ipRGC-sensitive blue light exposure combined with exercise alleviates cognitive disorders and reverses pathological oscillations in mice

Non-pharmacological interventions including ipRGC-sensitive flickering blue light and physical exercise exert beneficial effects on cognitive function. However, whether their combined application confers additional benefits within a short intervention window where single interventions lack obvious efficacy remains unclear, and the underlying neural oscillatory mechanisms are poorly defined. This study aimed to characterize the behavioral and electrophysiological effects of short-term combined blue light and exercise in cognitive disorder mice. 5×FAD mice and their wild-type littermates were randomized into 5 groups ( n = 8 each): wild-type control (CTRL), AD control (AD), AD with blue light (AD + B), AD with exercise (AD + E), and AD with combined intervention (AD + BE). All mice completed 7 days of exercise acclimatization before formal intervention. Cognitive function was assessed via Y-maze and novel object recognition (NOR) tests. Wireless electrophysiology recorded hippocampal CA1 local field potential (LFP) during rest and behavioral tasks. A one-week combined intervention effectively rescued cognitive deficits in AD mice, whereas single blue light or exercise alone produced no detectable behavioral improvement. The combined regimen corrected pathological elevation of δ band power, restored γ band deficits, and selectively enhanced cognition-related θ–γ phase-amplitude coupling (PAC). Notably, neural and PAC restoration exhibited clear task-dependent patterns: additional elevation of θ power in the NOR task, and concurrent improvement of δ–γ and θ–γ PAC in the Y-maze task. Short-term combined intervention with ipRGC-sensitive blue light and physical exercise ameliorates cognitive impairment at a time point when monotherapies have not yet produced significant beneficial effects. In addition, this combinatorial regimen remodels hippocampal oscillatory activity and phase-amplitude coupling, rendering combined treatment a promising therapeutic strategy for mitigating cognitive impairment.