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Global and local fMRI signals driven by neurons defined optogenetically by type and wiring

Lee, Jin Hyung and Durand, Remy and Gradinaru, Viviana and Zhang, Feng and Goshen, Inbal and Kim, Dae-Shik and Fenno, Lief E. and Ramakrishnan, Charu and Deisseroth, Karl (2010) Global and local fMRI signals driven by neurons defined optogenetically by type and wiring. Nature, 465 (7299). pp. 788-792. ISSN 0028-0836. PMCID PMC3177305.

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Despite a rapidly-growing scientific and clinical brain imaging literature based on functional magnetic resonance imaging (fMRI) using blood oxygenation level-dependent (BOLD) signals, it remains controversial whether BOLD signals in a particular region can be caused by activation of local excitatory neurons. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications. Using a novel integrated technology unifying optogenetic control of inputs with high-field fMRI signal readouts, we show here that specific stimulation of local CaMKIIα-expressing excitatory neurons, either in the neocortex or thalamus, elicits positive BOLD signals at the stimulus location with classical kinetics. We also show that optogenetic fMRI (ofMRI) allows visualization of the causal effects of specific cell types defined not only by genetic identity and cell body location, but also by axonal projection target. Finally, we show that ofMRI within the living and intact mammalian brain reveals BOLD signals in downstream targets distant from the stimulus, indicating that this approach can be used to map the global effects of controlling a local cell population. In this respect, unlike both conventional fMRI studies based on correlations and fMRI with electrical stimulation that will also directly drive afferent and nearby axons, this ofMRI approach provides causal information about the global circuits recruited by defined local neuronal activity patterns. Together these findings provide an empirical foundation for the widely-used fMRI BOLD signal, and the features of ofMRI define a potent tool that may be suitable for functional circuit analysis as well as global phenotyping of dysfunctional circuitry.

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Gradinaru, Viviana0000-0001-5868-348X
Additional Information:© 2010 Macmillan Publishers Limited. Received 4 September 2009; accepted 26 April 2010. Published online 16May; corrected 10 June 2010 (see full-text HTML version for details). J.H.L. is supported by NIH training grant 1K99EB008738. R.D. is supported by an NSF Graduate Research Fellowship. V.G. is supported by SGF and SIGF (Stanford Graduate Fellowships). We acknowledge Gary H. Glover, John M. Pauly and Dwight G. Nishimura for the generous support and advice, and Cholawat Pacharinsak for assistance with rat intubation. We would also like to thank the entire Deisseroth lab for discussions and support, and Vasiliy Karasev, Zhongnan Fang, and Cory Jones for help with histological quantification and fMRI data analysis. K.D. is supported by the Keck, Snyder, Woo, Yu, McKnight, and Coulter Foundations, as well as by CIRM, NIMH, NIDA, and the NIH Director’s Pioneer Award. AUTHOR CONTRIBUTIONS: J.H.L., F.Z., R.D., V.G., and K.D. designed the experiments. D.K. provided information on the animal fMRI setup, J.H.L. developed the fMRI methods, and J.H.L. and R.D. conducted the fMRI experiments. R.D., V.G., and F.Z. conducted animal surgery and preparation. J.H.L., L.E.F., R.D. and V.G. conducted optrode recordings. R.D., V.G. and I.G. acquired the confocal microscope images. J.H.L., R.D. and I.G. performed histology, confocal imaging for quantification. C. R. prepared the viral vectors. J.H.L., R.D., V.G., F.Z., D.K. and K.D. prepared the figures and wrote the paper. K.D. supervised all aspects of the work. The authors declare that they have no competing financial interests.
Funding AgencyGrant Number
NIH(K99/R00) 1K99EB008738
NSF Graduate Research FellowshipUNSPECIFIED
Stanford Graduate FellowshipUNSPECIFIED
Stanford Interdisciplinary Graduate Fellowship ProgramUNSPECIFIED
Wallace Coulter FoundationUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)UNSPECIFIED
National Institute of Mental Health (NIMH)UNSPECIFIED
National Institute on Drug AbuseUNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
H. L. Snyder Medical FoundationUNSPECIFIED
Albert Yu and Mary Bechmann FoundationUNSPECIFIED
McKnight FoundationUNSPECIFIED
Subject Keywords:Neuroscience; Physiology
Issue or Number:7299
PubMed Central ID:PMC3177305
Record Number:CaltechAUTHORS:20121206-103459856
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35853
Deposited By: Tony Diaz
Deposited On:07 Dec 2012 22:02
Last Modified:14 Apr 2020 17:39

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