[Transcriptomics study of total flavonoids from Hemerocallis citrina in improving emotional behaviors in chronic stress mice via regulating 5-hydroxytryptamine signaling pathways]

This study aims to investigate the improving effects and potential molecular mechanisms of total flavonoids from Hemerocallis citrina(HCFs) on depression-like behaviors induced by chronic unpredictable mild stress(CUMS) in mice. The mice were randomly divided into a control group, model group, low-dose HCFs group, middle-dose HCFs group, high-dose HCFs group, and fluoxetine group. After four consecutive weeks of gastric gavage administration, the sucrose preference test, forced swimming test, tail suspension test, and open-field test were conducted to evaluate depression-like behaviors. The levels of corticosterone(CORT), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), hippocampal 5-hydroxytryptamine(5-HT), and brain-derived neurotrophic factor(BDNF) in the serum were determined by enzyme-linked immunosorbent assay; hematoxylin-eosin staining was used to observe hippocampal pathological changes; transcriptome sequencing was performed to analyze differentially expressed genes and Western blot was performed to detect the expression levels of key proteins related to the neuronal function and inflammatory response. The results demonstrate that compared with the model group, HCFs groups with low, medium, and high doses can significantly increase sucrose preference, decrease immobility time, enhance central zone activity, reduce CORT, IL-6, and TNF-α levels, elevate BDNF and 5-HT contents, and alleviate hippocampal tissue injury. Transcriptomics and Western blot analyses reveal that HCFs can significantly up-regulate the pathways related to neurotransmitter synthesis, myelin formation, synaptic plasticity, and energy metabolism regulation, while down-regulating the pathways related to inflammatory response and excessive metabolism and regulating the expressions of proteins related to hippocampal neuronal function and inflammatory response. In conclusion, HCFs exert a significant antidepressant effect on CUMS-induced mice, and their mechanism may be related to the multi-target synergistic regulation involving monoamine neurotransmitter balance and neuroinflammation inhibition.