Transcutaneous auricular vagus nerve stimulation attenuates depressive-like behaviors via enhancing neuroplasticity and regulating the ALK5/Smad2/3/Gadd45β signaling pathway in rats with post-stroke depression

IntroductionPost-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 Gadd45β 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/Gadd45β signaling pathway in mediating these effects.MethodsA 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–eosin, 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.