lived with disability. Women, adolescents, and individuals exposed to chronic stress are particularly vulnerable.^1,2 Although antidepressant medications and psychotherapy are widely used, clinical practice continues to face challenges such as delayed onset of action, marked interindividual variability in efficacy, and high recurrence rates. Therefore, safer and multi-targeted intervention strategies are urgently needed.² Recent evidence has increasingly recognized that the pathophysiology of depression involves complex interactions across neurovascular, neurochemical, genetic, and psychosocial domains. Prakash and Bhatia³ synthesized current evidence indicating that the heritability of depression is estimated at 30–50%, with genome-wide association studies identifying multiple susceptibility loci in synaptic and immune pathways, while epigenetic modifications and gut-brain axis perturbations further modulate disease vulnerability and progression. This systems-level perspective suggests that strategies targeting single neurotransmitter systems may be insufficient to address the full complexity of depression, highlighting the need for multi-target interventions.

Electroacupuncture, which combines traditional acupuncture with modern electrical stimulation, has shown substantial advantages in improving depressive symptoms and comorbid sleep disturbance; its mechanisms may involve suppression of neuroinflammation and reconstruction of neuroplasticity.⁴ In recent years, the role of immune-neural crosstalk in depression has attracted increasing attention. Studies have shown that aberrant microglial activation can drive depressive phenotypes by releasing pro-inflammatory mediators, interfering with synaptic remodeling, and inhibiting hippocampal neurogenesis.⁵ Meanwhile, the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway, a central regulator of neuronal survival and emotional regulation, is susceptible to negative modulation by the neuroinflammatory milieu.⁶ On this basis, exploring whether electroacupuncture exerts antidepressant effects by regulating microglia-mediated BDNF signaling has important theoretical significance and potential clinical value. Such research may help clarify the biological basis of electroacupuncture in depression and provide scientific support for optimizing acupuncture-based clinical interventions. Against this background, the present review aims to systematically integrate evidence regarding the regulatory network of microglia‑BDNF‑hippocampal neurogenesis. On this basis, we put forward the following working hypothesis: electroacupuncture may inhibit M1‑phenotype microglial polarization and facilitate M2‑phenotype transition, thereby alleviating the inhibitory effect of neuroinflammation on the BDNF/TrkB pathway, restoring hippocampal neurogenesis and synaptic plasticity, and ultimately producing antidepressant effects. Verification of this hypothesis will help elucidate the core mechanistic cascade underlying the antidepressant action of electroacupuncture.

Regulatory Links Among Microglia, BDNF Signaling, and Hippocampal Neurogenesis

The pathogenesis of depression is complex and involves interactions among genetic, environmental, and psychosocial factors. Recent research has moved beyond the traditional monoamine neurotransmitter imbalance hypothesis toward mechanisms involving neuroplasticity, neuroinflammation, and dysfunction of neural circuits. Among these, microglia-mediated neuroinflammation, impaired BDNF signaling, and disrupted hippocampal neurogenesis are regarded as three core pathological processes in the onset and progression of depression. These processes do not act in isolation; rather, they form a tightly interconnected and mutually reinforcing regulatory network (Figure 1).

Figure 1.

Regulatory associations among microglia, BDNF signaling pathway, and hippocampal neurogenesis in depression.

Note: Chronic stress activates the TLR4/MyD88/NF-κB pathway and the HPA axis, promoting pro-inflammatory microglial activation, suppressing BDNF/TrkB signaling, and impairing hippocampal neurogenesis and synaptic plasticity. Conversely, anti-inflammatory microglia secrete BDNF, IL-10, and TGF-β, thereby promoting an anti-inflammatory microenvironment and neural repair. M1- and M2-like microglia represent simplified functional phenotypes within a dynamic activation spectrum. Red dashed arrows indicate promotion or increase, blue arrows indicate protection or promotion, blunt-ended lines indicate inhibition or decrease, and curved arrows indicate mutual feedback loops.

Abbreviations: TLR4, Toll-like receptor 4; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; HPA, hypothalamic-pituitary-adrenal axis; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; BDNF, brain-derived neurotrophic factor; IL-10, interleukin-10; TGF-β, transforming growth factor-β; mBDNF, mature brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; PLC-γ, phospholipase C-γ; CREB, cAMP response element-binding protein; PSD95, postsynaptic density protein 95; SYP, synaptophysin.

Role of Microglia in Depression

Microglia are resident immune cells of the central nervous system and play essential roles in maintaining neural microenvironmental homeostasis, synaptic remodeling, and neurogenesis. Evidence suggests that abnormal microglial activation and the neuroinflammatory response mediated by microglia are central components of depression pathogenesis.^7–9 Under physiological conditions, microglia remain in a surveillant or resting state (M0), continuously monitoring the microenvironment and secreting small amounts of neurotrophic factors to support normal neuronal function.

Under pathological conditions, such as chronic stress, inflammatory stimulation, or tissue injury, microglia may polarize into classically activated pro-inflammatory M1 phenotypes or alternatively activated anti-inflammatory and reparative M2 phenotypes. Importantly, M1/M2 polarization is not a static, binary state but a dynamic and reversible spectrum of functional phenotypes, with temporal dynamics that depend on the duration and severity of stress exposure.¹⁰ Acute stress typically triggers transient M1 activation as part of the homeostatic response, while chronic stress drives sustained M1 polarization and impairs the transition to the reparative M2 phenotype, leading to persistent neuroinflammation.¹¹ Disruption of the dynamic balance between these phenotypes directly influences the progression of neuroinflammation and the development of depressive symptoms.^12,13

Extensive research has confirmed significant abnormal microglial activation in key emotion-regulating brain regions, including the hippocampus and prefrontal cortex, in animal models of depression.^14,15 A review by Ge et al¹⁶ systematically summarized the regulatory role of Gal‑3 in microglia‑mediated neuroinflammation in central nervous system disorders, pointing out that Gal‑3 expression is markedly up‑regulated under diverse neuropathological conditions and may participate in disease progression by amplifying inflammatory signaling and promoting cell proliferation. Wu et al¹⁴ used a chronic unpredictable mild stress (CUMS) rat model and found that ionized calcium-binding adaptor molecule 1 (Iba-1)-positive microglia were markedly increased in the hippocampus. Microglial morphology shifted from a ramified resting state to an amoeboid activated state. In parallel, the M1 markers CD16 and inducible nitric oxide synthase (iNOS) were upregulated, whereas the M2 markers Arg1 and CD206 were downregulated, indicating a shift toward a pro-inflammatory phenotype. Zheng et al¹⁷ observed similar findings in rats with knee osteoarthritis-related chronic pain accompanied by pain-related affective disturbance: Iba-1 expression in the anterior cingulate cortex was significantly increased, CD68/Iba-1 co-expression was enhanced, and CD206/Iba-1 co-expression was reduced, suggesting not only microglial activation but also predominant M1 polarization. In an acute inflammation-induced depression model established with lipopolysaccharide (LPS), Zhao et al¹⁸ found a marked increase in hippocampal Iba-1-positive cells and enhanced co-localization with the M1 marker CD16/32, accompanied by clear depression-like behaviors. He et al¹⁹ further demonstrated, in a maternal separation-induced adolescent depression model, that early-life stress leads to persistent pro-inflammatory activation of microglia in the hippocampus and cortex. This was characterized by shortened cellular processes, enlarged soma area, increased hippocampal mRNA expression of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6, and reduced expression of anti-inflammatory factors such as Arg1 and transforming growth factor-β (TGF-β), as well as the microglial homeostatic markers P2RY12 and TMEM119. These findings suggest impaired microglial homeostatic regulation. M1 microglia mainly drive neuroinflammatory responses by releasing pro-inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), thereby damaging hippocampal neurogenesis and synaptic plasticity. Lu et al²⁰ demonstrated that minocycline promotes the M2 phenotype polarization of microglia and inhibit M1 polarization via modulating microglial polarization through the signal transducer and activator of transcription 1/signal transducer and activator of transcription 6 (STAT1/STAT6) pathways. Liu et al²¹ reported that hippocampal TNF-α and IL-6 levels were significantly increased, whereas IL-10 was decreased, in CUMS rats. These pro-inflammatory cytokine levels were positively correlated with the number of Iba-1-positive cells. Esketamine treatment inhibited microglial activation by suppressing the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappaB (TLR4/MyD88/NF-κB) pathway, reduced pro-inflammatory cytokine levels, and improved depression-like behaviors. These cytokines can inhibit the proliferation and differentiation of hippocampal neural progenitor cells, reduce the number of doublecortin-positive immature neurons, downregulate synapse-related proteins such as postsynaptic density protein 95 (PSD95) and synaptophysin (SYN), and impair dendritic spine structure and synaptic transmission.^22–24 Li et al²² systematically discussed the central role of hippocampal neuroinflammation in pain-related affective disturbance, noting that abnormal activation of microglia and astrocytes can affect synaptic plasticity and neurogenesis and amplify negative emotional responses such as depression and anxiety. In addition, microglia may mediate synaptic engulfment through complement pathways, further aggravating synaptic loss. Sun et al²⁵ found that hippocampal complement C1q expression was significantly increased and co-localized with microglia in a mouse model of postpartum depression. C1q-neutralizing antibodies improved depression-like behaviors by modulating the C1q/C3 pathway, suggesting that complement-mediated synaptic elimination may participate in depression pathology. Zhu et al²⁶ revealed that, in mice with high-fat diet-induced depression-like behaviors, dentate gyrus microglia underwent a dynamic process of initial activation followed by reduction; microglial loss and atrophy directly mediated depressive behaviors.

By contrast, M2 microglia exert neuroprotective effects by secreting IL-10, TGF-β, and BDNF, thereby promoting reconstruction of an anti-inflammatory microenvironment and tissue repair.^12–14 Fang et al¹² systematically reviewed the application of traditional Chinese medicine in modulating microglial metabolic reprogramming in depression and emphasized that restoring the M1/M2 polarization balance is an important strategy for antidepressant therapy. Ren et al²⁷ confirmed that Chaihu Shugan San exerts antidepressant effects by inhibiting the IL-1β/c-Jun N-terminal kinase (JNK) pathway and driving microglial polarization toward the M2 phenotype. Therefore, promoting the transition of microglia from the M1 to the M2 phenotype and restoring microglial homeostatic function have become important directions in depression intervention research.

Role of the BDNF Signaling Pathway in Depression

BDNF is the most abundant neurotrophic factor in the central nervous system. Importantly, BDNF is initially synthesized as a precursor protein (proBDNF), which is proteolytically cleaved to form mature BDNF (mBDNF).²⁸ While mBDNF binds with high affinity to TrkB to mediate neuronal survival, synaptic plasticity, and antidepressant effects, proBDNF preferentially signals through the p75 neurotrophin receptor (p75NTR) to promote apoptosis, synaptic depression, and negative behavioral outcomes.²⁹ The balance between proBDNF and mBDNF is tightly regulated under physiological conditions, and its disruption is increasingly recognized as a key pathological feature of depression.

BDNF-mediated signaling plays a crucial role in neuronal survival, differentiation, synaptic plasticity, and hippocampal neurogenesis. BDNF mainly binds to its high-affinity receptor TrkB and activates downstream signaling cascades, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and phospholipase C-gamma (PLC-γ). These pathways ultimately induce phosphorylation of cAMP response element-binding protein (CREB), promote target gene transcription, and mediate neuroprotective effects.^7,18,30 In addition to these canonical downstream cascades, BDNF-CREB signaling is also modulated by upstream regulators including mitogen and stress-activated kinase 1 (MSK1), a nuclear kinase activated downstream of ERK and p38 MAPK pathways. Hippocampal MSK1 has been shown to act as a defensive feedback regulator in chronic stress models, protecting against stress-induced BDNF-CREB dysfunction and impaired neurogenesis.³¹ Moreover, Gong et al³² established a “two-hit” depression model by combining maternal separation with restraint stress and observed significantly reduced hippocampal BDNF mRNA expression, which was closely associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and reduced monoamine neurotransmitter levels.

A large body of clinical and experimental evidence consistently shows that BDNF expression is significantly reduced in emotion-related brain regions in animal models and patients of depression, and that this reduction is negatively correlated with symptom severity.^32–35 Wang et al³⁴ found that the hippocampal BDNF/TrkB pathway was significantly inhibited in an LPS-induced mouse model of depression, accompanied by increased levels of IL-1β, IL-6, and TNF-α. Low-intensity pulsed ultrasound exerted antidepressant effects by inhibiting microglial P2X4 receptor (P2X4R) expression and activating the BDNF/TrkB pathway. A meta-analysis by de Albuquerque et al³⁵ showed that electroconvulsive therapy significantly increases peripheral blood BDNF levels in patients with depression and that these increases are positively associated with clinical efficacy, further supporting the central role of BDNF in antidepressant treatment. Wang et al³⁶ reported that duloxetine combined with olanzapine activated BDNF/TrkB signaling, increased hippocampal monoamine neurotransmitters such as 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE), inhibited neuroinflammation and apoptosis, and produced superior effects compared with monotherapy in chronic stress-induced depressive rats.

In chronic stress models, inhibition of BDNF signaling is one of the core pathological mechanisms. Wang et al³⁷ showed that corticosterone-induced depression-like mice exhibited decreased hippocampal BDNF expression and reduced dendritic spine density, whereas formononetin exerted neuroprotective effects by activating the estrogen receptor α (ERα)/ERK-CREB-BDNF pathway. Zan et al³⁸ found that hippocampal BDNF and vascular endothelial growth factor A (VEGFA) protein levels, as well as synapse-related proteins PSD95 and SYN, were significantly reduced in a rat model of post-stroke depression (PSD); Jiawei Chaihu Jia Longgu Muli Decoction effectively reversed these changes and improved synaptic plasticity. Wang et al³⁰ confirmed that the glucagon-like peptide-1/glucagon-like peptide-1 receptor (GLP-1/GLP-1R) and protein kinase A (PKA)/CREB/BDNF pathways in the hippocampal CA1 region were significantly suppressed in rats exposed to chronic restraint stress, with downregulated PSD95 and SYP mRNA expression. Xiaoyao San activated these pathways and improved anxiety- and depression-like behaviors. Zhao et al¹⁸ ssimilarly found, in an LPS-induced inflammatory depression model, that hippocampal BDNF levels decreased together with increased IL-1β and TNF-α, and that inhibition of BDNF/TrkB signaling was closely associated with depression-like behaviors. Cang-Ai volatile oil exerted antidepressant effects by regulating microglial BDNF/CREB signaling. Li et al²⁴ also confirmed, in a post-cerebral ischemia depression model, that hippocampal BDNF and TrkB protein levels and synapse-related proteins were reduced, whereas Baihe Zhimu Decoction improved depressive behaviors and inhibited neuroinflammation by activating the triggering receptor expressed on myeloid cells 2 (TREM2)/BDNF/TrkB pathway.

BDNF expression and activity are regulated by multiple factors, among which neuroinflammation and epigenetic modification are particularly important. Pro-inflammatory cytokines released by M1 microglia can directly inhibit BDNF gene transcription. IL-1β and TNF-α activate the NF-κB pathway and recruit inhibitory complexes to the BDNF promoter region, thereby reducing transcriptional activity.²¹ Liu et al²¹ recorded that esketamine indirectly restores BDNF expression by inhibiting the TLR4/MyD88/NF-κB pathway and reducing pro-inflammatory cytokine levels. Meanwhile, inflammation-induced activation of indoleamine 2.3-dioxygenase (IDO) can divert tryptophan metabolism toward the kynurenine pathway, reduce 5-HT synthesis, and indirectly affect BDNF expression.³⁹ Meng et al³⁹ found that Zhizichi Decoction upregulates tryptophan hydroxylase 2 (TPH2), downregulates IDO and kynurenine monooxygenase (KMO), inhibits the NF-κB/NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammatory pathway, activates TrkB/phosphorylated CREB signaling, and thereby increases BDNF expression by regulating tryptophan metabolism.

With regard to epigenetic regulation, histone deacetylation and DNA methylation in the BDNF promoter region are significantly enhanced in depression models.^32,40 Li and Hu⁴⁰ noted that BDNF DNA methylation plays a key role in epigenetic regulation in depression and is closely related to psychosocial factors, disease subtype characteristics, and treatment response. Feng et al³³ found that the miR-182 rs76481776 polymorphism is closely associated with antidepressant treatment response in patients with depression. miR-182 negatively regulates BDNF expression by binding to the 3’ untranslated region of BDNF mRNA. More recently, hippocampal miR-206-3p has been shown to be robustly upregulated in chronic social defeat stress models, where it suppresses BDNF biosynthesis, impairs hippocampal neurogenesis, and promotes depressive-like behaviors. Inhibition of miR-206-3p produces significant antidepressant-like effects in a BDNF-TrkB-dependent manner,⁴¹ further highlighting the critical role of BDNF regulation in depression pathogenesis. Therefore, relieving the inhibitory effects of inflammation and epigenetic modification on BDNF and restoring BDNF signaling activity have become key targets in antidepressant therapy.

Coordinated Regulation Between Microglia and BDNF Signaling

Microglia and the BDNF signaling pathway exhibit close bidirectional and coordinated regulatory interactions. They influence each other and jointly maintain homeostasis of the central nervous microenvironment; disruption of this regulation is an important mechanism in the onset and progression of depression. Functionally, hippocampal neurogenesis—long recognized as a core pathological hallmark of depression—represents a key downstream functional outcome of this microglia-BDNF regulatory network. M2-polarized microglia secrete BDNF and other trophic factors to support neural stem cell proliferation and differentiation, while excessive M1 activation and pro-inflammatory cytokine release suppress neurogenesis and impair neuronal maturation.^7,14 Kong et al⁷ systematically reviewed the biological functions and homeostatic disruption of microglia in depression and noted that microglia participate in depression pathology by regulating neuronal survival, apoptosis, and synaptic plasticity, with microglial dysfunction closely associated with abnormal BDNF signaling.

On one hand, the phenotypic state of microglia directly regulates BDNF synthesis and secretion. M2 microglia are an important source of BDNF and, after polarization, can supplement brain neurotrophic factor levels by secreting BDNF and activating neuronal TrkB receptors and downstream pathways.^12–14,18 Wu et al¹⁴ confirmed that electroacupuncture promotes hippocampal microglial transition from the M1 to the M2 phenotype in CUMS rats, and this change is accompanied by upregulated BDNF expression and improvement of depression-like behaviors. Zhao et al¹⁸ similarly found that Cang-Ai volatile oil reduced the number of M1 microglia co-localized with Iba1 and CD16/32, increased BDNF, IL-4, and IL-10 levels, and activated BDNF/CREB signaling in an LPS-induced depression model. Luo et al¹³ reported that Xiaoyao San inhibited M1 microglial polarization in the prefrontal cortex of depressive mice, as indicated by reduced iNOS and CD86 expression, while promoting M2 polarization, as indicated by increased Arg-1 and CD206 expression, and upregulating BDNF and its downstream signaling molecules. Conversely, pro-inflammatory cytokines released by M1 microglia not only inhibit neuronal BDNF synthesis but may also induce downregulation of BDNF expression in microglia themselves by activating NF-κB signaling, thereby forming a vicious cycle.^21,42

On the other hand, BDNF signaling can reciprocally regulate microglial phenotype and function. After BDNF binds to TrkB receptors on neurons and microglia, it activates PI3K/Akt and MAPK/ERK signaling, inhibits M1 polarization, and promotes transition toward the M2 phenotype.^18,34,43 Wang et al³⁴ found that low-intensity pulsed ultrasound inhibited microglial P2X4R expression and activated BDNF/TrkB signaling, thereby reducing Iba-1-positive cell numbers and pro-inflammatory cytokine release while promoting a protective microglial phenotype. These results suggest a negative feedback regulatory effect of BDNF signaling on microglial activation. In vitro experiments using LPS-stimulated BV2 microglia showed that exogenous BDNF pretreatment significantly reduced iNOS and IL-1β expression, increased Arg-1 and IL-10 expression, and inhibited NF-κB activation, directly demonstrating the regulatory effect of BDNF on microglial phenotype.¹⁸ In vivo studies have also confirmed that activation of BDNF/TrkB signaling attenuates microglia-mediated neuroinflammation and promotes hippocampal neurogenesis.^24,30,36 Wang et al³⁰ showed that Xiaoyao San improves hippocampal neuronal injury while activating GLP-1/PKA/CREB/BDNF signaling, and that this neuroprotective effect is partly attributable to indirect regulation of microglial function by BDNF. Thus, BDNF functions not only as a neuronal protective factor but also as an immunomodulator of microglial phenotype.

Loss-of-function studies further support the central mediating role of microglia in the regulation of BDNF signaling. Sun et al⁴⁴ found that lipocalin-2 (Lcn2) expression was upregulated in hippocampal microglia of chronic stress-induced depressive mice, whereas ginsenoside Rd inhibited microglial activation and neuroinflammation and reduced neuronal apoptosis by downregulating Lcn2 expression. Yu et al⁴⁵ recorded that downregulating Lcn2 alleviates depression-like behaviors in mice by modulating microglial activation, further suggesting that targeting microglia can regulate downstream neurotrophic signaling. Critically, microglial depletion studies provide direct evidence for the necessity of microglia in BDNF upregulation and antidepressant effects. Critically, microglial depletion studies provide direct evidence for the necessity of microglia in BDNF upregulation and antidepressant effects. In models of microglial depletion using the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622, multiple antidepressant interventions could no longer increase hippocampal BDNF expression or dendritic spine density in CUMS mice, strongly indicating that microglia are required for activation of BDNF signaling.¹⁴ Similarly, pharmacological blockade of TrkB receptors abolishes the promoting effect of electroacupuncture on M2 polarization, indicating that feedback regulation of microglial phenotype by BDNF signaling depends on intact TrkB receptor function.^18,34 Li et al²⁴ showed that Baihe Zhimu Decoction promotes M2 microglial polarization and improves myelin repair by activating the TREM2/BDNF/TrkB pathway, thereby providing pharmacological evidence for bidirectional coordinated regulation between microglia and BDNF signaling. Together, these findings suggest a causal model in which microglial phenotypic shift is upstream of BDNF signaling activation, which in turn provides feedback to stabilize the M2 phenotype and drive downstream neuroplasticity and neurogenesis.

Collectively, these findings indicate that microglia and BDNF constitute a bidirectional positive-feedback regulatory loop. M2 microglia secrete BDNF to activate neuronal protective signaling, while BDNF signaling helps maintain the M2 phenotype of microglia; together, they preserve neuroplasticity and anti-inflammatory microenvironmental homeostasis. Fang et al⁹ pointed out that M1/M2 phenotypic polarization is closely related to remodeling of metabolic pathways and that traditional Chinese medicine may restore the balance of the “metabolism-immunity-neural” axis by multi-target regulation of microglial metabolic homeostasis. Under depressive pathological conditions, this regulatory loop is disrupted by inflammatory stress, resulting in a vicious cycle of M1 polarization, reduced BDNF, and aggravated neuroinflammation. Restoring the dynamic balance of this loop has therefore become an important strategy for antidepressant therapy.

However, it must be noted that current evidence linking microglia, BDNF signaling, and hippocampal neurogenesis is primarily based on correlative observations—that is, M2 markers and BDNF levels covary with neurogenesis indices. Rigorous causal inference still requires validation through loss-of-function experiments. Especially, one could examine whether electroacupuncture still upregulates BDNF and promotes neurogenesis after selective depletion of microglia using the CSF1R inhibitor PLX5622, or test whether BDNF signaling is required for microglial phenotypic transition using TrkB receptor blockers. From the perspective of regulatory hierarchy, hippocampal neurogenesis may be regarded as a downstream effect of repair of the microglia-BDNF axis. M2-phenotype microglia secrete BDNF to activate TrkB and its downstream PI3K/Akt and CREB pathways, ultimately promoting the proliferation and differentiation of neural stem cells in the hippocampal dentate gyrus.

Research Progress on Acupuncture Regulation of Microglia-Mediated BDNF Signaling in Depression

In recent years, increasing attention has been paid to the mechanisms by which acupuncture treats depression, and related studies have expanded across multiple levels. Current evidence indicates that acupuncture not only has therapeutic potential but also participates in the coordinated regulation of neuroimmunity and neuroplasticity by modulating microglia-mediated neuroinflammation and BDNF signaling, thereby exerting antidepressant effects at several key pathological nodes (Figure 2). Electroacupuncture, as an important form of acupuncture stimulation, has been more widely used in mechanistic studies and experimental models. Unless otherwise specified, this review discusses acupuncture and electroacupuncture as broad acupuncture-based interventions.

Figure 2.

Neuroimmune–neuroplasticity mechanisms underlying the antidepressant effects of acupuncture/electroacupuncture.

Note: This schematic illustrates the pathological changes associated with chronic stress and the neuroimmune–neuroplasticity mechanisms underlying the antidepressant effects of acupuncture/electroacupuncture. Chronic stress induces microglial overactivation, neuroinflammation, oxidative stress, suppression of BDNF/TrkB/CREB signaling, and impairment of synaptic plasticity and hippocampal neurogenesis. Conversely, acupuncture/electroacupuncture inhibits microglial overactivation and pro-inflammatory signaling, reduces NLRP3 inflammasome activation and oxidative stress, upregulates BDNF/TrkB/CREB signaling, and promotes synaptic remodeling, hippocampal neurogenesis, and neural circuit recovery, thereby improving depressive-like behaviors. These effects reflect coordinated regulation of neuroimmune and neuroplasticity processes. Directional connecting arrows indicate the sequence or direction of the depicted processes. Upward arrows (↑) indicate increases or upregulation, whereas downward arrows (↓) indicate decreases or downregulation.

Abbreviations: Iba1, ionized calcium-binding adapter molecule 1; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; TLR4, Toll-like receptor 4; p38, p38 mitogen-activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-like receptor familypyrin domain-containing 3; 4-HNE, 4-hydroxynonenal; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; CREB, cAMP response element-binding protein; miRNA, microRNA; proBDNF, precursor brain-derived neurotrophic factor; SYN, synapsin; PSD-95, postsynaptic density protein 95.

In terms of safety, existing clinical trials generally suggest that acupuncture for depression has a favorable safety profile, with serious adverse events being rare. The most common adverse reactions include mild pain, bleeding, and bruising at needle sites, which are usually transient and self-limiting.^46,47 When combined with antidepressant medications, acupuncture may help reduce certain drug-related adverse effects, such as gastrointestinal reactions and somnolence.⁴⁸

Clinical Studies of Acupuncture for Depression

Clinical research on acupuncture for depression has been widely conducted, and electroacupuncture, as a mainstream intervention, has shown therapeutic potential across major depressive disorder (MDD), PSD, and depression-related insomnia. However, the strength of the clinical evidence should be interpreted cautiously rather than as definitive proof of efficacy, because existing reviews differ in inclusion criteria, comparators, intervention dose, blinding feasibility, follow-up duration, and certainty ratings.

Regarding overall efficacy, a Cochrane review reported low-quality evidence that acupuncture, including manual acupuncture and electroacupuncture, reduced depression severity vs no treatment, wait-list, or treatment-as-usual controls by the end of treatment, and very-low-quality evidence supported several comparisons with medication or sham controls.⁴⁹ More recent systematic reviews and meta-analyses suggest that electroacupuncture may reduce Hamilton Depression Rating Scale (HAMD) scores and that electroacupuncture combined with antidepressants can outperform antidepressants alone in short-term depressive-symptom outcomes.^50–53 Specifically, Zhou et al included 16 RCTs and found that electroacupuncture significantly reduces HAMD scores (I² = 0.0%, SMD = −2.28, 95% CI −3.16 to −1.39, moderate-quality evidence), and that electroacupuncture plus antidepressants was superior to Western medicine alone (I² = 26.2%, SMD = −1.18, 95% CI −1.42 to −0.94, moderate-quality evidence).⁵⁰ Zhang et al included 34 trials and found low- to moderate-quality evidence that electroacupuncture or electroacupuncture plus selective serotonin reuptake inhibitors (SSRIs) produced comparable or earlier antidepressant effects and better safety than SSRIs, but the authors also rated the overall risk of bias as medium and noted that sensitivity analysis was mostly not feasible.⁵¹ Xu et al included 43 RCTs and found high-quality evidence that acupuncture or acupuncture combined with antidepressants was associated with greater reductions in HAMD and Self-Rating Depression Scale (SDS) scores, as well as fewer adverse effects than antidepressants; however, because this review included acupuncture broadly rather than electroacupuncture alone, it should be used as supporting rather than direct evidence for electroacupuncture, and the authors also stressed that more rigorous trials are still needed to determine the optimal acupuncture frequency for MDD.⁵² Chen et al included 22 RCTs in a network meta-analysis and ranked electroacupuncture plus antidepressant as the most favorable intervention for improving depressive symptoms, but the review also emphasized that clinical trial evidence remains controversial and influenced by heterogeneous study designs.⁵³

For PSD, Wang et al reported that electroacupuncture was not inferior to antidepressant medication in improving depressive symptoms and was associated with a significantly lower incidence of adverse events.⁵⁴ But this conclusion should be interpreted cautiously because the methodological quality of the included trials was suboptimal. A 2026 PSD meta-analysis including 22 studies and 1640 patients in China reported improvement in HAMD scores and adverse-event outcomes, but HAMD heterogeneity was high (I² = 89%), SDS improvement was not statistically significant, and GRADE certainty for HAMD was very low, indicating that clinical efficacy of electroacupuncture remain provisional.⁵⁵ In a 2024 non-inferiority RCT of mild-to-moderate PSD, EA showed no significant between-group difference from escitalopram in HAMD-17 or SDS scores at week 6, while HAMD-17 and SDS scores were lower in the electroacupuncture group at week 10.⁵⁶ Therefore, the current evidence for electroacupuncture as an alternative to antidepressants should be interpreted as condition-specific evidence for PSD, particularly mild-to-moderate PSD over short-term follow-up, rather than as evidence that electroacupuncture can replace antidepressant treatment across depressive disorders.

For depression-related insomnia, electroacupuncture has comparatively stronger support from sham-controlled RCTs than many other depression subtypes, but this evidence applies to a comorbid sleep phenotype and should not be generalized to all patients with depression.^4,57,58 In a multicenter patient- and assessor-blinded RCT involving 270 patients, eight weeks of electroacupuncture plus standard care improved sleep quality compared with sham acupuncture plus standard care and standard care alone, and improvements persisted during a 24-week follow-up period.⁴ A separate sham-controlled RCT of 90 patients found that electroacupuncture three times per week for eight weeks improved Pittsburgh Sleep Quality Index (PSQI) score, sleep efficiency, total sleep time, and depression/anxiety scores more than both shallow needling and non-insertion sham acupuncture.⁵⁷ A 2025 meta-analysis focused on depression-related insomnia further supported electroacupuncture for sleep and depressive symptoms, but its conclusions should still be interpreted in light of clinical heterogeneity, risk-of-bias variation, and the small number of high-quality trials testing identical parameter regimens.⁵⁸

Methodologically, positive findings should be balanced against several recurrent limitations. Across reviews, key concerns include small samples or limited power in some comparisons, heterogeneous comparator designs including sham/control acupuncture, wait-list or usual care, antidepressant medication, and add-on therapy, difficulty achieving complete participant and practitioner blinding, and incomplete or uneven reporting of adverse events and follow-up.^{49–51,55,59} Comparator choice is clinically important because these designs answer different questions: no-treatment, wait-list, or usual-care comparisons mainly estimate overall pragmatic benefit; sham or control-acupuncture comparisons assess acupuncture-specific effects beyond nonspecific treatment effects; medication comparisons examine comparative efficacy; and add-on designs estimate incremental benefit over antidepressants rather than equivalence to antidepressant monotherapy.^49–53 Therefore, current evidence most directly supports EA as an adjunct to antidepressant therapy in the populations studied,^50,51,53,60 as a protocol-defined intervention for selected PSD populations,^55,56 and as a potential treatment for depression-related insomnia,^4,57,58 whereas evidence remains insufficient to present electroacupuncture as a broadly established replacement for antidepressant therapy across all depressive disorders.^49,51,55

The clinical and mechanistic interpretation of electroacupuncture for depression is further complicated by substantial heterogeneity in stimulation parameters. Recent mechanistic reviews indicate that electroacupuncture protocols differ markedly across depression models, and that available preclinical evidence suggests model-dependent frequency effects: 2 Hz EA may be more effective for acute stress-induced depressive-like behavior, whereas 100 Hz EA may be more advantageous in pain-depression comorbidity; however, frequency effects in other depression models remain insufficiently verified.⁶¹ This model-specific pattern is consistent with earlier evidence showing that low- and high-frequency electroacupuncture activate different brain substrates and opioid-peptide gene-expression profiles, suggesting that electroacupuncture frequency should be treated as a biologically meaningful variable rather than a minor technical detail.⁶² Clinical evidence also points to a potential dose-response issue: one meta-regression suggested a relationship between acupuncture session number and HAMD improvement,⁶³ whereas a later exploratory network meta-analysis favored approximately 30 sessions, treatment courses longer than 6 weeks, three sessions per week, and 20–30 min needle retention.⁶⁴ For acupoint selection, GV20 (Baihui) and GV29/EX-HN3 (Yintang) are repeatedly used in EA depression studies, and combinations with LR3 (Taichong) and LI4 (Hegu) have been used in both clinical PSD protocols and preclinical depression models.^56,61 For intensity, many protocols titrate current to patient tolerance or local sensation, but inconsistent reporting prevents firm dose-response conclusions about amplitude, pulse width, or sensation threshold.^50,51,63,64 Accordingly, future clinical and translational studies should prespecify and fully report frequency, intensity, waveform, pulse width, session duration, treatment frequency, total number of sessions, acupoint combinations, co-interventions, and control procedures in accordance with STRICTA recommendations, so that efficacy estimates can be interpreted, replicated, and mechanistically compared across studies.^55,61,64,65

Regulation of Microglia by Acupuncture

Microglia are innate immune cells of the central nervous system. Their abnormal activation and the resulting neuroinflammatory cascade are considered important pathological substrates in the development of depression and key cellular targets for the antidepressant effects of acupuncture.⁶⁶ In recent years, studies on acupuncture regulation of microglia in depression models have gradually established a research framework encompassing different brain regions, signaling pathways, and functional levels, providing relatively solid experimental evidence for understanding the neuroimmune mechanisms of acupuncture in depression.

At the hippocampal level, current studies show that acupuncture significantly inhibits excessive microglial activation in the hippocampus of CUMS depression models, reduces Iba-1 expression, and decreases pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, suggesting effective attenuation of local hippocampal neuroinflammation.⁶⁷ Building on this, further studies have found that electroacupuncture induces microglial remodeling toward a pro-neurogenic phenotype and enhances physical interactions between microglia and immature neurons; this process is closely associated with enhanced hippocampal neurogenesis. Meanwhile, as an important regulatory node of neurogenesis, this microglia-mediated transition may also participate in electroacupuncture-induced regulation of BDNF signaling and repair of neuroplasticity.⁶⁸ Additionally, under chronic stress conditions, electroacupuncture can reverse hippocampal neuroinflammation, inhibit excessive microglial activation, and reduce pro-inflammatory cytokine levels, thereby improving the local inflammatory microenvironment.⁶⁹ Notably, the durability of these effects after treatment cessation remains understudied, with limited data on whether microglial homeostasis is maintained or whether inflammatory reactivation occurs following stress re-exposure.

Beyond the hippocampus, electroacupuncture regulates microglia in key emotion-processing circuits in a region-specific manner, thereby exerting distinct functional effects. Electroacupuncture suppresses excessive microglial activation in medial prefrontal cortex (mPFC), restores the ramified resting morphology of microglia, and reduces abnormal engulfment of synaptic structures by downregulating MERTK expression. These effects protect synaptic integrity and function, which likely contributes to improvements in cognitive control and emotion regulation.^70,71 In the lateral habenula, its effects may involve modulation of neuronal activity rather than direct microglial inhibition.⁷² However, direct parallel comparisons of electroacupuncture effects on microglia across different brain regions are lacking, and it remains unclear whether regional differences in microglial responses contribute to the improvement of specific depressive symptoms. Future studies employing systematic brain-region profiling are needed to address this gap.

At the molecular level, regulation of microglia by electroacupuncture is not limited to a single inflammatory factor but involves multi-level interactions between oxidative stress and inflammatory signaling. Existing studies show that electroacupuncture inhibits oxidative stress, increases antioxidant enzyme activity, and reduces levels of oxidative damage products such as 4-hydroxynonenal (4-HNE). These changes reduce oxidative stress-mediated activation of the NLRP3 inflammasome and thereby suppress excessive microglial activation and neuroinflammatory responses.⁷³ At the same time, electroacupuncture markedly inhibits activation of the hippocampal TLR4/p38/NF-kappaB/NLRP3 inflammatory signaling pathway and decreases levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, thereby reducing microglia-mediated neuroinflammation and improving depression-like behaviors.⁷⁴ These results suggest that electroacupuncture does not act on isolated inflammatory nodes but more likely exerts integrated antidepressant effects through a continuous regulatory chain involving oxidative stress, inflammasome activation, and pro-inflammatory signaling pathways.

Overall, systematic reviews further support the view that electroacupuncture improves central neuroinflammation at multiple pathway and target levels by inhibiting excessive microglial activation and regulating inflammation-related signaling pathways. Its effects involve several key regulatory layers, including cell membrane receptors, intracellular signal transduction, and gene expression.⁷⁵ These findings indicate that microglia are not only important targets of the antidepressant effects of electroacupuncture but also key hubs linking neuroinflammation, neurogenesis, synaptic plasticity, and functional remodeling of brain regions.

Regulation of the BDNF Signaling Pathway by Acupuncture

The BDNF signaling pathway is a core molecular basis for maintaining neuroplasticity, hippocampal neurogenesis, synaptic repair, and emotional homeostasis, and is also an important target through which acupuncture exerts antidepressant effects In recent years, abundant basic and clinical evidence has shown that acupuncture can build a multi-link and multi-target regulatory network across transcriptional regulation, protein maturation, receptor activation, epigenetic modification, and miRNA regulation. Through these mechanisms, acupuncture may systematically repair impaired BDNF signaling under depressive conditions, reverse abnormalities in neuroplasticity, and provide a stable molecular biological basis for its antidepressant effects.

Crucially, electroacupuncture regulates not only total BDNF levels but also the balance between proBDNF and mBDNF, a key determinant of the functional direction of BDNF signaling. At the molecular regulatory level, electroacupuncture can modulate the expression of miRNAs such as miR-16 and miR-124, thereby relieving their inhibitory effects on BDNF, increasing hippocampal BDNF levels in depression models, and improving neuroplasticity impairment.⁷⁶ In terms of protein maturation, acupuncture can activate the tissue plasminogen activator (tPA)/BDNF/TrkB pathway, promote proteolytic conversion of proBDNF to mBDNF, and restore the dynamic balance of proBDNF/mBDNF in the prefrontal cortex of rats with post-stroke depression.⁷⁷ Moreover, electroacupuncture reverses abnormal expression of BDNF and its receptor TrkB in the ventral midbrain and hippocampus of rats with 6-hydroxydopamine-induced Parkinson’s disease accompanied by depression, and improves anhedonia and behavioral despair.⁷⁸ Beyond the regulation of miRNAs and protein maturation, emerging evidence indicates that electroacupuncture also modulates BDNF expression at the epigenetic level. In a study investigating the effects of electroacupuncture at Baihui (GV20) and Taichong (LR3) on the epigenetic regulation of BDNF in a rat model of depression induced by social isolation combined with chronic unpredictable mild stress (CUMS), electroacupuncture treatment for 28 days significantly improved depressive-like behaviors, as evidenced by increased vertical and horizontal locomotor activities.⁷⁹ Mechanistically, electroacupuncture upregulated serum BDNF protein levels, enhanced hippocampal BDNF mRNA expression, and increased the protein expression of BDNF, acetylated histone H3 lysine 9 (Ach3K9),⁸⁰ and histone deacetylase 2 (HDAC2) in the hippocampus.⁷⁹ Furthermore, electroacupuncture increased DNA methylation at the BDNF promoter I region, suggesting that its antidepressant effects may involve the regulation of BDNF promoter I methylation and histone acetylation modifications.^79–81 Furthermore, acupuncture regulation of BDNF signaling shows clear brain region targeting and pathway specificity, with consistent regulatory trends across multiple models of depression comorbidity. At the transcriptional level, electroacupuncture activates the CREB/BDNF pathway and increases hippocampal CREB phosphorylation, thereby promoting BDNF transcription and expression, improving hippocampal neuronal injury, and inhibiting neuronal apoptosis in rats with perimenopausal depression.⁸² In the regulation of synaptic plasticity, electroacupuncture upregulates hippocampal BDNF/TrkB/CREB pathway activity in rats with chronic inflammatory pain-related depression, while increasing the expression of synapse-related proteins such as SYN and PSD95, improving synaptic ultrastructural damage, and alleviating depression-like behaviors.⁸³ Clinically, electroacupuncture combined with probiotics significantly improves mood and gastrointestinal symptoms in patients with depression and chronic diarrhea, accompanied by significant changes in serum BDNF levels.⁸⁴ Furthermore, electroacupuncture reverses downregulation of BDNF expression in the anterior cingulate cortex and spinal cord of mice with chronic neuropathic pain and depression, upregulates CREB levels, and exerts synergistic analgesic and antidepressant effects through the CREB-5-HT/BDNF pathway.⁸⁵

From a broader perspective, acupuncture regulation of BDNF signaling shows common patterns across diseases and brain regions and is highly consistent with mechanisms underlying neurodegenerative diseases comorbid with depression. Studies indicate that acupuncture participates in neuroplasticity regulation by modulating multiple BDNF-targeting miRNAs and upregulating BDNF expression. This effect has been observed in depression, stroke, Alzheimer’s disease, Parkinson’s disease, and other disorders.⁷⁶ Acupuncture also appears to have bidirectional regulatory characteristics on the BDNF pathway; in depressive states, it mainly upregulates BDNF expression, activates TrkB receptors and downstream signaling cascades, and thereby promotes synaptic plasticity and neurogenesis.⁸⁶ In addition, acupuncture can improve diabetes-depression comorbidity through coordinated regulation at the levels of neural function and metabolism by modulating the BDNF-TrkB-ERK-CREB pathway.⁸⁷ With regard to brain region specificity, acupuncture regulates the BDNF/TrkB/CREB pathway in the lateral habenula, reverses downregulation of related molecules in depressed rats, and restores synaptic plasticity-related protein levels.⁸⁸

However, direct evidence demonstrating that electroacupuncture shifts the proBDNF/mBDNF ratio toward the mature form in depression models remains limited. Whether microglia contribute to this conversion—through the secretion of proteases or regulation of the tPA/plasmin system—is an intriguing question that warrants further mechanistic investigation. Addressing this gap would not only refine our understanding of acupuncture’s neurotrophic effects but also identify potential biomarkers for treatment response.

Coordinated Antidepressant Mechanisms of Acupuncture Through Microglia-Mediated BDNF Signaling

Integrating the evidence on acupuncture effects in depression, microglial regulation, and BDNF signaling helps clarify the key biological basis of acupuncture antidepressant action from the perspective of coordinated neuroimmune and neuroplastic regulation. As detailed earlier, microglia and BDNF signaling form a bidirectional positive-feedback loop—M2 microglia secrete BDNF to support neuronal function, while BDNF signaling reinforces the M2 phenotype—and disruption of this loop under inflammatory stress drives depressive pathology. The therapeutic action of electroacupuncture appears to hinge on restoring this loop.

Aberrant microglial activation is an important convergence point between neuroinflammation and inhibition of BDNF signaling in depression. By regulating microglial function, acupuncture may relieve inflammatory suppression of the BDNF-TrkB pathway and exert antidepressant effects through neuroimmune-neuroplastic synergy. Studies have shown that electroacupuncture inhibits excessive activation of spinal microglia, reduces Iba1-positive cell levels, downregulates abnormal BDNF and TrkB expression, and thereby alleviates central sensitization and depression-like behaviors.⁸⁹ Acupuncture can also inhibit abnormal microglial activation and reduce pro-inflammatory cytokine release, thereby exerting anti-neuroinflammatory effects while upregulating BDNF expression and improving neuroplasticity.⁹⁰ Meanwhile, electroacupuncture upregulates hippocampal BDNF/TrkB signaling and promotes downstream CREB activation, thereby enhancing neuroplasticity and improving depression-related behaviors.⁹¹ Additionally, electroacupuncture may regulate neuroinflammatory responses, improve the central microenvironment, and upregulate BDNF-related signaling, thereby strengthening neuroprotection and promoting neuroplastic repair.⁹²

Overall, acupuncture regulation of the microglia-BDNF pathway shows a degree of brain region targeting and improves depression-like behaviors through coordinated regulation of the dynamic balance between the inflammatory microenvironment and neurotrophic signaling. Hippocampal neurogenesis, in particular, may represent a key functional endpoint of this regulatory cascade, linking microglial immune modulation and BDNF trophic signaling to structural brain remodeling and sustained antidepressant effects. These findings hint that microglia, as key intermediate nodes, serve as an important bridge in acupuncture-mediated inhibition of neuroinflammation and regulation of the BDNF pathway, forming an important cellular and molecular basis for its antidepressant effects.

Conclusion

In summary, microglia-mediated neuroinflammation, dysregulated BDNF signaling, and impaired hippocampal neurogenesis together constitute a complex regulatory network of neuroimmune-neurotrophic imbalance in depression. Through multi-target and multi-level coordinated actions, electroacupuncture can effectively inhibit excessive microglial activation, precisely modulate the inflammatory microenvironment, repair BDNF-related signal transduction, promote neurogenesis and reconstruction of synaptic plasticity, and exert significant antidepressant effects. This integrated regulatory mechanism is highly consistent with the multifactorial and coupled pathological features of depression.

However, several critical knowledge gaps remain. First, the temporal dynamics and durability of electroacupuncture’s effects on microglial phenotype and BDNF signaling remain poorly characterized, with limited data on how long these effects persist after treatment cessation or whether they can be maintained with intermittent maintenance therapy. Second, most mechanistic studies have focused on the hippocampus, and systematic investigations of region-specific effects across distributed emotion circuits—including the prefrontal cortex, amygdala, and lateral habenula—and their links to specific symptom domains are still lacking. Third, while correlational evidence is abundant, causal validation of the microglia-BDNF-neurogenesis cascade remains incomplete, with limited use of cell-specific genetic manipulation approaches. Fourth, the lack of standardized stimulation parameters across clinical and preclinical studies hinders direct comparison and clinical translation.

Future research should address these gaps through: (1) longitudinal studies characterizing the time course and durability of electroacupuncture’s effects on microglial phenotype, BDNF balance, and neurogenesis; (2) region-specific analyses mapping the effects of electroacupuncture across key emotion-processing circuits and linking regional changes to specific depressive symptoms; (3) functional validation studies using cell-specific gene knockout and microglial depletion approaches to establish causal relationships; and (4) standardized parameter studies to identify optimal stimulation protocols for clinical translation. Addressing these priorities will deepen understanding of the antidepressant mechanisms of acupuncture and provide a stronger theoretical basis for precision acupuncture intervention in depression.

Funding Statement

This work is supported by (1) Funding Programme for Young and Middle-aged Top Talents of Wuxi Municipal Health Commission (BJ2023072); (2) Natural Science Foundation Project of Nanjing University of Chinese Medicine (XZR2023091).

AI Statements

The author(s) declared that Generative AI was used in the preparation of this manuscript. ChatGPT was used to assist in improving the clarity, grammar, and flow of the manuscript text, as well as in refining the English expression of certain sections. In addition, generative AI (Gemini) was used to assist in the creation of schematic figures included in this article. All intellectual content, conceptualization, data interpretation, and conclusions were conceived, verified, and approved by the authors, who take full responsibility for the final version of the manuscript.

Author Contributions

Hong Liu and Jiapeng Wang share first authorship. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.