Substantial scientific evidence demonstrates the antidepressant effects of acupuncture through modulation of neuroplasticity. Researchers at the Heilongjiang University of Chinese Medicine, including contributors from the First Clinical Medical College and First Affiliated Hospital, synthesized data from over two decades of research on molecular and structural changes induced by acupuncture in animal models of depression [1].
Neuroplasticity is the brain’s ability to adapt by reorganizing its structure, forming new neural connections, and modifying synaptic strength in response to experience, injury, or stimulation. The research demonstrates that electroacupuncture enhances neuroplasticity in models of depression by increasing brain-derived neurotrophic factor (BDNF) expression, activating signaling pathways such as BDNF/TrkB/CREB, improving dendritic spine density, and upregulating synaptic proteins like PSD-95 and GluR1. These molecular and structural changes, observed in the hippocampus and prefrontal cortex, provide evidence that acupuncture promotes neural regeneration and functional recovery through measurable neuroplastic mechanisms.
Dendritic spine density refers to the number of small, protruding structures called dendritic spines on the branches (dendrites) of neurons. These spines are critical because they are the primary sites of excitatory synaptic transmission in the brain—essentially, where neurons communicate. Higher dendritic spine density generally correlates with enhanced synaptic connectivity, greater neuroplasticity, and improved cognitive and emotional function. Conversely, reduced spine density is commonly observed in conditions like depression and neurodegenerative diseases.
In the research, multiple studies cited demonstrated that electroacupuncture (EA) increased dendritic spine density, particularly in depression-model rats exposed to chronic stress. For example:
- Cai et al. (2023) reported that electroacupuncture from GV20 (Baihui) to EX-HN3 (Yintang), using 2 Hz at 1 mA for 30 minutes daily over two weeks, enhanced synaptic transmission in the ventromedial prefrontal cortex. This was measured electrophysiologically by increased amplitude of spontaneous excitatory postsynaptic currents and was accompanied by improved dendritic spine morphology [1].
- Gao et al. (2021) found that electroacupuncture reversed synaptic deficits by modulating hyper-cholinergic tone and increasing the density of both mature and immature dendritic spines, confirmed via Golgi-Cox staining and spine density analysis. Electroacupuncture was applied to GV20, EX-HN3 (Yintang), LI4 (Hegu), and LV3 (Taichong) daily for two weeks at 2 Hz [1].
- Gao et al. (2022) also demonstrated increased dendritic spine density in the prefrontal cortex alongside upregulation of synapse-related proteins such as PSD-95 and GluR1, suggesting synaptic remodeling driven by EA [1].
These findings collectively indicate that electroacupuncture not only enhances synaptic signaling but also structurally reinforces neural networks by increasing dendritic spine density—a key marker of restored neuroplasticity in depressive states.
Overall, the research identifies specific neurobiological mechanisms underlying acupuncture's therapeutic efficacy in major depressive disorder (MDD), with a focus on brain-derived neurotrophic factor (BDNF), serotonergic and glutamatergic neurotransmission, and glial cell modulation. Electroacupuncture (EA), particularly at acupoints GV20 (Baihui), EX-HN3 (Yintang), LI4 (Hegu), and LV3 (Taichong), was the primary technique evaluated in these trials, most often in chronic unpredictable mild stress (CUMS) rodent models of depression [1].
Standard EA treatment protocols consisted of 2 Hz frequency stimulation at intensities ranging from 0.3 to 2 mA, using 0.25 mm diameter stainless steel filiform needles retained for 20 to 30 minutes. Needle lengths ranged from 25 mm to 40 mm, inserted perpendicularly to depths of 5–10 mm for head points (e.g., GV20, Yintang) and 15–25 mm for limb points (e.g., LI4, LV3). Treatments were typically applied once daily for 14 to 28 consecutive days. In some studies, electroacupuncture was applied every other day or five to six days per week over similar durations [1].
The electrodes were connected bilaterally in pairs. A common configuration paired GV20 with Yintang across the forehead and vertex. For limb points, LI4 was paired with LV3, or SP6 with PC6 in bilateral arrangements. In animal studies using LI4 and LV3, electrodes were applied across the dorsum of the forelimb and lower hindlimb respectively, creating a longitudinal stimulation circuit along the central meridian axis. For abdominal protocols, CV12 (Zhongwan) was paired with CV4 (Guanyuan) to generate midline current along the Ren (Conception Vessel) channel. In some protocols, disperse-dense waveforms alternated between 2 Hz and 20 Hz [1].
Deqi sensation was mimicked in rodent models by adjusting the current until visible mild muscle twitches were observed. Stimulation intensity was never raised beyond levels that induced stress behaviors. Manual twirling techniques were used for control groups receiving acupuncture without electrical stimulation, maintaining needle manipulation for 10–15 seconds upon insertion and once every 10 minutes thereafter [1].
The hippocampus and prefrontal cortex (PFC) were the primary brain regions of interest. In multiple studies, EA significantly increased BDNF and its receptor TrkB expression in these regions. Upregulation of the BDNF/TrkB/CREB pathway was associated with increased dendritic spine density, enhanced synaptic protein expression (including PSD-95, GluR1, Synapsin I), and improved long-term potentiation (LTP) responses measured via electrophysiology in hippocampal slices [1].
In addition to BDNF, EA promoted serotonergic and dopaminergic neurotransmission. It enhanced 5-HT1A receptor expression in the hippocampus and cortex and increased levels of dopamine and serotonin. EA also regulated the serotonin transporter (5-HTT) and reduced c-Fos/AP-1 signaling, which is involved in stress responses [1].
Crucially, EA modulated glutamatergic activity. It upregulated AMPA receptor subunits GluR1 and GluR2, and downregulated extrasynaptic NMDA receptor subunit GluN2B, thereby improving synaptic transmission and reducing excitotoxic risk. EA also increased glial glutamate transporter EAAT2 expression in the hippocampus and PFC, suggesting improved glutamate reuptake and neuroprotection [1].
Glial cell modulation was another key mechanism. EA prevented astrocyte atrophy and upregulated glial fibrillary acidic protein (GFAP) and fibroblast growth factor 2 (FGF2), both critical for astrocyte survival and synaptic support. EA also downregulated markers of microglial activation, including Iba-1, IL-6, IL-1β, and HMGB1, indicating reduced neuroinflammation. Increased TREM2 expression suggested microglial phenotype normalization under EA treatment [1].
Neuroanatomical changes were confirmed through immunohistochemistry, Nissl staining, Golgi staining, and transmission electron microscopy. These analyses consistently revealed increased neuronal number, reduced apoptosis markers (e.g., caspase-3, AIF), and enhanced synaptic structure integrity in EA-treated animals. Some studies also demonstrated EA-mediated inhibition of hippocampal autophagy via activation of the PI3K/Akt/mTOR signaling pathway, with reduced LC3-II/LC3-I ratios and Beclin1 expression [1].
The cumulative data support EA as a robust modulator of neural plasticity. Its effect spans molecular signaling (e.g., BDNF, CREB, ERK, PKA), synaptic transmission, neuroinflammation control, and glial cell homeostasis. EA activates multiple neuroplasticity-related targets to reverse CUMS-induced depressive phenotypes in rats, offering a mechanistically grounded adjunctive therapy for MDD.
This comprehensive review underscores the importance of standardized EA protocols and acupoint selection. The most frequently used points in effective protocols were GV20, EX-HN3, LI4, LV3, SP6, PC6, and GB34. The consistent application of 2 Hz EA at 0.6–1.0 mA for 20–30 minutes daily across 2–4 weeks correlated with significant improvements in neuroplasticity and behavioral endpoints [1].
Source:
1. Ning Xu, Yue He, Yong-Nan Wei, Lu Bai, and Long Wang, "Possible Antidepressant Mechanism of Acupuncture: Targeting Neuroplasticity," Frontiers in Neuroscience 19 (2025): 1512073.
