Cell Type Specific Genomic and Functional Dissection of Fear-Off Amygdala Pathways

恐惧杏仁核通路的细胞类型特异性基因组和功能解剖

• 批准号: 10448508
• 负责人: VADIM BOLSHAKOV
• 金额: $ 62.92万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448508
• 关键词: Affect; Amygdaloid structure; Behavior; Behavior Therapy; CRH gene; Calcium; Cell Nucleus; Cell physiology; Cells; Chronic stress; Disease; Dissection; Electrophysiology (science); Emotions; Exhibits; Exposure to; Extinction (Psychology); Fiber; Fright; Functional disorder; Future; Genes; Genomics; Hippocampus (Brain); Impairment; Implant; Medial; Mediating; Memory; Methodology; Modeling; Modification; Molecular; Molecular Profiling; Molecular Target; Mus; National Institute of Mental Health; Neural Pathways; Neuronal Plasticity; Neurons; Neurosciences; Nuclear RNA; Outcome; Pathologic; Pathway interactions; Pattern; Pharmacology; Photometry; Physiological; Pilot Projects; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; RNA; Refractive Indices; Regulation; Reporter; Research Domain Criteria; Research Priority; Role; Signal Transduction; Slice; Strategic Planning; Stress; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Trauma; United States National Institutes of Health; Viral; Work; anxiety-related disorders; base; cell type; conditioned fear; designer receptors exclusively activated by designer drugs; fear memory; in vivo; innovation; learning extinction; lens; neural circuit; novel; prevent; promoter; rational design; response; tool; transcriptome sequencing; translational approach; translational study

Fear-related disorders such as Post-Traumatic Stress Disorder (PTSD) are often characterized by an inability to inhibit and extinguish fear memories leading to pathological expression of fear-related behaviors. For progress to occur with targeted rationally-designed therapeutic approaches, a greater understanding of the neural circuitry mediating fear inhibition and extinction is needed. This proposal utilizes cutting-edge, cell- type specific approaches targeting circuits that control amygdala fear inhibition and extinction, via medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) cell-type specific neural pathways, to align with NIMH research priorities by cutting across RDoC domains in the NIH strategic plan for identifying the pathophysiology of fear-related disorders. It is critical that we understand the role of specific cell types projecting to the amygdala supporting fear inhibition and fear extinction learning. This Competitive Renewal expands our prior work dissecting function of cell-type-specific mechanisms in the amygdala that differentially mediate fear and extinction. In addition to other neuronal subtypes, our prior work dissected roles of the CRF and Thy1-specific neuronal populations within the mouse Basolateral Amygdala (BLA) nuclei, demonstrating distinct molecular and physiological functions underlying fear and extinction pathways. Here we aim to extend this work using a variety of currently available intersectional circuit dissection tools, to understand the role of medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) projections in regulating amygdala CRF and Thy1 populations. We predict that this approach will identify novel pharmacological targets for fear inhibition and extinction, pursuing new pathways for fear-related anxiety disorders. Our central hypothesis is that the specific pathways within the mPFC and vHPC to BLA circuits, involving projections to fear-controlling amygdala CRF- and Thy1-positive cells, contribute to the mechanisms of fear retention. Targeting these specific pathways will provide greater understanding of fear inhibitory control. This hypothesis will be tested through the following Specific Aims: 1) Explore the role of mPFC and vHPC projections to CRF and Thy1 cells in amygdala in control of fear and extinction. 2) Identify activity patterns in mPFC and vHPC neurons projecting to fear-controlling cells in amygdala using GCaMP miniscope and fiber photometry. 3) Explore synaptic and network-level mechanisms of repeated stress-triggered fear renewal, focusing on mPFC and vHPC projections to amygdala CRF and Thy1 positive neurons, respectively. 4) Perform cell type specific RNA profiling of amygdala-projecting mPFC and vHPC neurons (both CRH/Thy1 targeted cells and engram activity dependent cells) with and without chronic stress. The identification of novel targets will advance our understanding of circuitry underlying fear behaviors and will provide unique avenues for therapeutics.

诸如创伤后应激障碍（PTSD）等与恐惧有关的疾病通常以 无法抑制和消除恐惧记忆，从而导致与恐惧相关行为的病理表达。 为了通过有针对性的合理设计的治疗方法进行进展，对 需要神经回路介导恐惧抑制和灭绝。该提议利用尖端的细胞 类型特定的方法针对控制杏仁核的恐惧抑制和灭绝的电路，通过内侧 前额叶皮层（MPFC）和腹侧海马（VHPC）细胞类型特异性神经途径，以与 NIMH研究优先级通过在NIH战略计划中切割RDOC领域来确定 与恐惧有关的疾病的病理生理学。 至关重要的是，我们了解投射给杏仁核的特定细胞类型的作用，支持恐惧 抑制和恐惧灭绝学习。这种竞争性更新扩大了我们先前的工作解剖功能 杏仁核中细胞型特异性机制差异介导了恐惧和灭绝。此外 其他神经元亚型，我们先前的工作剖析了CRF和Thy1特异性神经元种群的作用 在小鼠基底外侧杏仁核（BLA）核中，表现出独特的分子和生理 恐惧和灭绝途径的功能。在这里，我们旨在使用各种 目前可用的交叉路口解剖工具，以了解内侧前额叶皮层的作用 （MPFC）和腹侧海马（VHPC）预测杏仁核CRF和THY1种群。 我们预测，这种方法将确定恐惧抑制和 灭绝，追求与恐惧有关的焦虑症的新途径。我们的核心假设是 MPFC和VHPC内的特定途径到BLA电路，涉及恐惧控制的预测 杏仁核CRF和THY1阳性细胞有助于保留恐惧的机制。定位 这些特定的途径将对恐惧抑制性控制有更多的了解。这个假设将是 通过以下特定目的进行测试：1）探索MPFC和VHPC预测对CRF和 杏仁核中的thy1细胞控制恐惧和灭绝。 2）确定MPFC和VHPC中的活动模式 使用GCAMP Miniscope和纤维光度法投射到杏仁核中恐惧控制细胞的神经元。 3） 探索重复应力触发的恐惧更新的突触和网络级别机制，重点关注MPFC 和VHPC对杏仁核CRF和THY1阳性神经元的预测分别进行。 4）执行细胞类型 杏仁核测射MPFC和VHPC神经元的特定RNA分析（CRH/THY1靶向细胞和 带有和没有慢性应激的Engram活性依赖性细胞）。新目标的识别将 促进我们对恐惧行为基本电路的理解，并将为 疗法。