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: 10438780
• 负责人: Sachin Patel
• 金额: $ 48.36万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-21 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438780
• 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.

项目摘要的获取和灭绝的恐惧反应对生存至关重要，需要 分别促进或抑制恐惧表达的保守神经回路的修改。破坏 这些重要的生理过程被认为是压力源和创伤的发展的基础 相关疾病，包括创伤后应激障碍。了解神经元电路和突触 调节恐惧记忆形成和灭绝的机制可能对阐明 与压力有关的疾病的病理生理机制，并提供了有关基本机制的洞察力 扩展学习和记忆过程。杏仁核（CEA）的中央核是纹状体样 皮层脑结构在功能上位于边缘运动界面。最近的研究已经确定 该区域内的不同细胞类型足以产生各种以生存为导向的行为 响应包括冻结，飞行，狩猎和喂食。与当前的提案有关，非常最新的工作 已将CEA识别为恐惧学习的新颖源，并确定了负责的不同细胞类型 以冻结和类似飞行的逃生行为的形式产生恐惧的反应。尽管如此 进步，自上而下的皮质信号能够通过针对性激活选择不同的行为输出 不同的CEA细胞类型尚不清楚。在这里，我们将利用尖端的细胞类型的组合 特定的电生理学，光学遗传学，化学遗传和病毒记者方法与A结合 帕夫洛维亚人的恐惧条件和灭绝范式可以深入了解这个关键的开放问题。目标1 提案将检验以下假设，即有条件恐惧反应的获取和灭绝与 从基底外侧杏仁核（BLA）到CEA COTICOTROPHIN的相对谷氨酸能驱动的动态变化 释放因子表达（CRF+）和表达生长抑素（SOM+）神经元。我们假设恐惧 采集转移BLA兴奋性驱动器以支持SOM+神经元，这些神经元已被证明驱动了条件 冻结行为，而灭绝学习则逆转了相对输入偏见，从BLA偏爱CRF+ 神经元，我们表现出的有助于条件冻结行为的灭绝。 AIM 2将测试要求 在这种形式的经验依赖性可塑性及其必要性中，神经元活性 使用电路特异性的化学发生和行为方法表达条件恐惧和灭绝。 AIM 3将检验以下假设，即逆行内源性大麻素信号传导是重要的中介。 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+电路内的欧洲央行信号传导的调节促进了恐惧灭绝。完成 这些研究将为调节恐惧的电路和细胞类型特异性机制提供新的见解 获取和灭绝并增强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。