Identification and manipulation of fear extinction engrams in prefrontal cortex

项目摘要 广泛的影响：经历一个可怕的事件会产生一个长期的记忆，这涉及到一个人的可塑性。 分布在大脑中的神经元。各种神经精神障碍，包括后， 创伤性应激障碍（PTSD），恐惧症和广泛性焦虑症的特征是不能 调节病理性恐惧;因此，理解学习性恐惧的神经机制至关重要。 可以减弱，以制定有效的治疗策略。灭绝是主要的临床治疗方法 适应不良的恐惧，但灭绝背后的神经机制仍然知之甚少。具体 目的：最近的一项关于标记和操纵记忆痕迹（或记忆痕迹）的研究表明，恐惧 记忆是由跨越多个大脑区域的“记忆印迹细胞”编码的，这些区域的活动既是必要的， 足以驱动可怕的行为。该提案的主要目标是检验灭绝 学习将促进“灭绝印记”的产生：由灭绝激活的细胞的集合 重新激活会导致恐惧的抑制。重点将放在边缘下（IL）部分， 内侧前额叶皮层，已被确定为获取和巩固的关键区域 恐惧灭绝。拟议的实验将（1）确定IL中的独特神经元集合是否编码 灭绝的刺激特定的方式或作为一般抑制剂的恐惧行为，和（2）评估因果关系 IL神经元活性在恐惧和消退学习表达中的作用。方法：活动依赖 将使用ArcCreERT 2 x R26 R-STOP-Halo-eYFP小鼠系的神经标记系统， 永久标记在情境恐惧条件反射（CFC）或消退期间活跃的神经元群体。这些 标记的细胞可以可视化以量化神经再激活或光遗传学沉默以研究它们的功能。 在恐惧获得和消失中的因果作用。培训计划：这两年的培训计划将（1）提供 申请人在光遗传学和活动依赖性神经标签系统的技术专长，（2）增加 申请人的前脑解剖学知识，功能和理论处理能力，（3）提供 向更大的科学界传播研究成果的资源，以及（4）帮助开发 一些专业发展技能，将需要使下一步的成功， 申请人的科学生涯。

PROJECT SUMMARY Broad Impact: Experiencing a fearful event creates a long-term memory that involves the plasticity of a distributed population of neurons throughout the brain. A variety of neuropsychiatric disorders—including post- traumatic stress disorder (PTSD), phobias, and generalized anxiety disorder—are characterized by the inability to regulate pathological fear; thus, it is crucial to understand the neural mechanisms through which learned fear can be attenuated in order to develop effective treatment strategies. Extinction is the primary clinical treatment for maladaptive fear,  but the neural mechanisms underlying extinction remain poorly understood. Specific Aims: A recent development for tagging and manipulating memory traces, or engrams, have shown that fear memories are encoded by `engram cells' across multiple brain regions whose activity is both necessary and sufficient for driving fearful behavior. The main goal of the proposal is to test the hypothesis that extinction learning would promote the generation of an `extinction engram': an ensemble of cells activated by extinction learning whose reactivation would lead to suppression of fear. The focus will be on the infralimbic (IL) portion of the medial prefrontal cortex, which has been identified as a critical region for the acquisition and consolidation of fear extinction. The proposed experiments will (1) determine if unique neuronal ensembles in IL code for extinction in stimulus-specific manner or act as a general inhibitor of fear behavior, and (2) assess the causal role of IL neuronal activity in the expression of fear and extinction learning. Methods: The activity-dependent neural tagging system of the ArcCreERT2 x R26R-STOP-floxed-Halo-eYFP mouse line will be used to permanently tag populations of neurons active during contextual fear conditioning (CFC) or extinction. These tagged cells can be visualized to quantify neural reactivation or silenced optogenetically to investigate their causal role in fear acquisition and extinction. Training Program: This two year training plan will (1) provide the applicant with technical expertise in optogenetics and activity-dependent neural tagging systems, (2) increase the applicant's knowledge of forebrain anatomy, function, and theoretical processing capabilities, (3) provide resources for disseminating the research findings to the larger scientific community, and (4) aide in developing a number of professional development skills that will be needed to make the next successful step in the applicant's scientific career.