I propose a disruptive technology that will revolutionize our understanding of brain function, development, and disease. Because the study of neural circuits remains deeply limited by a paucity of data, we need massively parallel approaches to brain imaging that will raise data acquisition rates by over two orders of magnitude. High-throughput technologies have already revolutionized certain areas of biology such as genomics and proteomics, but neuroscience has yet to experience a growth spurt of comparable magnitude. I will construct instrumentation allowing the brain volumes of ~100 alert flies to be imaged simultaneously by two-photon fluorescence microscopy. I have chosen the fruit fly, Drosophila melanogaster, because of its small brain, its sophisticated behavioral repertoire, the large number of strains with genetically targeted alterations to brain circuitry, the utility of fluorescence imaging of neural activity in this species, and the importance of the fly as a model for the study of many brain diseases. Massively parallel brain imaging will open entirely new avenues: 1) The ability to track neural dynamics across the brains of large numbers of normal flies and those with genetically induced neural circuit perturbations will revolutionize our understanding of how neural circuits produce animal behavior;2) The now prominent role of the fruit fly as a model system for the study of developmental disorders, neurodegenerative diseases, and addiction implies we will gain significant medical insights into devastating conditions;3) Our technology will have important applications to drug screening, allowing the cellular effects of new compounds to be assessed rapidly in vivo;4) The ability to perform high-throughput time-lapse imaging of cellular events during the maturation of fly embryos will allow an additional revolution in developmental neurobiology. Applications of our technology will also be plentiful in other model organisms such as nematodes and zebrafish, profoundly impacting multiple areas of biomedicine.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1OD003560-04
Application #
7906877
Study Section
Special Emphasis Panel (ZGM1-NDPA-G (P2))
Program Officer
Jones, Warren
Project Start
2007-09-30
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$790,000
Indirect Cost
Name
Stanford University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Savall, Joan; Ho, Eric Tatt Wei; Huang, Cheng et al. (2015) Dexterous robotic manipulation of alert adult Drosophila for high-content experimentation. Nat Methods 12:657-660
Gong, Yiyang; Huang, Cheng; Li, Jin Zhong et al. (2015) High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor. Science 350:1361-6
Gong, Yiyang (2015) The evolving capabilities of rhodopsin-based genetically encoded voltage indicators. Curr Opin Chem Biol 27:84-9
Gong, Yiyang; Wagner, Mark J; Zhong Li, Jin et al. (2014) Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors. Nat Commun 5:3674
Ziv, Yaniv; Burns, Laurie D; Cocker, Eric D et al. (2013) Long-term dynamics of CA1 hippocampal place codes. Nat Neurosci 16:264-6
Chen, Jerry L; Andermann, Mark L; Keck, Tara et al. (2013) Imaging neuronal populations in behaving rodents: paradigms for studying neural circuits underlying behavior in the mammalian cortex. J Neurosci 33:17631-40
Deisseroth, Karl; Schnitzer, Mark J (2013) Engineering approaches to illuminating brain structure and dynamics. Neuron 80:568-77
Fitzgerald, James E; Lu, Ju; Schnitzer, Mark J (2012) Estimation theoretic measure of resolution for stochastic localization microscopy. Phys Rev Lett 109:048102
Fitzgerald, James E; Katsov, Alexander Y; Clandinin, Thomas R et al. (2011) Symmetries in stimulus statistics shape the form of visual motion estimators. Proc Natl Acad Sci U S A 108:12909-14
Wilt, Brian A; Burns, Laurie D; Wei Ho, Eric Tatt et al. (2009) Advances in light microscopy for neuroscience. Annu Rev Neurosci 32:435-506