Structural and Functional Neural Network Mediating Fear Memory and PTSD

 描述(申请人提供)：岛叶皮质是大脑中最不被了解的区域之一，因为复杂的神经解剖学涉及颗粒状、颗粒状和无颗粒状亚区，具有明显的连通性。虽然几项人类成像研究表明脑岛活动与恐惧条件反射和创伤后应激障碍(PTSD)有关，但很少有研究试图调查脑岛在啮齿类动物中的作用，在那里，更高分辨率的解剖和功能技术是可能的。以前的啮齿动物研究大多不确定使用钝性损伤策略来剖析脑岛在FER条件反射中的功能作用。现在，病毒跨突触追踪和光遗传学的最新进展使用于行为分析的离散神经回路的识别和实验操作成为可能。拟议的研究计划应用最新的单突触狂犬病病毒追踪和光遗传学方法来确定脑岛在恐惧学习过程中的作用。作为南加州大学洪-魏东博士实验室的小鼠连接组项目的一部分，向后、腹侧和背侧无颗粒岛叶皮质(AIP，AIV，AID)的顺行/逆行示踪剂共注射显示，每个区域向参与恐惧记忆的杏仁核亚核发送不同的输入模式。在这三个岛亚区中，AIP为杏仁中央核(CEAL)的外侧部分提供了最强的输入，其神经元对恐惧记忆的获得至关重要。在小鼠中使用单突触狂犬病病毒追踪方法，Aim 1实验将识别为CEA投射AIP神经元提供直接输入的神经回路，并将AIP建立为调节恐惧表达和记忆的结构性神经网络的一部分。在此解剖学基础上，在Li Zhang和Michael Fanselow博士的指导下，AIM 2实验将研究在行为恐惧条件反射和消退范式中，利用兴奋性和抑制性光遗传学向CEA投射AIP的功能作用。这些研究的结果对于我们理解调节恐惧学习的神经回路和确定治疗创伤后应激障碍的新的神经解剖学靶点具有重要的意义。为了追求这些目标，拟议中的培训补充了我强大的神经解剖学专业知识，能够调查解剖定义的神经回路的行为功能。使用最先进的病毒跟踪、光遗传学和行为技术，我将在这项培训拨款下获得的指导和指导对我成为一名研究神经网络结构/功能关系的独立首席研究员的个人目标非常重要。

 DESCRIPTION (provided by applicant): The insular cortex is one of the least understood regions of the brain due to a complex neuroanatomy involving granular, dysgranular, and agranular subregions with distinct connectivity. While several human imaging studies have implicated insula activity in fear conditioning and post-traumatic stress disorder (PTSD), few studies have attempted to investigate the role of the insula in rodents where higher resolution anatomical and functional techniques are possible. Previous rodent studies were mostly inconclusive in using blunt lesioning strategies to dissect the functional role of the insula in fer conditioning. Now, recent advances in viral transsynaptic tracing and optogenetics allow for the identification and experimental manipulation of discrete neural circuits for behavioral analysis. The proposed research plan applies the latest monosynaptic rabies viral tracing and optogenetic methods to determining the role of the insula in the fear learning process. As part of the Mouse Connectome Project in the lab of Dr. Hong-Wei Dong at USC, anterograde/retrograde tracer coinjections into the posterior, ventral, and dorsal agranular insular cortex (AIp, AIv, AId) have revealed that each subregion sends distinct patterns of input to the amygdala subnuclei involved in fear memory. Of these three insula subregions, the AIp provides the strongest input to the lateral part of the central nucleus of the amygdala (CEAl), whose neurons are critical for fear memory acquisition. Using a monosynaptic rabies viral tracing approach in mice, Aim 1 experiments will identify the neural circuits that provide direct input to CEA- projecting AIp neurons and establish the AIp as part of a structural neural network regulating the expression and memory of fear. Building upon this anatomical foundation, Aim 2 experiments under the mentorship of Drs. Li Zhang and Michael Fanselow will investigate the functional role of AIp projections to the CEA using excitatory and inhibitory optogenetics during behavioral fear conditioning and extinction paradigms. The results of these studies have important implications for our understanding of the neural circuits mediating fear learning and identifying a novel neuroanatomical target for PTSD treatment. In pursuit of these aims, the proposed training complements my strong neuroanatomical expertise with the ability to investigate the behavioral function of anatomically-defined neural circuits. Using the most advanced viral tracing, optogenetic, and behavioral techniques, the mentorship and guidance I will receive under this training grant is important for my personal goal of becoming an independent Principal Investigator studying structure/function relationships in neural networks.