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Millisecond-timescale, genetically targeted optical control of neural activity

Nature Neuroscience volume 8, pages 12631268 (2005) | Download Citation

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Abstract

Temporally precise, noninvasive control of activity in well-defined neuronal populations is a long-sought goal of systems neuroscience. We adapted for this purpose the naturally occurring algal protein Channelrhodopsin-2, a rapidly gated light-sensitive cation channel, by using lentiviral gene delivery in combination with high-speed optical switching to photostimulate mammalian neurons. We demonstrate reliable, millisecond-timescale control of neuronal spiking, as well as control of excitatory and inhibitory synaptic transmission. This technology allows the use of light to alter neural processing at the level of single spikes and synaptic events, yielding a widely applicable tool for neuroscientists and biomedical engineers.

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References

  1. 1.

    , & Electrophysiology of hippocampal neurons. I. Sequential invasion and synaptic organization. J. Neurophysiol. 24, 225–242 (1961).

  2. 2.

    , & Microstimulation of visual cortex affects the speed of perceptual decisions. Nat. Neurosci. 6, 891–898 (2003).

  3. 3.

    , & Cortical microstimulation influences perceptual judgements of motion direction. Nature 346, 174–177 (1990).

  4. 4.

    , & Circuit analysis of experience-dependent plasticity in the developing rat barrel cortex. Neuron 38, 277–289 (2003).

  5. 5.

    , , , & Local excitatory circuits in the intermediate gray layer of the superior colliculus. J. Neurophysiol. 81, 1424–1427 (1999).

  6. 6.

    , & Excitatory cortical neurons form fine-scale functional networks. Nature 433, 868–873 (2005).

  7. 7.

    & Rearrangements of synaptic connections in visual cortex revealed by laser photostimulation. Science 265, 255–258 (1994).

  8. 8.

    & Remote control of behavior through genetically targeted photostimulation of neurons. Cell 121, 141–152 (2005).

  9. 9.

    , , , & Light-activated ion channels for remote control of neuronal firing. Nat. Neurosci. 7, 1381–1386 (2004).

  10. 10.

    , , & Photochemical gating of heterologous ion channels: remote control over genetically designated populations of neurons. Proc. Natl. Acad. Sci. USA 100, 1352–1357 (2003).

  11. 11.

    , , & Selective photostimulation of genetically chARGed neurons. Neuron 33, 15–22 (2002).

  12. 12.

    et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl. Acad. Sci. USA 100, 13940–13945 (2003).

  13. 13.

    et al. Channelrhodopsin-1: a light-gated proton channel in green algae. Science 296, 2395–2398 (2002).

  14. 14.

    , & Two rhodopsins mediate phototaxis to low- and high-intensity light in Chlamydomonas reinhardtii. Proc. Natl. Acad. Sci. USA 99, 8689–8694 (2002).

  15. 15.

    et al. Archaeal-type rhodopsins in Chlamydomonas: model structure and intracellular localization. Biochem. Biophys. Res. Commun. 301, 711–717 (2003).

  16. 16.

    & Rhodopsin-regulated calcium currents in Chlamydomonas. Nature 351, 489–491 (1991).

  17. 17.

    & Reliability of spike timing in neocortical neurons. Science 268, 1503–1506 (1995).

  18. 18.

    , , & Critical dependence of cAMP response element-binding protein phosphorylation on L-type calcium channels supports a selective response to EPSPs in preference to action potentials. J. Neurosci. 20, 266–273 (2000).

  19. 19.

    & Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J. Neurosci. 18, 10464–10472 (1998).

  20. 20.

    & Scanning laser photostimulation: a new approach for analyzing brain circuits. J. Neurosci. Methods 54, 205–218 (1994).

  21. 21.

    & Laminar sources of synaptic input to cortical inhibitory interneurons and pyramidal neurons. Nat. Neurosci. 3, 701–707 (2000).

  22. 22.

    et al. Layer-specific intracolumnar and transcolumnar functional connectivity of layer V pyramidal cells in rat barrel cortex. J. Neurosci. 21, 3580–3592 (2001).

  23. 23.

    , , & Multiphoton stimulation of neurons. J. Neurobiol. 51, 237–247 (2002).

  24. 24.

    et al. Synfire chains and cortical songs: temporal modules of cortical activity. Science 304, 559–564 (2004).

  25. 25.

    , & Stereotyped position of local synaptic targets in neocortex. Science 293, 868–872 (2001).

  26. 26.

    & Routing of spike series by dynamic circuits in the hippocampus. Nature 429, 717–723 (2004).

  27. 27.

    , & Complex movements evoked by microstimulation of precentral cortex. Neuron 34, 841–851 (2002).

  28. 28.

    & Selective gating of visual signals by microstimulation of frontal cortex. Nature 421, 370–373 (2003).

  29. 29.

    et al. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42, 535–552 (2004).

  30. 30.

    et al. A third-generation lentivirus vector with a conditional packaging system. J. Virol. 72, 8463–8471 (1998).

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Acknowledgements

We would like to thank L. Meltzer and N. Adeishvili for experimental assistance; C. Niell, C. Chan and J.P. Levy for helpful discussions and D. Ollig for technical help. E.B. and G.N. are supported by the Max-Planck-Society and acknowledge a grant from the German Research Foundation (DFG) in the research unit 472 (Molekulare Bioenergetik). E.S.B. is supported by the Helen Hay Whitney Foundation, the Dan David Prize Foundation, and National Institute on Deafness and Other Communication Disorders, and F.Z. is supported by a US National Institutes of Health predoctoral fellowship. K.D. is supported by the National Institute of Mental Health, the Stanford Department of Bioengineering, the Stanford Department of Psychiatry and Behavioral Sciences, the Neuroscience Institute at Stanford, the National Alliance for Research On Schizophrenia and Depression and the Culpeper, Klingenstein, Whitehall, McKnight, and Albert Yu and Mary Bechmann Foundations.

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Author notes

    • Georg Nagel

    Present address: Julius-von-Sachs-Institut, University of Würzburg, Julius-von-Sachs-Platz 2–4, D-97082 Würzburg, Germany.

Affiliations

  1. Department of Bioengineering, Stanford University, 318 Campus Drive West, Stanford, California 94305, USA.

    • Edward S Boyden
    • , Feng Zhang
    •  & Karl Deisseroth
  2. Max-Planck-Institute of Biophysics, Department of Biophysical Chemistry, Max-von-Laue-Str. 3, D-60438 Frankfurt am Main, Germany.

    • Ernst Bamberg
    •  & Georg Nagel
  3. Department of Biochemistry, Chemistry and Pharmaceutics, University of Frankfurt, Marie-Curie-Str. 9, 60439 Frankfurt am Main, Germany.

    • Ernst Bamberg
  4. Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, 401 Quarry Road, Stanford, California 94305, USA.

    • Karl Deisseroth

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Karl Deisseroth.

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DOI

https://doi.org/10.1038/nn1525

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