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 min) 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 PAT, synaptoneurosomes were biochemically purified from the hippocampi of tDCS-treated 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 (LTP). IPA identified significant upstream regulators including bdnf, shank3, and gsk3b. Protein-protein interaction (PPI) and protein sequence similarity (PSS) 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 PAT by modifying hippocampal synaptic plasticity related proteins.

Preclinical Evidence for the Mechanisms of Transcranial Direct Current Stimulation in the Treatment of Psychiatric Disorders; A Systematic Review

“… 10 Moreover, Ca 2+ flows facilitated by glutamatergic transmissions 9 activate signal cascades, and phosphorylate CREB, 11 , 12 which promotes protein synthesis 9 , 11 – 15 and establishes the late LTP. 9 , 15 – 17 LTPs are considered to improve functional connectivity between brain regions 18 – 20 and efficiency of information processing 12 , 13 , 16 , 20 , 21 (see Table 3 ).…”

“…Several animal experiments with tDCS have targeted cognitive function (Table 2), some of which report facilitation of long-term memory. 12,16,21,37 Accordingly, anodal stimulation has been shown to produce LTPs in recent studies (Table 3). There are two types of LTPs, ie, early LTP and late LTP.…”

“…20 These effects on brain networks may improve performance on learning 20 and memory. 12,13,16,21 Abbreviations: LH, left hemisphere; RH, right hemisphere; M2, secondary motor cortex; M1, primary motor cortex; S2, secondary somatosensory cortex; S1FL, forelimb region of the primary somatosensory cortex; S1HL, hind limb region of the somatosensory cortex; V2, secondary visual cortex; FC, frontal cortex; NAcc, nucleus accumbens. may explain the ability of tDCS to alleviate several symptoms (eg, cognitive impairment) in psychiatric disorders.…”

“…Moreover, multi-session tDCS induces low-frequency oscillations in the underlying brain regions and alters functional connectivity between them 20. These effects on brain networks may improve performance on learning20 and memory 12,13,16,21. Abbreviations: LH, left hemisphere; RH, right hemisphere; M2, secondary motor cortex; M1, primary motor cortex; S2, secondary somatosensory cortex; S1FL, forelimb region of the primary somatosensory cortex; S1HL, hind limb region of the somatosensory cortex; V2, secondary visual cortex; FC, frontal cortex; NAcc, nucleus accumbens.…”

The Modulation of Hippocampus Plasticity

“…More research is needed to understand the effects of tDCS during nighttime sleep and wakefulness [98]. Anodal tDCS has been shown to enhance memory through molecular adjustments in the hippocampal synaptic system.…”