Artificial light at night, especially the blue wavelength spectrum (ALAN-BL), is an increasingly prevalent environmental contributor to cognitive impairment. However, the underlying mechanisms remain poorly understood. This study established a dose-dependent mouse model of ALAN-BL exposure (5, 10, and 20 lux) to systematically investigate the effects of ALAN-BL on behavioral performance and hippocampal function. To further elucidate the core molecular alterations, we performed a multi-omics analysis combining transcriptomics and metabolomics on hippocampal tissue, followed by preliminary molecular validation of the identified pathways. Behavioral and morphological assessments revealed that ALAN-BL exposure was associated with dose-dependent impairments in cognitive function and hippocampal integrity. At the molecular level, ALAN-BL dose-dependently decreased the expression of synaptic plasticity markers PSD-95 and SYN and the neurotrophic factor BDNF, while upregulating the pro-inflammatory cytokines IL-1β and TNF-α, and promoting microglial transition to an ameboid phenotype. Metabolomic profiling revealed that ALAN-BL exposure was associated with widespread metabolic reprogramming, with the majority of differential metabolites being downregulated, predominantly involving glycerophospholipid, amino acid, and energy metabolism pathways. Transcriptomic analysis showed that differentially expressed genes (DEGs) were significantly enriched in immune-related pathways, particularly the TYROBP causal network in microglia and microglial pathogen phagocytosis pathways. Multi-omics integration further indicated that disruption of glycerophospholipid metabolism may impair the function of the TREM2-TYROBP signaling pathway. Subsequent experimental validation further showed dose-dependent downregulation of the mRNA and protein expression of TREM2, TYROBP, and SYK, with upregulation of PLCG2, collectively suggesting alterations in the TREM2-TYROBP signaling axis. In summary, this study provides the first multi-omics characterization of hippocampal responses to ALAN-BL, suggesting that ALAN-BL exposure is associated with impaired hippocampal function through alterations in microglial immune-metabolic function, particularly involving the TREM2-TYROBP pathway. These findings offer novel insights into the potential neurological risks of ALAN-BL and identify potential targets for public health intervention.
