Effects Of Different Ways Of Exercise On Learning And Memory Ability And Hippocampal Autophagy In T2DM Mice

Background:Type 2 diabetes mellitus(T2DM)is a metabolic syndrome,often accompanied by learning and memory ability decline.Previous studies have shown that the decrease of autophagy activity is one of the important reasons for the decline of learning and memory ability in T2DM.Exercise can improve learning and memory ability dysfunction in patients with T2DM,however,the underlying mechanism is still unclear.The current research shows that high intensity interval training(HIIT)and moderate intensity continuous training(MICT)have positive effects on brain health,but there is no definite conclusion on which exercise is better.Objective:To investigate the effect of HIIT and MICT on learning and memory impairment in T2DM and its possible mechanism;Secondly,the improvement effect of two kinds of exercise on learning and memory ability of T2DM model mice was compared.Methods:(1)Modeling:4 weeks old C57BL/6J male mice were fed with high fat diet(HFD)for 8 weeks,and then streptozotocin(STZ)was injected intraperitoneally to establish T2DM mice model.(2)Grouping:Wild type mice were normal control group(NC).The mice with successful modeling were divided into three groups:type 2 diabetes mellitus(T2DM),T2DM model plus MICT group(MICT),T2DM model plus HIIT group(HIIT).(3)Exercise intervention:T2DM mice were intervened with HIIT and MICT for 8 weeks,5 days a week.(4)Experimental test:on the last day of the seventh week of exercise intervention,the elevated plus maze test was conducted,and Morris water maze test was conducted in the eighth week of exercise intervention.24 hours after the end of behavioral test,3 mice in each group were randomly selected for heart perfusion,whole brain was taken and paraffin sections were made;the remaining mice in each group were killed by decapitation and blood was taken from eyeballs,hippocampus on both sides was separated,one side was used for real-time quantitative PCR,the other side was used for Western blotting;blood serum was separated for ELISA.The detection indexes are as follows:①Behavioral test indicators:Morris water maze(MWM)was used to test the learning and memory ability of mice,and elevated plus maze was used to evaluate the anxiety like level of mice.②Blood glucose and serum insulin:blood glucose was measured by blood glucose meter,and serum insulin was measured by ELISA.③Autophagy and PI3K/Akt/mTOR pathway related indicators:the mRNA expression of related protein was detected by RT-PCR;the protein expression of related protein was detected by Western blotting;the distribution of Beclinl protein was detected by immunofluorescence staining.Results:(1)The results of Morris water maze showed that compared with NC group,the escape latency of T2DM group increased,the number of crossing and the percentage of platform quadrant time decreased significantly(P<0.05);compared with T2DM group,the escape latency of MICT group and HIIT group decreased,the number of crossing and the percentage of platform quadrant time increased significantly(P<0.05).There was no significant difference in escape latency,crossing times and percentage of platform quadrant time between MICT group and HIIT group(P>0.05).The results of elevated plus maze showed that compared with NC group,the percentage of open am entry and the percentage of open arm residence time in T2DM group decreased significantly(P<0.05);compared with T2DM group,there was no significant difference in the percentage of open arm entry and the percentage of open arm residence time between MICT group and HIIT group,and there was no difference between MICT group and HIIT group(P>0.05).(2)The results of fasting blood glucose and serum insulin showed that compared with NC group,the blood glucose level of T2DM group was significantly increased(P<0.001),and the serum insulin level was significantly decreased(P<0.001);compared with T2DM group,the blood glucose level of MICT group and HIIT group was decreased(P<0.05),and the serum insulin level was significantly increased(P<0.01);compared with the MICT group,there were no significant changes in blood glucose and serum insulin in the HIIT group(P>0.05).(3)Compared with NC group,Beclinl in T2DM group was significantly decreased(P<0.001);compared with T2DM group,Beclinl in MICT group and HIIT group was significantly increased(P<0.05);there was no significant difference between MICT and HIIT groups(P>0.05).(4)Compared with NC group,Beclinl in hippocampus of T2DM group was significantly increased Compared with T2DM group,the expression of Beclinl protein and LC3 Ⅱ/Ⅰ ratio in MICT group and HIIT group were significantly increased(P<0.05),while the expression of p62 protein was significantly decreased(P<0.05),In addition,the expression of LC3 mRNA in MICT group was significantly higher than that in T2DM group(P<0.05);there was no significant difference in the expression of Beclinl,LC3 and p62 mRNA and protein between MICT group and HIIT group(P>0.05).(5)Compared with NC group,p-Akt/Akt and mTOR in hippocampus of T2DM group were higher Compared with T2DM group,the expression of p-Akt/Akt and p-mTOR/mTOR in MICT group and HIIT group were significantly decreased(P<0.05);compared with MICT group,the expression of p-mTOR/mTOR in HIIT group was significantly decreased(P<0.05);in addition,the expression of PI3K,Akt,mTOR mRNA and p-PI3K/PI3K,p-Akt/Akt in MICT group and HIIT group were not significantly different There are obvious differences(P>0.05).Conclusion:The learning and memory abilities of T2DM mice were decreased and anxiety like behaviors were observed.At the same time,PI3K/Akt/mTOR was over activated and autophagy was abnormal in the hippocampus of T2DM mice.Both HIIT and mict can inhibit the decline of spatial learning and memory ability in T2DM mice.The mechanism may be that exercise can improve the learning and memory ability of mice by inhibiting the over activated PI3K/Akt/mTOR signaling pathway and increasing autophagy activity.