Electroacupuncture ameliorates depressive-like behaviors by activating Sirt1 to enhance oligodendrocyte differentiation and myelination in the prefrontal cortex of rats.

Introduction: This study investigated the therapeutic mechanisms of electroacupuncture (EA) in chronic unpredictable stress (CUS)-induced depression rat model. Since SIRT1 plays in oligodendrocyte differentiation and neuroprotection, we hypothesize that it may mediate the effect of electroacupuncture (EA) on myelin regeneration in depression.

Material and methods: Sixty adult male Sprague-Dawley rats were divided into control, CUS, EA + CUS and CUS + EA + SIRT1-specific inhibitor - EX527 (EX) groups. We established a CUS-induced depression rat model by subjecting rats to 4-week CUS paradigm.Four weeks of post-modeling, EA treatment and intraperitoneal administration of EX527 were applied. Behavioral tests including open field test, forced swim test and sucrose preference test were performed to assess the depressive-like state. Immunohistochemistry and stereological analysis for quantification of oligodendroglial cell populations was performed. Immunohistochemical staining and transmission electron microscope were performed for evaluation of myelination. Western blot and qRT-PCR analyses were performed to detect the mRNA and protein expression of SIRT1 in the prefrontal cortex (PFC) of rats in each group.

Results: Four weeks of EA intervention significantly alleviated depressive-like behaviors in CUS rats, as evidenced by increased sucrose preference (P < 0.05), enhanced exploratory activity (P < 0.01), and reduced immobility time (P < 0.05) compared to the CUS group. Histopathological and ultrastructural analyses demonstrated that EA restored myelin integrity in the PFC, with myelin basic protein immunoreactivity significantly higher in the EA+CUS group than in untreated CUS rats (P < 0.05). EA promoted oligodendrocyte differentiation, reversing the chronic stress-induced reduction in CC1+/Olig2+/BrdU+ progenitor cells (31.5 ± 3.1% vs. 3.23 ± 1.4% in CUS+EA+EX group, P < 0.01). Mechanistically, EA upregulated SIRT1 mRNA and protein expression in the PFC (P < 0.05 vs. CUS), while pharmacological inhibition of Sirt1 with EX-527 abolished these effects, reducing Sirt1 mRNA and SIRT1 protein expression (P < 0.01, P < 0.01, respectively) and Olig2 expression (P < 0.05). EX-527 treatment also blocked EA-induced behavioral improvements and myelin regeneration, confirming the critical role of the Sirt1.

Conclusions: The findings indicate that EA ameliorates depression-like behavior by enhancing oligodendrocyte maturation and myelin repair via activating SIRT1 signaling. These findings provide novel mechanistic insights into non-pharmacological interventions for depression.