Noradrenergic modulation of emotional arousal and learning

项目摘要 动物的觉醒水平极大地影响其过滤、分类和关联刺激的能力 有结果的环境。这些过程对于动物快速评估危险和 奖励，以及预测它们的线索。将欲望或厌恶的价值分配给刺激是 经过了广泛的研究，并被广泛理解为累及杏仁核。然而，人们对此知之甚少。 性唤醒影响情绪学习和行为。这个问题至关重要，因为具有 焦虑、上瘾、抑郁、精神分裂症和注意力缺陷障碍具体表现为唤醒功能受损。 以及被扰乱的情绪处理。这项建议解决了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)介导觉醒并与杏仁基底外侧核(BLA)有联系， 但目前尚不清楚LC如何动态调节BLA内的神经活动以引起 情绪化学习和行为。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中的表现，并利用这些信息来探索 潜在的干预措施。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、二价态的 结合双光子成像研究小鼠情绪学习和行为的行为测试 研究情绪效价和唤醒的操作如何调节BLA中的神经表征。在AIM 2，我将光遗传学和成像相结合来操纵LC中的神经活动，同时测量 对BLA内的神经表征和动物行为的影响。在目标3中，我研究了自然活动模式 作为动物的LC在不同的唤醒水平之间转换。然后我将构建一个行为闭合环 从LC神经活动中解码唤醒水平的范式，以触发对CS和USS的呈现 检查LC活动的自发波动是否可以被利用来重新编程BLA及其习得的 刺激-结果关联。因为神经调节系统是很保守的，这项努力将发现 神经调节的机制在其他物种中可能是相似的。 我的K01培训计划得益于具有广泛、成熟的专业知识的联合导师和顾问团队 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，以及对精神疾病的了解。此外，我将完成课程作业，以 加强我对大脑功能的当代观点的培训，包括关于神经网络和 图形模型。我将向哥伦比亚大学理论研究中心的计算神经学家展示数据 神经科学以及纽约州精神病学研究所的精神病学家。科学与事业 在这笔赠款中详细介绍的培训将使我能够在一家学术研究机构获得终身教职。

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.