Role Of Stress In Unconditioned Stimulus Induced Reconsolidation Of Pathologic Emotional Memories

Objective: Drug addiction or post-traumatic stress disease(PTSD)is not only an individual health problem,but also has a serious impact on social public health and economic development.Drug addiction and PTSD have the common characteristics,including persistence,difficult to be extinguished pathological behaviors and high rate of relapse.Drug addiction is defined as a chronic,relapsing brain disease with main manifestations including compulsive drug-taking and drug-seeking behavior and a high-rate relapse even after long-term withdrawal.The characteristic manifestations of PTSD include repeatedly pathological recurrence of traumatic experiences.The persistence of pathological emotional memories is considered as the fundamental basis of relapse for addicts and PTSD patients.Therefore,the destruction of pathological emotional memory is an effective treatment strategy to prevent relapse in addicts and PTSD patients.A large number of studies have shown that impairment of reconsolidation of pathological emotional memories is effective to prevent the reinstatement both in drug addiction memory and classical conditioned fear memory models.Either conditioned stimulus(CS)or unconditioned stimulus(UCS)exposure can induce the reconsolidation process of pathological emotional memories,and the effect of intervening UCS-induced memory reconsolidation process is more effective than that of CS-induced memory reconsolidation process.Stress plays important and complicated roles in different stages of learning and memory.Different strength of stress has different regulating effects on the process of memory consolidation,retrieval,or reconsolidation.Studies have shown that stress can disrupt the morphine reward memory reconsolidation process induced by CS.However,the role of stress in the UCS-induced reconsolidation of pathological emotional memories,including drug reward memory and conditioned fear memory,is unclear.Therefore,we intend to use the animal model of conditioned place preference,self-administration,and conditioned fear to explore the effects of stress on the reconsolidation of unconditional stimulus-induced pathological emotional memories.Methods: In the current study,firstly,we use the morphine-induced mice conditioned place preference(CPP)model mice and the cocaine rats self-administration model(SA)to study the role of stress in UCS-induced reconsolidation of drug memories.In the mice morphine-induced CPP model,mice were trained for consecutive 8 days morphine-induce CPP;in the rat cocaine SA model,rats were trained for consecutive 10 days self-administration of cocaine to establish a stable drug rewarding memory.24 hours after last training session of CPP or SA animals received a UCS retrieval,during which mice were given a subcutaneous morphine injection(0.3 mg/kg,s.c.)or rats were given an intraperitoneal cocaine injection(3 mg/kg,i.p.)to activate drug rewarding memories.After the UCS-induced retrieval of drug rewarding memories,animals were exposed to ice water stress(forced swimming in ice water for 5 minutes)immediately or 9 hours after UCS exposure.Then test the drug-seeking behaviors under the drug priming and spontaneous recovery condition either in CPP or SA animal model.Secondly,we further studied the effect of stress on the UCS-induced reconsolidation of conditioned fear memory using the classic conditioned fear memory model.After the establishment of contextual fear conditioning(CFC)memory in mice,during which the mice received 3 foot shocks(0.8 mA,1 s/time).UCS exposure(0.3 mA,1 s)was given 24 hours after obtaining stable conditioned fear memory to activate conditioned fear memory in mice.Mice received ice water stress(forced swimming in ice water for 5 minutes)immediately or after 9 hours after UCS exposure.Then the mice were tested for the conditional fear response behaviors under the priming and spontaneous recovery condition in the CFC model.Results: First,we found that in both mice morphine CPP model and the rats cocaine SA model,ice water stress given immediately after UCS exposure could effectively reduce the drug-seeking behaviors of animals both in drug-priming-induced reinstatement test and spontaneous recovery test,but ice water stress given 9 hours after UCS exposure or without UCS exposure did not affect the expression of drug reward memories.Second,we found that in the mice CFC model,ice water stress given immediately after UCS exposure effectively attenuated the conditioned fear response,but ice water stress given 9 hours after UCS exposure or without UCS exposure did not affect the expression of fear memory in CFC model.Conclusion: 1.The administration of ice water stress during the UCS-induced drug reward memory reconsolidation impairs the drug reward memories,thereby inhibiting the drug-seeking behaviors of animals in drug-priming-induced reinstatement test and spontaneous recovery.2.The administration of ice water stress during the UCS-induced reconsolidation of conditioned fear memory impairs the reconsolidation of conditioned fear memory,thereby inhibiting fear response induce by footshock-priming reinstatement and spontaneous recovery.3.The impairment effect of ice water stress on UCS-induced reconsolidation of pathological emotional memories is UCS exposure induced retrieval-dependent and temporally specific.