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Electroacupuncture Upregulates ERK Signaling Pathways and Promotes Adult Hippocampal Neural Progenitors Proliferation in a Rat Model of Depression

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Electroacupuncture Upregulates ERK Signaling Pathways and Promotes Adult Hippocampal Neural Progenitors Proliferation in a Rat Model of Depression

Liu Yang et al. BMC Complement Altern Med.

Abstract

Background: In this study, we investigate the proliferation of adult neural stem cells (NSCs) in a chronic unpredictable stress (CUS) rat model of depression, the effects of electroacupunture (EA) on depressive-like symptoms and the corresponding signaling pathways.

Methods: SD rats were subjected to 4 weeks of CUS to induce depressive-like behaviors. EA was performed at the Du-20 (Bai-Hui) and GB-34 (Yang-Ling-Quan) acupoints. Rats were injected with BrdU and the brains were cut into sections. Double-labeling with BrdU/Sox2 and p-ERK/Nestin was performed to demonstrate the in vivo proliferation of adult NSCs in hippocampus and ERK activation in NSCs. Hippocampal microdialysates of different groups were collected to observe the in vitro effects on NSCs.

Results: After 8 treatments, EA generated a clear antidepressant effect on the stressed rats and promoted the NSC proliferation. ERK activation might be involved in the antidepressant-like effects of EA treatment. Hippocampal microdialysates from EA-treated stressed rats influenced NSCs to form larger neural spheres and exhibit higher p-ERK level in vitro, compared to the untreated stressed rats. Meanwhile, the antidepressant-like effects of EA involved contribution from both acupoint specificity and electrical stimulus.

Conclusions: EA might interfere with the hippocampal microenvironment and enhance the activation of ERK signaling pathways. This could mediate, at least in part, the beneficial effects of EA on NSC proliferation and depressive-like behaviors.

Figures

Figure 1
Figure 1
EA reversed the depressive-like behavior of the stressed rats. The normal group underwent no stress; the Model group received the chronic unpredictable stress (CUS) for 4 weeks; the EA group received CUS for 4 weeks, as well as EA treatment for the latter part of the CUS (2 weeks). (A) The immobility times in the forced swimming test (FST) decreased after 3 and 4 weeks of CUS (1 or 2 weeks of treatment) in the EA group compared with the Model group. (B) The climbing time in the FST was reversed to normal levels by EA treatment. (C) &(D) The percentage of open-arms entries and open-arms time in the elevated plus maze (EPM). The values are presented as the mean ± SE, n = 8 or 18 in each group. Significance of “Model vs Normal” is marked by * (P <0.05) or ** (P <0.01), and that of “EA vs. Model” is marked by # (P <0.05) or ## (P <0.01).
Figure 2
Figure 2
The effects of EA on stem cell proliferation in the hippocampal dentate gyrus (DG) after 4 weeks. (A) Representative triple immunofluorescence staining for BrdU + (red), Sox2+ (green) and Hoechst (blue) in the central region of the DG. Scale bar = 100 μm. (B) Quantitative representation of Sox2/BrdU double-positive cells in the DG zone (not only those regions in A) per section. EA treatment significantly improved the stem cell proliferation compared with the CUS Model. The values are the mean ± SE, n = 5 in each group. ** P <0.01 (Model vs. Normal); # P <0.05 (EA vs. Model).
Figure 3
Figure 3
Induction of ERK phosphorylation (p-ERK) in DG stem cells by EA (8 treatments). (A) Representative triple immunofluorescence staining for Nestin (red), p-ERK (green) and Hoechst (blue) in the central region of the DG. Scale bar = 100 μm. (B) A quantitative representation of Nestin/p-ERK double-positive cell numbers in the DG zone (not only those regions in A) per section. EA treatment significantly elevated p-ERK levels in NSCs in the hippocampal DG of stressed rats. ## P <0.01.
Figure 4
Figure 4
EA microdialysates enhanced neurosphere growth and p-ERK level of NSCs. (A) % cell viability of stem cells in the Model and EA medium; (B) The formation of big-spheres (diameter ≥ 100 μm) number/100 μl in different mediums; (C) The p-ERK + stem cells in an average visual field under the 10× objective lens after 100 μl NSC suspension was fixed to a 96-well plate and stained. The values are presented as the mean ± SE, n = 3, # P <0.05 (EA vs. Model).
Figure 5
Figure 5
Antidepressant-like effects of EA involved contribution from both acupoint specificity and electrical stimulus. Tests were performed after five treatments. (A) The immobility times in the FST; (B) The climbing time in the FST; (C) &(D) The percentage of open-arms entries and open-arms time in the EPM. The values are the mean ± SE, n = 8 or 9. # P <0.05, ## P <0.01 (Acupuncture or EA vs. Model).

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