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.

与恐惧相关的疾病，如创伤后应激障碍(PTSD)，通常以 不能抑制和消除恐惧记忆，导致与恐惧相关的行为的病理性表达。 为了通过有针对性的合理设计的治疗方法取得进展，更好地理解 调节恐惧、抑制和消退的神经回路是必要的。这项提议利用了尖端的、细胞- 针对控制杏仁核恐惧抑制和消退的回路的特定类型的方法，通过内侧 前额叶皮质(MPFC)和腹侧海马(VHPC)细胞类型的特定神经通路，以对齐 NIMH研究优先事项，通过在NIH战略计划中跨越RDoC域来确定 恐惧相关障碍的病理生理学。 我们必须了解特定类型的细胞投射到杏仁核支持恐惧的作用 抑制和恐惧消退学习。这一竞争性更新扩展了我们之前的工作解剖功能 杏仁核细胞类型特有的机制，不同地调节恐惧和消亡。除了……之外 其他神经元亚型，我们先前的工作剖析了CRF和Thy1特异性神经元群体的作用 在小鼠杏仁基底外侧核内，表现出明显的分子和生理 恐惧和灭绝路径的潜在功能。在这里，我们的目标是使用各种 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)在调节杏仁核CRF和Thy1种群中的投射。 我们预测，这种方法将识别新的药理靶点，用于恐惧抑制和 灭绝，为与恐惧相关的焦虑症寻找新的途径。我们的中心假设是 MPFC和vHPC到BLA回路中的特定通路，涉及到恐惧控制的投射 杏仁核CRF和Thy1阳性细胞参与了恐惧保留的机制。瞄准 这些特定的途径将提供对恐惧抑制控制的更多了解。这一假设将是 通过以下具体目标进行测试：1)探讨mPFC和vHPC投影对CRF和 杏仁核中控制恐惧和消亡的Thy1细胞。2)确定mPFC和vHPC中的活动模式 使用GCaMP微型显微镜和纤维光度法在杏仁核投射到恐惧控制细胞的神经元。3) 探索反复应激引发恐惧更新的突触和网络水平的机制，重点是mPFC VHPC分别投射至杏仁核CRF和Thy1阳性神经元。4)执行单元格类型 杏仁核投射mPFC和vHPC神经元(CRH/Thy1靶细胞和 具有和不具有慢性应激的细胞)。新目标的识别将 促进我们对恐惧行为背后的回路的理解，并将提供独特的途径 治疗学。