Vagus nerve stimulation induced cognitive enhancement: Hippocampal neuroplasticity in healthy male rats

Vagus nerve stimulation (VNS) is reported to improve learning and memory, but the mechanisms of this cognitive enhancement have yet to be elucidated. Behavioral performance, electrophysiology, and brain derived nerve growth factor (BDNF) expression were measured after VNS to investigate changes in cognition and hippocampal neuroplasticity. Healthy male Sprague-Dawley rats (N = 47) aged 10-12 weeks were implanted with a platinum/iridium electrode cuff around the unsheathed left VN. After recovery, VNS was administered as fifteen 100 μs biphasic pulses at 30 Hz, 0.8 mA constant current every 18 s for 30 min. Novel Object Recognition (NOR) and Passive Avoidance Task (PAT) training were paired with VNS (N = 28). NOR/PAT testing was measured 24 hr after training and post-mortem tissue was collected 48 hr after VNS. Electrophysiology recordings were obtained using a microelectrode array system to assess functional effects on hippocampus slices 90 min after VNS (N=19). Experimenters were blinded throughout and sham rats received the same treatments without VNS. Stimulated rats exhibited enhanced memory performance in NOR (p < 0.05, n = 12) and PAT (p < 0.05, n = 14). Also, stimulated rats exhibited enhanced hippocampal plasticity as an increase in long-term potentiation from CA1 neurons was detected (p < 0.05, n = 7-12) after VNS. Immunohistochemical analysis of fixed hippocampal tissue from behavioral experiments demonstrated a VNS induced increase in BDNF expression in the CA1 (p < 0.05, n = 8-9) and CA2 (p < 0.01, n = 7-8). This study suggests VNS-induced cognitive enhancement may be due to increased hippocampal neuroplasticity during memory consolidation. Also, a single session of VNS may lead to sustained enhancement of hippocampal neuroplasticity via increased neurotrophic factor expression. These findings significantly contribute to a better understanding of VNS mediated hippocampal neuroplasticity, which may improve clinical utilization of VNS for cognitive enhancement.

Keywords: VNS, Hippocampus, Neuroplasticity, Electrophysiology