Vagus nerve stimulation enhances context discrimination and dentate gyrus neurogenesis through Trk signaling

Adult-born neurons in the hippocampal dentate gyrus support the encoding of distinct representations for similar contexts, a dentate gyrus-dependent function underlying contextual discrimination. Impairment in this function contributes to fear generalization observed in posttraumatic stress disorder. Vagus nerve stimulation is under investigation as a treatment for posttraumatic stress disorder and has been shown to influence hippocampal plasticity, including adult neurogenesis. This raises the question of how vagus nerve stimulation-induced changes in dentate gyrus neurogenesis and plasticity relate to contextual discrimination behaviour. Here, we tested whether vagus nerve stimulation enhances contextual fear discrimination in male and female Sprague-Dawley rats and whether these effects depend on BDNF-TrkB signalling. Rats received 3 days of home cage vagus nerve stimulation using parameters previously shown to enhance memory. Home cage vagus nerve stimulation increased markers of dentate gyrus neurogenesis. The number of Ki67- and doublecortin-expressing cells was greater in the dentate gyrus of vagus nerve stimulation-treated rats than in controls (P < 0.005) and (P < 0.05), respectively. However, home cage vagus nerve stimulation did not alter contextual discrimination when delivered alone, compared with control treatment (P = 0.45). Similarly, vagus nerve stimulation delivered only during conditioning had no behavioural effect (P = 0.64). In contrast, combining home cage stimulation with vagus nerve stimulation during conditioning significantly enhanced contextual discrimination between shock-associated and similar contexts (P < 0.001). Pharmacological blockade of tyrosine kinase activity at TrkB receptors with K252a prevented both the behavioural enhancement and the vagus nerve stimulation-associated increase in neurogenesis markers. Rats treated with vagus nerve stimulation and vehicle showed better discrimination than rats treated with vagus nerve stimulation and the TrkB inhibitor K252a (P < 0.001), and K252a treatment significantly reduced the number of cells expressing Ki67 (P < 0.005) and doublecortin (P < 0.05) following vagus nerve stimulation. These findings demonstrate that vagus nerve stimulation is associated with BDNF-TrkB signalling-dependent increases in markers of dentate gyrus neurogenesis and enhancement of contextual fear discrimination.