Objective: Chronic cerebral hypoperfusion (CCH) can cause long-term changes in gene expression and increase susceptibility to spatial memory impairment, in which the histone acetylation plays a crucial role. Studies have found that electroacupuncture (EA), a non-drug therapy, is beneficial to alleviate spatial memory impairment. However, the underlying mechanism of the histone acetylation is not yet completely clear. The goal of this study was to investigate the mechanisms by which EA stimulation of acupoints on the head region ameliorates histone acetylation in CCH.
Methods: The spatial memory of CCH rats were evaluated before and after the EA intervention using two behavioral tests: Barnes maze (before EA treatment) and Morris water maze (after EA treatment). To further investigate the mechanism by which EA improves spatial memory, Western blotting, real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), chromatin immunoprecipitation (ChIP), Golgi staining, and neuroelectrophysiology were used. Furthermore, we used Adeno-associated virus vector expressing cyclic AMP response element-binding protein (CBP)/E1A binding protein p300 (P300)-specific short hairpin RNAs (sh CBP/P300) to inhibit the acetylation levels of histones H3 and H4 in the hippocampus.
Results: CCH rats showed changes in spatial memory, including a decline in acquisition and maintenance. Compared to the sham group, there were significantly lower levels of total histone acetylation in the CCH rats and the acetylation levels of histone H3 and H4 in the hippocampus of rats decreased in the CCH group. The ChIP experiment results showed that the enrichment of acetylation tags of histone 3 at lysine 9 occurred at the promoter sites of Finkel-Biskis-Jinkins osteosarcoma oncogene (c-Fos), early growth response 1 (Egr1), and activity-regulated cytoskeleton-associated protein (Arc). Western blotting and RT-qPCR detection showed that the transcriptional and expression level of c-Fos and Egr1 decreased. Golgi staining showed that the density of dendritic spines decreased in the hippocampal cornu ammonis 1 area. In contrast, with the EA intervention, the behavior performance and molecular biological indexes were improved. Furthermore, we observed a significant decrease in the histone H3 and H4 acetylation after inhibition of CBP/P300 expression with sh CBP/P300, which resulted in the abrogation of EA's beneficial effect.
Conclusion: EA can improve spatial memory impairment in CHH rats by regulating the expression of the hippocampal imprinted genes c-Fos and Egr1 and by enhancing synaptic plasticity through the epigenetic modification of histone H3 and H4 acetylation. Please cite this article as: Ding YY, Wang WJ, Chen LW, Yang MG, Dai YL, Li R, Cao YJ, Wang SN, Wang LM, Wu B, Chen LM, Liu WL. Electroacupuncture regulates histone acetylation to improve spatial memory impairment in rats with chronic cerebral hypoperfusion. J Integr Med. 2026; 24(2):224-237.

Key words: Chronic cerebral hypoperfusion, Electroacupuncture, Histone acetylation, Memory-imprinted gene, Spatial memory