Objective   To study the effects of 7week treadmill exercise combined with black lycium polysaccharide on depression-like behaviors and explore the alterations of hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor （AMPAR）associated pathways in mice.  Methods   Fifty male Kunming (KM) mice were randomly divided into blank group (K, n=10) and chronic unpredictable mild stress group（CUMS, n=40）. For the CUMS group, 13 random chronic unpredictable mild stress method  were used to induce depression-like behaviors. After successful modeling, the mice were further divided into model group (M), treadmill exercise group (E), black lycium polysaccharide group (L), and treadmill exercise combined with black lycium polysaccharide group (EL); each group contained 10 mice, and intervention lasted for 7 weeks. The behavioral assessment was performed; the contents of 5-hydroxytryptamine（5-HT）, brain-derived neurotrophic factor (BDNF) and dopamine (DA) in hippocampal tissue, and the levels of S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE）in serum were detected; Nissl staining was carried out to observe the structure of brain tissue; AMPAR, glutamate receptor 1(GluR1) and calcium/calmodulin-dependent protein kinase α (CaMKⅡα) proteins in hippocampal tissue were detected; Real-time PCR was used to verify the expression of hippocampal AMPAR, GluR1 and CaMKⅡα mRNA obtained by mRNA sequencing.  Results   1. Compared with the blank group, the mice in CUMS group had obvious depression-like behaviors (P<0.01); the contents of 5-HT, BDNF and DA in hippocampal tissue decreased significantly, while those of S100B and NSE increased (P<0.01); Neurons in the prefrontal cortex were absent, the Nissl nacleus was condensed, and the arrangement was irregular and sparse. 2. Compared with the model group, the behavioral assessment of the mice in the E, L and EL groups were significantly improved, reflecting that the contents of 5-HT, BDNF and DA in hippocampal tissue increased, and the serous S100B and NSE levels decreased (P<0.01 or P<0.05); for sucrose preference test (SPT) and forced swimming test (FST), S100B and NSE content result  showed that treadmill exercise and black lycium polysaccharide intervention had a synergistic effect on behavioral improvement. 3. Compared with the model group, the contents of AMPAR, GluR1, and CaMKⅡα proteins in hippocampal tissue of mice in the E, L and EL groups increased (P<0.01), and there was a synergistic effect between treadmill exercise and black lycium polysaccharides; the Illumina high-throughput sequencing data showed that there were 49 upregulated genes and 18 down-regulated genes involving learning and memory, and neuronal damage repair, etc. which were closely related to postsynaptic membrane location of AMPA receptors and synaptic long-term potentiation and long-term depression, The increased transcriptions of AMPAR, GluR1 and CaMKⅡα revealed by the sequencing were verified by Real-time PCR data, and there was a synergistic effect between the treatments of treadmill exercise and black lycium polysaccharides.  Conclusion   Seven weeks of treadmill exercise and administration of black lycium polysaccharides can improve depression-like behaviors in mice, possibly by affecting the phosphorylation of CaMKⅡα to regulate AMPAR activity, promote neuronal damage repair and improve synaptic plasticity and function.