The ECBs In The Prefrontal Cortex Are Involved In The Regulation Of The Generalization Of Fear Memory

Post-traumatic stress disorder(PTSD)is a kind of abnormal mental reaction which is caused by serious trauma stress,it harms people's physical and mental health,but nowadays,there is no ideal clinical treatment.When PTSD patients see and hear the clues which are similar to original traumatic experience,he/she may associate with original fear traumas,re-experience traumas,avoid things related to traumas,alert highly,feel frightening.Nightmares,insomnia,emotional numbness and personality change are also symptoms of PTSD.They could not distinguish present safe circumstances and original traumatic circumstances.The symptom is related with over-generalization of fear memory.The combination of human experiments and animal experiments are used in this research in order to collectively explore the neural mechanism of fear generalization.Human studies have shown that,hippocampus,amygdala,hypothalamus and PFC(prefrontal cortex)regulate fear generalization.PFC is a critical brain region to regulate fear generalization,fear stimulus and generalization stimuli which are similar to fear stimulus may contribute to different activation of PFC.Different attentional processes to different stimuli may lead to this phenomenon occurs.ERP(event-related potential)tool could be conducive to understand the mechanics of attention.This study wants to use ERP experiment exploring electrophysiological characteristics of fear generalization for PFC of human.The results are as follows:(1)From behavioral data,subjects rated risk level of all stimuli:values of CS ?and CS ± 20%were about 5.0.Subjects think that CS + and CS ± 20%are fear stimuli,fear generalization occurs.(2)From ERP data,afert stimuli onset 400ms,LPP was induced at PFC.LPP amplitude between CS + and CS ± 20%had no significant difference,being significantly greater than CS ± 40%and CS ± 60%.The result suggests that the participants begin to distinguish different stimuli from 400 ms,fear generalization arises.The result is consistent with the behavioral data.PFC is related with fear generalization,the more scared stimulus causes higher amplitude at PFC.Animal studies also show that mPFC is a critical brain region to regulate fear generalization,PL is associated with emotional regulation and cognitive process.Studies find that eCBs affect the regulation of fear memory,being involved in acquirement,consolidate,retrive and extinction of fear memory,regulating the emotional state as well.Clinical studies reveal that patients with PTSD smoke marijuana and its derivatives to relieve effectively symptoms.However,it is not clear that whether eCBs participate in the generalization of fear memory.Based on ERP experiment results,this experiment uses animal model of fear conditioning based on pavlov theory simulating fear generalization and injects drugs into PL of mPFC with stereotactic surgery,finally testing the behaviors of animals after drug intervention.Main results are as follows:(1)CB1 receptor antagonist(AM281)could significantly increase the freezing time of mice and significantly decrease the discrimination index of mice.It shows that AM281 could enhance fear memory generalization,eCBs are involved in and regulate the generalization of fear conditioning memory.(2)We explored low dose(“ineffective”)GABAA receptor agonist/antagonist which had no effect on fear generalization behavior by microinjection of different doses of drugs,laying the foundation for further verify pathways of the eCB.Compared with saline+AM281 group,we found that the freezing time of mice significantly increased/decreased and the discrimination index significantly decreased/increased by combining“ineffective”dose GABAA receptor agonist/antagonist with AM281.These results suggest that“ineffective”dose of GABAA receptor agonist/antagonist can significantly enhance/offset fear memory over-generalization induced by AM281.GABA pathway is involved in eCB induced fear memory generalization.(3)We explored "ineffective" NR2A antagonist by microinjection of different doses of drugs.Combining“ineffective”dose NR2A antagonist with AM281,we found:compared with saline+AM281 group,the freezing time of mice significantly decreased,being same basically with saline+vehicle group.The discrimination index of mice had no significant difference compared with saline+vehicle group.These results suggest that"ineffective" dose of NMDA receptor antagonist could completely offset fear memory generalization induced by AM281.Glutamate pathway is also involved in eCB induced fear memory generalization.To sum up,eCBs in PFC are involved in regulating the generalization of fear memory.The reason may be that eCBs activate CB1 receptor on GABAergic neurons,decreasing GABA neurotransmitters release,causing animals natural fear memory generalization for similar traumatic scenes and avoiding over-generalization.In addition,glutaminergic systems are involved in fear memory generalization,but the neural mechanisms needs to be explored further.This study provides a new research idea and research data for the pathogenesis of PTSD.eCBs may become a target for treating PTSD.It has important research and clinical significance.