Dissection of the anxiety suppression circuitry

焦虑抑制电路的剖析

• 批准号: 9415481
• 负责人: Avishek Adhikari
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9415481
• 关键词: Affect; Amygdaloid structure; Anatomy; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Aversive Stimulus; Behavior; Behavioral; Biological Assay; Brain; Brain region; Calcium; California; Cell Nucleus; Cells; Chronic; Communication; Controlled Environment; Data; Diffusion Magnetic Resonance Imaging; Dissection; Electrophysiology (science); Environment; Exposure to; Extinction (Psychology); Fright; Functional disorder; Future; Generalized Anxiety Disorder; Human; Hydrocortisone; Hyperactive behavior; In Vitro; Institution; Intercalated Cell; Lead; Life; Link; Los Angeles; Maps; Measures; Medial; Mediating; Mental disorders; Mentors; Monitor; Mus; Names; Neurons; Output; Pathway interactions; Patients; Phase; Physiology; Placebos; Prefrontal Cortex; Presynaptic Terminals; Risk; Rodent; Role; Stimulus; Symptoms; Synapses; Testing; Time; Universities; Work; anxiety-related behavior; conditioned fear; disability; excessive anxiety; experimental study; in vivo; insight; interest; neural circuit; neurophysiology; optogenetics; relating to nervous system; response

4R00MH106649-03 PI: Avishek Adhikari Modified Project Summary/Abstract Section This proposal will be moved from the mentored phase institution (Stanford University) to the R00 institution (University of California, Los Angeles). No changes have been made to the experimental plans. The current proposal is specific to the R00 phase. Avoidance of potential threats is highly adaptive, and decreases exposure to risks. However, excessive anxiety and fear leads to anxiety disorders, which impact many aspects of life, from the interpersonal to professional spheres. Although each anxiety disorder has different symptoms, they all share a core feature: mal-adaptive expression of high levels anxiety. Here, we will study how the brain suppresses anxiety. Prior studies showed the amygdala is largely responsible for generating high anxiety and fear, while the ventral medial prefrontal cortex (vmPFC) decreases these behaviors, possibly by inhibiting amygdala output. Indeed, in humans higher vmPFC activation correlates with lower amygdala activation and decreased anxiety. These data suggest the vmPFC-amygdala pathway may decrease anxiety and fear, but they rely on correlative measures, and can't directly test this hypothesis. I used optogenetics to directly test if the vmPFC-amygdala projection suppresses anxiety and fear. Activation of the vmPFCamygdala pathway robustly inhibits innate anxiety and learned fear, while inhibition of this pathway increases anxiety. Intriguingly, these behavioral effects were mediated by a poorly studied region of the amygdala called the basomedial amygdala (BMA), as direct activation of the BMA also decreases anxiety. Now, I will map neural activity in the vmPFC-BMA circuit and dissect how activation of this circuit decreases anxiety. We first showed how vmPFC activity affects the BMA in vitro (Aim 1), uncovering the microcircuit-level dynamics underlying our behavioral findings. Next, to map the activity of the vmPFC-BMA projection, I will monitor calcium transients in the vmPFC terminals in the BMA during exploration of control and anxiogenic environments (Aim 2), revealing how activity of this projection differs in animals with high and low anxiety. In Aim 3, I will characterize activity of the BMA and of its output projections during anxiety and fear. The insights resulting from this project will guide future studies on anxiety.

4R00MH106649-03 PI：Avishek Adhikari 修改项目摘要/摘要部分 本提案将从指导阶段机构（斯坦福大学）移至R 00机构（加州大学，洛杉矶）。实验计划没有改变。目前的建议是针对R 00阶段的。避免潜在的威胁是高度适应性的，并减少风险暴露。然而，过度的焦虑和恐惧会导致焦虑症，影响生活的许多方面，从人际关系到专业领域。虽然每种焦虑症都有不同的症状，但它们都有一个核心功能：高度焦虑的适应不良表达。在这里，我们将研究大脑如何抑制焦虑。先前的研究表明，杏仁核主要负责产生高度焦虑和恐惧，而腹内侧前额叶皮层（vmPFC）可能通过抑制杏仁核输出来减少这些行为。事实上，在人类中，较高的vmPFC激活与较低的杏仁核激活和减少焦虑相关。这些数据表明，vmPFC-杏仁核通路可能会减少焦虑和恐惧，但它们依赖于相关的措施，不能直接验证这一假设。我使用光遗传学直接测试VMPFC-杏仁核投射是否抑制焦虑和恐惧。vmPF Camygdala通路的激活强烈抑制先天性焦虑和习得性恐惧，而抑制该通路会增加焦虑。有趣的是，这些行为效应是由杏仁核中一个研究很少的区域介导的，称为基底内侧杏仁核（BMA），因为直接激活BMA也会降低焦虑。现在，我将绘制vmPFC-BMA回路中的神经活动，并分析该回路的激活如何减少焦虑。我们首先展示了vmPFC活动如何影响体外BMA（目标1），揭示了我们行为发现背后的微电路水平动力学。接下来，为了绘制vmPFC-BMA投射的活动，我将在探索控制和致焦虑环境（目标2）期间监测BMA中vmPFC终末的钙瞬变，揭示这种投射的活动在高焦虑和低焦虑动物中的差异。在目标3中，我将描述焦虑和恐惧期间BMA及其输出投射的活动。该项目产生的见解将指导未来对焦虑的研究。