Electroacupuncture combined with NSCs-Exo alters the response of hippocampal neurons in a chronic unpredictable mild stress paradigm in ovx rats

Electroacupuncture (EA) is a form of Traditional Chinese Medicine (TCM) that combines acupuncture with microcurrents mimicking the body's bioelectricity to prevent and treat diseases. Previous studies have demonstrated its antidepressant-like effects in chronic unpredictable mild stress (CUMS)-induced ovariectomy (OVX) rats. Neural stem cell-derived exosomes (NSCs-Exo) are heterogeneous and targeted, effectively promoting nerve regeneration and repairing neuronal damage, while potentially conveying the effects of EA. However, the precise mechanism remains unclear. In this study, perimenopausal depressive disorder (PDD) rat model were established using a two-step protocol CUMS + OVX. Treatment with EA combined with NSCs-Exo (EA-Exo) significantly improved depression-like behaviors in PDD rats, as indicated by increased sucrose intake in the Sucrose Preference Test (SPT), reduced immobility in the Forced Swimming Test (FST), and prolonged activity in the Out-of-Field Test (OFT). EA-Exo treatment improved depression-like behaviors by increasing serum levels of 5-hydroxytryptamine (5-HT) and decreasing immobility in the FST. It also alleviated OVX-CUMS-induced disturbances in energy metabolism, inflammation, and oxidative stress responses by enhancing serum levels of 5-HT, dopamine (DA), ATP, superoxide dismutase (SOD), and interleukin-10 (IL-10), while reducing cyclic AMP (cAMP), interleukin-6 (IL-6), reactive oxygen species (ROS), and malondialdehyde (MDA). Furthermore, EA-Exo treatment reversed structural and functional impairments in hippocampal synapses and mitochondria. This was evidenced by reductions in hippocampal synaptic plasticity proteins PSD95, SYN, and GAP43, as well as decreased expression of energy metabolism pathway proteins AMPK, NRF1, PGC1α, and TFAM. These findings suggest that EA-Exo ameliorates depressive behavior in OVX-CUMS rats by modulating synaptic plasticity and activating the AMPK/NRF1/PGC1α/TFAM signaling pathway.