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
目的研究百会穴久留针法通过脑源性神经营养因子(BDNF)/酪氨酸受体激酶B(TrkB)通路改善缺血性脑卒中小鼠神经功能的作用及机制。方法选择雄性C57BL/6J小鼠48只,随机分为假手术1组、模型1组、久留针1组、普通留针组,每组12只。后3组采用...目的研究百会穴久留针法通过脑源性神经营养因子(BDNF)/酪氨酸受体激酶B(TrkB)通路改善缺血性脑卒中小鼠神经功能的作用及机制。方法选择雄性C57BL/6J小鼠48只,随机分为假手术1组、模型1组、久留针1组、普通留针组,每组12只。后3组采用线栓法制备缺血性脑卒中模型,手术造模后第1天起久留针1组和普通留针组分别给予百会穴久留针和普通留针治疗,连续14 d。另选择雄性C57BL/6J小鼠40只,随机分为假手术2组、模型2组、久留针2组、久留针3组,每组10只。后3组采用线栓法制备缺血性脑卒中模型,针灸治疗前分别给予腺相关病毒100μl单次尾静脉注射。采用改良神经功能缺损评分(mNSS)及水迷宫实验的逃避潜伏期、目标象限停留时间、穿越原平台次数评价神经功能。结果与假手术1组比较,模型1组mNSS评分、目标象限停留时间、穿越原平台次数及缺血脑组织BDNF、TrkB表达明显降低,细胞凋亡率及裂解型半胱氨酸天冬氨酸蛋白酶3(Caspase-3)表达明显增加,差异有统计学意义(P<0.05);与模型1组比较,久留针1组和普通留针组mNSS评分、目标象限停留时间、穿越原平台次数及缺血脑组织BDNF、TrkB表达明显增加,细胞凋亡率及裂解型Caspase-3表达明显降低,且久留针1组上述变化较普通留针组更为显著,差异有统计学意义(P<0.05)。与久留针2组比较,久留针3组mNSS评分、目标象限停留时间、穿越原平台次数及缺血脑组织中BDNF表达明显降低(P<0.05),细胞凋亡率及裂解型Caspase-3表达明显增加[(16.41±2.25)%vs(7.59±1.09)%;1.46±0.16 vs 0.94±0.12,P<0.05]。结论百会穴久留针治疗对缺血性脑卒中小鼠神经功能的改善作用更为显著,激活BDNF/TrkB通路是其发挥神经保护作用的相关分子机制。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.
文摘目的研究百会穴久留针法通过脑源性神经营养因子(BDNF)/酪氨酸受体激酶B(TrkB)通路改善缺血性脑卒中小鼠神经功能的作用及机制。方法选择雄性C57BL/6J小鼠48只,随机分为假手术1组、模型1组、久留针1组、普通留针组,每组12只。后3组采用线栓法制备缺血性脑卒中模型,手术造模后第1天起久留针1组和普通留针组分别给予百会穴久留针和普通留针治疗,连续14 d。另选择雄性C57BL/6J小鼠40只,随机分为假手术2组、模型2组、久留针2组、久留针3组,每组10只。后3组采用线栓法制备缺血性脑卒中模型,针灸治疗前分别给予腺相关病毒100μl单次尾静脉注射。采用改良神经功能缺损评分(mNSS)及水迷宫实验的逃避潜伏期、目标象限停留时间、穿越原平台次数评价神经功能。结果与假手术1组比较,模型1组mNSS评分、目标象限停留时间、穿越原平台次数及缺血脑组织BDNF、TrkB表达明显降低,细胞凋亡率及裂解型半胱氨酸天冬氨酸蛋白酶3(Caspase-3)表达明显增加,差异有统计学意义(P<0.05);与模型1组比较,久留针1组和普通留针组mNSS评分、目标象限停留时间、穿越原平台次数及缺血脑组织BDNF、TrkB表达明显增加,细胞凋亡率及裂解型Caspase-3表达明显降低,且久留针1组上述变化较普通留针组更为显著,差异有统计学意义(P<0.05)。与久留针2组比较,久留针3组mNSS评分、目标象限停留时间、穿越原平台次数及缺血脑组织中BDNF表达明显降低(P<0.05),细胞凋亡率及裂解型Caspase-3表达明显增加[(16.41±2.25)%vs(7.59±1.09)%;1.46±0.16 vs 0.94±0.12,P<0.05]。结论百会穴久留针治疗对缺血性脑卒中小鼠神经功能的改善作用更为显著,激活BDNF/TrkB通路是其发挥神经保护作用的相关分子机制。
