Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction

中央杏仁核谷氨酸回路在恐惧学习和消退中的作用

• 批准号: 10013294
• 负责人: Sachin Patel
• 金额: $ 54.08万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013294
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Amygdaloid structure; Anxiety; Anxiety Disorders; Back; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Cells; Corpus striatum structure; Corticotropin-Releasing Hormone; Cues; Data; Dependence; Development; Disease; Electrophysiology (science); Emotional; Endocannabinoids; Environment; Extinction (Psychology); Freezing; Fright; Functional disorder; Generalized Anxiety Disorder; Generations; Genetic Models; Glutamates; Impairment; Lateral; Learning; Literature; Major Depressive Disorder; Mediating; Mediator of activation protein; Mental disorders; Modeling; Modification; Mood Disorders; Motor; Mus; Neurons; Output; Pathway interactions; Pharmacology; Physiological; Physiological Processes; Play; Population; Post-Traumatic Stress Disorders; Production; Reporter; Research; Role; Signal Transduction; Somatostatin; Structure; Synapses; Synaptic plasticity; Testing; Training; Transgenic Organisms; Trauma; Viral; Work; anxiety states; base; behavioral response; behavioral study; cell type; cognitive process; conditioned fear; designer receptors exclusively activated by designer drugs; emotional experience; endocannabinoid signaling; experience; fear memory; feeding; insight; learning extinction; memory process; neural circuit; neuromechanism; neuronal circuitry; novel; optogenetics; presynaptic; prevent; response; stress related disorder; stressor

PROJECT SUMMARY Acquisition and extinction of learned fear responses are critical for survival and require modification of conserved neural circuits that promote or suppress fear expression, respectively. Disruption of these important physiological processes are thought to underlie the development of stressor and trauma- related disorders including posttraumatic stress disorders. Understanding the neuronal circuits and synaptic mechanisms regulating fear memory formation and extinction could have important implications for elucidating pathophysiological mechanisms of stress-related disorders and provide insight into fundamental mechanisms subserving learning and memory processes. The central nucleus of the amygdala (CeA) is a striatal-like subcortical brain structure that sits functionally at the limbic-motor interface. Recent studies have identified distinct cell-types within this region that are sufficient to generate diverse survival-oriented behavioral responses including freezing, flight, hunting, and feeding. Relevant to the current proposal, very recent work has identified the CeA as a novel locus of fear-learning and identified distinct cell-types responsible for generating learned fear responses in the form of freezing and flight-like escape behavior. Despite these advances, how top-down cortical signals are able to select distinct behavioral outputs via targeted activation of different CeA cell-types is not well understood. Here we will utilize a combination of cutting-edge cell-type- specific electrophysiological, optogenetic, chemogenetic and viral reporter approaches combined with a Pavlovian fear-conditioning and extinction paradigm to gain insight into this critical open question. Aim 1 of this proposal will test the hypothesis that acquisition and extinction of conditioned fear responses is associated with dynamic shifts in the relative glutamatergic drive from the basolateral amygdala (BLA) to CeA corticotrophin releasing factor expressing (CRF+) and somatostatin-expressing (SOM+) neurons. We hypothesize that fear acquisition shifts BLA excitatory drive to favor SOM+ neurons, which have been shown to drive conditioned freezing behavior, while extinction learning reverses the relative input bias from the BLA to favor CRF+ neurons, which we show facilitate extinction of conditioned freezing behavior. Aim 2 will test the requirement for neuronal activity in the induction of this form of experience-dependent plasticity and its necessity for the expression of conditioned fear and extinction using circuit-specific chemogenetic and behavioral approaches. Aim 3 will test the hypothesis that retrograde endocannabinoid signaling is an important mediator of experience-dependent changes in synaptic strength between the BLA and CeA CRF+ and SOM+ neurons, and that modulation of eCB signaling within the BLA-CeA-SOM+ circuit promotes fear extinction. Completion of these studies will provide novel insight into the circuit and cell-type-specific mechanisms regulating fear acquisition and extinction and enhance our understanding of the pathophysiology of stressor and trauma- related psychiatric disorders.

习得性恐惧反应的获得和消退对生存至关重要， 分别对促进或抑制恐惧表达的保守神经回路进行修改。破坏 这些重要的生理过程被认为是压力源和创伤发展的基础- 包括创伤后应激障碍。了解神经元回路和突触 调节恐惧记忆形成和消退的机制可能对阐明 应激相关疾病的病理生理机制，并提供对基本机制的见解 帮助学习和记忆过程。杏仁核中央核（CeA）是一个纹状体样的 位于边缘-运动界面的皮层下大脑结构。最近的研究表明， 不同的细胞类型在这个区域，足以产生不同的生存导向的行为 反应包括冻结，飞行，狩猎和进食。与当前提案相关，最近的工作 已经将CeA确定为恐惧学习的新位点，并确定了负责恐惧学习的不同细胞类型。 以冻结和类似逃跑的逃跑行为的形式产生习得的恐惧反应。尽管有这些 进展，自上而下的皮层信号如何能够通过有针对性的激活选择不同的行为输出， 不同的CeA细胞类型还不清楚。在这里，我们将利用尖端的细胞类型的组合， 特异性电生理学、光遗传学、化学遗传学和病毒报告基因方法， 巴甫洛夫恐惧条件反射和灭绝范式，以深入了解这个关键的开放问题。目标1 一项提案将检验条件恐惧反应的获得和消退与以下因素有关的假设： 从基底外侧杏仁核（BLA）到CeA促肾上腺皮质激素的相对兴奋性驱动的动态变化 释放因子表达（CRF+）和生长抑素表达（SOM+）神经元。我们假设恐惧 获得将BLA兴奋性驱动转移到有利于SOM+神经元，SOM+神经元已被证明可以驱动条件性 冻结行为，而消退学习逆转了BLA的相对输入偏差，有利于CRF+ 神经元，我们显示促进条件冻结行为的灭绝。目标2将测试需求 神经元活动在诱导这种形式的经验依赖性可塑性和它的必要性， 表达条件性恐惧和灭绝使用特定电路化学发生和行为的方法。 目的3将检验这一假设，即逆行内源性大麻素信号是一个重要的介导者， BLA和CeA CRF+和SOM+神经元之间突触强度的经验依赖性变化，以及 BLA-CeA-SOM+回路中eCB信号的调节促进恐惧消退。完成 这些研究将为调节恐惧的回路和细胞类型特异性机制提供新的见解 获取和灭绝，并提高我们对压力源和创伤的病理生理学的理解- 相关的精神疾病。