Circadian Disruption Induces Cognitive Impairment Through Tryptophan-5-HT Metabolic Pathway Dysregulation

Circadian disruption is a common phenomenon that can cause various physiological and psychological problems, including cognitive impairment. The tryptophan-5-HT pathway, a crucial neurotransmitter system, plays a vital role in regulating circadian rhythms and cognitive functions. However, whether it mediates the cognitive impairment induced by circadian disruption remains unclear. In this study, C57BL/6 mice were exposed to irregular light–dark cycles for 15 weeks in a rhythmic box. Cognitive behavioural and histopathological assessments were conducted to evaluate the impact on cognitive function, while metabolomics was used to explore the underlying mechanisms. The results revealed that circadian disruption impaired spatial exploration, novel object recognition, and spatial memory in mice and caused pathological damage to the dentate gyrus (DG) region of the hippocampus. Metabolomic analysis revealed 787 differentially abundant metabolites in serum and 349 in hippocampal tissue, highlighting the dysregulation of tryptophan metabolism. Targeted tryptophan metabolomics revealed a decrease in the activity of the tryptophan metabolism 5-hydroxytryptamine (5-HT) pathway. Further tests confirmed that circadian rhythm disorder reduced the expression levels of tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 2 (TPH2), key rate-limiting enzymes of the 5-HT pathway, in the mouse hippocampus. Furthermore, supplementation with a 5-HT precursor (5-HTP) improved the novel object recognition ability of the alternating light–dark cycle (LD-DL) group. In conclusion, circadian disruption downregulated key rate-limiting enzymes in the tryptophan metabolism 5-HT pathway, decreasing 5-HT levels and leading to cognitive impairment. These findings offer new insights into the understanding of cognitive impairment caused by circadian disruption and its metabolic mechanisms in mice.