Discovery and characterization of brain-wide neuromodulatory circuits regulating arousal

项目摘要 该提案将从指导阶段机构（斯坦福大学）移至R 00机构（加州大学圣地亚哥分校）。实验计划未做任何变更，当前提案针对R 00阶段。我已经完成了我最初为该奖项的K99指导阶段提出的目标，产生了两篇第一作者出版物：Lovett-Barron等人，Cell 2017和Lovett-Barron等人，bioRxiv 2019（在Nature Neuroscience上修订）。使用全脑成像和回路操纵行为斑马鱼，我已经证明，多种神经调质在唤醒的内部状态是共同活跃的-一个全球性的大脑状态，动物将以更大的概率，准确性，速度和活力对感官刺激做出反应。正如本申请修订后的R 00目标中所详述的那样，我的新实验室将研究多种神经调质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鱼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信号的传导和接收。通过将神经调节的细胞和有机体水平联系起来，我们在这里的工作对于理解脊椎动物状态依赖行为的机制基础将具有广泛的重要意义。完成这些目标将使我能够在最初的18-24个月内申请NIMH的DP 2和R 01资助，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.