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: 10202438
• 负责人: Sachin Patel
• 金额: $ 37.17万
• 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 2022-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202438
• 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.

项目摘要习得性恐惧反应的获得和消除对于生存和需要 分别对促进或抑制恐惧表达的保守神经回路进行修饰。中断 这些重要的生理过程被认为是应激源和创伤发展的基础。 相关障碍，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 应激相关障碍的病理生理机制，并提供对基本机制的洞察 从属于学习和记忆过程。杏仁中央核(CEA)是一种纹状体样核。 大脑皮质下的结构，功能上位于边缘-运动交界处。最近的研究发现 该区域内的不同细胞类型足以产生不同的以生存为导向的行为 反应包括冰冻、逃跑、狩猎和觅食。与目前的提案相关，最近的工作 已经确定CEA是一种新的恐惧学习场所，并确定了负责 以僵硬和逃逸行为的形式产生习得的恐惧反应。尽管如此 进展，自上而下的皮质信号如何能够通过靶向激活 不同的CEA细胞类型尚不清楚。在这里，我们将利用尖端细胞类型的组合- 特定的电生理、光遗传、化学发生和病毒报告方法与 巴甫洛夫式的恐惧制约和消亡范式，以洞察这一关键的开放问题。目标1 该提案将检验这样一种假设，即条件性恐惧反应的获得和消退与 杏仁基底外侧核(BLA)相对谷氨酸能驱动区向CEA促肾上腺皮质激素的动态转变 表达释放因子(CRF+)和生长抑素(SOM+)神经元。我们假设恐惧 习得改变了BLA的兴奋性驱动，有利于SOM+神经元，已被证明驱动条件性 冻结行为，而消亡学习逆转了来自血乳酸的相对输入偏向，有利于CRF+ 我们发现，神经元有助于消除条件性冰冻行为。目标2将测试需求 对于神经元在诱导这种形式的经验依赖性可塑性中的活动及其对 使用电路特定的化学发生和行为方法表达条件性恐惧和消亡。 目标3将检验这样的假设，即逆行内源性大麻素信号是 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 在BLA-CEA-SOM+电路中对ECB信号的调制促进了恐惧的消退。完成 这些研究将为调节恐惧的电路和特定细胞类型的机制提供新的见解 获得和消亡，并加强我们对应激源和创伤的病理生理学的理解- 相关的精神障碍。