Discovery and characterization of brain-wide neuromodulatory circuits regulating arousal

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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.