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The dried fruit of Schisandra chinensis (Turcz.) Baill (S. chinensis) is widely used in treating central nervous system disorders. Increasing evidence has suggested that alcohol-soluble extracts and lignans from S. chinensis could significantly ameliorate depression-like behaviors in animal models, while there was little research on the potential of alcohol-insoluble polysaccharides as a candidate in the treatment of depression. Our research was designed to explore both the physicochemical characteristics and antidepressant-like effects of an alcohol-insoluble polysaccharide-rich fraction named SCP from S. chinensis. Simultaneously, the underlying mechanisms were elucidated in the study. The physicochemical characteristics were accomplished by colorimetric assays, CE, HPGPC, and FT-IR. Behavioral despair testing accompanied by LAT were processed to promptly assess the antidepressant-like effects of SCP in mice. Then OBX-induced mice were established to explore the impacts of chronic co-treatments with SCP. Furthermore, effects of SCP on the HPA axis, oxidant/antioxidant system, neurotrophic and synaptic factors, and gut microbiota in OBX-induced mice were detected through ELISA and 16S rDNA (V3 + V4 regions) gene sequencing. SCP is a polysaccharide-rich fraction mainly comprised of xylose, glucose, rhamnose, galactose, mannose, and galacturonic acid in ratios of 0.27, 5.09, 0.24, 1.00, 0.63, and 2.86, of which the MW distribution ranges from 681 to 3232 Da. Acute pre-treatment with SCP (200 mg/kg, i.g.) remarkably reduced mice's immobility in the FST without motor stimulation. Prolonged pre-treatments effectively enhanced the effects of SCP on the behavioral despair testing in mice. Chronic co-treatments with SCP (50, 200, and 800 mg/kg, i.g.) could ameliorate the slow increase of body weight and behavioral abnormality of OBX-induced mice in systemic behavioral testing. SCP (200 mg/kg) also successfully restored hyperactivity of the HPA axis, oxidative damage in the liver, neurotrophic disturbance and abnormal synaptic plasticity in the hippocampus, and dysregulation of gut microbiota in OBX-induced mice. SCP exerts noteworthy antidepressant-like impacts on behavioral despair mice and OBX-induced mice via multiple targets, indicating a potential therapeutic candidate in depression therapy. [Display omitted] • SCP was obtained from S. chinensis and chemically elucidated across the board. • Sub-chronic pre-treatments with SCP exerted better effects in behavioral despair mice. • Chronic co-treatments with SCP displayed significant effects in OBX-induced mice. • The modulatory effects in OBX-induced mice might be achieved via multiple targets. • Gut microbiota noteworthily mediated the antidepressant-like effects of SCP. [ABSTRACT FROM AUTHOR]