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Optogenetics enlightens neuroscience drug discovery

Key Points

  • Optogenetics uses light and genetics to manipulate and monitor the activities of defined cell populations, and this technique has transformed basic neuroscience research.

  • Optogenetic tools are genetically encoded proteins designed to manipulate and monitor neuronal circuits, and there are two types of proteins used: actuators (proteins that transduce light into neuronal signals for manipulation) and indicators (proteins that transduce neuronal signals into optical signals for monitoring).

  • An optogenetic approach involves light-based (optical) interventions and/or recordings of natural neural activity to elucidate the role of specified neuronal circuit elements in mammalian behaviour.

  • Numerous cognitive and emotional functions have already been studied using optogenetic approaches, including sensory perception, pain, decision-making, preference and avoidance, social interactions, and feeding behaviour; optogenetics has also been used in animal models of neuropsychiatric conditions.

  • Animal models for optogenetically induced disease states may facilitate the evaluation of drug candidates.

  • Optogenetics paves the way to novel therapeutic approaches in which chemistry is replaced by micro-optoelectronics and genetic modification of specific cells and in which modulation of specific neuronal circuits is the central mechanism of action.

Abstract

Optogenetics — the use of light and genetics to manipulate and monitor the activities of defined cell populations — has already had a transformative impact on basic neuroscience research. Now, the conceptual and methodological advances associated with optogenetic approaches are providing fresh momentum to neuroscience drug discovery, particularly in areas that are stalled on the concept of 'fixing the brain chemistry'. Optogenetics is beginning to translate and transit into drug discovery in several key domains, including target discovery, high-throughput screening and novel therapeutic approaches to disease states. Here, we discuss the exciting potential of optogenetic technologies to transform neuroscience drug discovery.

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Figure 1: Genetically encoded targetable actuator and reporter proteins that allow the use of light to either control or report electrical activity of neurons.
Figure 2: Cell- and pathway-specific targeting of optogenetic tools.
Figure 3: Anxiety-related projections at the level of whole mouse brain, amygdala and the bed nucleus of stria terminalis.

References

  1. 1

    Zheng, W., Thorne, N. & McKew, J. C. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today 18, 1067–1073 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Belzung, C. & Lemoine, M. Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression. Biol. Mood Anxiety Disord. 1, 9 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Griebel, G. & Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat. Rev. Drug Discov. 12, 667–687 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Cobos, E. J. & Portillo-Salido, E. “Bedside-to-bench” behavioral outcomes in animal models of pain: beyond the evaluation of reflexes. Curr. Neuropharmacol. 11, 560–591 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Simonato, M. et al. The challenge and promise of anti-epileptic therapy development in animal models. Lancet Neurol. 13, 949–960 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Pitkanen, A. et al. Issues related to development of antiepileptogenic therapies. Epilepsia 54 (Suppl. 4), 35–43 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Knopfel, T. Genetically encoded optical indicators for the analysis of neuronal circuits. Nat. Rev. Neurosci. 13, 687–700 (2012). An introductory review on light-based circuit-centric approaches in circuit neurosciences.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005). One of the original descriptions of opsin-based neuromodulation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Li, X. et al. Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. Proc. Natl Acad. Sci. USA 102, 17816–17821 (2005). One of the original descriptions of opsin-based neuromodulation.

    CAS  Article  Google Scholar 

  11. 11

    Deisseroth, K. et al. Next-generation optical technologies for illuminating genetically targeted brain circuits. J. Neurosci. 26, 10380–10386 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Fenno, L., Yizhar, O. & Deisseroth, K. The development and application of optogenetics. Annu. Rev. Neurosci. 34, 389–412 (2011). An introductory review on optogenetic actuators and their application in basic neurosciences.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Steinberg, E. E., Christoffel, D. J., Deisseroth, K. & Malenka, R. C. Illuminating circuitry relevant to psychiatric disorders with optogenetics. Curr. Opin. Neurobiol. 30, 9–16 (2015). A review on the potential of optogenetic approaches for the investigation of neuropsychiatric disorders.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Hausser, M. Optogenetics: the age of light. Nat. Methods 11, 1012–1014 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Deisseroth, K. Optogenetics. Nat. Methods 8, 26–29 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Dugue, G. P., Akemann, W. & Knopfel, T. A comprehensive concept of optogenetics. Prog. Brain Res. 196, 1–28 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Adamantidis, A. R., Zhang, F., de Lecea, L. & Deisseroth, K. Optogenetics: opsins and optical interfaces in neuroscience. Cold Spring Harb. Protoc. 2014, 815–822 (2014).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Zhang, F. et al. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nat. Protoc. 5, 439–456 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Zhang, F., Aravanis, A. M., Adamantidis, A., de Lecea, L. & Deisseroth, K. Circuit-breakers: optical technologies for probing neural signals and systems. Nat. Rev. Neurosci. 8, 577–581 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Miesenbock, G. & Kevrekidis, I. G. Optical imaging and control of genetically designated neurons in functioning circuits. Annu. Rev. Neurosci. 28, 533–563 (2005). An early perspective on optogenetics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Yizhar, O., Fenno, L. E., Davidson, T. J., Mogri, M. & Deisseroth, K. Optogenetics in neural systems. Neuron 71, 9–34 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Klapoetke, N. C. et al. Independent optical excitation of distinct neural populations. Nat. Methods 11, 338–346 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Chuong, A. S. et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat. Neurosci. 17, 1123–1129 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Chow, B. Y. et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 463, 98–102 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Govorunova, E. G., Sineshchekov, O. A., Janz, R., Liu, X. & Spudich, J. L. Natural light-gated anion channels: a family of microbial rhodopsins for advanced optogenetics. Science 349, 647–650 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Govorunova, E. G., Sineshchekov, O. A., Li, H., Janz, R. & Spudich, J. L. Characterization of a highly efficient blue-shifted channelrhodopsin from the marine alga Platymonas subcordiformis. J. Biol. Chem. 288, 29911–29922 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Cosentino, C. et al. Optogenetics. Engineering of a light-gated potassium channel. Science 348, 707–710 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Tamamaki, N. et al. Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J. Comp. Neurol. 467, 60–79 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Madisen, L. et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 85, 942–958 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Huang, Z. J. & Zeng, H. Genetic approaches to neural circuits in the mouse. Annu. Rev. Neurosci. 36, 183–215 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Zeng, H. & Madisen, L. Mouse transgenic approaches in optogenetics. Prog. Brain Res. 196, 193–213 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Fenno, L. E. et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat. Methods 11, 763–772 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).

    CAS  Article  Google Scholar 

  34. 34

    Deisseroth, K. & Schnitzer, M. J. Engineering approaches to illuminating brain structure and dynamics. Neuron 80, 568–577 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).

    CAS  Article  Google Scholar 

  37. 37

    Jorgenson, L. A. et al. The BRAIN Initiative: developing technology to catalyse neuroscience discovery. Philos. Trans. R. Soc. Lond B Biol. Sci. 370 (2015).

  38. 38

    Tye, K. M. & Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat. Rev. Neurosci. 13, 251–266 (2012). A review on the potential use of optogenetic approaches in animal models of brain diseases.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Lee, S. H. et al. Activation of specific interneurons improves V1 feature selectivity and visual perception. Nature 488, 379–383 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Iyer, S. M. et al. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat. Biotech. 32, 274–278 (2014).

    CAS  Article  Google Scholar 

  41. 41

    Warden, M. R. et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492, 428–432 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Chaudhury, D. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013).

    CAS  Article  Google Scholar 

  43. 43

    Felix-Ortiz, A. C. & Tye, K. M. Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. J. Neurosci. 34, 586–595 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Allsop, S. A., Vander Weele, C. M., Wichmann, R. & Tye, K. M. Optogenetic insights on the relationship between anxiety-related behaviors and social deficits. Front. Behav. Neurosci. 8, 241 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Carter, M. E., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Lammel, S., Tye, K. M. & Warden, M. R. Progress in understanding mood disorders: optogenetic dissection of neural circuits. Genes Brain Behav. 13, 38–51 (2014).

    CAS  Article  Google Scholar 

  48. 48

    Touriño, C., Eban-Rothschild, A. & de Lecea, L. Optogenetics in psychiatric diseases. Curr. Opin. Neurobiol. 23, 430–435 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Felix-Ortiz, A. C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Anthony, T. E. et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156, 522–536 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Kim, S. Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Tye, K. M. et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471, 358–362 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Jennings, J. H. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Redondo, R. L. et al. Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513, 426–430 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Bero, A. W. et al. Early remodeling of the neocortex upon episodic memory encoding. Proc. Natl Acad. Sci. USA 111, 11852–11857 (2014).

    CAS  Article  Google Scholar 

  56. 56

    Ramirez, S., Tonegawa, S. & Liu, X. Identification and optogenetic manipulation of memory engrams in the hippocampus. Front. Behav. Neurosci. 7, 226 (2013).

    Google Scholar 

  57. 57

    Miyazaki, K. W. et al. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards. Curr. Biol. 24, 2033–2040 (2014).

    CAS  Article  Google Scholar 

  58. 58

    Irmak, S. O. & de Lecea. L. Basal forebrain cholinergic modulation of sleep transitions. Sleep 37, 1941–1951 (2014).

    Article  Google Scholar 

  59. 59

    Lerner, T. N. et al. Intact-brain analyses reveal distinct information carried by SNc dopamine subcircuits. Cell 162, 635–647 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Deisseroth, K., Etkin, A. & Malenka, R. C. Optogenetics and the circuit dynamics of psychiatric disease. JAMA 313, 2019–2020 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Luthi, A. & Luscher, C. Pathological circuit function underlying addiction and anxiety disorders. Nat. Neurosci. 17, 1635–1643 (2014).

    CAS  Article  Google Scholar 

  62. 62

    Salzman, C. D. & Fusi, S. Emotion, cognition, and mental state representation in amygdala and prefrontal cortex. Annu. Rev. Neurosci. 33, 173–202 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Dolan, R. J. Emotion, cognition, and behavior. Science 298, 1191–1194 (2002).

    CAS  Article  Google Scholar 

  64. 64

    Bressler, S. L. & Menon, V. Large-scale brain networks in cognition: emerging methods and principles. Trends Cogn. Sci. 14, 277–290 (2010).

    Article  Google Scholar 

  65. 65

    Varela, F., Lachaux, J. P., Rodriguez, E. & Martinerie, J. The brainweb: phase synchronization and large-scale integration. Nat. Rev. Neurosci. 2, 229–239 (2001).

    CAS  Article  Google Scholar 

  66. 66

    Steinbeck, J. A. et al. Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model. Nat. Biotech. 33, 204–209 (2015).

    CAS  Article  Google Scholar 

  67. 67

    Doudna, J. A. & Charpentier, E. Genome editing. The new frontier of genome engineering with CRISPR–Cas9. Science 346, 1258096 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Maggio, I. & Goncalves, M. A. Genome editing at the crossroads of delivery, specificity, and fidelity. Trends Biotechnol. 33, 280–291 (2015).

    CAS  Article  Google Scholar 

  69. 69

    Xiao-Jie, L., Hui-Ying, X., Zun-Ping, K., Jin-Lian, C. & Li-Juan, J. CRISPR–Cas9: a new and promising player in gene therapy. J. Med. Genet. 52, 289–296 (2015).

    Article  CAS  Google Scholar 

  70. 70

    Ding, Q. et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ. Res. 115, 488–492 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Polstein, L. R. & Gersbach, C. A. A light-inducible CRISPR–Cas9 system for control of endogenous gene activation. Nat. Chem. Biol. 11, 198–200 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Konermann, S. et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500, 472–476 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Wendland, J. R. & Ehlers, M. D. Translating neurogenomics into new medicines. Biol. Psychiatry http://dx.doi.org/10.1016/j.biopsych.2015.04.027 (2015).

  74. 74

    Noebels, J. Pathway-driven discovery of epilepsy genes. Nat. Neurosci. 18, 344–350 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Wang, H., Pati, S., Pozzo-Miller, L. & Doering, L. C. Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes. Front. Cell Neurosci. 9, 55 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Abrahams, B. S. & Geschwind, D. H. Connecting genes to brain in the autism spectrum disorders. Arch. Neurol. 67, 395–399 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Lotharius, J. & Brundin, P. Pathogenesis of Parkinson's disease: dopamine, vesicles and α-synuclein. Nat. Rev. Neurosci. 3, 932–942 (2002).

    CAS  Article  Google Scholar 

  78. 78

    Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).

    CAS  Article  Google Scholar 

  79. 79

    Nutt, D. J., Lingford-Hughes, A., Erritzoe, D. & Stokes, P. R. The dopamine theory of addiction: 40 years of highs and lows. Nat. Rev. Neurosci. 16, 305–312 (2015).

    CAS  Article  Google Scholar 

  80. 80

    Howes, O. D. et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch. Gen. Psychiatry 69, 776–786 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Barbeau, A. L-dopa therapy in Parkinson's disease: a critical review of nine years' experience. Can. Med. Assoc. J. 101, 59–68 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Cools, R., Barker, R. A., Sahakian, B. J. & Robbins, T. W. L-dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson's disease. Neuropsychologia 41, 1431–1441 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Lawrence, A. D., Evans, A. H. & Lees, A. J. Compulsive use of dopamine replacement therapy in Parkinson's disease: reward systems gone awry? Lancet Neurol. 2, 595–604 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Jenner, P. Dopamine agonists in Parkinson's disease — focus on non-motor symptoms. Eur. J. Neurol. 15 (Suppl. 2), 1 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Noyes, K., Liu, H. & Holloway, R. G. What is the risk of developing parkinsonism following neuroleptic use? Neurology 66, 941–943 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Hall, R. A., Jackson, R. B. & Swain, J. M. Neurotoxic reactions resulting from chlorpromazine administration. J. Am. Med. Assoc. 161, 214–218 (1956).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Araragi, N. & Lesch, K. P. Serotonin (5-HT) in the regulation of depression-related emotionality: insight from 5-HT transporter and tryptophan hydroxylase-2 knockout mouse models. Curr. Drug Targets 14, 549–570 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Gartside, S. E., Umbers, V., Hajos, M. & Sharp, T. Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT. Br. J. Pharmacol. 115, 1064–1070 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Trivedi, M. H. et al. Medication augmentation after the failure of SSRIs for depression. N. Engl. J. Med. 354, 1243–1252 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Rush, A. J. et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N. Engl. J. Med. 354, 1231–1242 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Mayberg, H. S. et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Floresco, S. B., West, A. R., Ash, B., Moore, H. & Grace, A. A. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat. Neurosci. 6, 968–973 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Radhu, N. et al. A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders. Clin. Neurophysiol. 124, 1309–1320 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Zhang, Z. & Sun, Q. Q. The balance between excitation and inhibition and functional sensory processing in the somatosensory cortex. Int. Rev. Neurobiol. 97, 305–333 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Carter, M. E., de Lecea, L. & Adamantidis, A. Functional wiring of hypocretin and LC-NE neurons: implications for arousal. Front. Behav. Neurosci. 7, 43 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Williams, R. H. et al. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J. Neurosci. 34, 6023–6029 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Weiler, H. T. et al. Differential modulation of hippocampal signal transfer by tuberomammillary nucleus stimulation in freely moving rats dependent on behavioral state. Synapse 28, 294–301 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Dobolyi, A. et al. Receptors of peptides as therapeutic targets in epilepsy research. Curr. Med. Chem. 21, 764–787 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Schone, C. et al. Optogenetic probing of fast glutamatergic transmission from hypocretin/orexin to histamine neurons in situ. J. Neurosci. 32, 12437–12443 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Carter, M. E., Han, S. & Palmiter, R. D. Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. J. Neurosci. 35, 4582–4586 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Carter, M. E. et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Aston-Jones, G. & Bloom, F. E. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1, 876–886 (1981).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Adamantidis, A. & Carter, M. C. & de Lecea, L. Optogenetic deconstruction of sleep–wake circuitry in the brain. Front. Mol. Neurosci. 2, 31 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Carter, M. E. et al. Mechanism for hypocretin-mediated sleep-to-wake transitions. Proc. Natl Acad. Sci. USA 109, E2635–E2644 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Bonnavion, P., Jackson, A. C. & Carter, M. E. & de Lecea L. Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses. Nat. Commun. 6, 6266 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Saper, C. B., Chou, T. C. & Scammell, T. E. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 24, 726–731 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Shan, L., Bao, A. M. & Swaab, D. F. The human histaminergic system in neuropsychiatric disorders. Trends Neurosci. 38, 167–177 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Coppen, A. The biochemistry of affective disorders. Br. J. Psychiatry 113, 1237–1264 (1967).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Liu, Z. et al. Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron 81, 1360–1374 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Ito, H. et al. Analysis of sleep disorders under pain using an optogenetic tool: possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons. Mol. Brain 6, 59 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Ohmura, Y., Tanaka, K. F., Tsunematsu, T., Yamanaka, A. & Yoshioka, M. Optogenetic activation of serotonergic neurons enhances anxiety-like behaviour in mice. Int. J. Neuropsychopharmacol. 17, 1777–1783 (2014).

    CAS  Article  Google Scholar 

  113. 113

    Dugue, G. P. et al. Optogenetic recruitment of dorsal raphe serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice. PLoS ONE 9, e105941 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Alford, S. C., Wu, J., Zhao, Y., Campbell, R. E. & Knopfel, T. Optogenetic reporters. Biol. Cell 105, 14–29 (2013).

    CAS  Article  Google Scholar 

  115. 115

    Prigge, M., Rosler, A. & Hegemann, P. Fast, repetitive light-activation of CaV3.2 using channelrhodopsin 2. Channels (Austin.) 4, 241–247 (2010).

    CAS  Article  Google Scholar 

  116. 116

    Agus, V. et al. Bringing the light to high throughput screening: use of optogenetic tools for the development of recombinant cellular assays. Proc. SPIE 9305, 93052T (2015).

    Article  Google Scholar 

  117. 117

    Esch, E. W., Bahinski, A. & Huh, D. Organs-on-chips at the frontiers of drug discovery. Nat. Rev. Drug Discov. 14, 248–260 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Birmingham, K. et al. Bioelectronic medicines: a research roadmap. Nat. Rev. Drug Discov. 13, 399–400 (2014).

    CAS  Article  Google Scholar 

  119. 119

    Okun, M. S. Deep-brain stimulation — entering the era of human neural-network modulation. N. Engl. J. Med. 371, 1369–1373 (2014).

    Article  Google Scholar 

  120. 120

    Deep-Brain Stimulation for Parkinson's Disease Study Group. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N. Engl. J. Med. 345, 956–963 (2001).

  121. 121

    Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Schlaepfer, T. E., Bewernick, B. H., Kayser, S., Hurlemann, R. & Coenen, V. A. Deep brain stimulation of the human reward system for major depression — rationale, outcomes and outlook. Neuropsychopharmacology 39, 1303–1314 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Ressler, K. J. & Mayberg, H. S. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat. Neurosci. 10, 1116–1124 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Creed, M., Pascoli, V. J. & Luscher, C. Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science 347, 659–664 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Valjent, E. et al. Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol. Neuropsychopharmacology 35, 401–415 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Pascoli, V. et al. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509, 459–464 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Pascoli, V., Turiault, M. & Luscher, C. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71–75 (2012).

    CAS  Article  Google Scholar 

  129. 129

    Shabel, S. J., Proulx, C. D., Piriz, J. & Malinow, R. Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science 345, 1494–1498 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Sulzer, D. et al. Dopamine neurons make glutamatergic synapses in vitro. J. Neurosci. 18, 4588–4602 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Trudeau, L. E. et al. The multilingual nature of dopamine neurons. Prog. Brain Res. 211, 141–164 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Trudeau, L. E. Glutamate co-transmission as an emerging concept in monoamine neuron function. J. Psychiatry Neurosci. 29, 296–310 (2004).

    PubMed  PubMed Central  Google Scholar 

  133. 133

    Perucca, P. & Gilliam, F. G. Adverse effects of antiepileptic drugs. Lancet Neurol. 11, 792–802 (2012).

    CAS  Article  Google Scholar 

  134. 134

    Krook-Magnuson, E. & Soltesz, I. Beyond the hammer and the scalpel: selective circuit control for the epilepsies. Nat. Neurosci. 18, 331–338 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    de Tisi, J. et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 378, 1388–1395 (2011).

    Article  Google Scholar 

  136. 136

    Wykes, R. C. et al. Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci. Transl. Med. 4, 161ra152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Krook-Magnuson, E., Armstrong, C., Oijala, M. & Soltesz, I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat. Commun. 4, 1376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Paz, J. T. et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat. Neurosci. 16, 64–70 (2013).

    CAS  Article  Google Scholar 

  139. 139

    Grosenick, L., Marshel, J. H. & Deisseroth, K. Closed-loop and activity-guided optogenetic control. Neuron 86, 106–139 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Barrett, J. M., Berlinguer-Palmini, R. & Degenaar, P. Optogenetic approaches to retinal prosthesis. Vis. Neurosci. 31, 345–354 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Picaud, S. & Sahel, J. A. Retinal prostheses: clinical results and future challenges. C. R. Biol. 337, 214–222 (2014).

    Article  Google Scholar 

  142. 142

    Pearson, R. A. et al. Restoration of vision after transplantation of photoreceptors. Nature 485, 99–103 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Bi, A. et al. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron 50, 23–33 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Busskamp, V. et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 329, 413–417 (2010).

    CAS  Article  Google Scholar 

  145. 145

    Lagali, P. S. et al. Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat. Neurosci. 11, 667–675 (2008).

    CAS  Article  Google Scholar 

  146. 146

    Alilain, W. J. et al. Light-induced rescue of breathing after spinal cord injury. J. Neurosci. 28, 11862–11870 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Bryson, J. B. et al. Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice. Science 344, 94–97 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Garcia-Bennett, A. E. et al. Delivery of differentiation factors by mesoporous silica particles assists advanced differentiation of transplanted murine embryonic stem cells. Stem Cells Transl. Med. 2, 906–915 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Apati, A. et al. Characterization of calcium signals in human embryonic stem cells and in their differentiated offspring by a stably integrated calcium indicator protein. Cell Signal. 25, 752–759 (2013).

    CAS  Article  Google Scholar 

  150. 150

    Wang, S. J., Weng, C. H., Xu, H. W., Zhao, C. J. & Yin, Z. Q. Effect of optogenetic stimulus on the proliferation and cell cycle progression of neural stem cells. J. Membr. Biol. 247, 493–500 (2014).

    CAS  Article  Google Scholar 

  151. 151

    Stroh, A. et al. Tracking stem cell differentiation in the setting of automated optogenetic stimulation. Stem Cells 29, 78–88 (2010).

    Article  CAS  Google Scholar 

  152. 152

    Flax, J. D. et al. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat. Biotech. 16, 1033–1039 (1998).

    CAS  Article  Google Scholar 

  153. 153

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

    CAS  Article  Google Scholar 

  154. 154

    Famm, K., Litt, B., Tracey, K. J., Boyden, E. S. & Slaoui, M. Drug discovery: a jump-start for electroceuticals. Nature 496, 159–161 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Mattis, J. et al. Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. Nat. Methods 9, 159–172 (2012).

    CAS  Article  Google Scholar 

  157. 157

    Gerfen, C. R., Paletzki, R. & Heintz, N. GENSAT BAC Cre-recombinase driver lines to study the functional organization of cerebral cortical and basal ganglia circuits. Neuron 80, 1368–1383 (2013).

    CAS  Article  Google Scholar 

  158. 158

    Fishell, G. & Heintz, N. The neuron identity problem: form meets function. Neuron 80, 602–612 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159

    Warden, M. R., Cardin, J. A. & Deisseroth, K. Optical neural interfaces. Annu. Rev. Biomed. Eng. 16, 103–129 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Rossi, M. A. et al. A wirelessly controlled implantable LED system for deep brain optogenetic stimulation. Front. Integr. Neurosci. 9, 8 (2015).

    PubMed  PubMed Central  Google Scholar 

  161. 161

    Bin, F., Ki, Y. K., Weber, A. J. & Wen, L. An implantable, miniaturized SU-8 optical probe for optogenetics-based deep brain stimulation. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2014, 450–453 (2014).

    Google Scholar 

  162. 162

    Urban, D. J. & Roth, B. L. DREADDs (designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility. Annu. Rev. Pharmacol. Toxicol. 55, 399–417 (2015). A description of chemogenetic approaches to target drugs to genetically specified cell classes.

    CAS  Article  Google Scholar 

  163. 163

    Maguire, C. A., Ramirez, S. H., Merkel, S. F., Sena-Esteves, M. & Breakefield, X. O. Gene therapy for the nervous system: challenges and new strategies. Neurotherapeutics 11, 817–839 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Izpisua Belmonte, J. C. et al. Brains, genes, and primates. Neuron 86, 617–631 (2015).

    Article  CAS  Google Scholar 

  165. 165

    Diester, I. et al. An optogenetic toolbox designed for primates. Nat. Neurosci. 14, 387–397 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Dai, J. et al. Modified toolbox for optogenetics in the nonhuman primate. Neurophotonics 2, 031202 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Zhang, F. et al. The microbial opsin family of optogenetic tools. Cell 147, 1446–1457 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H. & Deisseroth, K. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025–1029 (2009).

    CAS  Article  Google Scholar 

  169. 169

    Hochbaum, D. R. et al. All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. Nat. Methods 11, 825–833 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Rickgauer, J. P., Deisseroth, K. & Tank, D. W. Simultaneous cellular-resolution optical perturbation and imaging of place cell firing fields. Nat. Neurosci. 17, 1816–1824 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Packer, A. M., Russell, L. E., Dalgleish, H. W. & Hausser, M. Simultaneous all-optical manipulation and recording of neural circuit activity with cellular resolution in vivo. Nat. Methods 12, 140–146 (2015).

    CAS  Article  Google Scholar 

  172. 172

    Vogt, C. C. et al. Systemic gene transfer enables optogenetic pacing of mouse hearts. Cardiovasc. Res. 106, 338–343 (2015).

    CAS  Article  Google Scholar 

  173. 173

    Bruegmann, T. et al. Optogenetic control of heart muscle in vitro and in vivo. Nat. Methods 7, 897–900 (2010).

    CAS  Article  Google Scholar 

  174. 174

    Ambrosi, C. M., Klimas, A., Yu, J. & Entcheva, E. Cardiac applications of optogenetics. Prog. Biophys. Mol. Biol. 115, 294–304 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. 175

    Quinn, T. A. et al. Cell-specific expression of voltage-sensitive protein confirms cardiac myocyte to non-myocyte electrotonic coupling in healed murine infarct border tissue. Circulation. 130 (Suppl. 2), A11749 (2014).

    Google Scholar 

  176. 176

    Reinbothe, T. M., Safi, F., Axelsson, A. S., Mollet, I. G. & Rosengren, A. H. Optogenetic control of insulin secretion in intact pancreatic islets with β-cell-specific expression of channelrhodopsin-2. Islets 6, e28095 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  177. 177

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

    CAS  Article  Google Scholar 

  178. 178

    Knopfel, T., Gallero-Salas, Y. & Song, C. Genetically encoded voltage indicators for large scale cortical imaging come of age. Curr. Opin. Chem. Biol. 27, 75–83 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. 179

    Mishina, Y., Mutoh, H., Song, C. & Knopfel, T. Exploration of genetically encoded voltage indicators based on a chimeric voltage sensing domain. Front. Mol. Neurosci. 7, 78 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Knopfel, T., Diez-Garcia, J. & Akemann, W. Optical probing of neuronal circuit dynamics: genetically encoded versus classical fluorescent sensors. Trends Neurosciences 29, 160–166 (2006).

    Article  CAS  Google Scholar 

  181. 181

    Broussard, G. J., Liang, R. & Tian, L. Monitoring activity in neural circuits with genetically encoded indicators. Front. Mol. Neurosci. 7, 97 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  182. 182

    Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. 183

    Akemann, W., Song, C., Mutoh, H. & Knopfel, T. Route to genetically targeted optical electrophysiology: development and applications of voltage-sensitive fluorescent proteins. Neurophotonics 2, 021008 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Rose, T., Goltstein, P. M., Portugues, R. & Griesbeck, O. Putting a finishing touch on GECIs. Front. Mol. Neurosci. 7, 88 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge D. Nutt and P. M. Matthews and two anonymous expert reviewers for critically reading the manuscript and their many helpful suggestions. The authors also acknowledge the many other important contributions from the optogenetics community that, regrettably, could not be included in the present review owing to focus and space constraints.

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Glossary

Neuronal circuits

Functional entities of interconnected neurons that typically include both excitatory and inhibitory neurons.

Systems of circuits

The functional integration of local circuits; for example, sensory motor integration involves the system of sensory and motor circuitries.

PET and functional MRI imaging

PET and functional MRI are imaging modalities that produce a three-dimensional image of functional processes in the body. PET uses a radioactive substance and functional MRI uses strong magnetic fields and radio waves.

Forced swim test

The forced swim test is a rodent behavioural test used for the evaluation of endurance and motivation. This test is traditionally used to evaluate experimental manipulations that are aimed at rendering or preventing depressive-like states.

Deep-brain stimulation

(DBS). A neurosurgical procedure involving the implantation of electrodes, to electrically stimulate specific parts of the brain for the treatment of movement and neuropsychiatric disorders.

Locomotor sensitization

The locomotor response induced by acute drug administration, which is progressively augmented with repeated administration. This technique is used to evaluate addictive drug effects.

Recombinase

An enzyme that catalyses the recombination between two specific short DNA sequences (loxP sites in the case of the most widely used Cre recombinase), leading to excision or inversion of the intervening sequence. Genes that are artificially flanked with loxP sites are said to be 'floxed'. Recombination occurs if the cells both carry the floxed genes and express the recombinase. Expression of a recombinase in specific cell classes can be used to precisely target an optogenetic tool to these cells.

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Song, C., Knöpfel, T. Optogenetics enlightens neuroscience drug discovery. Nat Rev Drug Discov 15, 97–109 (2016). https://doi.org/10.1038/nrd.2015.15

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