Transcutaneous vagus nerve stimulation alleviates post-stroke depressive symptoms by enhancing hippocampal CA1 neuroplasticity via upregulation of ALK5 expression

Abstract Poststroke depression critically hampers neurological recovery, and although transcutaneous auricular vagus nerve stimulation exhibits antidepressant potential, its mechanistic basis remains incompletely defined. Given that activin receptorlike kinase 5 (ALK5) regulates neuroplasticity through the Smad2/3/growth arrest and DNA-damage-inducible 45β (Gadd45b) axis, we postulated that transcutaneous auricular vagus nerve stimulation alleviates poststroke depression via this cascade. Using a rat poststroke depression model established by middle cerebral artery occlusion combined with chronic unpredictable mild stress, we knocked down ALK5 in hippocampal CA1 area and administered 14-day transcutaneous auricular vagus nerve stimulation. Behavioral assessments, histopathological and ultrastructural analyses, neurotransmitter measurements, and immunoblotting for neuroplasticity markers revealed that transcutaneous auricular vagus nerve stimulation reversed post-stroke depression-induced ALK5 downregulation and concurrently ameliorated depressive-like behaviors, restored monoamine levels, and enhanced neuronal survival, dendritic arborization, and synaptic integrity. Crucially, ALK5 knockdown abolished all these beneficial effects and blocked transcutaneous auricular vagus nerve stimulationmediated activation of the Smad2/3/Gadd45b pathway. Collectively, our findings demonstrate that transcutaneous auricular vagus nerve stimulation exerts its anti-depressant and proneuroplastic actions in poststroke depression by engaging the hippocampal ALK5 signaling cascade, thereby supporting transcutaneous auricular vagus nerve stimulation as a promising therapeutic strategy for poststroke affective and functional recovery.