Historical Commentary | Published:

Optogenetics: 10 years of microbial opsins in neuroscience

Nature Neuroscience 18, 1213–1225 (2015) | Download Citation

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Abstract

Over the past 10 years, the development and convergence of microbial opsin engineering, modular genetic methods for cell-type targeting and optical strategies for guiding light through tissue have enabled versatile optical control of defined cells in living systems, defining modern optogenetics. Despite widespread recognition of the importance of spatiotemporally precise causal control over cellular signaling, for nearly the first half (2005–2009) of this 10-year period, as optogenetics was being created, there were difficulties in implementation, few publications and limited biological findings. In contrast, the ensuing years have witnessed a substantial acceleration in the application domain, with the publication of thousands of discoveries and insights into the function of nervous systems and beyond. This Historical Commentary reflects on the scientific landscape of this decade-long transition.

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References

  1. 1.

    Nat. Methods 8, 26–29 (2011).

  2. 2.

    , , , & Nat. Neurosci. 8, 1263–1268 (2005).

  3. 3.

    et al. J. Neurosci. 26, 10380–10386 (2006).

  4. 4.

    , & Neuron 86, 106–139 (2015).

  5. 5.

    et al. Cell 147, 1446–1457 (2011).

  6. 6.

    Proc. Natl. Acad. Sci. USA 93, 557–559 (1996).

  7. 7.

    & Nat. New Biol. 233, 149–152 (1971).

  8. 8.

    Biochemistry 3rd edn. 962 (Freeman, 1988).

  9. 9.

    et al. Nature 482, 369–374 (2012).

  10. 10.

    , , & Science 344, 420–424 (2014).

  11. 11.

    et al. Science 344, 409–412 (2014).

  12. 12.

    , , , & Science 349, 647–650 (2015).

  13. 13.

    & Science 349, 590–591 (2015).

  14. 14.

    , , & Proc. Natl. Acad. Sci. USA 91, 9367–9371 (1994).

  15. 15.

    et al. Science 296, 2395–2398 (2002).

  16. 16.

    et al. Proc. Natl. Acad. Sci. USA 100, 13940–13945 (2003).

  17. 17.

    , , , & Proc. Natl. Acad. Sci. USA 85, 7917–7921 (1988).

  18. 18.

    et al. Cell 141, 154–165 (2010).

  19. 19.

    , , & Neuron 33, 15–22 (2002).

  20. 20.

    , , & Proc. Natl. Acad. Sci. USA 100, 1352–1357 (2003).

  21. 21.

    , , , & Nat. Neurosci. 7, 1381–1386 (2004).

  22. 22.

    & Cell 121, 141–152 (2005).

  23. 23.

    et al. Nat. Chem. Biol. 2, 47–52 (2006).

  24. 24.

    , , & Nat. Methods 3, 785–792 (2006).

  25. 25.

    et al. J. Neural Eng. 4, S143–S156 (2007).

  26. 26.

    , , , & Nature 450, 420–424 (2007).

  27. 27.

    et al. Proc. Natl. Acad. Sci. USA 102, 17816–17821 (2005).

  28. 28.

    et al. Curr. Biol. 15, 2279–2284 (2005).

  29. 29.

    , , & Neurosci. Res. 54, 85–94 (2006).

  30. 30.

    et al. Neuron 50, 23–33 (2006).

  31. 31.

    et al. Curr. Biol. 16, 1741–1747 (2006).

  32. 32.

    et al. Curr. Biol. 17, 2105–2116 (2007).

  33. 33.

    et al. Nature 446, 633–639 (2007).

  34. 34.

    , , & Nat. Neurosci. 10, 663–668 (2007).

  35. 35.

    et al. Proc. Natl. Acad. Sci. USA 104, 8143–8148 (2007).

  36. 36.

    et al. Neuron 54, 205–218 (2007).

  37. 37.

    et al. J. Neurosci. 27, 14231–14238 (2007).

  38. 38.

    et al. Nature 451, 61–64 (2008).

  39. 39.

    in Larry Katz Memorial Lecture, Cold Spring Harbor Laboratory Meeting on Neuronal Circuits (Cold Spring Harbor Laboratory Press, 2008).

  40. 40.

    , , & J. Neurosci. 28, 7025–7030 (2008).

  41. 41.

    , , & Nature 459, 698–702 (2009).

  42. 42.

    et al. Science 324, 1080–1084 (2009).

  43. 43.

    , , & Nat. Neurosci. 13, 246–252 (2010).

  44. 44.

    et al. Curr. Biol. 18, 1133–1137 (2008).

  45. 45.

    , , , & Science 324, 354–359 (2009).

  46. 46.

    & Nature 351, 489–491 (1991).

  47. 47.

    et al. Nat. Neurosci. 11, 631–633 (2008).

  48. 48.

    , , , & Nat. Neurosci. 12, 229–234 (2009).

  49. 49.

    , , , & Biochemistry 49, 267–278 (2010).

  50. 50.

    , & Brain Cell Biol. 36, 129–139 (2008).

  51. 51.

    et al. Brain Cell Biol. 36, 141–154 (2008).

  52. 52.

    et al. J. Biol. Chem. 284, 5685–5696 (2009).

  53. 53.

    , , & Biophys. J. 96, 1803–1814 (2009).

  54. 54.

    et al. Nat. Methods 11, 763–772 (2014).

  55. 55.

    et al. Cell 154, 1023–1035 (2013).

  56. 56.

    et al. Nature 519, 233–236 (2015).

  57. 57.

    , , , & Nat. Neurosci. 15, 1454–1459 (2012).

  58. 58.

    , & Neuron 83, 679–691 (2014).

  59. 59.

    et al. J. Neurophysiol. 113, 3574–3587 (2015).

  60. 60.

    et al. Phil. Trans. R. Soc. Lond. B (30 March 2015).

  61. 61.

    et al. Nature 466, 622–626 (2010).

  62. 62.

    et al. Nat. Neurosci. 17, 1233–1239 (2014).

  63. 63.

    , , & Nature 508, 357–363 (2014).

  64. 64.

    , , & Nat. Neurosci. 17, 1767–1775 (2014).

  65. 65.

    et al. Nat. Neurosci. 14, 1562–1568 (2011).

  66. 66.

    , , & Cell 146, 992–1003 (2011).

  67. 67.

    et al. Cell 151, 645–657 (2012).

  68. 68.

    , & Nature 520, 349–352 (2015).

  69. 69.

    et al. Cell 160, 516–527 (2015).

  70. 70.

    et al. Science 329, 571–575 (2010).

  71. 71.

    , , & J. Neurosci. 31, 16410–16422 (2011).

  72. 72.

    et al. Nat. Neurosci. 13, 1526–1533 (2010).

  73. 73.

    et al. Nat. Neurosci. 16, 1637–1643 (2013).

  74. 74.

    et al. Nat. Neurosci. 17, 1217–1224 (2014).

  75. 75.

    , & Nat. Neurosci. 18, 373–375 (2015).

  76. 76.

    , , , & Nature 479, 397–400 (2011).

  77. 77.

    et al. Cell 146, 1004–1015 (2011).

  78. 78.

    & Neuron 80, 1010–1024 (2013).

  79. 79.

    & Nature 497, 482–485 (2013).

  80. 80.

    et al. Nature 488, 379–383 (2012).

  81. 81.

    , & Neuron 84, 202–213 (2014).

  82. 82.

    et al. Nat. Neurosci. 16, 958–965 (2013).

  83. 83.

    et al. Nature 509, 617–621 (2014).

  84. 84.

    et al. Nat. Neurosci. 16, 665–667 (2013).

  85. 85.

    et al. Nat. Neurosci. 17, 1276–1285 (2014).

  86. 86.

    , , , & Nature 482, 85–88 (2012).

  87. 87.

    et al. Nature 465, 788–792 (2010).

  88. 88.

    et al. J. Neurosci. 33, 6343–6349 (2013).

  89. 89.

    et al. Nature 459, 663–667 (2009).

  90. 90.

    et al. Nature 477, 171–178 (2011).

  91. 91.

    , , & Neuron 77, 141–154 (2013).

  92. 92.

    et al. Nat. Neurosci. 16, 227–234 (2013).

  93. 93.

    et al. Neuron 83, 467–480 (2014).

  94. 94.

    , & Nat. Neurosci. 17, 1371–1379 (2014).

  95. 95.

    et al. Cell 158, 808–821 (2014).

  96. 96.

    et al. Neuron 82, 1367–1379 (2014).

  97. 97.

    et al. Proc. Natl. Acad. Sci. USA 112, 3535–3540 (2015).

  98. 98.

    & Elife 3, e03061 (2014).

  99. 99.

    et al. J. Neurosci. 29, 10695–10705 (2009).

  100. 100.

    et al. Nature 468, 263–269 (2010).

  101. 101.

    , , , & Nat. Neurosci. 16, 1068–1076 (2013).

  102. 102.

    et al. Nat. Neurosci. 17, 1362–1370 (2014).

  103. 103.

    et al. Nat. Neurosci. 17, 269–279 (2014).

  104. 104.

    et al. Nature 503, 521–524 (2013).

  105. 105.

    , , & Nat. Neurosci. 15, 370–372 (2012).

  106. 106.

    et al. Neuron 79, 1208–1221 (2013).

  107. 107.

    et al. Science 335, 1506–1510 (2012).

  108. 108.

    & Nat. Neurosci. 16, 1315–1323 (2013).

  109. 109.

    , , & Neuron 76, 1175–1188 (2012).

  110. 110.

    et al. Nat. Neurosci. 15, 607–612 (2012).

  111. 111.

    et al. Cell 157, 1535–1551 (2014).

  112. 112.

    , , , & Nature 509, 325–330 (2014).

  113. 113.

    et al. Nature 470, 221–226 (2011).

  114. 114.

    et al. Nature 509, 627–632 (2014).

  115. 115.

    et al. Elife 4, (2015).

  116. 116.

    , & Neuron 85, 1344–1358 (2015).

  117. 117.

    et al. Nature 492, 428–432 (2012).

  118. 118.

    et al. Nature 496, 224–228 (2013).

  119. 119.

    et al. Science 330, 1677–1681 (2010).

  120. 120.

    et al. Science 330, 385–390 (2010).

  121. 121.

    et al. Nature 475, 377–380 (2011).

  122. 122.

    et al. Neuron 72, 721–733 (2011).

  123. 123.

    et al. Nat. Neurosci. 16, 966–973 (2013).

  124. 124.

    et al. Cell Reports 8, 1857–1869 (2014).

  125. 125.

    et al. Nature 468, 270–276 (2010).

  126. 126.

    et al. Nature 468, 277–282 (2010).

  127. 127.

    et al. Nature 480, 331–335 (2011).

  128. 128.

    et al. Nature 471, 358–362 (2011).

  129. 129.

    et al. Nature 496, 219–223 (2013).

  130. 130.

    et al. Neuron 79, 658–664 (2013).

  131. 131.

    et al. Nature 509, 453–458 (2014).

  132. 132.

    et al. Neuron 84, 1034–1048 (2014).

  133. 133.

    et al. Cell 156, 522–536 (2014).

  134. 134.

    et al. Nature 498, 363–366 (2013).

  135. 135.

    et al. Neuron 81, 428–437 (2014).

  136. 136.

    Nature 505, 309–317 (2014).

  137. 137.

    et al. Neuron 83, 455–466 (2014).

  138. 138.

    et al. Cell 147, 678–689 (2011).

  139. 139.

    et al. Nature 484, 381–385 (2012).

  140. 140.

    & Science 339, 1290–1295 (2013).

  141. 141.

    et al. Neuron 84, 432–441 (2014).

  142. 142.

    et al. Nature 513, 426–430 (2014).

  143. 143.

    et al. Proc. Natl. Acad. Sci. USA 107, 12692–12697 (2010).

  144. 144.

    et al. Nature 492, 452–456 (2012).

  145. 145.

    et al. Neuron 77, 955–968 (2013).

  146. 146.

    et al. Science 340, 1232627 (2013).

  147. 147.

    , & Nat. Neurosci. 17, 710–718 (2014).

  148. 148.

    et al. Cell Reports 10, 75–87 (2015).

  149. 149.

    et al. Neuron 83, 879–893 (2014).

  150. 150.

    et al. Cell 149, 173–187 (2012).

  151. 151.

    , & Nat. Neurosci. 17, 1198–1207 (2014).

  152. 152.

    et al. Neuron 82, 1289–1298 (2014).

  153. 153.

    , , & Cell 158, 793–807 (2014).

  154. 154.

    et al. Science 344, 1252304 (2014).

  155. 155.

    et al. Nature 489, 150–154 (2012).

  156. 156.

    et al. Neuron 85, 116–130 (2015).

  157. 157.

    et al. Eur. J. Neurosci. 36, 1971–1983 (2012).

  158. 158.

    et al. Nat. Neurosci. 16, 64–70 (2013).

  159. 159.

    , , & Nat. Commun. 4, 1376 (2013).

  160. 160.

    et al. Nat. Biotechnol. 32, 274–278 (2014).

  161. 161.

    et al. Nat. Biotechnol. 33, 204–209 (2015).

  162. 162.

    et al. Nat. Neurosci. 16, 613–621 (2013).

  163. 163.

    et al. Cell Reports 11, 859–865 (2015).

  164. 164.

    et al. Cell 161, 803–816 (2015).

  165. 165.

    et al. J. Neurosci. 33, 7393–7406 (2013).

  166. 166.

    et al. Science 329, 413–417 (2010).

  167. 167.

    , , & J. Neurosci. 34, 16455–16466 (2014).

  168. 168.

    et al. Proc. Natl. Acad. Sci. USA 111, 12913–12918 (2014).

  169. 169.

    et al. Nature 496, 359–362 (2013).

  170. 170.

    et al. Nat. Neurosci. 17, 1092–1099 (2014).

  171. 171.

    , & Science 347, 659–664 (2015).

  172. 172.

    et al. Science 340, 1234–1239 (2013).

  173. 173.

    , , & Science 340, 1243–1246 (2013).

  174. 174.

    , , , & Neuron 71, 9–34 (2011).

  175. 175.

    et al. Nat. Methods 9, 1171–1179 (2012).

  176. 176.

    et al. Nat. Methods 9, 1202–1205 (2012).

  177. 177.

    et al. Nat. Neurosci. 17, 1816–1824 (2014).

  178. 178.

    , , & Nat. Methods 12, 140–146 (2015).

  179. 179.

    , & ACS Chem. Neurosci. 3, 585–592 (2012).

  180. 180.

    et al. Neuron 86, 92–105 (2015).

  181. 181.

    et al. Science 348, 707–710 (2015).

  182. 182.

    , , , & Nature 458, 1025–1029 (2009).

  183. 183.

    et al. Biochemistry 44, 2284–2292 (2005).

  184. 184.

    et al. Eur. J. Pharmacol. 705, 42–48 (2013).

  185. 185.

    et al. Neuron 86, 923–935 (2015).

  186. 186.

    et al. Mol. Psychiatry (17 February 2015).

  187. 187.

    , , , & J. Biol. Chem. 285, 30825–30836 (2010).

  188. 188.

    et al. PLoS Biol. 13, e1002143 (2015).

  189. 189.

    & Annu. Rev. Pharmacol. Toxicol. 55, 399–417 (2015).

  190. 190.

    et al. Nature 461, 104–108 (2009).

  191. 191.

    et al. J. Biol. Chem. 286, 1181–1188 (2011).

  192. 192.

    , , & Angew. Chem. Int. Edn. Engl. 54, 5933–5938 (2015).

  193. 193.

    et al. Nature 500, 472–476 (2013).

  194. 194.

    , , & Science 330, 971–974 (2010).

  195. 195.

    , , , & Science 347, 1477–1480 (2015).

  196. 196.

    et al. Neuron 86, 207–217 (2015).

  197. 197.

    et al. Neuron 81, 800–813 (2014).

  198. 198.

    & Biochem. Biophys. Res. Commun. 78, 237–243 (1977).

  199. 199.

    & J. Biol. Chem. 257, 10306–10313 (1982).

  200. 200.

    et al. Nature 311, 756–759 (1984).

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Acknowledgements

I am deeply grateful to all of our collaborators and lab members from the first 5 years of optogenetics development (for more on these scientists, see http://www.scientificamerican.com/article/optogenetics-controlling/) to the present (http://web.stanford.edu/group/dlab/group_members.html), and to the funders who supported the lab from the earliest time, corresponding to Figure 2a (http://optogenetics.org/funding/), to the present. From those early years there were wonderful collaborations with P. Hegemann and L. de Lecea, and I am notably grateful to G. Nagel for promptly sending the initial channelrhodopsin clone in response to my e-mail request. I am also grateful for discussions, experiments and analysis with all of the students and postdoctoral fellows, including, for ref. 2, E. Boyden and F. Zhang; for Figure 1, F. Zhang, A. Berndt, V. Gradinaru, S.Y. Lee, C. Ramakrishnan and L. Stryer; and for Figure 2b–e, F. Zhang as well as A. Adamantidis, A. Aravanis, E. Boyden, L. Grosenick, S.Y. Lee and L. Wang. Tools and reagents developed are freely available (http://www.optogenetics.org/, http://addgene.org/).

Author information

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  1. Karl Deisseroth is in the Departments of Bioengineering and of Psychiatry and Behavioral Sciences and the Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.

    • Karl Deisseroth

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The author declares no competing financial interests.

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Correspondence to Karl Deisseroth.

Supplementary information

Videos

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    Supplementary Video 1

    Optogenetic mouse behavioral modulation. Initial optogenetic behavioral control in mammals with the fiber-optic neural interface. Stimulation of the right anterior motor cortex in a Thy1::ChR2-EYFP transgenic mouse35,36 with 20-Hz blue light flashes elicits contralateral circling. Mouse line generated with support of the US National Institute of Mental Health (principal investigators G. Feng, G. Augustine and K. Deisseroth). Recorded 14 July 2007 by F. Zhang, Deisseroth laboratory, Stanford University.

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https://doi.org/10.1038/nn.4091

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