Peripheral Electrical Nerve Stimulation Rescues Spatial Memory Deficits in Vascular Cognitive Impairment Rats by Engaging a Central Cholinergic Circuit

BACKGROUND: Vascular cognitive impairment (VCI) is a prevalent and heterogeneous condition, both clinically and pathophysiologically, that still lacks approved treatment. Peripheral electrical nerve stimulation (PENS) shows promise for VCI management, yet its underlying neurobiological mechanisms are not well understood. METHODS: VCI was induced in rats via permanent bilateral common carotid artery occlusion. Cognitive function was assessed using the Morris water maze, Y-maze, and novel object recognition. Synaptic plasticity was evaluated through long-term potentiation recordings and Golgi staining. The nucleus tractus solitarius (NTS)–medial septum–hippocampus circuit was dissected using fiber photometry recording, immunofluorescence multiplex labeling, in vivo multichannel recordings, anterograde/retrograde tracing, and chemogenetic manipulation. RESULTS: We found that PENS at Zusanli (ST36) acupoint significantly elevated hippocampal acetylcholine levels, enhanced synaptic plasticity, and rescued spatial and nonspatial memory deficits in VCI rats. Chemogenetic activation of cholinergic neurons in the NTS enhanced the cognitive function of VCI rats, whereas chemogenetic inhibition of these neurons counteracted the cognitive benefits of PENS. The NTS sends cholinergic projections to the hippocampal CA1 region through the medial septum. Specific inhibition of NTS ChAT -medial septum ChAT -CA1 circuit reversed the enhancement of spatial memory observed in VCI rats treated with PENS, while leaving the nonspatial memory unaffected. CONCLUSIONS: Our findings identify the NTS–medial septum–CA1 cholinergic circuit as a critical mechanism mediating PENS-induced reversal of spatial memory deficits in VCI, revealing a novel and spatially selective therapeutic target for VCI.