| Objectives:Alzheimer ’s disease(AD)is a neurodegenerative disease with memory impairment as its main manifestation.A large number of epidemiological studies in recent years have found that there is a strong pathophysiological connection between Type 2 diabetes mellitus(T2DM)and AD.Anti-diabetic drugs have increasingly become a research hotspot in the treatment of AD.Glucagon-like peptide-1(GLP-1)is a kind of glucagon-like peptide 1(GLP-1)that is secreted by intestinal cells to lower blood sugar by stimulating insulin,inhibiting glycemic hormone,inhibiting gastric emptying and regenerating islet cells.An incretin.In recent years,research on GLP-1 receptor agonists for neurodegenerative diseases has been increasingly recognized.Subsequently,in order to continuously improve the efficacy and half-life of the drugs,researchers synthesized more and more analogs for clinical treatment and scientific research.The previous research of this research group showed that based on the neuroprotective effect of GLP-1 receptor activation,many of its analogs have certain improvements in learning and memory,synaptic plasticity,Aβ clearance,etc.in AD patients or animal models.Anti-AD effect.Among them,a GLP-1 and glucagon(Glucagon,Gcg)dual receptor agonist(D-ser2)oxm can exert anti-apoptotic neuroprotective effect on primary hippocampal neurons by inhibiting calcium overload Significantly improve anti-AD effects such as spatial learning and memory ability,working memory,synaptic plasticity,and removal of Aβ deposition in AD transgenic mice.According to the previous research results,we speculate that this neuroprotective effect may be simultaneous with the activation of both GLP-1 and Gcg receptors.After a series of signal pathway protein adjustments,the glycometabolism balance of neurons in the brain is corrected,and finally it is effectively reduced.Neuronal damage.However,it is well known that the basic principle of brain formation and memory maintenance is that nerve cells send normal electrical signals to each other in a neural network.According to reports,abnormal electrical activity occurs in the brain of AD patients and this phenomenon is earlier than the pathological changes of Aβ or Tau.Therefore,we suspect that(D-ser2)oxm may also contribute to electrophysiology in the mechanism of improving the pathological phenotype of AD.Therefore,this study used wireless neural telemetry combined with behavioral detection methods to simultaneously record the behavioral performance of AD transgenic mice after intraperitoneal injection of the dual receptor agonist(D-ser2)oxm and the local field potential of the hippocampus.Theta oscillation changes,with a view to reveal(D-ser2)oxm the mechanism correlation between AD’s cognitive function and electrical activity.In addition,we found that AD transgenic mice were accompanied by abnormal Gamma oscillation and Spike distribution in LFP during the behavioral experiment.Therefore,in this study,low-month-old AD transgenic mice were used to observe LFP in the early stage of AD.Gamma oscillation and the distribution of Spike,and attempts to use the concept of entropy in mathematics to initially analyze the correlation between various electrical activity changes in the early stage of AD,aiming to provide a deeper understanding of the electrophysiological mechanism of AD development in the future,and to explore new treatment strategies to provide theoretical basis.Materials and Methods:This subject is divided into two parts:(1)Observation of 9-month-old APP / PS1 / tau transgenic mice(3xTg)after treating(D-ser2)oxm,the hippocampal tissue field potential during working memory and fear memory behavior Synchronized changes in Theta oscillation;(2)Correlation analysis of LFP(Gamma oscillation)and Spike in the formation and maintenance of conditional fear memory in 6-month-old 3xTg mice.The first part of the experiment:(1)9-month-old male 3xTg mice and C57 background mice of the same month were selected and injected intraperitoneally(D-ser2)oxm and saline for two weeks,so they were divided into WT + saline,WT +(D-ser2)oxm,3xTg + saline and 3xTg +(D-ser2)oxm four groups of mouse models;(2)Multi-channel electrodes are embedded in the hippocampal CA1 area of each group of mice:(3)embedded two weeks later,the electrodes were subjected to Y Maze and fear conditioning test,and the changes of the peak and frequency of Theta oscillation in LFP of each group of mice were simultaneously recorded;density.The second part of the experiment:(1)6-month-old 3xTg male mice and C57 control mice of the same month were selected and named the 3xTg group and the WT group;Conduct a behavioral experiment of a fear conditioning test;(3)Simultaneously monitor two groups of mice by a wireless telemetry device embedded in their heads.Analyze a series of electrophysiological indicators Gamma oscillation,Spike,Burst against the freezing ratio in the fear conditioning test,and finally use the entropy value to calculate the correlation between Gamma oscillation and Spike.Results:The(D-ser2)oxm drug experiment results show that:(1)In the Y maze,the correct rate of spontaneous alternation of 3xTg mice is significantly lower than that of normal WT mice.After(D-ser2)oxm is treating,the working memory of 3xTg mice is obtained.Significant improvement.At the same time,the peak power of Theta oscillation of 3xTg mice decreased,but the Theta oscillation was also improved as a result of behavior after treating(D-ser2)oxm;(2)During the training session,with as the number of enhancements increased,the freezing ratios of the four groups of mice gradually increased.There was no significant difference in the freezing ratios between the four groups of mice at the beginning and end of training,indicating that APP / PS1 / tau gene mutation and(D-ser2)oxm There has no significant effect.However,in the testing session,the rate of freezing induced by conditioned stimulation in 3xTg mice was significantly lower than that in WT mice,and the rate of freezing was significantly increased after treatment with(D-ser2)oxm;(3)3xTg mice In the CS session,Theta’s power distribution is lower than that of WT mice,indicating that 3xTg mice have impaired memory ability.After the(D-ser2)oxm treatment,the peak and frequency of 3xTg mice in the CS session were restored;(4)Golgi staining results showed that the density of neuronal dendritic spines in the hippocampal CA1 area of 3xTg mice decreased.The number and density of dendritic spines increased significantly after oxm treatment.The correlation experiment results of Gamma and Spike showed that:(1)the Gamma oscillation distribution of 3xTg mice in the experimental stage of fear conditioning test was significantly lower than that of WT mice;(2)The Spike distribution of WT mice was significantly higher than that of 3xTg mice;(3)The burst of electrical activity released by 3xTg mice is significantly lower than that of WT mice;(4)Then we use the entropy calculation correlation of Gamma oscillation and Spike to find that there are relatively High correlation,but the correlation of 3xTg mice is poor.Conclusion:(D-ser2)Oxm can effectively improve the short-term working memory and fear memory of 3xTg mice,and restore the structural damage of synapses,as well as the Theta oscillation abnormalities accompanied by its behavior.In addition,the defect of AD fear memory may be caused by the incoordination of Spike-LFP(Gamma)distribution. |
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