The Mechanism Of Propofol On The Fear Memory Extinction

Background: Intrusive re-experiencing is a core symptom of post-traumatic stress disorder(PTSD)and can take various forms,including intrusive images,nightmares,etc.However,it is unclear whether such responses have unique associated neuropathology,and understanding interaction of them might be conducive to launch a new therapeutic strategy for PTSD.The hippocampus plays a key role in the regulation of the stress response,and stress exposure impairs hippocampal dependent memory in both humans and animals.Propofol is a widely used intravenous anesthetic that is well-known for its protective effect in various human and animal disease models.However,the direct functional of propofol on hippocampus is still unknown.Propofol was delivered to PTSD model mice to observe the changes in mice’s fear,learning and memory,so that clinical medication is rationalized.Further study about the mechanism of synaptic plasticity may bring light to the molecular mechanism of fear memory extinction effects of propofol.Methods: C57BL/6 male mice,7-8 weeks old,were applied to set PTSD mice model.They were randomly divided in to three groups that are shock + Propofol group(propofol anesthesia after shock),shock + Normal Saline group(normal saline application after shock),sham group(without shock).Shock was delivered by Fear Conditioning apparatus to pair the unconditioned stimulus(US,electric foot shock)and conditioned stimulus(CS,environment and tone).Electric foot shock is 0.7m A in intensity and lasts for 0.5s.The temperature is set at 22℃,wet maintained at 50-60%,light 80 Lux,and tone 90 d B and 1000 Hz.Thirty minutes after shock,the mice were intraperitoneally infused with propofol(150 mg/kg)or normal saline(of the same volume)respectively.When the mice’s righting reflex recovered,half dose of propofol(75mg/kg)was given again.The sham group and also stayed in the Fear Conditioning apparatus for the same time,just without electric foot shock.Contextual test and cued test were done at one week,two weeks,four weeks and six weeks.Elevated O maze(EPM)、 open field(OF)、light/dark box(LDB),sucrose preference test(SPT)were done at four weeks,Morris water maze(MWM)was done at six weeks after shock.Comparing the freezing time,anxiety behavior and learning ability of mice,the effect of propofol on PTSD would be predicted.The mice’s brains were taken out six weeks after shock.Hippocampus was taken for Western Blot to investigate the expression of PSD95.The brain tissue of mice was collected for electrophysiology.Experiments were performed to compare LTP and LTD in each group to observe the effect of propofol on synaptic plasticity.Results: After fear conditioning,the mice were feared of the conditioned stimulus even six weeks later.After 4 weeks of shock,the PTSD mice show anxiety behavior in open field test 、Elevated O maze(EPM)、light/dark box(LDB)and sucrose preference test(SPT).Typical post-traumatic stress disorder syndrome was show in PTSD mice.The freezing time of the shock + Normal Saline group was significantly increased,compared with that of the sham group(P < 0.05).Meanwhile,propofol can protect mice from PTSD,because of that the freezing time of the shock +Propofol group is much less than that of the shock + Normal Saline group(P < 0.05).Such protective effect lasts for 6 weeks.In Morris water maze,the time spent in target area and cross times were decreased in the PTSD mice,which may predict that the ability of learning and memory was damaged in such mice.The expression level of PSD95 in hippocampus of PTSD mice decreased.In mice with post-traumatic stress disorder,LTP and LTD in the hippocampal CA3-CA1 area were impaired 6 weeks after stimulation.Adult neurogenesis in PTSD mice is inhibited.Propofol,on the other hand,reverses these changes and shows protection against post-traumatic stress disorder.Conclusion: Fear Conditioning Test can manage to set post-traumatic stress disorder mice model.Porpofol,given at the early phase after shock,can alleviate PTSD syndrome and protect the mice from PTSD.Propofol can enhance synaptic plasticity.Propofol also can up regulate the expression of PSD95 of hippocampus dentate gyrus.Propofol enhances adult neurogenesis in the hippocampus.This study showed that anesthetic dose of propofol may enhance synaptic plasticity and neurogenesis,thereby reducing the fear symptoms of PTSD mice,improving the learning and memory ability of PTSD mice,and exerting protective effects on PTSD.