| Objective:To study the impairment of memory function in mice exposed to methamphetamine during different withdrawal periods and to explore its possible neural mechanism.Methods:According to the discharge standard,we recruited 171 methamphetamine users,154 heroin users and 112 normal controls.Their demographic information and drug use information were collected.Seven tasks of Cambridge Neuropsychological Test Automated Battery,including Paired Associates Learning,Rapid Visual information Processing,Reaction Time,Cambridge Gambling Test,Stop Signal Task,Spatial Working Memory,Intra-Extra Dimensional Set Shift,were used to test the neurocognitive function of the subjects in different dimensions,then the differences were compared.Results:1.There was significant difference in age among the three groups.The age of heroin group was significantly higher than that of the other two groups.There was no significant difference in education level and family monthly income.The duration of drug abuse in heroin group was significantly higher than that in methamphetamine group,and there was no significant difference in the starting age and withdrawal time between the two groups;2.Age,education level and abstinence time are significant factors affecting cognitive function,which need further hierarchical analysis;3.In the age stratification,there was no significant difference in cognitive function among the three groups at the age of 18-29;at the age of 30-39,heroin group was significantly worse than methamphetamine group in psychomotor speed,and methamphetamine group was significantly impaired in inhibition control;at the age of 40-49,heroin group was significantly better than methamphetamine group in visual learning,episodic memory,psychomotor speed and spatial working memory In methamphetamine group,the performance of mental motor speed and spatial working memory in heroin group was significantly worse than that in normal control group;in the age of 50 and above,the performance of inhibition control and spatial working memory in heroin group was significantly worse than that in normal group;4.In the education level stratification,the performance of methamphetamine group in episodic memory was better than that of the normal control group in the education level of primary school and below.The inhibition and control of methamphetamine group and heroin group were significantly impaired,and the performance of heroin group in sustained attention was better than that of the normal control group.At the junior high school level,the performance of episodic memory in methamphetamine group was better than that in normal control group and heroin group,the performance of attention and psychomotor speed in heroin group was worse than that in normal control group and methamphetamine group,the performance of risk adjustment in heroin group was significantly worse than that in normal control group,and the performance of impulse control in methamphetamine group was significantly worse than that in normal control group In the control group and heroin group,the performance of cognitive flexibility in heroin group was better than that in normal control group;5.In the stratification of abstinent time,methamphetamine group showed significantly impaired impulse control and cognitive flexibility after 30 days of withdrawal,while heroin showed impaired spatial working memory and episodic memory.Conclusion(s):Methamphetamine and heroin abstinent patients have multidimensional neurocognitive dysfunction and they two have their similarities and specificity.These cognitive impairments are age-specific,and education level can be used as a protective factor of cognitive function.Different cognitive dysfunction has its different recovery time window in abstinent period.In the future work of drug abstinence,it is necessary to comprehensively evaluate the neurocognitive function of drug abstinence personnel,carry out longitudinal follow-up observation,and delineate its change track,so as to give personalized intervention measures and further organize scientific stages of abstinence time nodes.Objective:To study the learning and memory deficits after methamphetamine treatment and its underlying neurobiological mechanismMethods:C57BL/6J mice were intraperitoneal injection of methamphetamine and normal saline for 5-day model building.In the early stage of abstinence,open field test,new object recognition test and Morris water maze test were performed,and hippocampal transcriptional sequencing was performed.ELISA was used to detect the serum LEVELS of BDNF in patients with methamphetamine abstinence for 1 week,3 months and 1 year and healthy controls.The mRNA level of BDNF in the hippocampus of methamphetamine-exposed mice was detected by QRT-PCR and its protein expression was detected by WB.Primary astrocytes from C57BL/6J newborn mice were cultured and treated with methamphetamine.After STIM1 was silenced by lentivirus,SOCE activation was detected by calcium imaging,CREB activity and inflammatory factor release were detected by ELISA,BDNF mRNA level was detected by QRT-PCR,and BDNF protein expression was detected by WB.A methamphetamine-related memory impairment mouse model was constructed.STIM1 was injected into the hippocampus with lentivirus containing sh STIM1 plasmid,and STIM1 was confirmed to be involved in methamphetamine-induced activation of CREB/BDNF pathway and release of pro-inflammatory factors,as well as methamphetamine-related learning and memory impairment in vivo.Results:1.Compared with normal saline group,the stay time of methamphetamineexposed mice in the open field experiment in the central area and the entry times of the central area were significantly reduced,the discrimination index in new object recognition was significantly reduced,and the escape incubation period of the Morris water maze training phase on the third and fourth days was significantly increased.In the detection and testing stage,the number of platform crossings and the time spent in the target quadrant were significantly reduced;2.The gene expression in the hippocampus of methamphetamine-exposed mice was significantly different from that of the normal saline group,and the TOP 10 upregulated genes were Gh,Ctcfl,Egr2,BC051142,Tfrc,SH3BP2,Lyvel,Lars2,BDNF and Sikl,respectively.The differential gene enrichment pathways are mainly"negative regulation of kinase activity","negative regulation of phosphorylation","long range memory","rhythmic process" and "ensheathment of neuron".3.The serum BDNF level of methamphetamine abstinence for 1 week and 3 months was significantly higher than that of the normal control,while the serum BDNF level of methamphetamine abstinence for 1 year was not significantly different from that of the normal control.The mRNA and protein expression of BDNF in the hippocampus of methamphetamine-exposed mice were significantly up-regulated;4.Methamphetamine can up-regulate the expression of STIM1,activate SOCE,and increase cytoplasmic Ca2+influx in primary astrocytes.5.BDNF can activate Ca2+influx in astrocytes,which can be inhibited by SOCE inhibitor SKF96365.6.Silencing STIM1 can reverse the methamphetamine-induced SOCE activation,CREB activity,BDNF expression up-regulation,and pro-inflammatory factor release.7.Injection of sh STIM1-lentivirus into the hippocampus of mice could reverse the increased CREB activity,up-regulated BDNF expression and increased release of pro-inflammatory factors induced by methamphetamine,thus improving the anxietylike state and learning and memory deficits induced by methamphetamine exposure.Conclusion:STIM1 knockdown attenuates MA-induced neuroinflammation and improves impaired spatial learning and memory by regulating cAMP/CREB-BDNF signaling... |
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