Abstract
ObjectivesTo explore the effect of electro-acupuncture (EA) treatment on pattern separation and investigate the neural circuit mechanism involved in five familial mutations (5 × FAD) mice.MethodsFive familial mutations mice were treated with EA at Baihui (DU20) and Shenting (DU24) acupoints for 30 min each, lasting for 4 weeks. Cognitive-behavioral tests were performed to evaluate the effects of EA treatment on cognitive functions. 1H-MRS, Nissl staining, immunohistochemistry, and immunofluorescence were performed to examine the cholinergic system alteration. Thioflavin S staining and 6E10 immunofluorescence were performed to detect the amyloid-β (Aβ). Furthermore, hM4Di designer receptors exclusively activated by designer drugs (DREADDs) virus and long-term clozapine-N-oxide injection were used to inhibit the medial septal and vertical limb of the diagonal band and dentate gyrus (MS/VDB-DG) cholinergic neural circuit. Cognitive-behavioral tests and immunofluorescence were performed to investigate the cholinergic neural circuit mechanism of EA treatment improving cognition in 5 × FAD mice.ResultsElectro-acupuncture treatment significantly improved spatial recognition memory and pattern separation impairment, regulated cholinergic system via reduction neuron loss, upregulation of choline/creatine, choline acetyltransferase, vesicular acetylcholine transporter, and downregulation of enzyme acetylcholinesterase in 5 × FAD mice. Aβ deposition was reduced after EA treatment. Subsequently, the monosynaptic hM4Di DREADDs virus tracing and inhibiting strategy showed that EA treatment activates the MS/VDB-DG cholinergic neural circuit to improve the early pattern separation. In addition, EA treatment activates this circuit to upregulating M1 receptors positive cells and promoting hippocampal neurogenesis in the dentate gyrus (DG).ConclusionElectro-acupuncture could improve the early pattern separation impairment by activating the MS/VDB-DG cholinergic neural circuit in 5 × FAD mice, which was related to the regulation of the cholinergic system and the promotion of neurogenesis by EA treatment.
Highlights
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease characterized by gradual cognitive impairment
In novel location recognition (NLR), 5 × five familial mutation (FAD) group showed a lower location exploration compared with the wild-type mice (WT) group pre-treatment (p < 0.001), and 5 × FAD + EA mice performed significantly better than 5 × FAD mice (p < 0.001) and 5 × FAD + NA (p = 0.027) mice post-treatment (Figures 3I,J)
In location discrimination reversal (LDR), all groups shown similar trials at high separation (p = 0.386), whereas the 5 × FAD group had more trials than the WT group (p < 0.001), and a significant decrease in trials to reversal of 5 × FAD + EA group in comparison to 5 × FAD group (p = 0.033) and 5 × FAD + NA group (p = 0.023) at low separation (Figure 3M). These data indicated that EA treatment improved spatial recognition memory and pattern separation impairment in the early stage of 5 × FAD mice
Summary
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease characterized by gradual cognitive impairment. Electro-acupuncture (EA) is a complementary alternative medicine therapy, which is accepted by the World Health Organization and National Institutes of Health It uses the acupuncture method by applying an electrical current to acupuncture needles. Our previous studies found that EA treatment could ameliorate the ability of 12-month-old mice with AD to recognize novel objects and familiar objects which was accompanied by increasing neural activity in the hippocampus (Liu et al, 2017).
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