Postnatal treadmill exercise alleviates cognitive deficits in offspring exposed to gestational diabetes mellitus via reactivation of the hippocampal Wnt/β-catenin signaling pathway

Gestational diabetes mellitus (GDM) exposes the developing fetal brain to hyperglycemia and has been linked to adverse neurocognitive outcomes in offspring; however, effective postnatal strategies and underlying mechanisms remain incompletely defined. Here, we tested whether early-life aerobic exercise rescues hippocampus-dependent memory impairment and canonical Wnt/β-catenin signaling deficits in offspring born to dams with streptozotocin-induced GDM. Pregnant C57BL/6 mice received streptozotocin (40 mg/kg, gestational day 7) or saline. Male offspring were weaned and assigned to sedentary control or treadmill exercise (15 m/min, 60 min/day, 5 days/wk, 2 weeks), generating four groups: saline control (Sal-CON, n=12), saline exercise (Sal-Ex, n=12), GDM control (GDM-CON, n=12), and GDM exercise (GDM-Ex, n=12). Spatial learning and reference memory were assessed using the Morris water maze, and spatial working memory was evaluated with a T-maze task. Hippocampal expression of Wnt3, β-catenin, and glycogen synthase kinase-3β (GSK-3β) was quantified by Western blotting. GDM offspring exhibited impaired hippocampal memory performance, evidenced by a reduced hidden-to-visible platform latency ratio in the Morris water maze and loss of novelty preference in the T-maze. These behavioral deficits were accompanied by suppression of canonical Wnt signaling, with decreased hippocampal Wnt3 and β-catenin and increased GSK-3β in GDM-CON compared with controls. Notably, postnatal treadmill exercise significantly improved both reference and working memory and normalized Wnt/β-catenin pathway components in GDM offspring. Collectively, these findings indicate that early-life aerobic exercise mitigates GDM-associated cognitive vulnerability, at least in part, by reactivating hippocampal Wnt/β-catenin signaling.