Discovery and characterization of brain-wide neuromodulatory circuits regulating arousal

项目摘要 这项建议将从导师阶段机构(斯坦福大学)转移到R00机构(加州大学圣地亚哥分校)。实验计划没有任何变化，目前的提议是专门针对R00阶段的。我已经完成了我最初为该奖项的K99指导阶段提出的目标，产生了两本第一作者出版物：Lovett-Barron等人，Cell 2017和Lovett-Barron等人，BioRxiv 2019(在自然神经科学的修订中)。通过使用全脑成像和电路操作来表现斑马鱼的行为，我已经证明了在唤醒的内部状态中，多个神经调节器是协同作用的--唤醒是一种全局大脑状态，在这种状态下，动物将以更高的概率、准确性、速度和活力对感觉刺激做出反应。正如本申请修订的R00目标中详细描述的那样，我的新实验室将研究多个神经调节剂共同调节的行为后果，以及它们背后的细胞机制。这些研究将利用斑马鱼幼体的独特功能来测量和操纵复杂唤醒依赖的视觉运动行为中神经调节器信号的发送者和接收者。通过将神经调节的细胞和机体水平联系起来，我们在这里的工作将对理解脊椎动物状态依赖行为的机制基础具有广泛的重要意义。实现这些目标将使我在最初的18-24个月内向NIMH申请DP2和R01资金，以发展我的实验室，并继续为神经科学界做出贡献。

Project Summary This proposal will be moved from the mentored phase institution (Stanford University) to the R00 institution (University of California, San Diego). No changes have been made to the experimental plans, and the current proposal is specific to the R00 phase. I have completed the aims I originally proposed for the K99 mentored phase of this award, resulting in two first-author publications: Lovett-Barron et al., Cell 2017, and Lovett-Barron et al., bioRxiv 2019 (in revision at Nature Neuroscience). Using brain-wide imaging and circuit manipulation in behaving zebrafish, I have demonstrated that multiple neuromodulators are co-active during the internal state of arousal – a global brain state where animals will respond to sensory stimuli with greater probability, accuracy, speed, and vigor. As detailed in the revised R00 aims of this application, my new lab will study the behavioral consequences of co-modulation by multiple neuromodulators, and the cellular mechanisms that underlie them. These studies will capitalize on the unique features of larval zebrafish to measure and manipulate the senders and receivers of neuromodulator signaling during complex arousal-dependent visuo-motor behavior. By linking the cellular and organismal levels of neuromodulation, our work here will be broadly important for understanding the mechanistic basis for state-dependent behaviors in vertebrates. Completing these aims will position me to apply for DP2 and R01 funding from the NIMH within my first 18-24 months, to grow my lab and continue to contribute to the neuroscience community.