Objective To investigate the effects of melatonin on the cognitive dysfunction induced by D-galactose in mice and the underlying mechanisms involved.Methods Eight-week-old male C57BL/6 mice were randomly divided into three groups:the control group,D-galactose group and D-galactose+melatonin group.D-galactose was administered by intraperitoneal injection(100 mg/kg),and melatonin was administered by gavage(10 mg/kg)once a day for three months.The Morris water maze was used to assess cognitive function.The effect of melatonin on synaptic plasticity was observed by long-term potentia-tion(LTP).The expression levels of PSD95,SYN,SIRT1 and BDNF in the hippocampus and cortex of the mice were determined by Western blotting.Results Compared with the control group,the D-gal group presented a longer escape latency,significantly shorter target quadrant dwell time(P＜0.05),impaired LTP(P＜0.01),and significantly lower PSD95,Synaptophysin and BD-NF protein levels in the hippocampus and cortical tissues(P＜0.05).The escape latency of the mice in the D-gal+MLT group significantly decreased(P＜0.05),and LTP induction significantly improved(P＜0.01).PSD95,Synaptophysin,SIRT1 and BD-NF protein levels in the hippocampus and cortex were significantly increased in the D-gal+MLT group(P＜0.05).Conclusion Melatonin can significantly improve the cognitive function of mice treated with D-galactose via a mechanism related to increasing the expression level of SIRT1-BDNF and improving the synaptic plasticity of mice,as shown by increased LTP in the hippocam-pal CA1 region.