皮层-杏仁核环路在恐惧重现中的作用及机制

As the theoretic basis for clinical exposure therapy, fear extinction can be used to relieve affective symptoms in neuropsychiatric disorders such as anxiety disorder and posttraumatic stress disorder. A large body of evidence indicates that fear extinction is actually a type of new learning rather than forgetting or the erasure of the original fear memory, the extinguished fear memory thus usually relapses under certain conditions, although the underlying neural circuits and their adaptation mechanisms remain largely understood. The applicant has been well-trained on electrophysiology and behavioral analysis, especially good at mechanistic studies of neural circuit plasticity (Sci Signal, 2018; EBioMedicine, 2018). Here, based on the preliminary results that fear renewal, a prevailing animal model of context-dependent relapse of extinguished fear, resulted in an enhancement of lateral amygdala (LA) neuronal excitability and the specific excitatory synaptic transmission from auditory cortex to LA, the applicant proposes to deepen the mechanistic studies on the LA-related neural circuits and their adaptation mechanisms for driving fear renewal. By taking advantages of electrophysiology, behavioral analysis, optogenetics, and pharmacology, we are going to investigate the roles of different neural projections to LA, including the cue- and context-related inputs, respectively, in fear renewal. Moreover, we expect to delineate the basic rules for the behavioral regulation of synaptic adaptions in LA and to elucidate the molecular mechanisms that different neural projections coordinate to drive fear renewal. Those results would bring more lights on understanding the dynamic regulation of fear memory after extinction and help to guide the research of translational medicine.

作为临床脑疾病暴露疗法的理论基础，恐惧消退用以纠正焦虑症、创伤后应激障碍等情感障碍症状，但其并不能消除固有恐惧记忆，记忆消退后恐惧反应在特定条件下往往重现，其相关的神经环路可塑性机制尚不清晰。申请者基于自身开展突触与神经环路可塑性的研究经验（Sci Signal, 2018; EBioMedicine, 2010），结合恐惧重现导致外侧杏仁核神经元高兴奋性以及听觉皮层特异性突触输入增强的预实验结果，提出以皮层-杏仁核环路为切入点开展恐惧消退后重现的神经机制研究，通过综合运用电生理学、行为学、光遗传学、药理学等多学科手段，探究外侧杏仁核不同输入性投射（包括线索和情景信息输入）在恐惧消退后重现中的作用，解析投射特异性突触适应性调节的规律，阐明不同神经投射协同驱动恐惧重现的环路基础及其分子机制，预期将为揭示恐惧消退后的记忆命运动态调节机理提供新思路，指导转化医学研究。

作为临床脑疾病暴露疗法的理论基础，恐惧消退用以纠正焦虑症、创伤后应激障碍等神经精神疾病，但其并不能消除固有恐惧记忆，恐惧消退后恐惧反应在特定条件下往往重现表达，其相关的神经环路可塑性机制目前尚不清晰。申请者基于自身开展离子通道与神经环路可塑性的研究经验，结合恐惧消退后重现表达导致外侧杏仁核神经元高兴奋性以及听觉皮层特异性突触输入增强的预实验结果，提出以外侧杏仁核为切入点开展恐惧消退和重现的神经环路可塑性机制研究，通过综合运用电生理学、行为学、光遗传学、药理学等多学科手段，探究外侧杏仁核不同输入性投射（包括线索和情景信息输入）在恐惧消退后重现中的作用，解析投射特异性突触适应性调节的规律，阐明不同神经投射协同驱动恐惧重现的环路基础及其分子机制，预期将为揭示恐惧消退后的记忆命运动态调节机理提供新思路，指导转化医学研究。本项目在《National Science Review》、《Molecular Psychiatry》、《Nature Communications》等国际学术期刊发表论文3篇。协助培养博士研究生毕业2人，并以联合培养的方式为国内合作单位培养研究生毕业2人；培养项目成员获各类资助项目、奖励或人才计划6项；项目组成员参加国内学术会议4人次，圆满完成了预期目标。

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