Dissection of the anxiety suppression circuitry

焦虑抑制电路的剖析

• 批准号: 8867829
• 负责人: Avishek Adhikari
• 金额: $ 11.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867829
• 关键词: Affect; Amygdaloid structure; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Aversive Stimulus; Behavior; Behavior Control; Behavioral; Biological Assay; Brain; Brain region; Calcium; Cell Nucleus; Cells; Chronic; Communication; Consult; Controlled Environment; Data; Diffusion Magnetic Resonance Imaging; Dissection; Electrophysiology (science); Ensure; Environment; Exposure to; Extinction (Psychology); Foundations; Fright; Functional disorder; Generalized Anxiety Disorder; Human; Hydrocortisone; Hyperactive behavior; In Vitro; Intercalated Cell; Lead; Learning; Life; Link; Maps; Measures; Medial; Mediating; Mental disorders; Mentors; Methods; Monitor; Mus; Names; Neurons; Output; Pathway interactions; Patients; Phase; Physiology; Placebos; Post-Traumatic Stress Disorders; Prefrontal Cortex; Presynaptic Terminals; Research; Research Personnel; Risk; Rodent; Specific Phobia; Stimulus; Symptoms; Synapses; Testing; Time; Training; Work; anxiety treatment; anxiety-related behavior; conditioned fear; disability; excessive anxiety; experience; in vivo; insight; interest; learning extinction; neural circuit; neuronal cell body; neurophysiology; optogenetics; patch clamp; public health relevance; relating to nervous system; research study; response; skills

 DESCRIPTION (provided by applicant): Avoidance of potential threats is highly adaptive, and decreases unnecessary 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. Remarkably, optogenetic activation of the vmPFC-amygdala 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. I will first investigate how vmPFC activiy 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. Lastly, during the independent phase, in Aim 3, I will use the skills acquired during the mentored year to characterize activity of the BMA and of its output projections during anxiety and fear. Completion of these aims will make me proficient in patch-clamping and in vivo calcium monitoring. I will learn these skills under the guidance of a mentoring (Profs. K. Deisseroth and R.C. Malenka) and consulting (Profs. A. Losonczy and M.R. Warden) teams who have pioneering experience in using these methods and in training other researchers to employ them. Combining these new skills with my prior expertise in vivo electrophysiology will ensure a methodologically strong foundation to launch an independent lab, while dissecting how the poorly-studied BMA decreases anxiety will provide new research avenues. Importantly, my mentors have a remarkable track record in training independent researchers. This project involves experiments ranging from microcircuit dissection to optogenetic control of behavior, and will give us critical insight about how the brain dampens anxiety, and how and when it fails to do so.

 描述（由申请人提供）：避免潜在威胁具有高度适应性，并减少不必要的风险暴露。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。值得注意的是，vmPFC-杏仁核通路的光遗传学激活强烈抑制先天性焦虑和习得性恐惧，而抑制该通路则增加焦虑。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。我将首先研究vmPFC活动如何影响体外BMA（目标1），揭示我们的行为发现背后的微电路水平的动态。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。最后，在独立阶段，在目标3中，我将使用在指导年中获得的技能来描述BMA的活动及其在焦虑和恐惧期间的输出预测。完成这些目标将使我精通膜片钳和体内钙监测。我将在导师的指导下学习这些技能。K. Deisseroth和R.C. Malenka）和咨询（教授。A. Losonczy和M.R.在使用这些方法和培训其他研究人员使用这些方法方面具有开创性经验的团队。将这些新技能与我先前在体内电生理学方面的专业知识相结合，将确保建立一个独立实验室的方法论基础，同时剖析研究不足的BMA如何降低焦虑将提供新的研究途径。重要的是，我的导师在培训独立研究人员方面有着出色的记录。该项目涉及从微电路解剖到行为光遗传学控制的实验，并将为我们提供关于大脑如何抑制焦虑以及如何以及何时无法做到这一点的关键见解。