The Role And Cholinergic Mechanism Of Elevated Blood Pressure Variability In Learning And Memory In Rats

BackgroundHigher visit-to-visit blood pressure variability(BPV),independent ofhypertension,was associated with injury of cognitive function in elderly persons,which mechanism was not clear.Cholinergic function is involved in learning and memory,and cholinergic disfunction may result in learning and memory deficits.Sino-aortic denervated(SAD)rats were a kind of animal model of simple higher BPV.Ketanserin could improve BPV in SAD rats.AimsThis study was designed to investigate the effect of increased BPV on learning and memory in rats and explore the possible mechanism of cholinergic function.MethodSprague-Dawley(SD)rats were randomly divided into two groups.One group was SAD,and the other sham operation(Sham).Femoral artery and venous catheterization was performed two weeks after operation ofSAD.Heart period,blood pressure,blood pressure variation and arterial baroreflex sensitivity were measured continuouslyin conscious,freely moving rats.Behavioral experiments such as novel object recognition trial(NORT),passiveavoidance trial(PAT)and Morris water maze(MWM)were carried out at 2 weeks,4 weeks,8 weeks and 16 weeks after SAD respectively.After the behavioral test,animals were decapitated and hippocampus and cerebral cortex were collected.Theexpression of cholinergic associated protein including choline acetyltransferase,vesicular acetylcholine transporter and α7nicotinic acetylcholine receptorin hippocampus and cerebral cortex were detectedby using RT-QPCR and Western-blot assay.Also,the level of tau protein and phosphorylated tau proteinwas tested.(2)SD rats were divided into two groups randomly: SAD and Sham group.Two weeks after operation,SAD group was randomly divided into SAD group and ketanserin(0.3mg/kg/d)group.Sham rats were givenbygavagewith pure water.Blood pressure paramerers,NORT,PAT,MWM and protein level were determinated with the above methods.Results1.Hemodynamic changes in SAD ratsCompared with Sham group,the mean systolic blood pressure and mean diastolic pressure were not significantly changed,but the mean BPV and mean BPV were signifycantly increased(P<0.01).BRS significantly decreased(P<0.01).2.Behavioral experiment results2.1 NORT resultsCompared with the Sham group,there was no significant difference in the index of recognition between the two objects in the experiment of training after 2 weeks,4 weeks,8weeks and 16 weeks of SAD operation.There was no significant difference in the recognition index at the experiment of retention after 2 weeks of SAD operation,but there was significant difference in RI after 4 weeks,8 weeks and 16 weeks after SAD operation(P<0.05,P<0.01).2.2 PAT resultsCompared with Sham group,there was no significant difference in the latency of passive avoidance in the first day of adaption trial.The latency of avoiding darkness in SAD group was significantly lower than that in Sham group from 2 weeks to16 weeks after SAD operation in the third day of retention trial(P<0.05,P<0.01).2.3 MWM resultsCompared with the sham group,there was no significant difference in the escape latency in the navigation experiment of 2 weeks,4 weeks SAD group rats.In 8 weeks SAD group,the escape latency was significantly increased on the first day,the second day and the fifth day.In 16 weeks SAD group,the escape latency was significantly increased on the first day and the second day.There was no significant difference in the number of platform crossings between the 2 weeks SAD group,4 weeks SAD group and their control group.While the number of platform crossings was significantly decreased in the 8 weeks SAD group and 16 weeks SAD group(P<0.05,P<0.01).3.Molecular pathology experiments results3.1 Changes of tau protein and phosphorylated tau protein in cerebral cortex and hippocampus of SAD ratsThere was no significant difference in cerebral cortex and hippocampus of Tau protein and phosphorylated Tau protein between the 2 weeks,4 weeks and 8 weeks SAD group and their Sham group.The total Tau protein in the cortex and hippocampus had no significant difference in 16 weeks SAD group,while the phosphorylation of tau protein was signify-cantly increased(P<0.05,P<0.01).3.2 Changes of α7nAChR,ChAT and VAChTprotein in cerebral cortex and hippocampusof SAD ratsCompared with the sham group,there was no significant difference in ChAT,VAChT and α7nAChR in the cerebral cortex and hippocampus of the 2 weeks SAD group and 4weeks SAD group,while they significantly decreased in 8 weeks SAD group and 16 weeks SAD group(P<0.05,P<0.01).3.3 Changes of α7nAChR,ChAT,VAChT mRNA levelin cerebral cortex and hip-pocampusof SAD ratsThere was no significant difference in the relative content of α 7nAChR,ChAT mRNA in hippocampus between the sham group and the 2 weeks SAD group(except for the significant decrease of ChAT in the cerebral cortex).In SAD group,the relative content of α7nAChR,ChAT mRNA in hippocampus decreased significantly 4 weeks,8 weeks and16 weeks after operation(P<0.05,P<0.01).4.Effect of ketanserin on hemodynamic in SAD ratsCompared with Sham group,SBPV and DBPVsignificantlyincreased,and BRS significantly decreased in SAD group.Compared with SAD group,SBPV and DBPV significantly decreased,and BRS significantly increased in ketanserin group(P<0.05,P<0.01).5.Effect of ketanserin on learning and memory in SAD rats5.1 NORT resultsIn the training stage,there was no significant difference in the recognition index among the three groups of rats for the two same objects.Compared with Sham group,the recog-nition index of SAD group decreased significantly(P<0.05),while compared with SAD group,the recognition index of ketanserin group decreased significantly in the retention stage(P<0.05).5.2 PAT resultsIn the adaption experiment,there was no significant difference in the passive avoidance latency among the three groups of rats.After electrical stimulation,compared with Sham group,the passive avoidance latency of SAD decreased significantly(P<0.01).Compared with SAD group,the passive avoidance latency of rats treated with ketanserinincreased significantly(P<0.05).5.3 MWM resultsCompared with sham group,there was no significant difference in escape latency of the SAD group,while the number of platform crossings decreased significantly in spatial probe test(P<0.05).Compared with SAD group,the escape latency of the ketanserin group decreased significantly in the first and fifth day of place navigation test(P<0.05,P<0.01),and the number of platform crossings increased significantly in spatial probe test(P<0.05).6.Effect of ketanserin on tau protein and phosphorylated tau protein in cerebral cortex and hippocampus of SAD ratsThere was no significant difference in the total tau protein and the phosphorylated tau protein at S199 and T231 site between the sham group and the SAD group.Compared with SAD group,the total tau protein and the phosphorylated tau protein at T231 site in ketanserin group showed no significant change,while the phosphorylation of tau protein at S199 site was significantly decreased in ketanserin group(P<0.05).7.Effect of ketanserin on cholinergic associated protein in cerebral cortex and hippocampus of SAD ratsCompared with Sham group,the relative contents of α7nAChR,ChATand VAChT in cerebral cortex and hippocampus of rats in SAD group were significantly decreased.Compared with SAD group,the relative content of α7nAChR,and VAChT in cerebral cortex and hippocampus in ketanserin group were significantly increased(P<0.05).Conclusions1.The increase of BPV reduces the learning and memory ability in SAD rats,which is related to the cholinergic mechanism.2.Ketanserin could improve the learning and memory disorder in SAD rats.