Abstract WP371: Alpha 7 nicotinic acetylcholine receptor Signaling Drives Long-Term Cognitive Recovery and Neurorepair After Ischemic Stroke in young mice

Introduction: Stroke is commonly associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh mediates many of its effects via the alpha 7 nicotinic acetylcholine receptor (alpha7nAChR), involved in synaptic plasticity, learning, and memory. In experimental stroke models, impaired alpha7nAChR signaling has been linked to heightened neuroinflammation. This study investigates whether alpha7nAChR signaling contributes to long-term cognitive recovery following ischemic stroke in young male mice. We hypothesized that alpha7nAChR signaling mitigates neuroinflammation and enhances cognitive repair. Methods: Wild-type (WT) and alpha7nAChR knockout (alpha7n 0 KO) mice underwent 60-minute middle cerebral artery occlusion (MCAO). Cognitive performance was assessed using novel object recognition (day 10), object location testing (day 20), Barnes maze, and open field tests (day 28). Mass spectrometry at 24 hours post-MCAO quantified ipsilateral brain ACh levels. Flow cytometry at 24 hours and 7 days post-MCAO measured alpha7nAChR microglia, TNF-alpha expression, and myeloid infiltration. Immunohistochemistry at day 30 evaluated gliosis and neurogenesis. Results: Twenty-four hours after MCAO, WT mice showed reduced ipsilateral ACh, decreased alpha7nAChR microglia, and elevated TNF-alpha than sham mice (p<0.05). After MCAO, alpha7n o KO mice showed increased myeloid infiltration than WT mice. At day 30 post-MCAO, alpha7n o KO mice exhibited greater tissue loss, demyelination, inflammation, and reduced subventricular zone neurogenesis. These deficits were associated with impaired cognitive recovery. Furthermore, at day 7 after MCAO, alpha7n o KO mice exhibited a lower proportion of IL-6-producing microglia and macrophages, together with reduced SOCS3 levels, a critical negative regulator of IL-6, indicating defective reparative function. In conclusion, our findings suggest alpha7nAChR is essential for modulating inflammation and promoting neurorepair after stroke.