Aerobic Exercise Improves Learning And Memory In PD Mice By Regulating Hippocampus ERK1/2-related Molecules

Objective: The purpose of this study was to investigate the effects of aerobic exercise on learning and memory ability and hippocampal synaptic markers in chronic MPTP-induced PD mice,and to explore the role of ERK1/2 related signal molecules in aerobic exercise intervention on learning and memory ability in PD mice,so as to provide laboratory basis for the secondary prevention effect of aerobic exercise on PD cognitive impairment.Method:(1)72 female C57BL / 6 mice at 8 weeks of age were randomly divided into a normal saline control group(SC),normal saline + aerobic exercise group(SE),chronic MPTP induced PD model group(PD),chronic MPTP induced PD model + aerobic exercise Group(PDE),chronic MPTP induced PD model + aerobic exercise group + 10% DMSO group(PDED)and chronic MPTP induced PD model + aerobic exercise group + PD98059 group(PDEP),12 rats in each group.(2)The PD,PDE,PDED PDEP group was intraperitoneally injected with MPTP solution to induce PD mouse model according to 30mg/kg body weight,injected twice a week,at an interval of 3.5 days,for a total of 5 weeks.Aerobic exercise should be carried out in a gradual manner,with the running speed gradually increasing from 6m/min to 12m/min,and the running speed should be maintained at 50 min,totaling 60min/ day,for 6 weeks.(3)In PDEP group,the ERK1/2 blocking model was constructed by injecting PD98059 solution at 10mg/kg body weight.(4)The Morris water maze experiment and the eight-arm maze experiment were used to detect the behavioral changes in each group.(5)TH immunohistochemical staining was used to evaluate DA depletion of substantia nigra in mice,The expression level of DAT in substantia nigra was observed by immunofluorescence staining.(6)Western Blot,immunofluorescence staining and rt-pcr were used to detect the expression and m RNA levels of SYN,psd-95,BDNF,ERK1/2 and CREB proteins in hippocampal neurons of mice.Result:(1)Chronic mptp-induced mice showed similar characteristics to PD,specifically,the time and total time to complete the upper stage of pole climbing were significantly longer,the activity in the open field was decreased and the total walking distance was significantly shorter than that in SC group.TH positive dopaminergic neurons in nigra nigra were significantly decreased,TH positive signal expression was impaired by 54.27%,and the positive signal of nigra nigra DAT immune product was significantly decreased by 54.21% compared with the SC group(P<0.05).At the same time,The Times of crossing the original platform in Morris water maze space exploration were significantly reduced,the swimming distance in the original platform quadrant was significantly shortened,and The Times of working memory and reference memory errors in the eight-arm maze were significantly increased(P<0.01 or P<0.05).(2)During the induction of chronic MPTP,aerobic exercise intervention significantly increased the number of times the mice crossed the original platform and the swimming distance of the original platform quadrant,and significantly reduced the number and error rate of working memory and reference memory.Chronic MPTP induced PD mice hippocampal neurons total SYN and PSD-95 protein expression and m RNA level significantly lower,after the exercise intervention in mice hippocampal CA1 and CA3 area neurons SYN protein showed strong fluorescence optical density,a significant rise in immune positive material relative to express,total protein and m RNA SYN and CA3 area of PSD-95 immune positive physical expression was also significantly increased(P < 0.05 or P < 0.01).At the same time,perason-related data showed that hippocampal SYN and psd-95 total protein expression was positively correlated with the original platform quadrant swimming distance to a low degree,and negatively correlated with working memory and reference memory error rate or times to a low degree(0.3< r 0.5,P<0.05 or P<0.01).(3)The expressions of BDNF ERK1/2 and CREB protein in hippocampal CA3 neurons of PD mice were significantly decreased by chronic MPTP,and the levels of BDNF m RNA were significantly down-regulated,and ERK1/2 and CREB m RNA were downregulated.Aerobic exercise intervention significantly increased the expression of hippocampal neuron BDNF ERK1/2 and CREB total protein,and up-regulated the m RNA level of hippocampal neuron BDNF(P<0.05 or P<0.01).At the same time,ERK1/2 and CREB m RNA levels were up-regulated.At the same time,Perason data showed that the total proteins of hippocampal BDNF,erk1/2 and CREB were significantly positively correlated with the swimming distance in the original platform quadrant,were negatively correlated with the number of reference memory errors and working memory errors,and were highly positively correlated with the expression of SYN protein(P < 0.01).There was a significant positive correlation between CREB and psd-95(r=0.507,P < 0.01).(4)Compared with the PDE group of mice,PD98059 treatment significantly reduced the aerobic exercise for chronic MPTP induced PD mice BDNF ERK1/2 and after CREB m RNA level and ERK1/2 and total protein and CA3 area of BDNF protein expression after CREB gain effect,and significantly lowered the hippocampal neurons synaptic proteins SYN and PSD-95 total protein expression and the SYN m RNA level,increase the working memory in the eight arm maze and reference memory error rate(P < 0.05).Conclusion:(1)Aerobic exercise effectively improved the overexpression of proteins and genes such as BDNF,ERK1/2 and CREB in hippocampal neurons of PD mice induced by chronic MPTP,which may be one of the potential mechanisms that aerobic exercise alleviated the decline of learning and memory ability during the pathogenesis of PD.(2)Aerobic exercise effectively improved the protein and gene expression of hippocampal neuron BDNF and the ERK1/2 signaling pathway mediated by chronic mptp-induced PD mice,which may be one of the potential mechanisms that aerobic exercise alleviates the decline of learning and memory ability in the pathogenesis of PD.(3)After er K1/2 blockade,aerobic exercise intervention significantly reduced the learning and memory ability gain of chronic MPTP mice,further confirming that aerobic exercise can improve the learning and memory ability of chronic MPTP mice by regulating ERK1/2 related signal molecules.