恐惧记忆消退后重现的神经生物学机制

恐惧记忆是导致焦虑症、创伤后应激障碍的病理性因素。记忆消退是从认知层面矫正情感障碍的有效治疗途径，但其并不能将固有恐惧记忆遗忘或消除，在特定条件下已消退的恐惧反应会再次出现，称为恐惧重现。这些记忆调控的规律大多是在行为学水平上得到阐释，尚缺乏系统的生物学机制解析。申请人率先揭示出岛叶皮层突触可塑性在味觉厌恶记忆消退中的意义，完善了海马-前额叶皮层神经环路驱动恐惧记忆消退的精细可塑性机制。本项目旨在前期工作的基础上，进一步聚焦恐惧记忆消退后重现的神经生物学机制，重点研究恐惧重现（fear renewal）中场景调节、感觉刺激、厌恶-喜好性质动态转换等基本要素的细胞和环路编码机理，鉴定海马-杏仁核-前额叶神经环路、感觉传递通路、中脑皮质边缘多巴胺神经环路在恐惧重现中的意义及其机制，预期将为揭示恐惧记忆重现的基本工作原理提供新思路，促进建立情感障碍有效治疗与管控的新策略。

Fear memory is a critical pathological factor leading to anxiety disorder and post-traumatic stress disorder. Memory extinction training is an effective cognitive behavior therapeutic approach to correct these affective disorders, which differs from forgetting and does not erase the original fear memory but only dampens the expression of fear memory. Consequently, the extinguished fear ‘relapses’ under a number of circumstances, giving rise to the behavioral phenomena including fear renewal, reinstatement, and spontaneous recovery. These rules on memory regulation are largely revealed at the behavioral level, and there is still lack of systematic analysis of the biological mechanisms underlying relapse of extinguished fear. The applicant pioneered the study on the role of insular long-term depression plasticity on extinction learning of conditioned taste aversion (Nature Communications, 2016), and identified a fine synaptic adaption mechanism of hippocampal-prefrontal correlates for driving consolidation of fear extinction memory (Science Advances, 2018). Based on these progresses, here we propose to further advance mechanistic studies on the contextual dependent relapse of extinguished fear, a particular behavioral paradigm termed as fear renewal. We will focus on the decoding the cellular and neural circuit bases for the basic components in fear renewal, including contextual regulation, sensory stimulus, in addition to the rapid switch between aversiveness and appetitiveness, respectively, by deciphering the physiological significance and its underlying mechanisms in neuronal circuits including hippocampus, amygdala, and medial prefrontal cortex, multilevel sensory pathways, in addition to the mesocorticolimbic projection. We expect to shed more lights on the basic operation rules for the relapse of extinguished fear and promote the development of novel therapeutic strategies for affective disorders.