Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Nature volume 465, pages 788–792 (2010)Cite this article

Subjects

This article has been updated

Abstract

Despite a rapidly-growing scientific and clinical brain imaging literature based on functional magnetic resonance imaging (fMRI) using blood oxygenation level-dependent (BOLD)1 signals, it remains controversial whether BOLD signals in a particular region can be caused by activation of local excitatory neurons2. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications3. Using a novel integrated technology unifying optogenetic4,5,6,7,8,9,10,11,12,13 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 correlations14 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: ofMRI: optogenetic excitation of CaMKIIα neocortical cells drives local positive BOLD.
Figure 2: Nonlocal mapping of the causal role of cells defined by location and genetic identity.
Figure 3: Control of cells defined by location, genetic identity and wiring during ofMRI.
Figure 4: Recruitment of bilateral cortices by the anterior thalamus.

Change history

  • 10 June 2010

    Minor corrections were made to Fig. 1d and to the text of the paragraph beginning, 'To assess fMRI signals ...'

References

  1. Ogawa, S. et al. Intrinsic signal changes accompanying sensory stimulation: Functional brain mapping with magnetic resonance imaging. Proc. Natl Acad. Sci. USA 89, 5951–5955 (1992)

    Article  ADS  CAS  PubMed Central  Google Scholar 

  2. Logothetis, N. K., Pauls, J., Augath, M., Trinath, T. & Oeltermann, A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412, 150–157 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Cohen, J. D. & Blum, K. I. Reward and decision. Neuron 36, 193–198 (2002)

    Article  CAS  PubMed Central  Google Scholar 

  4. Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neurosci. 8, 1263–1268 (2005)

    Article  CAS  PubMed Central  Google Scholar 

  5. Zhang, F., Wang, L. P., Boyden, E. S. & Deisseroth, K. Channelrhodopsin-2 and optical control of excitable cells. Nature Methods 3, 785–792 (2006)

    Article  CAS  PubMed Central  Google Scholar 

  6. Deisseroth, K. et al. Next-generation optical technologies for illuminating genetically targeted brain circuits. J. Neurosci. 26, 10380–10386 (2006)

    Article  CAS  PubMed Central  Google Scholar 

  7. Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007)

    Article  ADS  CAS  PubMed Central  Google Scholar 

  8. Zhang, F., Aravanis, A. M., Adamantidis, A., de Lecea, L. & Deisseroth, K. Circuit-breakers: optical technologies for probing neural signals and systems. Nature Rev. Neurosci. 8, 577–581 (2007)

    Article  CAS  Google Scholar 

  9. Aravanis, A. M. et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J. Neural Eng. 4, S143–S156 (2007)

    Article  PubMed Central  Google Scholar 

  10. Sohal, V. S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009)

    Article  ADS  CAS  PubMed Central  Google Scholar 

  11. Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009)

    Article  ADS  CAS  Google Scholar 

  12. Zhang, F. et al. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nature Protocols 5, 439–456 (2010)

    Article  CAS  PubMed Central  Google Scholar 

  13. Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010)

    Article  CAS  PubMed Central  Google Scholar 

  14. Friston, K. J. Functional and effective connectivity in neuroimaging: a synthesis. Hum. Brain Mapp. 2, 56–78 (1994)

    Article  Google Scholar 

  15. Uğurbil, K. et al. Functional mapping in the human brain using high magnetic fields. Phil. Trans. R. Soc. Lond. B 354, 1195–1213 (1999)

    Article  Google Scholar 

  16. Logothetis, N. K. What we can do and what we cannot do with fMRI. Nature 453, 869–878 (2008)

    Article  ADS  CAS  Google Scholar 

  17. Douglas, R. J. & Martin, K. A. A functional microcircuit for cat visual cortex. J. Physiol. (Lond.) 440, 735–769 (1991)

    Article  CAS  Google Scholar 

  18. Sirotin, Y. B. & Das, A. Anticipatory haemodynamic signals in sensory cortex not predicted by local neuronal activity. Nature 457, 475–479 (2009)

    Article  ADS  CAS  PubMed Central  Google Scholar 

  19. Cauli, B. et al. Cortical GABA Interneurons in neurovascular coupling: relays for subcortical vasoactive pathways. J. Neurosci. 24, 8940–8949 (2004)

    Article  CAS  PubMed Central  Google Scholar 

  20. Masamoto, K., Kim, T., Fukuda, M., Wang, P. & Kim, S. G. Relationship between neural, vascular, and BOLD signals in isoflurane-anesthetized rat somatosensory cortex. Cereb. Cortex 17, 942–950 (2007)

    Article  PubMed Central  Google Scholar 

  21. Lee, J. H. et al. Full-brain coverage and high-resolution imaging capabilities of passband b-SSFP fMRI at 3T. Magn. Reson. Med. 59, 1099–1110 (2008)

    Article  PubMed Central  Google Scholar 

  22. Lee, J. H., Hargreaves, B. A., Hu, B. S. & Nishimura, D. G. Fast 3D imaging using variable-density spiral trajectories with applications to limb perfusion. Magn. Reson. Med. 50, 1276–1285 (2003)

    Article  PubMed Central  Google Scholar 

  23. Glover, G. H. & Lee, A. T. Motion artifacts in fMRI: comparison of 2DFT with PR and spiral scan methods. Magn. Reson. Med. 33, 624–635 (1995)

    Article  CAS  PubMed Central  Google Scholar 

  24. Buxton, R. B., Wong, E. C. & Frank, L. R. Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magn. Reson. Med. 39, 855–864 (1998)

    Article  CAS  PubMed Central  Google Scholar 

  25. Boynton, G. M., Engel, S. A., Glover, G. H. & Heeger, D. J. Linear systems analysis of functional magnetic resonance imaging in human V1. J. Neurosci. 16, 4207–4221 (1996)

    Article  CAS  PubMed Central  Google Scholar 

  26. Donahue, M. J. et al. Theoretical and experimental investigation of the VASO contrast mechanism. Magn. Reson. Med. 56, 1261–1273 (2006)

    Article  PubMed Central  Google Scholar 

  27. Lauritzen, M. Reading vascular changes in brain imaging: is dendritic calcium the key? Nature Rev. Neurosci. 6, 77–85 (2005)

    Article  CAS  Google Scholar 

  28. Nir, Y., Dinstein, I., Malach, R. & Heeger, D. J. BOLD and spiking activity. Nature Neurosci. 11, 523–524, author reply 524 (2008)

    Article  CAS  PubMed Central  Google Scholar 

  29. Alloway, K. D., Olson, M. L. & Smith, J. B. Contralateral corticothalamic projections from MI whisker cortex: potential route for modulating hemispheric interactions. J. Comp. Neurol. 510, 100–116 (2008)

    Article  PubMed Central  Google Scholar 

  30. Kuramoto, E. et al. Two types of thalamocortical projections from the motor thalamic nuclei of the rat: a single neuron-tracing study using viral vectors. Cereb. Cortex 19, 2065–2077 (2009)

    Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.H.L. is supported by NIH pathway to independence grant (K99/R00) 1K99EB008738. R.D. is supported by an NSF Graduate Research Fellowship. V.G. is supported by SGF and SIGF (Stanford Graduate Fellowships). We acknowledge G. H. Glover, J. M. Pauly and D. G. Nishimura for generous support and advice, and C. Pacharinsak for assistance with rat intubation. We would also like to thank the entire Deisseroth laboratory for discussions and support, and Lee laboratory students, V. Karasev, Z. Fang and C. 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 information

Author notes

  1. Jin Hyung Lee and Remy Durand: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Electrical Engineering, Psychiatry and Biobehavioral Sciences, Bioengineering, and Radiology, University of California, Los Angeles, California 90095, USA,

    Jin Hyung Lee

  2. Department of Bioengineering, Stanford University, Stanford, California 94305, USA,

    Jin Hyung Lee, Remy Durand, Viviana Gradinaru, Feng Zhang, Inbal Goshen, Lief E. Fenno, Charu Ramakrishnan & Karl Deisseroth

  3. Department of Electrical Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea

    Dae-Shik Kim

  4. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA,

    Dae-Shik Kim

  5. Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA ,

    Karl Deisseroth

  6. CNC Program, Stanford University, Stanford, California 94305, USA ,

    Karl Deisseroth

  7. Department of Psychiatry and Behavioral Sciences, Stanford, California 94305, USA,

    Karl Deisseroth

Authors
  1. Jin Hyung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Remy Durand
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Viviana Gradinaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Inbal Goshen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dae-Shik Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lief E. Fenno
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Charu Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karl Deisseroth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.H.L., F.Z., R.D., V.G. and K.D. designed the experiments. D.-S.K. provided information on the animal fMRI setup, J.H.L. developed the fMRI methods, and J.H.L. and R.D. conducted all ofMRI 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 and confocal imaging for quantification. C.R. prepared the viral vectors. J.H.L., R.D., V.G., F.Z., D.-S.K. and K.D. prepared the figures and wrote the paper. K.D. supervised all aspects of the work.

Corresponding authors

Correspondence to Jin Hyung Lee or Karl Deisseroth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, References and Supplementary Figures S1-S5 with legends. (PDF 5117 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee, J., Durand, R., Gradinaru, V. et al. Global and local fMRI signals driven by neurons defined optogenetically by type and wiring. Nature 465, 788–792 (2010). https://doi.org/10.1038/nature09108

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09108

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing