Published Dec 2, 2020

Fuzhou Wang  


Optogenetics is an emerging branch of biology that combines genetics and optics to achieve precise light control of specific cells in organisms. It is a method of studying excitable cells that uses proteins that are embedded in the cell membrane and are activated by light (i.e. “opto”). Such proteins (opsins) are found in most animals in the retina of the eyes, as well as in some plants, such as green algae. In order to integrate photoactivated proteins into neuronal membranes, it is necessary to introduce rhodopsin genes obtained from other organisms into neurons, hence the “genetics”. Optogenetics is widely used in the field of modern neurobiology, and plays an essential role in the study of the mechanism of neural circuits, behaviors, central nervous system diseases, and mental disorders. Based on the development of optogenetics technology, this paper introduces its optimization and localization expression, which not only provides references for the research and development of optogenetics, but also provides the possibility for in-depth research and treatment of neurological diseases.



Optogenetics, Bioengineering, Neurological Disease, Mechanism, Treatment

1. Prestori F, Montagna I, D’Angelo E, Mapelli L. The Optogenetic Revolution in Cerebellar Investigations. Int J Mol Sci 2020; 21(7):2494. DOI: https://doi.org/10.3390/ijms21072494

2. De La Crompe B, Coulon P, Diester I. Functional interrogation of neural circuits with virally transmitted optogenetic tools. J Neurosci Methods 2020; 345:108905. DOI: https://doi.org/10.1016/j.jneumeth.2020.108905

3. Oesterhelt D, Stoeckenius W. Rhodopsin-like protein from the purple membrane of Halobacterium halobium. Nat New Biol 1971; 233(39):149-152. DOI: https://doi.org/10.1038/newbio233149a0

4. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 2005; 8(9):1263-1268. DOI: https://doi.org/10.1038/nn1525

5. Suresh J, Khor IW, Kaur P, Heng HL, Torta F, Dawe GS, Tai ES, Tolwinski NS. Shared signaling pathways in Alzheimer’s and metabolic disease may point to new treatment approaches. FEBS J 2020; DOI: https://doi.org/10.1111/febs.15540

6. Shiri Z, Simorgh S, Naderi S, Baharvand H. Optogenetics in the Era of Cerebral Organoids. Trends Biotechnol 2019; 37(12):1282-1294. DOI: https://doi.org/10.1016/j.tibtech.2019.05.009

7. Patel AV, Kawai T, Wang L, Rubakhin SS, Sweedler JV. Chiral Measurement of Aspartate and Glutamate in Single Neurons by Large-Volume Sample Stacking Capillary Electrophoresis. Anal Chem 2017; 89(22):12375-12382. DOI: https://doi.org/10.1021/acs.analchem.7b03435

8. Bartelle BB, Barandov A, Jasanoff A. Molecular fMRI. J Neurosc. 2016 Apr 13;36(15):4139-4148. DOI: https://doi.org/10.1523/jneurosci.4050-15.2016

9. Parvizi J, Kastner S. Promises and limitations of human intracranial electroencephalography. Nat Neurosc. 2018; 21(4):474-483. DOI: https://doi.org/10.1038/s41593-018-0108-2

10. Wang A, Feng J, Li Y, Zou P. Beyond Fluorescent Proteins: Hybrid and Bioluminescent Indicators for Imaging Neural Activities. ACS Chem Neuros 2018; 9(4):639-650. DOI: https://doi.org/10.1021/acschemneuro.7b00455

11. Gong Y, Huang C, Li JZ, Grewe BF, Zhang Y, Eismann S, Schnitzer MJ. High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor. Science 2015; 350(6266):1361-1366. DOI: https://doi.org/10.1126/science.aab0810

12. Bassett DS, Cullen KE, Eickhoff SB, Farah MJ, Goda Y, Haggard P, Hu H, Hurd YL, Josselyn SA, Khakh BS, Knoblich JA, Poirazi P, Poldrack RA, Prinz M, Roelfsema PR, Spires-Jones TL, Sur M, Ueda HR. Reflections on the past two decades of neuroscience. Nat Rev Neurosci 2020; 21(10):524-534. DOI: https://doi.org/10.1038/s41583-020-0363-6

13. Lillicrap TP, Santoro A, Marris L, Akerman CJ, Hinton G. Backpropagation and the brain. Nat Rev Neurosci 2020; 21(6):335-346. DOI: https://doi.org/10.1038/s41583-020-0277-3

14. Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna) 2014; 121(8):799-817. DOI: https://doi.org/10.1007/s00702-014-1180-8

15. Matsuno-Yagi A, Mukohata Y. Two possible roles of bacteriorhodopsin; a comparative study of strains of Halobacterium halobium differing in pigmentation. Biochem Biophysic Res Comm 1977; 78(1):237-243. DOI: https://doi.org/10.1016/0006-291x(77)91245-1

16. Nagel G, Ollig D, Fuhrmann M, Kateriya S, Musti AM, Bamberg E, Hegemann P. Channelrhodopsin-1: A light-gated proton channel in green algae. Science 2002; 296(5577):2395-2398. DOI: https://doi.org/10.1126/science.1072068

17. Fromm J, Lautner S. Electrical signals and their physiological significance in plants. Plant Cell Environ 2007; 30(3):249-257. DOI: https://doi.org/10.1111/j.1365-3040.2006.01614.x

18. Guru A, Post RJ, Ho YY, Warden MR. Making Sense of Optogenetics. Int J Neuropsychopharmacol 2015; 18(11):pyv079. DOI: https://doi.org/10.1093/ijnp/pyv079

19. Zemelman BV, Lee GA, Ng M, Miesenböck G. Selective photostimulation of genetically chARGed neurons. Neuron 2002; 33(1):15-22. DOI: https://doi.org/10.1016/s0896-6273(01)00574-8

20. Lima SQ, Miesenböck G. Remote control of behavior through genetically targeted photostimulation of neurons. Cell 2005; 121(1):141-152. DOI: https://doi.org/10.1016/j.cell.2005.02.004

21. Chambers JJ, Kramer RH. Light-activated ion channels for remote control of neural activity. Methods Cell Biol 2008; 90:217-232. DOI: https://doi.org/10.1016/s0091-679x(08)00811-x

22. Ernst OP, Lodowski DT, Elstner M, Hegemann P, Brown LS, Kandori H. Microbial and animal rhodopsins: structures, functions, and molecular mechanisms. Chem Rev 2014; 114(1):126-163. DOI: https://doi.org/10.1021/cr4003769

23. Deisseroth K. Optogenetics. Nat Methods 2011; 8(1):26-29. DOI: https://doi.org/10.1038/nmeth.f.324

24. Hososhima S, Shigemura S, Kandori H, Tsunoda SP. Novel optogenetics tool: Gt_CCR4, a light-gated cation channel with high reactivity to weak light. Biophys Rev 2020; 12(2):453-459. DOI: https://doi.org/10.1007/s12551-020-00676-7

25. Mali S. Delivery systems for gene therapy. Indian J Hum Genet 2013; 19(1):3-8. DOI: https://doi.org/10.4103/0971-6866.112870

26. Berglund K, Birkner E, Augustine GJ, Hochgeschwender U. Light-emitting channelrhodopsins for combined optogenetic and chemical-genetic control of neurons. PLoS One 2013; 8(3):e59759. DOI: https://doi.org/10.1371/journal.pone.0059759

27. Lammel S, Tye KM, Warden MR. Progress in understanding mood disorders: optogenetic dissection of neural circuits. Genes Brain Behav 2014; 13(1):38-51. DOI: https://doi.org/10.1111/gbb.12049

28. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007; 450(7168):420-424. DOI: https://doi.org/10.1038/nature06310

29. Aravanis AM, Wang LP, Zhang F, Meltzer LA, Mogri MZ, Schneider MB, Deisseroth K. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng 2007; 4(3):S143-S156. DOI: https://doi.org/10.1088/1741-2560/4/3/s02

30. Peixoto HM, Cruz RMS, Moulin TC, Leão RN. Modeling the Effect of Temperature on Membrane Response of Light Stimulation in Optogenetically-Targeted Neurons. Front Comput Neurosci 2020; 14:5. DOI: https://doi.org/10.3389/fncom.2020.00005

31. Wiegert JS, Mahn M, Prigge M, Printz Y, Yizhar O. Silencing neurons: Tools, applications, and experimental constraints. Neuron 2017; 95(3):504-529. DOI: https://doi.org/10.1016/j.neuron.2017.06.050

32. Zorzos AN, Scholvin J, Boyden ES, Fonstad CG. Three-dimensional multiwaveguide probe array for light delivery to distributed brain circuits. Opt Lett 2012; 37(23):4841-4843. DOI: https://doi.org/10.1364/ol.37.004841

33. Nazemi H, Joseph A, Park J, Emadi A. Advanced micro- and nano-gas sensor technology: A review. Sensors (Basel) 2019; 19(6):1285. DOI: https://doi.org/10.3390/s19061285

34. Katz Y, Sokoletsky M, Lampl I. In-vivo optogenetics and pharmacology in deep intracellular recordings. J Neurosci Methods 2019; 325:108324. DOI: https://doi.org/10.1016/j.jneumeth.2019.108324

35. Royer S, Zemelman BV, Barbic M, Losonczy A, Buzsáki G, Magee JC. Multi-array silicon probes with integrated optical fibers: light-assisted perturbation and recording of local neural circuits in the behaving animal. Eur J Neurosci 2010; 31(12):2279-2291. DOI: https://doi.org/10.1111/j.1460-9568.2010.07250.x

36. Zhang F, Vierock J, Yizhar O, Fenno LE, Tsunoda S, Kianianmomeni A, Prigge M, Berndt A, Cushman J, Polle J, Magnuson J, Hegemann P, Deisseroth K. The microbial opsin family of optogenetic tools. Cell 2011; 147(7):1446-1457. DOI: https://doi.org/10.1016/j.cell.2011.12.004

37. Shichida Y, Matsuyama T. Evolution of opsins and phototransduction. Philos Trans R Soc Lond B Biol Sci 2009; 364(1531):2881-2895. DOI: https://doi.org/10.1098/rstb.2009.0051

38. Mattingly M, Weineck K, Costa J, Cooper RL. Hyperpolarization by activation of halorhodopsin results in enhanced synaptic transmission: Neuromuscular junction and CNS circuit. PLoS One 2018; 13(7):e0200107. DOI: https://doi.org/10.1371/journal.pone.0200107

39. Kandori H. Ion-pumping microbial rhodopsins. Front Mol Biosci 2015; 2:52. DOI: https://doi.org/10.3389/fmolb.2015.00052

40. Spangler SM, Bruchas MR. Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits. Curr Opin Pharmacol 2017; 32:56-70. DOI: https://doi.org/10.1016/j.coph.2016.11.001

41. Airan RD, Thompson KR, Fenno LE, Bernstein H, Deisseroth K. Temporally precise in vivo control of intracellular signalling. Nature 2009; 458(7241):1025-1029. DOI: https://doi.org/10.1038/nature07926

42. Carter ME, de Lecea L. Optogenetic investigation of neural circuits in vivo. Trends Mol Med 2011; 17(4):197-206. DOI: https://doi.org/10.1016/j.molmed.2010.12.005

43. Oh E, Maejima T, Liu C, Deneris E, Herlitze S. Substitution of 5-HT1A receptor signaling by a light-activated G protein-coupled receptor. J Biol Chem 2010; 285(40):30825-30836. DOI: https://doi.org/10.1074/jbc.m110.147298

44. Ramdya P, Lichocki P, Cruchet S, Frisch L, Tse W, Floreano D, Benton R. Mechanosensory interactions drive collective behaviour in Drosophila. Nature 2015; 519(7542):233-236. DOI: https://doi.org/10.1038/nature14024

45. Ramirez S, Liu X, Lin PA, Suh J, Pignatelli M, Redondo RL, Ryan TJ, Tonegawa S. Creating a false memory in the hippocampus. Science 2013; 341(6144):387-391. DOI: https://doi.org/10.1126/science.1239073

46. Ryan TJ, Roy DS, Pignatelli M, Arons A, Tonegawa S. Memory. Engram cells retain memory under retrograde amnesia. Science 2015; 348(6238):1007-1013. DOI: https://doi.org/10.1126/science.aaa5542

47. Han W, Tellez LA, Rangel MJ Jr, Motta SC, Zhang X, Perez IO, Canteras NS, Shammah-Lagnado SJ, van den Pol AN, de Araujo IE. Integrated Control of Predatory Hunting by the Central Nucleus of the Amygdala. Cell 2017; 168(1-2):311-324.e18. DOI: https://doi.org/10.1016/j.cell.2016.12.027

48. Chow M, Cao M. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nat Sci Sleep 2016; 8:81-86. DOI: https://doi.org/10.2147/NSS.S76711

49. Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol 2008; 6(4):367-378. DOI: https://doi.org/10.2174/157015908787386050

50. Deisseroth K. Circuit dynamics of adaptive and maladaptive behaviour. Nature 2014; 505(7483):309-317. DOI: https://doi.org/10.1038/nature12982

51. Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, Kim SY, Adhikari A, Thompson KR, Andalman AS, Gunaydin LA, Witten IB, Deisseroth K. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 2013; 493(7433):537-541. DOI: https://doi.org/10.1038/nature11740

52. Polter AM, Kauer JA. Stress and VTA synapses: implications for addiction and depression. Eur J Neurosci 2014; 39(7):1179-1188. DOI: https://doi.org/10.1111/ejn.12490

53. Bouarab C, Thompson B, Polter AM. VTA GABA Neurons at the Interface of Stress and Reward. Front Neural Circuits 2019; 13:78. DOI: https://doi.org/10.3389/fncir.2019.00078

54. Knowland D, Lim BK. Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond. Pharmacol Biochem Behav 2018; 174:42-52. DOI: https://doi.org/10.1016/j.pbb.2017.12.010

55. Cheng Z, Cui R, Ge T, Yang W, Li B. Optogenetics: What it has uncovered in potential pathways of depression. Pharmacol Res 2020; 152:104596. DOI: https://doi.org/10.1016/j.phrs.2019.104596

56. Fakhoury M. Optogenetics: A revolutionary approach for the study of depression. Prog Neuropsychopharmacol Biol Psychiatry 2020; 110094. DOI: https://doi.org/10.1016/j.pnpbp.2020.110094

57. Gos T, Krell D, Brisch R, Bielau H, Trübner K, Steiner J, Bernstein HG, Bogerts B. Demonstration of decreased activity of dorsal raphe nucleus neurons in depressed suicidal patients by the AgNOR staining method. J Affect Disord 2008; 111(2-3):251-260. DOI: https://doi.org/10.1016/j.jad.2008.03.002

58. Lener MS, Niciu MJ, Ballard ED, et al. Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine. Biol Psychiatry 2017; 81(10):886-897. DOI: https://doi.org/10.1016/j.biopsych.2016.05.005

59. Dela Cruz JA, Coke T, Bodnar RJ. Simultaneous Detection of c-Fos Activation from Mesolimbic and Mesocortical Dopamine Reward Sites Following Naive Sugar and Fat Ingestion in Rats. J Vis Exp 2016; 2016(114):53897. DOI: https://doi.org/10.3791/53897

60. Nieh EH, Matthews GA, Allsop SA, Presbrey KN, Leppla CA, Wichmann R, Neve R, Wildes CP, Tye KM. Decoding neural circuits that control compulsive sucrose seeking. Cell 2015;160(3):528-541. DOI: https://doi.org/10.1016/j.cell.2015.01.003

61. Liu D, Tang QQ, Yin C, Song Y, Liu Y, Yang JX, Liu H, Zhang YM, Wu SY, Song Y, Juarez B, Ding HL, Han MH, Zhang H, Cao JL. Brain-derived neurotrophic factor-mediated projection-specific regulation of depressive-like and nociceptive behaviors in the mesolimbic reward circuitry. Pain 2018; 159(1):175. DOI: https://doi.org/10.1097/j.pain.0000000000001083

62. Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci 2011; 7:121-147. DOI: https://doi.org/10.1007/7854_2010_108

63. Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, LaPlant Q, Mouzon E, Ghose S, Tamminga CA, Neve RL, Deisseroth K, Nestler EJ. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci 2010; 30(48):16082-16090. DOI: https://doi.org/10.1523/jneurosci.1731-10.2010

64. Avery SN, Clauss JA, Blackford JU. The Human BNST: Functional Role in Anxiety and Addiction. Neuropsychopharmacology 2016; 41(1):126-141. DOI: https://doi.org/10.1038/npp.2015.185

65. Vranjkovic O, Pina M, Kash TL, Winder DG. The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective. Neuropharmacology 2017; 122:100-106. DOI: https://doi.org/10.1016/j.neuropharm.2017.03.028

66. Walker DL, Miles LA, Davis M. Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(8):1291-1308. DOI: https://doi.org/10.1016/j.pnpbp.2009.06.022

67. Daniel SE, Rainnie DG. Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis. Neuropsychopharmacology 2016; 41(1):103-125. DOI: https://doi.org/10.1038/npp.2015.178

68. Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 2012; 484(7394):381-385. DOI: https://doi.org/10.1038/nature11028

69. Perusini JN, Cajigas SA, Cohensedgh O, Lim SC, Pavlova IP, Donaldson ZR, Denny CA. Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer’s disease mice. Hippocampus 2017; 27(10):1110-1122. DOI: https://doi.org/10.1002/hipo.22756

70. Wang KW, Ye XL, Huang T, Yang XF, Zou LY. Optogenetics-induced activation of glutamate receptors improves memory function in mice with Alzheimer’s disease. Neural Regen Res 2019; 14(12):2147-2155. DOI: https://doi.org/10.4103/1673-5374.262593

71. Bostanc?kl?o?lu M. Optogenetic stimulation of serotonin nuclei retrieve the lost memory in Alzheimer’s disease. J Cell Physiol 2020; 235(2):836-847. DOI: https://doi.org/10.1002/jcp.29077

72. Tanaka KZ, Pevzner A, Hamidi AB, Nakazawa Y, Graham J, Wiltgen BJ. Cortical representations are reinstated by the hippocampus during memory retrieval. Neuron 2014; 84(2):347-354. DOI: https://doi.org/10.1016/j.neuron.2014.09.037

73. O’Neal TB, Luther EE. Retinitis Pigmentosa. 2020 Aug 10. In: StatPearls (Internet). Treasure Island (FL): StatPearls Publishing; 2020 Jan. PMID: 30137803.

74. Chuong AS, Miri ML, Busskamp V, Matthews GA, Acker LC, Sørensen AT, Young A, Klapoetke NC, Henninger MA, Kodandaramaiah SB, Ogawa M, Ramanlal SB, Bandler RC, Allen BD, Forest CR, Chow BY, Han X, Lin Y, Tye KM, Roska B, Cardin JA, Boyden ES. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat Neurosci 2014; 17(8):1123-1129. DOI: https://doi.org/10.1038/nn.3752
How to Cite
Wang, F. (2020). Optogenetics: The Key to Deciphering and Curing Neurological Diseases. Science Insights, 35(4), 224–235. https://doi.org/10.15354/si.20.re081