This study aims to investigate the effects of Atractylodes macrocephala polysaccharides (AMP) on depression-like behavior,the brain-gut axis,and the hypothalamic-pituitary-adrenal axis (HPA) in chronic unpredictable mild stress (CUMS) model mice,as well as to elucidate the multi-target effects of AMP in combating depression.Mice were randomly assigned to a control group,a model group,a low dose AMP group (2.5 mg/kg),a middle dose AMP group (5 mg/kg),a high dose AMP group (10 mg/kg) and a fluoxetine group (0.6 mg/kg).Behavioral indices influenced by AMP were assessed across all groups,including sucrose preference test,tail suspension test and forced swimming test.Neurotransmitter levels in the hypothalamus included serotonin (5-HT),norepinephrine (NE) and dopamine (DA) were detected.Serum concentrations of inflammatory factors and hormones such as interleukin-6 (IL-6),adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were also evaluated.The expression of chromogranin A (CgA) was analyzed in mouse colon tissues alongside nissl-stained neurons within the hippocampus.Results indicated that AMP at doses of 2.5,5 and 10 mg/kg significantly improved behavioral indices in CUMS-induced depressed mice (P<0.05)， and recovery of damaged nissl staining was observed in these subjects as well (P<0.05).Furthermore,both CgA expression levels and serotonin concentrations in mouse colons returned to baseline values following treatment with AMP (P<0.05),demonstrating a dose-dependent relationship.Concurrently,levels of 5-HT,NE,DA within brain tissue along with IL-6,CORT,ACTH serum concentrations among CUMS-depressed mice were markedly reduced by AMP (P<0.05).These findings suggest that AMP has potential therapeutic implications for intervening in depression-like behaviors through modulation of multiple targets within both the brain-gut axis and HPA axis.