Abstract OBJECTIVE: This study aimed to investigate the potential positive effects of the alcoholic extract of Hemerocallis citrina Baroni on depressive behaviors in zebrafish larvae (Danio rerio) induced by reserpine. METHODS: Zebrafish larvae were divided into various groups, which included a control group, a model group, a model group with fluoxetine (a positive drug), a model group with a low dose of HCE (1.5 mg/L), a model group with a medium dose of HCE (3 mg/L), and a model group with a high dose of HCE (4.5 mg/L). Depression-like behaviors were analyzed using sound and light stimulation. RT-qPCR was utilized to investigate the effects of the alcoholic extracts of HCE on depression-related astrocyte markers (GFAP, C3, C4B, EMP-1, S100α-10) as well as the neurotrophic factor (BDNF) and its receptor genes (P75, TrkB). RESULTS: In comparison to the control group, the model group demonstrated significantly shorter movement distance and reduced movement time under sound and light stimulation (P<0.05, P<0.0001). Following the administration of the alcoholic extract of HCE, zebrafish larvae exhibited significantly heightened sensitivity to light and sound stimulation when compared to the model group (P<0.05, P<0.01). Astrocyte marker genes were up-regulated in the zebrafish brain in the model group compared to the control group (P<0.01). However, when the model group was administered with the alcoholic extract, the expression of astrocyte markers was significantly down-regulated compared to the model group (P<0.01). Neurotrophic factor and its receptor genes (BDNF, P75, TrkB) were down-regulated in the zebrafish brain in the model group compared to the control group (P<0.01). However, in the group administered with Brassica campestris alcoholic extract, the expression of BDNF, P75, and TrkB was significantly up-regulated compared to the model group (P<0.001). These findings suggest that the alcoholic extract of HCE suppresses the inflammatory response caused by astrocyte activation and promotes the production of neurotrophic factors and their receptor genes, thereby exerting an ameliorative effect on depression. CONCLUSION: Alcoholic extracts of HCE can improve depression-like behavioral changes induced by reserpine in zebrafish larvae . They reduce the expression of astrocyte markers in the zebrafish brain and promote the production of neurotrophic factors and their receptor genes, playing an antidepressant role.