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

Abstract 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 behavior. 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 signaling. Rats received three 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 to control treatment (p = 0.45). Similarly, vagus nerve stimulation delivered only during conditioning had no behavioral 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 behavioral 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 signaling-dependent increases in markers of dentate gyrus neurogenesis and enhancement of contextual fear discrimination.