Cerebellar iTBS ameliorates post-stroke cognitive impairment via the dentate nucleus-ventromedial thalamus pathway.

Abstract

This study investigated whether the cognitive benefits of intermittent theta-burst stimulation (iTBS) in post-stroke cognitive impairment (PSCI) are mediated through modulation of the cerebellar dentate nucleus-contralateral ventromedial thalamus (DN-VM) circuit. The PSCI mice model were created using photothrombotic stroke, and the animals were assigned to five groups: Sham, PSCI, PSCI + iTBS, PSCI + iTBS + chemogenetic inhibition, and PSCI + chemogenetic excitation. Each group received its corresponding intervention. Behavioral changes were assessed before and after the intervention, and local field potentials (LFPs) were recorded from the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) using in vivo electrophysiology. We analyzed oscillatory power within each region, as well as interregional coherence and theta-gamma coupling between the mPFC and vHPC. After 21 days of cerebellar iTBS, PSCI mice showed significant improvements in Y-maze performance, accompanied by increased theta band power in both the mPFC and vHPC, as well as enhanced interregional coherence and theta-gamma coupling. When chemogenetic inhibition of DN-VM excitability was applied with iTBS, these improvements were markedly reduced. Conversely, 21 days of chemogenetic excitation of the DN-VM circuit produced behavioral and electrophysiological effects comparable to those observed in the iTBS group. These findings suggest that cerebellar iTBS improves post-stroke cognition in mice by modulating the DN-VM circuit. Furthermore, the DN-VM pathway appears closely associated with cognitive function and may serve as a novel neuromodulatory target for PSCI.