Noninvasive brain stimulation enhances memory acquisition and is associated with synaptoneurosome modification in the rat hippocampus

ABSTRACT

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation approach previously shown to enhance memory acquisition, but more studies are needed to elucidate the underlying mechanisms. Here, we examined the effects of anodal tDCS (0.25 mA for 30 minutes) on the memory performance of male Sprague Dawley rats in the passive avoidance test (PAT) and the associated modifications to the hippocampal proteomes. Results indicate anodal tDCS applied before the acquisition period significantly enhanced memory performance in the PAT. Following passive avoidance testing, synaptoneurosomes were biochemically purified from the hippocampi of tDCS- or sham-treated rats and individual protein abundances were determined by bottom-up liquid chromatography mass spectrometry analysis. Proteomic analysis identified 184 differentially expressed hippocampal proteins when comparing the sham to the tDCS before memory acquisition treatment group. Ingenuity pathway analysis (IPA) showed anodal tDCS before memory acquisition significantly enhanced pathways associated with memory, cognition, learning, transmission, neuritogenesis, and long-term potentiation. IPA identified significant upstream regulators including bdnf, shank3, and gsk3b. Protein-protein interaction and protein sequence similarity networks show that glutamate receptor pathways, ion channel activity, memory, learning, cognition and long-term memory were significantly associated with anodal tDCS. Centrality measures from both networks identified key proteins including dlg, shank, grin, and gria that were significantly modified by tDCS applied before the acquisition period. Together, our results provide descriptive molecular evidence that anodal tDCS enhances memory performance in the passive avoidance test by modifying hippocampal synaptic plasticity related proteins.

SIGNIFICANCE STATEMENT We investigated whether anodal tDCS affects memory performance and the underlying protein modifications in hippocampal synaptoneurosomes. We found that anodal tDCS administered before memory acquisition significantly enhanced memory performance by enhancing the expression of hippocampal proteins associated with glutamate signaling and ion channel activity. Our results identify molecular targets for tDCS-induced memory enhancement and the associated signaling pathways. Our behavioral and proteomics study further elucidates the mechanism for tDCS effects on acquisition memory and may lead to the development of therapeutics to enhance memory and learning process for neurological diseases and psychological disorders.