Abstract

The rapid increase in the number and quality of fluorescent reporters and optogenetic actuators has yielded a powerful set of tools for recording and controlling cellular state and function. To achieve the full benefit of these tools requires improved optical systems with high light collection efficiency, high spatial and temporal resolution, and patterned optical stimulation, in a wide field of view (FOV). Here we describe our ‘Firefly’ microscope, which achieves these goals in a Ø6 mm FOV. The Firefly optical system is optimized for simultaneous photostimulation and fluorescence imaging in cultured cells. All but one of the optical elements are commercially available, yet the microscope achieves 10-fold higher light collection efficiency at its design magnification than the comparable commercially available microscope using the same objective. The Firefly microscope enables all-optical electrophysiology (‘Optopatch’) in cultured neurons with a throughput and information content unmatched by other neuronal phenotyping systems. This capability opens possibilities in disease modeling and phenotypic drug screening. We also demonstrate applications of the system to voltage and calcium recordings in human induced pluripotent stem cell derived cardiomyocytes.

© 2017 Optical Society of America

Full Article  |  PDF Article
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References

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2017 (3)

H. E. Johnson, Y. Goyal, N. L. Pannucci, T. Schüpbach, S. Y. Shvartsman, and J. E. Toettcher, “The Spatiotemporal Limits of Developmental Erk Signaling,” Dev. Cell 40(2), 185–192 (2017).
[PubMed]

C. M. Hempel, C. A. Werley, G. T. Dempsey, D. J. Gerber, I. Ellen, and L. B. Biomap, “Targeting neuronal function for CNS drug discovery,” Drug Discov. Today. Technol. 23, 17–25 (2017).
[PubMed]

C. A. Werley, M.-P. Chien, J. Gaublomme, K. Shekhar, V. Butty, B. A. Yi, J. M. Kralj, W. Bloxham, L. A. Boyer, A. Regev, and A. E. Cohen, “Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing,” PLoS One 12(3), e0172671 (2017).
[PubMed]

2016 (10)

J. N. Stirman, I. T. Smith, M. W. Kudenov, and S. L. Smith, “Wide field-of-view, multi-region, two-photon imaging of neuronal activity in the mammalian brain,” Nat. Biotechnol. 34(8), 857–862 (2016).
[PubMed]

G. McConnell, J. Trägårdh, R. Amor, J. Dempster, E. Reid, and W. B. Amos, “A novel optical microscope for imaging large embryos and tissue volumes with sub-cellular resolution throughout,” eLife 5, e18659 (2016).
[PubMed]

N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, 1–20 (2016).
[PubMed]

G. T. Dempsey, K. W. Chaudhary, N. Atwater, C. Nguyen, B. S. Brown, J. D. McNeish, A. E. Cohen, and J. M. Kralj, “Cardiotoxicity screening with simultaneous optogenetic pacing, voltage imaging and calcium imaging,” J. Pharmacol. Toxicol. Methods 81, 240–250 (2016).
[PubMed]

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

A. E. Cohen, “Optogenetics: Turning the Microscope on Its Head,” Biophys. J. 110(5), 997–1003 (2016).
[PubMed]

M. Z. Lin and M. J. Schnitzer, “Genetically encoded indicators of neuronal activity,” Nat. Neurosci. 19(9), 1142–1153 (2016).
[PubMed]

H. Yumerefendi, A. M. Lerner, S. P. Zimmerman, K. Hahn, J. E. Bear, B. D. Strahl, and B. Kuhlman, “Light-induced nuclear export reveals rapid dynamics of epigenetic modifications,” Nat. Chem. Biol. 12(6), 399–401 (2016).
[PubMed]

H. Wang, M. Vilela, A. Winkler, M. Tarnawski, I. Schlichting, H. Yumerefendi, B. Kuhlman, R. Liu, G. Danuser, and K. M. Hahn, “LOVTRAP: An Optogenetic System for Photoinduced Protein Dissociation,” Nat. Methods 13(9), 755–758 (2016).
[PubMed]

T. H. Kim, Y. Zhang, J. Lecoq, J. C. Jung, J. Li, H. Zeng, C. M. Niell, and M. J. Schnitzer, “Long-Term Optical Access to an Estimated One Million Neurons in the Live Mouse Cortex,” Cell Reports 17(12), 3385–3394 (2016).
[PubMed]

2015 (6)

M.-P. Chien, C. A. Werley, S. L. Farhi, and A. E. Cohen, “Photostick: a method for selective isolation of target cells from culture,” Chem. Sci. (Camb.) 6(3), 1701–1705 (2015).
[PubMed]

P. S. Tsai, C. Mateo, J. J. Field, C. B. Schaffer, M. E. Anderson, and D. Kleinfeld, “Ultra-large field-of-view two-photon microscopy,” Opt. Express 23(11), 13833–13847 (2015).
[PubMed]

K. Zhang and B. Cui, “Optogenetic control of intracellular signaling pathways,” Trends Biotechnol. 33(2), 92–100 (2015).
[PubMed]

V. Emiliani, A. E. Cohen, K. Deisseroth, and M. Häusser, “All-Optical Interrogation of Neural Circuits,” J. Neurosci. 35(41), 13917–13926 (2015).
[PubMed]

F. Schneider, C. Grimm, and P. Hegemann, “Biophysics of Channelrhodopsin,” Annu. Rev. Biophys. 44, 167–186 (2015).
[PubMed]

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
[PubMed]

2014 (3)

J. H. Hou, J. M. Kralj, A. D. Douglass, F. Engert, and A. E. Cohen, “Simultaneous mapping of membrane voltage and calcium in zebrafish heart in vivo reveals chamber-specific developmental transitions in ionic currents,” Front. Physiol. 5(AUG), 344 (2014).
[PubMed]

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

2013 (6)

T.-W. Chen, T. J. Wardill, Y. Sun, S. R. Pulver, S. L. Renninger, A. Baohan, E. R. Schreiter, R. A. Kerr, M. B. Orger, V. Jayaraman, L. L. Looger, K. Svoboda, and D. S. Kim, “Ultrasensitive fluorescent proteins for imaging neuronal activity,” Nature 499(7458), 295–300 (2013).
[PubMed]

T. Terai and T. Nagano, “Small-molecule fluorophores and fluorescent probes for bioimaging,” Pflugers Arch. 465(3), 347–359 (2013).
[PubMed]

L. J. Bugaj, A. T. Choksi, C. K. Mesuda, R. S. Kane, and D. V. Schaffer, “Optogenetic protein clustering and signaling activation in mammalian cells,” Nat. Methods 10(3), 249–252 (2013).
[PubMed]

B. Kim and M. Z. Lin, “Optobiology: optical control of biological processes via protein engineering,” Biochem. Soc. Trans. 41(5), 1183–1188 (2013).
[PubMed]

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Methods 10(5), 413–420 (2013).
[PubMed]

J. Birk, M. Meyer, I. Aller, H. G. Hansen, A. Odermatt, T. P. Dick, A. J. Meyer, and C. Appenzeller-Herzog, “Endoplasmic reticulum: reduced and oxidized glutathione revisited,” J. Cell Sci. 126(Pt 7), 1604–1617 (2013).
[PubMed]

2012 (2)

G. Katona, G. Szalay, P. Maák, A. Kaszás, M. Veress, D. Hillier, B. Chiovini, E. S. Vizi, B. Roska, and B. Rózsa, “Fast two-photon in vivo imaging with three-dimensional random-access scanning in large tissue volumes,” Nat. Methods 9(2), 201–208 (2012).
[PubMed]

H. Liu, G. Gomez, S. Lin, S. Lin, and C. Lin, “Optogenetic Control of Transcription in Zebrafish,” PLoS One 7(11), e50738 (2012).
[PubMed]

2011 (4)

R. H. Newman, M. D. Fosbrink, and J. Zhang, “Genetically encodable Fluorescent Biosensors for Tracking Signaling Dynamics in Living Cells,” Chem. Rev. 111(5), 3614–3666 (2011).
[PubMed]

S. Mehta and J. Zhang, “Reporting from the field: genetically encoded fluorescent reporters uncover signaling dynamics in living biological systems,” Annu. Rev. Biochem. 80, 375–401 (2011).
[PubMed]

J. Y. Lin, “A user’s guide to channelrhodopsin variants: features, limitations and future developments,” Exp. Physiol. 96(1), 19–25 (2011).
[PubMed]

J. M. Kralj, A. D. Douglass, D. R. Hochbaum, D. Maclaurin, and A. E. Cohen, “Optical recording of action potentials in mammalian neurons using a microbial rhodopsin,” Nat. Methods 9(1), 90–95 (2011).
[PubMed]

2010 (2)

A. Cretu, P. Castagnino, and R. Assoian, “Studying the effects of matrix stiffness on cellular function using acrylamide-based hydrogels,” J. Vis. Exp. 42, 7–11 (2010).
[PubMed]

D. Qin, Y. Xia, and G. M. Whitesides, “Soft lithography for micro- and nanoscale patterning,” Nat. Protoc. 5(3), 491–502 (2010).
[PubMed]

2009 (1)

L. M. DiPilato and J. Zhang, “The role of membrane microdomains in shaping β2-adrenergic receptor-mediated cAMP dynamics,” Mol. Biosyst. 5(8), 832–837 (2009).
[PubMed]

2008 (1)

M. Gutscher, A.-L. Pauleau, L. Marty, T. Brach, G. H. V. Wabnitz, Y. Samstag, A. J. Meyer, and T. P. Dick, “Real-time imaging of the intracellular glutathione redox potential,” Nat. Methods 5(6), 553–559 (2008).
[PubMed]

2006 (1)

S. Terhzaz, T. D. Southall, K. S. Lilley, L. Kean, A. K. Allan, S. A. Davies, and J. A. T. Dow, “Differential gel electrophoresis and transgenic mitochondrial calcium reporters demonstrate spatiotemporal filtering in calcium control of mitochondria,” J. Biol. Chem. 281(27), 18849–18858 (2006).
[PubMed]

2005 (1)

M. Geraerts, M. Michiels, V. Baekelandt, Z. Debyser, and R. Gijsbers, “Upscaling of lentiviral vector production by tangential flow filtration,” J. Gene Med. 7(10), 1299–1310 (2005).
[PubMed]

2004 (1)

J. Huisken, J. Swoger, F. Del Bene, J. Wittbrodt, and E. H. K. Stelzer, “Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).

2001 (2)

N. Mochizuki, S. Yamashita, K. Kurokawa, Y. Ohba, T. Nagai, A. Miyawaki, and M. Matsuda, “Spatio-temporal images of growth-factor-induced activation of Ras and Rap1,” Nature 411(6841), 1065–1068 (2001).
[PubMed]

C. C. H. Petersen and B. Sakmann, “Functionally Independent Columns of Rat Somatosensory Barrel Cortex Revealed with Voltage-Sensitive Dye Imaging,” J. Neurosci. 21(21), 8435–8446 (2001).
[PubMed]

1998 (1)

G. Miesenböck, D. A. De Angelis, and J. E. Rothman, “Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins,” Nature 394(6689), 192–195 (1998).
[PubMed]

Ahrens, M. B.

M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Methods 10(5), 413–420 (2013).
[PubMed]

Allan, A. K.

S. Terhzaz, T. D. Southall, K. S. Lilley, L. Kean, A. K. Allan, S. A. Davies, and J. A. T. Dow, “Differential gel electrophoresis and transgenic mitochondrial calcium reporters demonstrate spatiotemporal filtering in calcium control of mitochondria,” J. Biol. Chem. 281(27), 18849–18858 (2006).
[PubMed]

Aller, I.

J. Birk, M. Meyer, I. Aller, H. G. Hansen, A. Odermatt, T. P. Dick, A. J. Meyer, and C. Appenzeller-Herzog, “Endoplasmic reticulum: reduced and oxidized glutathione revisited,” J. Cell Sci. 126(Pt 7), 1604–1617 (2013).
[PubMed]

Amor, R.

G. McConnell, J. Trägårdh, R. Amor, J. Dempster, E. Reid, and W. B. Amos, “A novel optical microscope for imaging large embryos and tissue volumes with sub-cellular resolution throughout,” eLife 5, e18659 (2016).
[PubMed]

Amos, W. B.

G. McConnell, J. Trägårdh, R. Amor, J. Dempster, E. Reid, and W. B. Amos, “A novel optical microscope for imaging large embryos and tissue volumes with sub-cellular resolution throughout,” eLife 5, e18659 (2016).
[PubMed]

Anderson, M. E.

Anderson, S. A.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Appenzeller-Herzog, C.

J. Birk, M. Meyer, I. Aller, H. G. Hansen, A. Odermatt, T. P. Dick, A. J. Meyer, and C. Appenzeller-Herzog, “Endoplasmic reticulum: reduced and oxidized glutathione revisited,” J. Cell Sci. 126(Pt 7), 1604–1617 (2013).
[PubMed]

Assoian, R.

A. Cretu, P. Castagnino, and R. Assoian, “Studying the effects of matrix stiffness on cellular function using acrylamide-based hydrogels,” J. Vis. Exp. 42, 7–11 (2010).
[PubMed]

Atwater, N.

G. T. Dempsey, K. W. Chaudhary, N. Atwater, C. Nguyen, B. S. Brown, J. D. McNeish, A. E. Cohen, and J. M. Kralj, “Cardiotoxicity screening with simultaneous optogenetic pacing, voltage imaging and calcium imaging,” J. Pharmacol. Toxicol. Methods 81, 240–250 (2016).
[PubMed]

Avery, M. C.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Baek, M.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Baekelandt, V.

M. Geraerts, M. Michiels, V. Baekelandt, Z. Debyser, and R. Gijsbers, “Upscaling of lentiviral vector production by tangential flow filtration,” J. Gene Med. 7(10), 1299–1310 (2005).
[PubMed]

Baldwin, H. A.

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
[PubMed]

Baohan, A.

T.-W. Chen, T. J. Wardill, Y. Sun, S. R. Pulver, S. L. Renninger, A. Baohan, E. R. Schreiter, R. A. Kerr, M. B. Orger, V. Jayaraman, L. L. Looger, K. Svoboda, and D. S. Kim, “Ultrasensitive fluorescent proteins for imaging neuronal activity,” Nature 499(7458), 295–300 (2013).
[PubMed]

Bear, J. E.

H. Yumerefendi, A. M. Lerner, S. P. Zimmerman, K. Hahn, J. E. Bear, B. D. Strahl, and B. Kuhlman, “Light-induced nuclear export reveals rapid dynamics of epigenetic modifications,” Nat. Chem. Biol. 12(6), 399–401 (2016).
[PubMed]

Biomap, L. B.

C. M. Hempel, C. A. Werley, G. T. Dempsey, D. J. Gerber, I. Ellen, and L. B. Biomap, “Targeting neuronal function for CNS drug discovery,” Drug Discov. Today. Technol. 23, 17–25 (2017).
[PubMed]

Birdsey-Benson, A.

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Birk, J.

J. Birk, M. Meyer, I. Aller, H. G. Hansen, A. Odermatt, T. P. Dick, A. J. Meyer, and C. Appenzeller-Herzog, “Endoplasmic reticulum: reduced and oxidized glutathione revisited,” J. Cell Sci. 126(Pt 7), 1604–1617 (2013).
[PubMed]

Bloxham, W.

C. A. Werley, M.-P. Chien, J. Gaublomme, K. Shekhar, V. Butty, B. A. Yi, J. M. Kralj, W. Bloxham, L. A. Boyer, A. Regev, and A. E. Cohen, “Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing,” PLoS One 12(3), e0172671 (2017).
[PubMed]

Boccardo, S.

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
[PubMed]

Boulting, G. L.

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

Boyden, E. S.

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Boyer, L. A.

C. A. Werley, M.-P. Chien, J. Gaublomme, K. Shekhar, V. Butty, B. A. Yi, J. M. Kralj, W. Bloxham, L. A. Boyer, A. Regev, and A. E. Cohen, “Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing,” PLoS One 12(3), e0172671 (2017).
[PubMed]

Brach, T.

M. Gutscher, A.-L. Pauleau, L. Marty, T. Brach, G. H. V. Wabnitz, Y. Samstag, A. J. Meyer, and T. P. Dick, “Real-time imaging of the intracellular glutathione redox potential,” Nat. Methods 5(6), 553–559 (2008).
[PubMed]

Brown, B. S.

G. T. Dempsey, K. W. Chaudhary, N. Atwater, C. Nguyen, B. S. Brown, J. D. McNeish, A. E. Cohen, and J. M. Kralj, “Cardiotoxicity screening with simultaneous optogenetic pacing, voltage imaging and calcium imaging,” J. Pharmacol. Toxicol. Methods 81, 240–250 (2016).
[PubMed]

Bugaj, L. J.

L. J. Bugaj, A. T. Choksi, C. K. Mesuda, R. S. Kane, and D. V. Schaffer, “Optogenetic protein clustering and signaling activation in mammalian cells,” Nat. Methods 10(3), 249–252 (2013).
[PubMed]

Butty, V.

C. A. Werley, M.-P. Chien, J. Gaublomme, K. Shekhar, V. Butty, B. A. Yi, J. M. Kralj, W. Bloxham, L. A. Boyer, A. Regev, and A. E. Cohen, “Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing,” PLoS One 12(3), e0172671 (2017).
[PubMed]

Callaway, E. M.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Campbell, R. E.

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

Carpenter, E. J.

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Castagnino, P.

A. Cretu, P. Castagnino, and R. Assoian, “Studying the effects of matrix stiffness on cellular function using acrylamide-based hydrogels,” J. Vis. Exp. 42, 7–11 (2010).
[PubMed]

Chaudhary, K. W.

G. T. Dempsey, K. W. Chaudhary, N. Atwater, C. Nguyen, B. S. Brown, J. D. McNeish, A. E. Cohen, and J. M. Kralj, “Cardiotoxicity screening with simultaneous optogenetic pacing, voltage imaging and calcium imaging,” J. Pharmacol. Toxicol. Methods 81, 240–250 (2016).
[PubMed]

Chen, Q.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Chen, T.-W.

T.-W. Chen, T. J. Wardill, Y. Sun, S. R. Pulver, S. L. Renninger, A. Baohan, E. R. Schreiter, R. A. Kerr, M. B. Orger, V. Jayaraman, L. L. Looger, K. Svoboda, and D. S. Kim, “Ultrasensitive fluorescent proteins for imaging neuronal activity,” Nature 499(7458), 295–300 (2013).
[PubMed]

Chien, M.-P.

C. A. Werley, M.-P. Chien, J. Gaublomme, K. Shekhar, V. Butty, B. A. Yi, J. M. Kralj, W. Bloxham, L. A. Boyer, A. Regev, and A. E. Cohen, “Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing,” PLoS One 12(3), e0172671 (2017).
[PubMed]

M.-P. Chien, C. A. Werley, S. L. Farhi, and A. E. Cohen, “Photostick: a method for selective isolation of target cells from culture,” Chem. Sci. (Camb.) 6(3), 1701–1705 (2015).
[PubMed]

Chiovini, B.

G. Katona, G. Szalay, P. Maák, A. Kaszás, M. Veress, D. Hillier, B. Chiovini, E. S. Vizi, B. Roska, and B. Rózsa, “Fast two-photon in vivo imaging with three-dimensional random-access scanning in large tissue volumes,” Nat. Methods 9(2), 201–208 (2012).
[PubMed]

Cho, Y. K.

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Choksi, A. T.

L. J. Bugaj, A. T. Choksi, C. K. Mesuda, R. S. Kane, and D. V. Schaffer, “Optogenetic protein clustering and signaling activation in mammalian cells,” Nat. Methods 10(3), 249–252 (2013).
[PubMed]

Chow, B. Y.

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Chu, J.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Chuong, A. S.

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Cohen, A. E.

C. A. Werley, M.-P. Chien, J. Gaublomme, K. Shekhar, V. Butty, B. A. Yi, J. M. Kralj, W. Bloxham, L. A. Boyer, A. Regev, and A. E. Cohen, “Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing,” PLoS One 12(3), e0172671 (2017).
[PubMed]

G. T. Dempsey, K. W. Chaudhary, N. Atwater, C. Nguyen, B. S. Brown, J. D. McNeish, A. E. Cohen, and J. M. Kralj, “Cardiotoxicity screening with simultaneous optogenetic pacing, voltage imaging and calcium imaging,” J. Pharmacol. Toxicol. Methods 81, 240–250 (2016).
[PubMed]

A. E. Cohen, “Optogenetics: Turning the Microscope on Its Head,” Biophys. J. 110(5), 997–1003 (2016).
[PubMed]

M.-P. Chien, C. A. Werley, S. L. Farhi, and A. E. Cohen, “Photostick: a method for selective isolation of target cells from culture,” Chem. Sci. (Camb.) 6(3), 1701–1705 (2015).
[PubMed]

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
[PubMed]

V. Emiliani, A. E. Cohen, K. Deisseroth, and M. Häusser, “All-Optical Interrogation of Neural Circuits,” J. Neurosci. 35(41), 13917–13926 (2015).
[PubMed]

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

J. H. Hou, J. M. Kralj, A. D. Douglass, F. Engert, and A. E. Cohen, “Simultaneous mapping of membrane voltage and calcium in zebrafish heart in vivo reveals chamber-specific developmental transitions in ionic currents,” Front. Physiol. 5(AUG), 344 (2014).
[PubMed]

J. M. Kralj, A. D. Douglass, D. R. Hochbaum, D. Maclaurin, and A. E. Cohen, “Optical recording of action potentials in mammalian neurons using a microbial rhodopsin,” Nat. Methods 9(1), 90–95 (2011).
[PubMed]

Constantine-Paton, M.

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Cretu, A.

A. Cretu, P. Castagnino, and R. Assoian, “Studying the effects of matrix stiffness on cellular function using acrylamide-based hydrogels,” J. Vis. Exp. 42, 7–11 (2010).
[PubMed]

Cui, B.

K. Zhang and B. Cui, “Optogenetic control of intracellular signaling pathways,” Trends Biotechnol. 33(2), 92–100 (2015).
[PubMed]

Danuser, G.

H. Wang, M. Vilela, A. Winkler, M. Tarnawski, I. Schlichting, H. Yumerefendi, B. Kuhlman, R. Liu, G. Danuser, and K. M. Hahn, “LOVTRAP: An Optogenetic System for Photoinduced Protein Dissociation,” Nat. Methods 13(9), 755–758 (2016).
[PubMed]

Dasen, J. S.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Davies, S. A.

S. Terhzaz, T. D. Southall, K. S. Lilley, L. Kean, A. K. Allan, S. A. Davies, and J. A. T. Dow, “Differential gel electrophoresis and transgenic mitochondrial calcium reporters demonstrate spatiotemporal filtering in calcium control of mitochondria,” J. Biol. Chem. 281(27), 18849–18858 (2006).
[PubMed]

De Angelis, D. A.

G. Miesenböck, D. A. De Angelis, and J. E. Rothman, “Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins,” Nature 394(6689), 192–195 (1998).
[PubMed]

Debyser, Z.

M. Geraerts, M. Michiels, V. Baekelandt, Z. Debyser, and R. Gijsbers, “Upscaling of lentiviral vector production by tangential flow filtration,” J. Gene Med. 7(10), 1299–1310 (2005).
[PubMed]

Deisseroth, K.

V. Emiliani, A. E. Cohen, K. Deisseroth, and M. Häusser, “All-Optical Interrogation of Neural Circuits,” J. Neurosci. 35(41), 13917–13926 (2015).
[PubMed]

Del Bene, F.

J. Huisken, J. Swoger, F. Del Bene, J. Wittbrodt, and E. H. K. Stelzer, “Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).

Dempsey, G. T.

C. M. Hempel, C. A. Werley, G. T. Dempsey, D. J. Gerber, I. Ellen, and L. B. Biomap, “Targeting neuronal function for CNS drug discovery,” Drug Discov. Today. Technol. 23, 17–25 (2017).
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G. T. Dempsey, K. W. Chaudhary, N. Atwater, C. Nguyen, B. S. Brown, J. D. McNeish, A. E. Cohen, and J. M. Kralj, “Cardiotoxicity screening with simultaneous optogenetic pacing, voltage imaging and calcium imaging,” J. Pharmacol. Toxicol. Methods 81, 240–250 (2016).
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G. McConnell, J. Trägårdh, R. Amor, J. Dempster, E. Reid, and W. B. Amos, “A novel optical microscope for imaging large embryos and tissue volumes with sub-cellular resolution throughout,” eLife 5, e18659 (2016).
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Dick, T. P.

J. Birk, M. Meyer, I. Aller, H. G. Hansen, A. Odermatt, T. P. Dick, A. J. Meyer, and C. Appenzeller-Herzog, “Endoplasmic reticulum: reduced and oxidized glutathione revisited,” J. Cell Sci. 126(Pt 7), 1604–1617 (2013).
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M. Gutscher, A.-L. Pauleau, L. Marty, T. Brach, G. H. V. Wabnitz, Y. Samstag, A. J. Meyer, and T. P. Dick, “Real-time imaging of the intracellular glutathione redox potential,” Nat. Methods 5(6), 553–559 (2008).
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J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
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L. M. DiPilato and J. Zhang, “The role of membrane microdomains in shaping β2-adrenergic receptor-mediated cAMP dynamics,” Mol. Biosyst. 5(8), 832–837 (2009).
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J. H. Hou, J. M. Kralj, A. D. Douglass, F. Engert, and A. E. Cohen, “Simultaneous mapping of membrane voltage and calcium in zebrafish heart in vivo reveals chamber-specific developmental transitions in ionic currents,” Front. Physiol. 5(AUG), 344 (2014).
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J. M. Kralj, A. D. Douglass, D. R. Hochbaum, D. Maclaurin, and A. E. Cohen, “Optical recording of action potentials in mammalian neurons using a microbial rhodopsin,” Nat. Methods 9(1), 90–95 (2011).
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Dow, J. A. T.

S. Terhzaz, T. D. Southall, K. S. Lilley, L. Kean, A. K. Allan, S. A. Davies, and J. A. T. Dow, “Differential gel electrophoresis and transgenic mitochondrial calcium reporters demonstrate spatiotemporal filtering in calcium control of mitochondria,” J. Biol. Chem. 281(27), 18849–18858 (2006).
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Ellen, I.

C. M. Hempel, C. A. Werley, G. T. Dempsey, D. J. Gerber, I. Ellen, and L. B. Biomap, “Targeting neuronal function for CNS drug discovery,” Drug Discov. Today. Technol. 23, 17–25 (2017).
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V. Emiliani, A. E. Cohen, K. Deisseroth, and M. Häusser, “All-Optical Interrogation of Neural Circuits,” J. Neurosci. 35(41), 13917–13926 (2015).
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J. H. Hou, J. M. Kralj, A. D. Douglass, F. Engert, and A. E. Cohen, “Simultaneous mapping of membrane voltage and calcium in zebrafish heart in vivo reveals chamber-specific developmental transitions in ionic currents,” Front. Physiol. 5(AUG), 344 (2014).
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M.-P. Chien, C. A. Werley, S. L. Farhi, and A. E. Cohen, “Photostick: a method for selective isolation of target cells from culture,” Chem. Sci. (Camb.) 6(3), 1701–1705 (2015).
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D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
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J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Field, J. J.

Fishell, G.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
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J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
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N. J. Sofroniew, D. Flickinger, J. King, and K. Svoboda, “A large field of view two-photon mesoscope with subcellular resolution for in vivo imaging,” eLife 5, 1–20 (2016).
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J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
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C. A. Werley, M.-P. Chien, J. Gaublomme, K. Shekhar, V. Butty, B. A. Yi, J. M. Kralj, W. Bloxham, L. A. Boyer, A. Regev, and A. E. Cohen, “Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing,” PLoS One 12(3), e0172671 (2017).
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C. M. Hempel, C. A. Werley, G. T. Dempsey, D. J. Gerber, I. Ellen, and L. B. Biomap, “Targeting neuronal function for CNS drug discovery,” Drug Discov. Today. Technol. 23, 17–25 (2017).
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M. Geraerts, M. Michiels, V. Baekelandt, Z. Debyser, and R. Gijsbers, “Upscaling of lentiviral vector production by tangential flow filtration,” J. Gene Med. 7(10), 1299–1310 (2005).
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H. Liu, G. Gomez, S. Lin, S. Lin, and C. Lin, “Optogenetic Control of Transcription in Zebrafish,” PLoS One 7(11), e50738 (2012).
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H. E. Johnson, Y. Goyal, N. L. Pannucci, T. Schüpbach, S. Y. Shvartsman, and J. E. Toettcher, “The Spatiotemporal Limits of Developmental Erk Signaling,” Dev. Cell 40(2), 185–192 (2017).
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J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
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F. Schneider, C. Grimm, and P. Hegemann, “Biophysics of Channelrhodopsin,” Annu. Rev. Biophys. 44, 167–186 (2015).
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J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
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Gutscher, M.

M. Gutscher, A.-L. Pauleau, L. Marty, T. Brach, G. H. V. Wabnitz, Y. Samstag, A. J. Meyer, and T. P. Dick, “Real-time imaging of the intracellular glutathione redox potential,” Nat. Methods 5(6), 553–559 (2008).
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Hahn, K.

H. Yumerefendi, A. M. Lerner, S. P. Zimmerman, K. Hahn, J. E. Bear, B. D. Strahl, and B. Kuhlman, “Light-induced nuclear export reveals rapid dynamics of epigenetic modifications,” Nat. Chem. Biol. 12(6), 399–401 (2016).
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Hahn, K. M.

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Hansen, H. G.

J. Birk, M. Meyer, I. Aller, H. G. Hansen, A. Odermatt, T. P. Dick, A. J. Meyer, and C. Appenzeller-Herzog, “Endoplasmic reticulum: reduced and oxidized glutathione revisited,” J. Cell Sci. 126(Pt 7), 1604–1617 (2013).
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Harrison, D. J.

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
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Harvey, B. K.

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
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Häusser, M.

V. Emiliani, A. E. Cohen, K. Deisseroth, and M. Häusser, “All-Optical Interrogation of Neural Circuits,” J. Neurosci. 35(41), 13917–13926 (2015).
[PubMed]

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F. Schneider, C. Grimm, and P. Hegemann, “Biophysics of Channelrhodopsin,” Annu. Rev. Biophys. 44, 167–186 (2015).
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Hempel, C. M.

C. M. Hempel, C. A. Werley, G. T. Dempsey, D. J. Gerber, I. Ellen, and L. B. Biomap, “Targeting neuronal function for CNS drug discovery,” Drug Discov. Today. Technol. 23, 17–25 (2017).
[PubMed]

Henderson, M. J.

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
[PubMed]

Hillier, D.

G. Katona, G. Szalay, P. Maák, A. Kaszás, M. Veress, D. Hillier, B. Chiovini, E. S. Vizi, B. Roska, and B. Rózsa, “Fast two-photon in vivo imaging with three-dimensional random-access scanning in large tissue volumes,” Nat. Methods 9(2), 201–208 (2012).
[PubMed]

Hochbaum, D. R.

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

J. M. Kralj, A. D. Douglass, D. R. Hochbaum, D. Maclaurin, and A. E. Cohen, “Optical recording of action potentials in mammalian neurons using a microbial rhodopsin,” Nat. Methods 9(1), 90–95 (2011).
[PubMed]

Holt, G. T.

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
[PubMed]

Hou, J. H.

J. H. Hou, J. M. Kralj, A. D. Douglass, F. Engert, and A. E. Cohen, “Simultaneous mapping of membrane voltage and calcium in zebrafish heart in vivo reveals chamber-specific developmental transitions in ionic currents,” Front. Physiol. 5(AUG), 344 (2014).
[PubMed]

Huisken, J.

J. Huisken, J. Swoger, F. Del Bene, J. Wittbrodt, and E. H. K. Stelzer, “Live Embryos by Selective Plane Illumination Microscopy,” Science 305, 1007–1009 (2004).

Jacob, A. L.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Jayaraman, V.

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

T.-W. Chen, T. J. Wardill, Y. Sun, S. R. Pulver, S. L. Renninger, A. Baohan, E. R. Schreiter, R. A. Kerr, M. B. Orger, V. Jayaraman, L. L. Looger, K. Svoboda, and D. S. Kim, “Ultrasensitive fluorescent proteins for imaging neuronal activity,” Nature 499(7458), 295–300 (2013).
[PubMed]

Johnson, H. E.

H. E. Johnson, Y. Goyal, N. L. Pannucci, T. Schüpbach, S. Y. Shvartsman, and J. E. Toettcher, “The Spatiotemporal Limits of Developmental Erk Signaling,” Dev. Cell 40(2), 185–192 (2017).
[PubMed]

Jung, J. C.

T. H. Kim, Y. Zhang, J. Lecoq, J. C. Jung, J. Li, H. Zeng, C. M. Niell, and M. J. Schnitzer, “Long-Term Optical Access to an Estimated One Million Neurons in the Live Mouse Cortex,” Cell Reports 17(12), 3385–3394 (2016).
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Kane, R. S.

L. J. Bugaj, A. T. Choksi, C. K. Mesuda, R. S. Kane, and D. V. Schaffer, “Optogenetic protein clustering and signaling activation in mammalian cells,” Nat. Methods 10(3), 249–252 (2013).
[PubMed]

Kapoor, V.

D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
[PubMed]

Kaszás, A.

G. Katona, G. Szalay, P. Maák, A. Kaszás, M. Veress, D. Hillier, B. Chiovini, E. S. Vizi, B. Roska, and B. Rózsa, “Fast two-photon in vivo imaging with three-dimensional random-access scanning in large tissue volumes,” Nat. Methods 9(2), 201–208 (2012).
[PubMed]

Katona, G.

G. Katona, G. Szalay, P. Maák, A. Kaszás, M. Veress, D. Hillier, B. Chiovini, E. S. Vizi, B. Roska, and B. Rózsa, “Fast two-photon in vivo imaging with three-dimensional random-access scanning in large tissue volumes,” Nat. Methods 9(2), 201–208 (2012).
[PubMed]

Kaykas, A.

J. Dimidschstein, Q. Chen, R. Tremblay, S. L. Rogers, G. A. Saldi, L. Guo, Q. Xu, R. Liu, C. Lu, J. Chu, J. S. Grimley, A. R. Krostag, A. Kaykas, M. C. Avery, M. S. Rashid, M. Baek, A. L. Jacob, G. B. Smith, D. E. Wilson, G. Kosche, I. Kruglikov, T. Rusielewicz, V. C. Kotak, T. M. Mowery, S. A. Anderson, E. M. Callaway, J. S. Dasen, D. Fitzpatrick, V. Fossati, M. A. Long, S. Noggle, J. H. Reynolds, D. H. Sanes, B. Rudy, G. Feng, and G. Fishell, “A viral strategy for targeting and manipulating interneurons across vertebrate species,” Nat. Neurosci. 19(12), 1743–1749 (2016).
[PubMed]

Kean, L.

S. Terhzaz, T. D. Southall, K. S. Lilley, L. Kean, A. K. Allan, S. A. Davies, and J. A. T. Dow, “Differential gel electrophoresis and transgenic mitochondrial calcium reporters demonstrate spatiotemporal filtering in calcium control of mitochondria,” J. Biol. Chem. 281(27), 18849–18858 (2006).
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M. B. Ahrens, M. B. Orger, D. N. Robson, J. M. Li, and P. J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nat. Methods 10(5), 413–420 (2013).
[PubMed]

Kerr, R. A.

T.-W. Chen, T. J. Wardill, Y. Sun, S. R. Pulver, S. L. Renninger, A. Baohan, E. R. Schreiter, R. A. Kerr, M. B. Orger, V. Jayaraman, L. L. Looger, K. Svoboda, and D. S. Kim, “Ultrasensitive fluorescent proteins for imaging neuronal activity,” Nature 499(7458), 295–300 (2013).
[PubMed]

Kim, B.

B. Kim and M. Z. Lin, “Optobiology: optical control of biological processes via protein engineering,” Biochem. Soc. Trans. 41(5), 1183–1188 (2013).
[PubMed]

Kim, D. S.

M. J. Henderson, H. A. Baldwin, C. A. Werley, S. Boccardo, L. R. Whitaker, X. Yan, G. T. Holt, E. R. Schreiter, L. L. Looger, A. E. Cohen, D. S. Kim, and B. K. Harvey, “A low affinity GCaMP3 variant (GCaMPer) for imaging the endoplasmic reticulum calcium store,” PLoS One 10(10), e0139273 (2015).
[PubMed]

T.-W. Chen, T. J. Wardill, Y. Sun, S. R. Pulver, S. L. Renninger, A. Baohan, E. R. Schreiter, R. A. Kerr, M. B. Orger, V. Jayaraman, L. L. Looger, K. Svoboda, and D. S. Kim, “Ultrasensitive fluorescent proteins for imaging neuronal activity,” Nature 499(7458), 295–300 (2013).
[PubMed]

Kim, S. S.

N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
[PubMed]

Kim, T. H.

T. H. Kim, Y. Zhang, J. Lecoq, J. C. Jung, J. Li, H. Zeng, C. M. Niell, and M. J. Schnitzer, “Long-Term Optical Access to an Estimated One Million Neurons in the Live Mouse Cortex,” Cell Reports 17(12), 3385–3394 (2016).
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N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
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C. M. Hempel, C. A. Werley, G. T. Dempsey, D. J. Gerber, I. Ellen, and L. B. Biomap, “Targeting neuronal function for CNS drug discovery,” Drug Discov. Today. Technol. 23, 17–25 (2017).
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D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
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N. C. Klapoetke, Y. Murata, S. S. Kim, S. R. Pulver, A. Birdsey-Benson, Y. K. Cho, T. K. Morimoto, A. S. Chuong, E. J. Carpenter, Z. Tian, J. Wang, Y. Xie, Z. Yan, Y. Zhang, B. Y. Chow, B. Surek, M. Melkonian, V. Jayaraman, M. Constantine-Paton, G. K.-S. Wong, and E. S. Boyden, “Independent optical excitation of distinct neural populations,” Nat. Methods 11(3), 338–346 (2014).
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N. Mochizuki, S. Yamashita, K. Kurokawa, Y. Ohba, T. Nagai, A. Miyawaki, and M. Matsuda, “Spatio-temporal images of growth-factor-induced activation of Ras and Rap1,” Nature 411(6841), 1065–1068 (2001).
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T. H. Kim, Y. Zhang, J. Lecoq, J. C. Jung, J. Li, H. Zeng, C. M. Niell, and M. J. Schnitzer, “Long-Term Optical Access to an Estimated One Million Neurons in the Live Mouse Cortex,” Cell Reports 17(12), 3385–3394 (2016).
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D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
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H. Yumerefendi, A. M. Lerner, S. P. Zimmerman, K. Hahn, J. E. Bear, B. D. Strahl, and B. Kuhlman, “Light-induced nuclear export reveals rapid dynamics of epigenetic modifications,” Nat. Chem. Biol. 12(6), 399–401 (2016).
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D. R. Hochbaum, Y. Zhao, S. L. Farhi, N. Klapoetke, C. A. Werley, V. Kapoor, P. Zou, J. M. Kralj, D. Maclaurin, N. Smedemark-Margulies, J. L. Saulnier, G. L. Boulting, C. Straub, Y. K. Cho, M. Melkonian, G. K.-S. Wong, D. J. Harrison, V. N. Murthy, B. L. Sabatini, E. S. Boyden, R. E. Campbell, and A. E. Cohen, “All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins,” Nat. Methods 11(8), 825–833 (2014).
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Opt. Express (1)

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H. Hioki, H. Kameda, H. Nakamura, T. Okunomiya, K. Ohira, K. Nakamura, M. Kuroda, and T. Furuta, “Efficient gene transduction of neurons by lentivirus with enhanced neuron-specific promoters,” Gene Ther. 14, 872–882 (2007).

M. Born and E. Wolf, Principles of Optics, Seventh Ed (Cambridge University Press, 1999).

M. Tantama, Y. P. Hung, and G. Yellen, Optogenetic Reporters: Fluorescent Protein-Based Genetically Encoded Indicators of Signaling and Metabolism in the Brain., 1st ed. (Elsevier B.V., 2012), Vol. 196.

Supplementary Material (2)

NameDescription
» Visualization 1       A voltage recording (red/yellow colormap) of rat hippocampal neurons during CheRiff stimulation (blue square) is overlaid on the average grayscale fluorescence image. The 0.5 x 4 mm field of view was recorded at 1000 fps and is played back at 30 fps.
» Visualization 2       Calcium transients in hiPS cardiomyocytes patterned into 50 – 1000 µm square islands. Each island beats spontaneously and independently. The 6 x 6 mm field of view was recorded at 50 fps and is played back in real time.

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Figures (8)

Fig. 1
Fig. 1

Microscope optical diagram. Fluorescence from the sample passes through a pair of high NA, large field-of-view objectives to form an image at 2x magnification on an sCMOS camera. The camera records a Ø6 mm region with 3.25 μm spatial resolution and 10 ms temporal resolution. Illumination for optogenetic stimulation is patterned by reflection off a DMD, and focused onto a small mirror that couples the light into the objective en route to the sample. High-power red laser illumination passes through a custom fused silica prism to illuminate the sample at close to the angle for total internal reflection. This geometry maximizes illumination intensity at the sample while minimizing laser flux through on-axis optical components which would otherwise produce background autofluorescence. Six different color LEDs are combined and focused onto the sample from above for homogeneous illumination and high-speed modulation across much of the near-UV and visible spectrum. Omitted from the diagram is an iris in the LED system imaged onto the sample to control illumination size. Inset: design of the fused silica prism.

Fig. 2
Fig. 2

Light collection efficiency of the MVX10 zoom body as a function of zoom magnification. (a) Images of a pair of isolated fluorescent beads on the Olympus MVX microscope at different magnifications set by adjusting the zoom body. (b) Due to light losses in the zoom body, the total light collection efficiency, calculated by averaging the counts over the pair of beads, drops at low magnifications. The light collection efficiency at 2x magnification is only 10% of the efficiency at ≥8x magnification.

Fig. 3
Fig. 3

Optical performance of the Firefly microscope. (a) An image of 1 μm diameter beads, showing a 5 mm wide segment through the center of the field of view. The Zeiss tube lens provided 2.7x magnification. (b) Magnified view of sub-regions from the center of the FOV to the edge shown by colored boxes in (a). In the broad, central region the resolution was pixel limited, but astigmatism became detectable near the edges. (c) Left axis: FWHM diameter of single beads as a function of distance from image center, showing the degradation of resolution near the edges. Right axis: light collection efficiency of the optical system measured with a large, homogeneous sample illuminated with a distant source. (d) Chromatic focal shifts for beads of different colors. The color bands are defined as (central wavelength/pass band width): red (736/128 nm), orange (607/36 nm), and green (525/40). (e) Stripes of 2-pixels on/2-pixels off projected from the DMD onto a thin sample of dried dye, showing modulation at a 7 μm pitch. Diffraction orders off a 1 pixel-on/1-pixel off pattern missed the small mirror in the imaging path (Fig. 1) and were not resolved.

Fig. 4
Fig. 4

Near-TIR illumination. (a) Diagram of refraction and beam compression at the silica/water interface. (b) Angle of the transmitted beam near the critical angle as a function of the angle of the incident beam. (c) Transmission efficiency of the two light polarizations due to reflection loss. (d) The ray-optics beam compression due to refraction. (e) Net illumination intensity increases as the incidence angle approaches the critical angle because beam compression outweighs reflection losses.

Fig. 5
Fig. 5

Wide-field excitability recordings in rat hippocampal neurons. (a) QuasAr fluorescence image of cultured rat hippocampal neurons expressing voltage actuator CheRiff and voltage reporter QuasAr. See Visualization 1. Fluorescence recordings from the boxed cells are shown in (c). (b) White light trans-illumination image of the same FOV. (c) Voltage traces as recorded by fluorescence imaging of the selected neurons. The full FOV was stimulated simultaneously with successively more intense pulses of blue light to activate CheRiff. (d) An expanded view of the indicated spike train showing the details of the spiking waveform including after-hyperpolarizations.

Fig. 6
Fig. 6

Reduction of autofluorescent background and sample heating with fused silica coverslips. (a, b) The red laser was coupled into a clean, cell-free coverslip-bottomed dish where the coverslip was made of (a) glass or (b) fused silica. Fluorescence images, collected with the QuasAr emission filter, are plotted on the same scale. (c) Histogram of background pixel counts from the illuminated region in each image showing 8x reduced background in fused silica. (d) Fluorescent voltage recordings from mouse sensory neurons (including temperature sensing neurons) plated on glass (bottom) or fused silica (top). Initially there were 2 seconds of recording of spontaneous activity, followed by three periods of CheRiff stimulation with successively stronger pulses of blue light. Below the example fluorescence recordings are raster plots showing a tick for each recorded action potential from each of the roughly 10 cells per FOV. As the intensity of the red excitation laser increased, which improves the SNR but can also heat the sample, action potential bursts were induced on glass but not the fused silica.

Fig. 7
Fig. 7

High-throughput recordings from human iPSC motor neurons (adapted with permission from [23]). (a) Fluorescence image of the voltage sensor QuasAr in grayscale and the automatically identified single cells in color. (b) Example fluorescence recordings of voltage from three individual cells (top), and the blue light stimulus pattern (bottom). (c) Raster plot for one field of view showing the behavior of cells during initial (red) and repeat (teal) imaging. Each row is one neuron, and each point corresponds to one action potential. (d) Average firing rate of the population of neurons during the repeat imaging experiments. (e) The location of detected cell centroids from 4193 rat hippocampal neurons in 48 FOV’s in 16 wells, showing the homogeneous distribution of detected cells within the FOV. The SNR of each the detected spikes in each cell is indicated by color, showing uniform sensitivity across the FOV.

Fig. 8
Fig. 8

Wide-field recordings in human iPSC -derived cardiomyocytes. (a) A 6 x 6 mm image showing GCaMP6F fluorescence of several hundred islands of various sizes containing human iPSC-derived cardiomyocytes. See Visualization 2. (b) Fluorescent time traces from islands shown in (a) showing spontaneous calcium spiking. (c) A composite fluorescence image of a continuous syncytium of cardiomyocytes expressing CheRiff-EGFP (green) and QuasAr2-mOrange2 (red). (d) Top: voltage reported by averaging QuasAr2 fluorescence over the entire FOV (black). Bottom: blue light stimulus to activate CheRiff (blue). (e) Fluorescence time traces reporting voltage recorded from the left and right of the FOV (purple and cyan rectangles in (c)). Initially, the spontaneous voltage wave propagated from left to right (purple upstroke precedes cyan) but after optogenetic stimulation on the right edge of the FOV (dark blue rectangle in (c) and trace in (e)) the propagation direction reversed (cyan upstroke precedes purple).

Tables (1)

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Table 1 Comparison of commercially available objectives. In most microscope objectives there is a tradeoff between the numerical aperture (NA) and field of view (FOV). The total light collection is proportional to FOV area ∙ NA2. Here total light collection is measured relative to the 60x objective. The MVPLAPO 2 XC objective offers much higher light collection than the other objectives.

Equations (4)

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T p = sin 2 θ i sin 2 θ t sin 2 ( θ i + θ t ) cos 2 ( θ i θ t )
T s = sin 2 θ i sin 2 θ t sin 2 ( θ i + θ t )
η = d w d f s = cos θ t cos θ i
I = T / η .