消退学习的神经环路可塑性及其分子机制

Extinction learning is a type of inhibitory learning belonging to cognitive flexibility, and acts as an important part of executive function to adapt to the changing contexts. The infralimbic ventromedial prefrontal cortex (IL/vmPFC) has been recognized to play a key role in extinction learning, however, the anatomical basis of projection circuits connecting to this region in addition to the plasticity mechanisms in these particular neuronal circuits remain not clear. The applicant is long-term engaged in studies on synaptic physiology and inhibitory circuit plasticity with an emphasis on the involvement of ion channel in these processes. The present project will focus on the studies on the extinction learning of acquired fear and conditioned taste aversion memory, by deciphering the physiological significance and molecular mechanisms of plasticity in a neuronal circuit including the basolateral amygdala, ventral hippocampus, in addition to ventromedial prefrontal cortex, identifying the amygdala-related synaptic adaptions in response to the context-dependent fear renewal after extinction, and exploring the involvement of insular cortex plasticity in extinction learning of conditioned taste aversion. Here we aim to discover novel mechanisms and rules underpinning the extinction learning, to identify new therapeutic targets for neural diseases with extinction impairment such as post-traumatic stress disorder, anxiety disorder, anorexia nervosa, and expect to shed more lights on the neuronal circuit mechanisms underlying aversive extinction learning and to guide the translational research.

消退学习是一种抑制性学习，属于认知灵活性的范畴，作为执行功能的重要组成部分，对个体适应改变的情景起到重要作用。腹内侧前额叶缘下回在消退学习中发挥关键作用，然而其上下游投射神经环路的解剖学基础和特定环路的可塑性机制并不清楚。申请者等长期开展离子通道与突触生理学及抑制性神经环路可塑性的机制研究。本项目将以习得性恐惧和条件性味觉厌恶的消退学习为模型，研究基底外侧杏仁核-腹侧海马-前额叶神经环路可塑性在恐惧消退学习中的意义及其分子机制，鉴定情景变换诱发已消退恐惧记忆重现相关的杏仁核环路的特定突触适应性改变，同时探索味觉中枢——岛叶皮层相关环路可塑性在条件性味觉厌恶消退学习中的意义，致力于发现消退学习的新机制和新规律，建立消退异常相关脑疾病如创伤后应激障碍、焦虑症、厌食症等的新靶标，预期研究结果将为揭示负性情绪依赖消退学习的神经环路机制提供新思路，指导转化医学研究。

学习和记忆是大脑的基本功能，其中消退学习是生物体适应复杂环境变化的保障。许多脑疾病，如焦虑症、创伤后应激障碍，都与消退学习障碍密切相关。基于习得性恐惧记忆的消退学习（即恐惧消退）机制研究一直是神经科学的热点。该项目面向《情感和记忆的神经环路基础》重大研究计划凝练的记忆神经环路的结构和功能这一集成方向，以生理性学习和记忆为研究对象，围绕消退学习的神经环路可塑性及其分子机制这一核心科学问题，按计划综合运用行为学、电生理学、光/化学遗传学、基于工具病毒的神经环路示踪技术、活体微尺度在体光学成像等多学科交叉手段，深入系统地研究了恐惧消退学习依赖的杏仁核-前额叶-海马相关神经环路的结构特点、功能特征及其可塑性机制，阐述了中脑皮质边缘多巴胺神经环路动态调控的细胞类型特异性编码规律，为发展靶向调控消退学习环路可塑性机制的新策略奠定了基础。项目在《Neuron》、《Science Advances》、《Science Signaling》、《Journal of Neuroscience》等国际学术期刊发表论文10篇，获得中国发明专利授权2项。培养博士后和青年教师8人次、博士研究生毕业4人，以联合培养的方式为国内合作单位培养研究生毕业3人；培养项目组成员获各类资助、奖励或人才计划5项；项目组参与组织学术会议10次，接待学术来访交流17场，项目组成员参加国内外学术会议52人次，圆满完成了预期目标。