Extinction of aversive memories has been a major concern in neuropsychiatric disorders such as anxiety disorders and drug addiction. The ventromedial prefrontal cortex(vmPFC) is important for memory extinction,but the...Extinction of aversive memories has been a major concern in neuropsychiatric disorders such as anxiety disorders and drug addiction. The ventromedial prefrontal cortex(vmPFC) is important for memory extinction,but the underlying mechanisms are little known. Here,we report that extinction of conditioned place aversion(CPA),a type of aversive memory associated with drug withdrawal,required activation of Rho GTPase Rac1 in the vmPFC in a brain-derived neurotrophic factor(BDNF)-dependent manner,which triggers actin polymerization via Pak1-cofilin signaling pathway,leading to synaptic localization of activity-regulated cytoskeleton-associated protein(Arc) in the vmPFC. The synaptic Arc further determines GABA_Areceptor(GABA_AR) endocytosis that is necessary and sufficient for vmP FC long-term potentiation and CPA extinction. Thus,extinction of an aversive memory associated with drug withdrawal is intriguingly controlled by Rac1-dependent GABA_AR endocytosis in the vmPFC,thereby suggesting therapeutic targets to promote extinction of the unwanted memory.展开更多
Aim:Extinction of aversive memories associated with drug withdrawal has been proposed as a therapeutic strategy for the treatment of drug addiction.However,the mechanisms underlying extinction of such memory are poorl...Aim:Extinction of aversive memories associated with drug withdrawal has been proposed as a therapeutic strategy for the treatment of drug addiction.However,the mechanisms underlying extinction of such memory are poorly understood.This study was,therefore,undertaken to investigate the role of Rho GTPase Rac1-mediated GABAAR endocytosis in the vmPFC in extinction of aversive memories associated with drug withdrawal.Methods:conditioned place aversion(CPA)was used as a model for measurement of the aversive memories of opiate withdrawal.Extinction experiments were performed as described in our previous study(Wang et al.,2012).Results:we found that extinction of CPA required activation of Rac1 in the vmPFC in a brain-derived neurotrophic factor(BDNF)-dependent manner,which triggers actin polymerization via Pak1-cofilin signaling pathway,leading to synaptic localization of activity-regulated cytoskeleton-associated protein(Arc)in the vmPFC.The synaptic Arc further determines GABAA receptor(GABAAR)endocytosis that is necessary and sufficient for vmPFC long-term potentiation and CPA extinction.Thus,extinction of an aversive memory associated with drug withdrawal is intriguingly controlled by Rac1-dependent GABAAR endocytosis in the vmPFC,thereby suggesting therapeutic targets to promote extinction of the unwanted memory.Conclusion:BDNF dependent Rac1 GTPase activation in the vmPFC contributes to aversive memory extinction by Arc-mediated GABAA receptor endocytosis.展开更多
文摘Extinction of aversive memories has been a major concern in neuropsychiatric disorders such as anxiety disorders and drug addiction. The ventromedial prefrontal cortex(vmPFC) is important for memory extinction,but the underlying mechanisms are little known. Here,we report that extinction of conditioned place aversion(CPA),a type of aversive memory associated with drug withdrawal,required activation of Rho GTPase Rac1 in the vmPFC in a brain-derived neurotrophic factor(BDNF)-dependent manner,which triggers actin polymerization via Pak1-cofilin signaling pathway,leading to synaptic localization of activity-regulated cytoskeleton-associated protein(Arc) in the vmPFC. The synaptic Arc further determines GABA_Areceptor(GABA_AR) endocytosis that is necessary and sufficient for vmP FC long-term potentiation and CPA extinction. Thus,extinction of an aversive memory associated with drug withdrawal is intriguingly controlled by Rac1-dependent GABA_AR endocytosis in the vmPFC,thereby suggesting therapeutic targets to promote extinction of the unwanted memory.
文摘Aim:Extinction of aversive memories associated with drug withdrawal has been proposed as a therapeutic strategy for the treatment of drug addiction.However,the mechanisms underlying extinction of such memory are poorly understood.This study was,therefore,undertaken to investigate the role of Rho GTPase Rac1-mediated GABAAR endocytosis in the vmPFC in extinction of aversive memories associated with drug withdrawal.Methods:conditioned place aversion(CPA)was used as a model for measurement of the aversive memories of opiate withdrawal.Extinction experiments were performed as described in our previous study(Wang et al.,2012).Results:we found that extinction of CPA required activation of Rac1 in the vmPFC in a brain-derived neurotrophic factor(BDNF)-dependent manner,which triggers actin polymerization via Pak1-cofilin signaling pathway,leading to synaptic localization of activity-regulated cytoskeleton-associated protein(Arc)in the vmPFC.The synaptic Arc further determines GABAA receptor(GABAAR)endocytosis that is necessary and sufficient for vmPFC long-term potentiation and CPA extinction.Thus,extinction of an aversive memory associated with drug withdrawal is intriguingly controlled by Rac1-dependent GABAAR endocytosis in the vmPFC,thereby suggesting therapeutic targets to promote extinction of the unwanted memory.Conclusion:BDNF dependent Rac1 GTPase activation in the vmPFC contributes to aversive memory extinction by Arc-mediated GABAA receptor endocytosis.
