Papermulberry fruit is commonly used for patients with chronic cerebral circulatoryinsufficiency(CCCI),which has the function of the tonifying liver and kidney.The present study focused on the efficacy and underlying mechanism of the Papermulberry fruit in protecting CCCI rats.CCCI was induced by permanent bilateral common carotid artery ligation(BCCA)in rats.Daily oral administered of Papermulberry fruit decoction for treatment group(n=12).Meanwhile,Sham group and Model group were given the medium-saline(n=12).The administration was initiated 30 min after postoperative recovery,and continued for 42 days.Behavior tests as Morris Water Maze test was performed at 6 days before executing.Six rats were performance western blotting analyses and six rats were allocated for immunofluorescence staining.Our results revealed that Papermulberry fruit mitigates the memory impairments induced by BCCA via the restoration of neural plasticity and altered the abnormal activation and polarization of microglial/macrophages.The neuroprotective effect of Papermulberry fruit appeared it could shorten the escape latency(s)and increase the platform crossing which showed by MWM test.Further investigation showed that Papermulberry fruit restored the neural plasticity,adjusted the abnormal expression of synaptophysin,MAP2,MBP and NF200 which caused by BCCA.Consistent with this,microglia/macrophages activated and induced M1 polarization caused by BCCA,while Papermulberry fruit inhibited the activation,M1 polarization and promoted M2 polarization.Collectively,we demonstrated that improvement of neural plasticity,altered the abnormal activation and polarization of microglial might contribute to neuroprotection of Papermulberry fruit against CCCI.