Vagus Nerve Stimulation Enhances Memory and Synaptic Plasticity via the Hippocampal NE/β-AR Signaling Pathway in Pilocarpine Model Rats

Background Vagus nerve stimulation (VNS) is recognized for its therapeutic potential in various neurological disorders, with clinical and preclinical evidence suggesting its capacity to enhance memory function beyond symptom alleviation. However, the mechanisms underlying VNS-mediated memory enhancement are not well understood. Given that the hippocampal noradrenergic (NE) system and β-adrenergic receptor (β-AR) pathway are linked to memory processes, this study investigated the effects of VNS on memory and hippocampal neuroplasticity in pilocarpine-induced memory-impaired rats, with a focus on the role of the NE/β-AR signaling pathway. Methods VNS was administered to pilocarpine-treated rats for two weeks via electrodes placed on the left cervical vagus nerve, with parameters set at a current intensity of 1 mA, frequency of 30 Hz, and pulse width of 250 µs for 2 hours daily. Poststimulation, the rats underwent contextual fear conditioning (CFC) and hippocampal long-term potentiation (LTP) testing. The protein expression levels of NE, β2-AR, and key downstream signaling molecules (protein kinase A, CaMKII) were quantified. To ascertain β-AR receptor involvement, a β-AR antagonist was administered in the hippocampus prior to VNS. Results VNS increased hippocampal NE neurotransmitter release, and the expression of β-AR and its downstream pathway proteins PKA and CaMKII enhanced impaired hippocampal LTP and contextual fear conditioning memory in PILO rats. This VNS-induced increase was reversed by β-AR antagonist administration. Conclusion The enhancement of hippocampal neuroplasticity and memory by VNS is associated with the hippocampal NE/β-AR signaling pathway, indicating a potential therapeutic mechanism for VNS in memory-related disorders.