Vagus nerve stimulation enhances context discrimination and dentate gyrus neurogenesis through Trk signaling.
- 1Department of Neuroscience, University of Texas at Dallas, Richardson, TX 75080, USA.
- 2Texas Biomedical Devices Center, The University of Texas at Dallas, Richardson, TX 75080, USA.
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 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.
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BibTeX
@article{raza2026vagus,
title = {{Vagus nerve stimulation enhances context discrimination and dentate gyrus neurogenesis through Trk signaling.}},
author = {Syed Ahsan Raza and Débora R Calderón-Williams and Navya S Grandhe and Ishayu P Gupta and Christa K McIntyre},
journal = {Brain communications},
year = {2026},
month = oct,
doi = {10.1093/braincomms/fcag387},
url = {https://europepmc.org/article/MED/42927139},
note = {CC BY},
}
RIS
TY - JOUR
TI - Vagus nerve stimulation enhances context discrimination and dentate gyrus neurogenesis through Trk signaling.
AU - Syed Ahsan Raza
AU - Débora R Calderón-Williams
AU - Navya S Grandhe
AU - Ishayu P Gupta
AU - Christa K McIntyre
PY - 2026
DA - 2026/10/10
JO - Brain communications
DO - 10.1093/braincomms/fcag387
UR - https://europepmc.org/article/MED/42927139
AB - 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.
SN - 2632-1297
ER -