Abstract

Optogenetic stimulation of genetically targeted cells is proving to be a powerful tool in the study of cellular systems, both in vitro and in vivo. However, most opsins are activated in the visible spectrum, where significant absorption and scattering of stimulating light occurs, leading to low penetration depth and less precise stimulation. Since we first (to the best of our knowledge) demonstrated two-photon optogenetic stimulation (TPOS), it has gained considerable interest in the probing of cellular circuitry by precise spatial modulation. However, all existing methods use microscope objectives and complex scanning beam geometries. Here, we report a nonscanning method based on multimode fiber to accomplish fiber-optic TPOS of cells.

© 2013 Optical Society of America

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  1. S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
    [CrossRef]
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    [CrossRef]
  4. E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
    [CrossRef]
  5. R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
    [CrossRef]
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    [CrossRef]
  7. J. D. Johansson, J. Biomed. Opt. 15, 057005 (2010).
    [CrossRef]
  8. A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
    [CrossRef]
  9. W. F. Cheong, S. A. Prahl, and A. J. Welch, IEEE J. Quantum Electron. 26, 2166 (1990).
    [CrossRef]
  10. F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat. Methods 3, 785 (2006).
    [CrossRef]
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    [CrossRef]
  12. M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
    [CrossRef]
  13. S. K. Mohanty, K. S. Mohanty, and M. W. Berns, J. Biomed. Opt. 13, 054049 (2008).
    [CrossRef]
  14. L. Fu, A. Jain, H. K. Xie, C. Cranfield, and M. Gu, Opt. Express 14, 1027 (2006).
    [CrossRef]

2012

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

2010

J. D. Johansson, J. Biomed. Opt. 15, 057005 (2010).
[CrossRef]

B. K. Andrasfalvy, B. V. Zemelman, J. Y. Tang, and A. Vaziri, Proc. Natl. Acad. Sci. USA 107, 11981 (2010).
[CrossRef]

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

2009

J. P. Rickgauer and D. W. Tank, Proc. Natl. Acad. Sci. USA 106, 15025 (2009).

2008

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

S. K. Mohanty, K. S. Mohanty, and M. W. Berns, J. Biomed. Opt. 13, 054049 (2008).
[CrossRef]

2006

L. Fu, A. Jain, H. K. Xie, C. Cranfield, and M. Gu, Opt. Express 14, 1027 (2006).
[CrossRef]

F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat. Methods 3, 785 (2006).
[CrossRef]

2005

E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat. Neurosci. 8, 1263 (2005).
[CrossRef]

2003

S. Yamaguchi and T. Tahara, Chem. Phys. Lett. 376, 237 (2003).
[CrossRef]

2002

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

1990

W. F. Cheong, S. A. Prahl, and A. J. Welch, IEEE J. Quantum Electron. 26, 2166 (1990).
[CrossRef]

Andrasfalvy, B. K.

B. K. Andrasfalvy, B. V. Zemelman, J. Y. Tang, and A. Vaziri, Proc. Natl. Acad. Sci. USA 107, 11981 (2010).
[CrossRef]

Anselmi, F.

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

Bamberg, E.

E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat. Neurosci. 8, 1263 (2005).
[CrossRef]

Bartkowiak, W.

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

Begue, A.

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

Berns, M. W.

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

S. K. Mohanty, K. S. Mohanty, and M. W. Berns, J. Biomed. Opt. 13, 054049 (2008).
[CrossRef]

Boyden, E. S.

F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat. Methods 3, 785 (2006).
[CrossRef]

E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat. Neurosci. 8, 1263 (2005).
[CrossRef]

Cheong, W. F.

W. F. Cheong, S. A. Prahl, and A. J. Welch, IEEE J. Quantum Electron. 26, 2166 (1990).
[CrossRef]

Cranfield, C.

de Sars, V.

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

Deisseroth, K.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat. Methods 3, 785 (2006).
[CrossRef]

E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat. Neurosci. 8, 1263 (2005).
[CrossRef]

Emiliani, V.

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

Fu, L.

Gluckstad, J.

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

Goshen, I.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Grewe, B.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Gu, M.

Isacoff, E. Y.

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

Jain, A.

Johansson, J. D.

J. D. Johansson, J. Biomed. Opt. 15, 057005 (2010).
[CrossRef]

Krasieva, T. B.

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

Liu, X. B.

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

Mendonca, C. R.

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

Misoguti, L.

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

Mohanty, K. S.

S. K. Mohanty, K. S. Mohanty, and M. W. Berns, J. Biomed. Opt. 13, 054049 (2008).
[CrossRef]

Mohanty, S. K.

S. K. Mohanty, K. S. Mohanty, and M. W. Berns, J. Biomed. Opt. 13, 054049 (2008).
[CrossRef]

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

Nagel, G.

E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat. Neurosci. 8, 1263 (2005).
[CrossRef]

Okamura, N.

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

Packer, A. M.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Papagiakoumou, E.

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

Peterka, D. S.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Prahl, S. A.

W. F. Cheong, S. A. Prahl, and A. J. Welch, IEEE J. Quantum Electron. 26, 2166 (1990).
[CrossRef]

Prakash, R.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Ramakrishnan, C.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Reinscheid, R. K.

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

Rickgauer, J. P.

J. P. Rickgauer and D. W. Tank, Proc. Natl. Acad. Sci. USA 106, 15025 (2009).

Schnitzer, M. J.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Schober, R.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

Schulze, P. C.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

Schwarzmaier, H. J.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

Silva, D. L.

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

Tahara, T.

S. Yamaguchi and T. Tahara, Chem. Phys. Lett. 376, 237 (2003).
[CrossRef]

Tang, J. Y.

B. K. Andrasfalvy, B. V. Zemelman, J. Y. Tang, and A. Vaziri, Proc. Natl. Acad. Sci. USA 107, 11981 (2010).
[CrossRef]

Tank, D. W.

J. P. Rickgauer and D. W. Tank, Proc. Natl. Acad. Sci. USA 106, 15025 (2009).

Ulrich, F.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

Vaziri, A.

B. K. Andrasfalvy, B. V. Zemelman, J. Y. Tang, and A. Vaziri, Proc. Natl. Acad. Sci. USA 107, 11981 (2010).
[CrossRef]

Vivas, M. G.

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

Wang, L. P.

F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat. Methods 3, 785 (2006).
[CrossRef]

Wang, N.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Welch, A. J.

W. F. Cheong, S. A. Prahl, and A. J. Welch, IEEE J. Quantum Electron. 26, 2166 (1990).
[CrossRef]

Xie, H. K.

Yamaguchi, S.

S. Yamaguchi and T. Tahara, Chem. Phys. Lett. 376, 237 (2003).
[CrossRef]

Yaroslavsky, A. N.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

Yaroslavsky, I. V.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

Yizhar, O.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Yuste, R.

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Zalesny, R.

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

Zemelman, B. V.

B. K. Andrasfalvy, B. V. Zemelman, J. Y. Tang, and A. Vaziri, Proc. Natl. Acad. Sci. USA 107, 11981 (2010).
[CrossRef]

Zhang, F.

F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat. Methods 3, 785 (2006).
[CrossRef]

E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat. Neurosci. 8, 1263 (2005).
[CrossRef]

Biophys. J.

S. K. Mohanty, R. K. Reinscheid, X. B. Liu, N. Okamura, T. B. Krasieva, and M. W. Berns, Biophys. J. 95, 3916 (2008).
[CrossRef]

Chem. Phys. Lett.

S. Yamaguchi and T. Tahara, Chem. Phys. Lett. 376, 237 (2003).
[CrossRef]

IEEE J. Quantum Electron.

W. F. Cheong, S. A. Prahl, and A. J. Welch, IEEE J. Quantum Electron. 26, 2166 (1990).
[CrossRef]

J. Biomed. Opt.

J. D. Johansson, J. Biomed. Opt. 15, 057005 (2010).
[CrossRef]

S. K. Mohanty, K. S. Mohanty, and M. W. Berns, J. Biomed. Opt. 13, 054049 (2008).
[CrossRef]

J. Phys. Chem. A

M. G. Vivas, D. L. Silva, L. Misoguti, R. Zalesny, W. Bartkowiak, and C. R. Mendonca, J. Phys. Chem. A 114, 3466 (2010).
[CrossRef]

Nat. Methods

F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat. Methods 3, 785 (2006).
[CrossRef]

E. Papagiakoumou, F. Anselmi, A. Begue, V. de Sars, J. Gluckstad, E. Y. Isacoff, and V. Emiliani, Nat. Methods 7, 848 (2010).
[CrossRef]

R. Prakash, O. Yizhar, B. Grewe, C. Ramakrishnan, N. Wang, I. Goshen, A. M. Packer, D. S. Peterka, R. Yuste, M. J. Schnitzer, and K. Deisseroth, Nat. Methods 9, 1171 (2012).
[CrossRef]

Nat. Neurosci.

E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat. Neurosci. 8, 1263 (2005).
[CrossRef]

Opt. Express

Phys. Med. Biol.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, Phys. Med. Biol. 47, 2059 (2002).
[CrossRef]

Proc. Natl. Acad. Sci. USA

J. P. Rickgauer and D. W. Tank, Proc. Natl. Acad. Sci. USA 106, 15025 (2009).

B. K. Andrasfalvy, B. V. Zemelman, J. Y. Tang, and A. Vaziri, Proc. Natl. Acad. Sci. USA 107, 11981 (2010).
[CrossRef]

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Figures (3)

Fig. 1.
Fig. 1.

(a) Schematic of conventional two-photon stimulation scanning pattern of targeted cell with femtosecond laser delivered by objective. (b) Schematic of fiber-optic two-photon activation. (c) Surface plot of the intensity pattern from a multimode fiber. Scale bar: 50 μm. (d) Composite image of two-photon fluorescence from polystyrene particles (green) and excitation intensity pattern (red).

Fig. 2.
Fig. 2.

(a) Schematic of the fiber-optic two-photon irradiation and patch-clamp setup. (b) Bright-field image of fluorescent polystyrene particles and (c) two-photon fluorescence excited by fiber-optic multimode beam. Scale bar: 100 μm. (d) Variation of fluorescence intensity of arrow-marked bead with incident laser power.

Fig. 3.
Fig. 3.

FO-TPOS of ChR2-expressing cells. (a) Bright-field image of a patch-clamped HEK cell; scale bar: 10 μm. (b) Inward current in response to macropulses (100 ms) composed of FO-TPOS pulses. Also shown is the current response due to the control laser beam. (c) Inward current responses due to FO-TPOS (at 850 nm) using different average power densities (in mW/μm2). (d) Dependence of inward current as a function of power densities (100 ms pulses) (N=4).

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