Noradrenergic modulation of emotional arousal and learning

项目摘要 动物的唤醒水平极大地影响其过滤、分类和关联刺激的能力。 环境与成果。这些过程对于动物快速评估危险和 奖励和预测它们的线索。对刺激物的欲望值或厌恶值的分配， 被广泛研究，并被广泛理解为涉及杏仁核。然而，人们对如何做到这一点知之甚少。 唤醒影响情绪学习和行为。这一问题至关重要，因为 焦虑、成瘾、抑郁、精神分裂症和注意力缺陷障碍具体表现为唤醒受损 也会扰乱情绪处理。这项建议涉及几个重要的、悬而未决的问题 关于唤醒、情绪学习和行为的神经基础。 蓝斑（LC）介导唤醒并与基底外侧杏仁核（BLA）连接， 但LC如何动态调节BLA内的神经活动以引起BLA的变化仍然是未知的。 情绪学习和行为。我打算描述LC信号如何塑造单细胞和整体 情绪效价和唤醒在BLA的表征，并使用这些信息来探测的功效 潜在的干预。我的建议有三个目标，使用最先进的行为，分子/遗传， 细胞成像和计算技术。在目标1中，我利用了一种新颖的、半自然主义的、双重的 行为测定结合双光子成像研究小鼠的情绪学习和行为， 研究情绪效价和唤醒的操纵如何调节BLA中的神经表征。在Aim中 2、我将联合收割机和成像技术结合起来，操纵LC中的神经活动，同时测量 对BLA和动物行为内的神经表征的影响。在目标3中，我研究了自然活动模式 当动物在不同的唤醒水平之间转换时，LC的变化。然后，我将构建一个闭环行为 从LC神经活动解码唤醒水平以触发CS和US的呈现， 检查是否可以利用LC活动的自发波动来重新编程BLA及其学习 刺激-结果关联由于神经调节系统是保守的，这项工作将揭示 神经调节机制可能与其他物种相似。 我的K 01培训计划受益于一个拥有广泛、成熟专业知识的共同导师和顾问团队 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， 机器技术和对精神疾病的理解。此外，我将完成课程， 加强我对大脑功能的当代观点的培训，包括神经网络课程， 图形模型我将向哥伦比亚理论研究中心的计算神经科学家展示数据， 神经科学以及纽约州精神病研究所的精神病学家。科学和职业 本奖学金中的详细培训将使我能够在学术研究机构获得终身职位。

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.