{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:09:29Z","timestamp":1778476169049,"version":"3.51.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Post-stroke depression (PSD) adversely affects neurological functional recovery in patients. Transcutaneous auricular vagus nerve stimulation (ta-VNS) has demonstrated antidepressant potential. As the receptor ALK5 may regulate neuroplasticity by modulating the Smad2\/3 and Gadd45\u03b2 signaling pathways, we hypothesized that ta-VNS alleviates PSD by activating this pathway. This study aimed to evaluate the therapeutic effects of ta-VNS on a PSD rat model and to investigate the involvement of the ALK5\/Smad2\/3\/Gadd45\u03b2 signaling pathway in mediating these effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A PSD rat model was established by combining middle cerebral artery occlusion (MCAO) with chronic unpredictable mild stress (CUMS). To investigate the underlying mechanisms, ALK5 expression was knocked down in the right prefrontal cortex (PFC) via AAV-shALK5 injection, followed by a 14-day ta-VNS treatment. Depression-like behaviors were evaluated using the sucrose preference, forced swimming, and open-field tests. Neuroprotection was assessed through hematoxylin\u2013eosin, Nissl, and TUNEL staining. Neurotransmitter expression was measured by enzyme-linked immunosorbent assay (ELISA). Neurogenesis, along with axonal, dendritic, and synaptic plasticity, was assessed by immunostaining and Western blot analysis of DCX, Nestin, NF-200, GAP-43, MAP-2, and PSD95, SYN. Additionally, dendritic morphology was visualized by Golgi-Cox staining, and in addition, synaptic ultrastructure was characterized using transmission electron microscopy. Protein levels of the ALK5\/Smad2\/3\/Gadd45\u03b2 pathway were analyzed by Western blot.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Ta-VNS treatment restored the PSD-induced downregulation of ALK5. Furthermore, the beneficial effects of ta-VNS\u2014including the amelioration of depressive-like behaviors, provision of neuroprotection, upregulation of serotonin (5-HT) and dopamine (DA) expression, promotion of neurogenesis, and enhancement of neuroplasticity\u2014were all abolished upon ALK5 knockdown. Finally, ta-VNS was found to activate the Smad2\/3\/Gadd45\u03b2 signaling pathway in an ALK5-dependent manner.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that ta-VNS ameliorates depressive-like behaviors and enhances neuroplasticity in PSD by activating the ALK5\/Smad2\/3\/Gadd45\u03b2 signaling pathway in the PFC. These results elucidate a novel molecular mechanism underlying the therapeutic effects of ta-VNS, highlighting its potential as a treatment strategy for PSD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1755707","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T04:26:50Z","timestamp":1778473610000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcutaneous auricular vagus nerve stimulation attenuates depressive-like behaviors via enhancing neuroplasticity and regulating the ALK5\/Smad2\/3\/Gadd45\u03b2 signaling pathway in rats with post-stroke depression"],"prefix":"10.3389","volume":"17","author":[{"given":"Qinghuan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]},{"name":"Department of Neurology, The First Affiliated 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