Circadian disruption induces cognitive impairment through tryptophan-5-HT metabolic pathway dysregulation

Abstract Study Objectives 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. Methods In this study, C57BL/6 mice were exposed to irregular light–dark (LD) cycles for 15 weeks in a rhythmic box. Cognitive behavioral and histopathological assessments were conducted to evaluate the impact on cognitive function, while metabolomics was used to explore the underlying mechanisms. Results The results revealed that circadian disruption impaired spatial exploration, novel object recognition (NOR), and spatial memory in mice and caused pathological damage to the dentate gyrus 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 NOR ability of the alternating LD cycle (LD-DL) group. Conclusions 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. Statement of Significance This study is significant because it simulates the circadian disruption induced by chronic irregular light exposure. A comprehensive evaluation of the impact of circadian disruption on cognitive function was conducted, and metabolomics technology was used to elucidate the metabolic alterations that occur during the process of cognitive impairment linked to circadian disruption. Our research findings underscore the significance of the tryptophan metabolic pathway in the process of cognitive impairment induced by circadian disruption and reveal that the downregulation of tryptophan-5-HT represents a pivotal metabolic change. These findings offer a novel perspective and preventive strategies for neurological disorders triggered by circadian disruption.