Faculty, Staff and Student Publications

Publication Date

3-1-2026

Journal

Experimental Neurology

DOI

10.1016/j.expneurol.2025.115562

PMID

41270982

Abstract

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n0KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance was assessed by novel object recognition (day 10), object location (day 20), and Barnes maze and open field testing (day 28). Mass spectrometry at 24 h quantified brain ACh. Flow cytometry at 24 h, 7 days, and 30 days measured microglial and brain F4/80 macrophages. Immunohistochemistry at day 30 evaluated gliosis and neurogenesis. WT mice showed reduced ipsilateral ACh and α7nAChR+ microglia with increased TNF-α versus sham. Compared with WT, α7n0KO mice exhibited greater myeloid infiltration at 24 h, fewer IL-6+microglia and F4/80+macrophages with impaired STAT3/SOCS3 signaling at day 7, and by day 30, reduced reparative microglia, fewer F4/80+ macrophages, greater tissue loss, demyelination, gliosis, reduced SVZ neurogenesis, and impaired cognitive recovery. GTS-21 treatment improved cognition and reduced gliosis, supporting a protective role for α7nAChR activation. In conclusion, α7nAChR signaling supports reparative immune programs and promotes neurorepair after stroke, thereby enhancing long-term cognitive recovery.

Keywords

Animals, alpha7 Nicotinic Acetylcholine Receptor, Mice, Male, Ischemic Stroke, Mice, Knockout, Recovery of Function, Mice, Inbred C57BL, Cognition, Benzylidene Compounds, Pyridines, Cognition recovery, IL-6, Ischemic stroke, Macrophages, Microglia, Neurogenesis, α7 nicotinic acetylcholine receptor

Published Open-Access

yes

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