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Published June 29, 2018 | Accepted Version + Supplemental Material
Journal Article Open

Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors


Neuromodulatory systems exert profound influences on brain function. Understanding how these systems modify the operating mode of target circuits requires measuring spatiotemporally precise neuromodulator release. We developed dLight1, an intensity-based genetically encoded dopamine indicator, to enable optical recording of dopamine dynamics with high spatiotemporal resolution in behaving mice. We demonstrated the utility of dLight1 by imaging dopamine dynamics simultaneously with pharmacological manipulation, electrophysiological or optogenetic stimulation, and calcium imaging of local neuronal activity. dLight1 enabled chronic tracking of learning-induced changes in millisecond dopamine transients in striatum. Further, we used dLight1 to image spatially distinct, functionally heterogeneous dopamine transients relevant to learning and motor control in cortex. We also validated our sensor design platform for developing norepinephrine, serotonin, melatonin, and opioid neuropeptide indicators.

Additional Information

© 2018 American Association for the Advancement of Science. Received 4 March 2018; accepted 17 May 2018. Published online 31 May 2018. We thank Brian Paul McGrew for assistance during in vitro sensor library screening and Huaiyang Cheng for producing AAV virus. Luke Lavis (Janelia Research Campus) kindly provide us NV-caged DA. Erin Carey performed cortical viral vector injections. Dr. Brett Mensh provided critical advice for writing and revising the manuscript. This project was made possible with generous help from Dr. Loren Looger (HHMI Janelia Research Campus). This work was supported by funding to L.T. (BRAIN Inititiave U01NS090604 and U01NS013522, DP2MH107056 from National Institute of Health), to A.N. (DP2NS083038, R01NS085938, P30CA014195), J.W., and M.V.Z (BRAIN Initiative U01NS013522 from National Institute of Health), to H.Z. (BRAIN Initiative U01NS094247 and R01NS104944), to D.D. (1R01MH110556 from National Institute of Health), and to V.G. (NIH DP2NS087949, NIH/NIA R01AG047664). K.M. is a DFG research fellow and recipient of a Catharina Foundation postdoctoral scholar award. V.G. is a Heritage Principal Investigator supported by the Heritage Medical Research Institute. Author contributions: L.T. and T.P conceived the project. T.P. and L.T. designed, screened and optimized sensors and characterized them in mammalian cells and cultured neurons. R.L. simulated structure of the sensor. A.M. and M.V.Z. characterized signaling properties of the sensor. W-H. X. and H.Z. characterized the sensor in organotypic brain slices. J.W. performed characterization in acute brain slices. M.H. and D.D. characterized the sensor in vivo in the dorsal striatum. J.R.C. and V.G. performed fiber photometry recordings coupled with optogenetic manipulations, calcium imaging and behavioral experiments in NAc, analyzed the data and prepared the related figures and text. M.J.J. performed hybridization chain reaction experiments and prepared relevant figures and text with input from J.R.C and V.G. K.M., R.F. and A. N. performed the two-photon imaging experiments in the cortex of behaving mice, analyzed the data and prepared the related figures and text. All authors analyzed the data. L.T. led the project. L.T., T.P. wrote the paper with contributions from all authors. Competing interests: L.T., R.L. and T.P. submitted a provisional patent application on sensor engineering. Data and materials availability: All DNA and viruses have been deposited in NCBI (accession number MH244549-MH244561), ADDGENE and The University of Pennsylvania Vector Core. All DNA plasmids and virus are available from UC Davis or designated repository under a material transfer agreement. Computer codes are deposited in github (https://github.com/GradinaruLab/dLight1/). All other data needed to evaluate the conclusion in the paper are present in the paper or the supplementary materials.

Attached Files

Accepted Version - nihms980652.pdf

Supplemental Material - aat4422-Data-S1.pdf

Supplemental Material - aat4422-Data-S2.xlsx

Supplemental Material - aat4422-Data-S3.docx

Supplemental Material - aat4422_Patriarchi_SM.pdf


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August 19, 2023
October 18, 2023