Axonal plasticity is important for neurofunctional recovery after
stroke. This study aimed to explore the role of transcutaneous auricular
vagus nerve stimulation (ta-VNS) on axonal plasticity and its underlying association with the α7
nicotinic acetylcholine receptor(α7nAchR) after
cerebral ischemia/reperfusion (I/R) injury. Adult male Sprague-Dawley rats were pretreated by
intraperitoneal injection with either
phosphate-buffered saline (PBS) or an α7nAchR antagonist and then subjected to
middle cerebral artery occlusion and ta-VNS treatment. α7nAchR expression and localization in the peri-
infarct cortex were examined after ta-VNS treatment. Subsequently, neurologic scores were assessed with a battery of tests. Axonal regeneration, indicated by upregulation of
growth-associated protein 43 (GAP-43) and neurofilament
protein 200 (NF-200), was assessed. Axonal reorganization was examined on the basis of anterograde movement of the neuronal
molecular probe biotin dextran amine. Additionally,
brain-derived neurotrophic factor (
BDNF)-associated signaling was measured 28d after I/R. Our findings showed that ta-VNS treatment enhanced α7nAchR expression in the ischemic cortex. α7nAchR colocalized with DCX and
Nestin after reperfusion. Furthermore, ta-VNS-treated I/R rats displayed enhanced neurobehavioral performance and increased axonal plasticity (axonal regeneration and axonal reorganization), as indicated by elevated levels of
BDNF/
cyclic AMP (
cAMP)/protein kinase A (PKA)/phosphorylated
cAMP response element-binding protein pathway (p-CREB) pathway members. Strikingly, the beneficial effects of ta-VNS were diminished after α7nAchR blockade. In conclusion, our study is the first to show that α7nAchR is a potential mediator of ta-VNS-induced neuroprotection in the chronic phase of
stroke and that its effects may be related to enhanced axonal plasticity through activation of the
BDNF/cAMP/PKA/p-CREB pathway.