Noradrenergic modulation of emotional arousal and learning

去甲肾上腺素能调节情绪唤醒和学习

• 批准号: 10041464
• 负责人: Pia-Kelsey Tiu O'Neill
• 金额: $ 17.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041464
• 关键词: Address; Affect; Air; Amygdaloid structure; Animal Behavior; Animals; Anxiety; Area; Arousal; Attention; Attention Deficit Disorder; Aversive Stimulus; Axon; Behavior; Behavioral; Behavioral Assay; Behavioral Paradigm; Behavioral trial; Biological Assay; Brain; Calcium; Cells; Code; Cognition; Computational Technique; Computer Models; Cues; Data; Decision Making; Desire for food; Detection; Development; Dimensions; Electrophysiology (science); Emotional; Emotional disorder; Environment; Exhibits; Fright; Grant; Head; Image; Imaging Techniques; Impairment; Individual; Institutes; Institution; Intervention; Laboratories; Lead; Learning; Link; Measures; Mediating; Mental Depression; Mental disorders; Mentors; Methods; Modeling; Molecular Genetics; Monitor; Motivation; Mus; Neuronal Plasticity; Neurons; Neurosciences; New York; Norepinephrine; Organism; Outcome; Pattern; Pharmacology; Phase; Physiological; Population; Positioning Attribute; Primates; Process; Property; Psychiatrist; Research; Rewards; Rodent; Role; Schizophrenia; Secure; Shapes; Signal Transduction; Stimulus; Structure; System; Techniques; Technology; Time; Training; Work; addiction; aversive conditioning; behavioral response; brain machine interface; career; cellular imaging; cognitive function; conditioning; emotional functioning; emotional stimulus; experience; experimental study; in vivo; insight; learned behavior; locus ceruleus structure; neural network; neuroregulation; noradrenergic; novel; novel therapeutic intervention; optogenetics; photoactivation; relating to nervous system; response; sensory stimulus; tenure track; two-photon; virtual

Project Summary An animal’s level of arousal dramatically influences its ability to filter, classify and associate stimuli in the environment with outcomes. These processes are necessary for an animal to rapidly evaluate dangers and rewards, and the cues that predict them. The assignment of appetitive or aversive value to a stimulus has been studied extensively and is well-understood to involve the amygdala. However, there is little known about how arousal affects emotional learning and behavior. This problem is of critical relevance because individuals with anxiety, addiction, depression, schizophrenia, and attention deficit disorder specifically exhibit impaired arousal as well as disrupted emotional processing. This proposal addresses several important, outstanding questions regarding the neural substrates of arousal, emotional learning and behavior. The locus coeruleus (LC) mediates arousal and has connections with the basolateral amygdala (BLA), but it remains unknown how the LC dynamically modulates neural activity within the BLA to cause changes in emotional learning and behavior. I intend to characterize how LC signaling shapes single-cell and ensemble representations of emotional valence and arousal in BLA, and use this information to probe the efficacy of potential interventions. My proposal has three aims that use state-of-the-art behavioral, molecular/genetic, cellular imaging, and computational techniques. In Aim 1, I utilize a novel, semi-naturalistic, dual-valence behavioral assay to study emotional learning and behavior in combination with two-photon imaging in mice to investigate how manipulations of emotional valence and arousal modulate neural representations in BLA. In Aim 2, I combine optogenetics and imaging to manipulate neural activity in LC while simultaneously measuring the effects on neural representations within the BLA and animal behavior. In Aim 3, I examine natural activity patterns of the LC as an animal transitions between different arousal levels. I will then construct a closed loop behavioral paradigm that decodes arousal levels from the LC neural activity to trigger presentations of CSs and USs to examine whether spontaneous fluctuations in LC activity can be harnessed to reprogram the BLA and its learned stimulus-outcome associations. Because neuromodulatory systems are well conserved, this effort will uncover mechanisms of neuromodulation that are likely similar in other species. My K01 training plan benefits from a team of co-mentors and advisors with extensive, proven expertise in computational approaches for describing neural dynamics, cutting-edge imaging, optogenetics, and brain- machine technologies, and understanding of psychiatric conditions. Additionally, I will complete coursework to enhance my training in contemporary perspectives on brain function, including courses on neural networks and graphical models. I will present data to computational neuroscientists at Columbia’s Center for Theoretical Neuroscience as well as to psychiatrists at the New York State Psychiatric Institute. The scientific and career training detailed in this grant will enable me to secure a tenure-track position at an academic research institution.

项目摘要 动物的唤醒水平极大地影响了其过滤，分类和关联刺激的能力 具有结果的环境。这些过程对于动物快速评估危险和 奖励以及预测它们的提示。对刺激的食欲或厌恶价值的分配已经 进行了广泛的研究，并充分理解涉及杏仁核。但是，关于如何 唤醒会影响情绪学习和行为。这个问题是至关重要的，因为与 焦虑，成瘾，抑郁，精神分裂症和注意力缺陷障碍特异性暴露于唤醒 以及破坏情感处理。该提案解决了几个重要的，杰出的问题 关于唤醒，情绪学习和行为的神经基础。 基因座（LC）介导了唤醒，并与基础杏仁核（BLA），有连接 但是，LC如何动态调节BLA内的神经活动以引起变化 情绪学习和行为。我打算表征LC信号如何形成单细胞和合奏 情感价和唤醒的表示，并使用此信息来探测效率 潜在干预措施。我的建议具有三个目标，可以使用最先进的行为，分子/遗传， 细胞成像和计算技术。在AIM 1中，我使用了一种小说，半自然的双价值 行为评估以研究情绪学习和行为以及在小鼠中的两光子成像结合使用 调查对情绪价和唤醒的操纵如何调节BLA中的神经表示。目标 2，我将光遗传学和成像结合在一起以操纵LC的神经活动，同时测量 对BLA和动物行为内神经表示的影响。在AIM 3中，我检查自然活动模式 LC作为不同唤醒水平之间的动物过渡。然后，我将构建封闭的循环行为 解码从LC神经活动到触发CSS和USS的呈现的范式 检查是否可以利用LC活性中的赞助波动来重新编程BLA及其学习 刺激结果关联。由于神经调节系统是良好的，因此这项工作将发现 在其他物种中可能相似的神经调节机制。 我的K01培训计划受益于一支拥有广泛，可靠的专业知识的联合会和顾问团队 在描述神经动力学，尖端成像，光遗传学和大脑的计算方法中 机器技术和对精神病状况的理解。此外，我将完成课程 在当代有关大脑功能的视角上加强我的培训，包括神经网络的课程和 图形模型。我将向哥伦比亚理论中心的计算神经科学家介绍数据 纽约州精神病学研究所的神经科学以及精神科医生。科学和职业 这笔赠款中详细介绍的培训将使我能够在学术研究机构获得终身任职地位。