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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

基本信息

批准号：
10836234
负责人：
VADIM BOLSHAKOV
金额：
$ 9.24万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/10836234
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 Fiber Fright Functional disorder Future Genes Genetic Genomics Hippocampus 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 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 cell type conditioned fear designer receptors exclusively activated by designer drugs fear memory in vivo innovation learning extinction lens neural circuit novel pharmacologic prevent promoter rational design response tool transcriptome sequencing translational approach translational study

项目摘要

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.

与恐惧有关的疾病，如创伤后应激障碍（PTSD），通常以无法抑制和消除恐惧记忆，导致恐惧相关行为的病理表达。为了使合理设计的靶向治疗方法取得进展，需要更好地了解需要调节恐惧抑制和消退的神经回路。这项提案利用了尖端的细胞- 类型特异性的方法，针对控制杏仁核恐惧抑制和灭绝的回路，通过中介前额叶皮层（mPFC）和腹侧海马（vHPC）细胞类型特异性神经通路，以与通过在NIH战略计划中跨越RDoC领域确定NIMH研究优先事项，恐惧相关疾病的病理生理学我们必须了解投射到杏仁核的特定细胞类型在支持恐惧中的作用抑制和恐惧消退学习。这次竞争性更新扩展了我们以前的工作解剖功能，杏仁核中差异介导恐惧和灭绝的细胞类型特异性机制。除了其他神经元亚型，我们先前的工作剖析了CRF和Thy 1特异性神经元群体的作用在小鼠基底外侧杏仁核（BLA）内，显示出不同的分子和生理学特征。恐惧和灭绝途径的潜在功能。在这里，我们的目标是扩展这项工作，使用各种目前可用的交叉回路解剖工具，以了解内侧前额叶皮质的作用，（mPFC）和腹侧海马（vHPC）的预测在调节杏仁核CRF和Thy 1人群。我们预测，这种方法将确定新的药理学目标的恐惧抑制，灭绝，寻求与恐惧相关的焦虑症的新途径。我们的中心假设是， mPFC和vHPC到BLA回路中的特定通路，涉及对恐惧控制的投射杏仁核CRF和Thy 1阳性细胞有助于恐惧保留的机制。靶向这些特定的通路将提供对恐惧抑制控制的更好理解。这一假设将是通过以下具体目标进行测试：1）探索mPFC和vHPC预测对CRF的作用，杏仁核中的Thy 1细胞控制恐惧和灭绝。2)确定mPFC和vHPC中的活动模式神经元投射到杏仁核的恐惧控制细胞使用GCaMP微型镜和纤维光度法。第三章探索重复压力触发恐惧更新的突触和网络水平机制，重点是mPFC vHPC分别向杏仁核CRF和Thy 1阳性神经元投射。4)执行单元类型杏仁核投射mPFC和vHPC神经元（CRH/Thy 1靶向细胞和印迹活性依赖细胞）。新目标的确定将推进我们对恐惧行为背后的电路的理解，并将为我们提供独特的途径，治疗学