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.
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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Zheng, W., Thorne, N. & McKew, J. C. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today 18, 1067–1073 (2013).
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).
Griebel, G. & Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat. Rev. Drug Discov. 12, 667–687 (2013).
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).
Simonato, M. et al. The challenge and promise of anti-epileptic therapy development in animal models. Lancet Neurol. 13, 949–960 (2014).
Pitkanen, A. et al. Issues related to development of antiepileptogenic therapies. Epilepsia 54 (Suppl. 4), 35–43 (2013).
Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).
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.
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.
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.
Deisseroth, K. et al. Next-generation optical technologies for illuminating genetically targeted brain circuits. J. Neurosci. 26, 10380–10386 (2006).
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.
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.
Hausser, M. Optogenetics: the age of light. Nat. Methods 11, 1012–1014 (2014).
Deisseroth, K. Optogenetics. Nat. Methods 8, 26–29 (2011).
Dugue, G. P., Akemann, W. & Knopfel, T. A comprehensive concept of optogenetics. Prog. Brain Res. 196, 1–28 (2012).
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).
Zhang, F. et al. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nat. Protoc. 5, 439–456 (2010).
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).
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.
Yizhar, O., Fenno, L. E., Davidson, T. J., Mogri, M. & Deisseroth, K. Optogenetics in neural systems. Neuron 71, 9–34 (2011).
Klapoetke, N. C. et al. Independent optical excitation of distinct neural populations. Nat. Methods 11, 338–346 (2014).
Chuong, A. S. et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat. Neurosci. 17, 1123–1129 (2014).
Chow, B. Y. et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 463, 98–102 (2010).
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).
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).
Cosentino, C. et al. Optogenetics. Engineering of a light-gated potassium channel. Science 348, 707–710 (2015).
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).
Madisen, L. et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 85, 942–958 (2015).
Huang, Z. J. & Zeng, H. Genetic approaches to neural circuits in the mouse. Annu. Rev. Neurosci. 36, 183–215 (2013).
Zeng, H. & Madisen, L. Mouse transgenic approaches in optogenetics. Prog. Brain Res. 196, 193–213 (2012).
Fenno, L. E. et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat. Methods 11, 763–772 (2014).
Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).
Deisseroth, K. & Schnitzer, M. J. Engineering approaches to illuminating brain structure and dynamics. Neuron 80, 568–577 (2013).
Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).
Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).
Jorgenson, L. A. et al. The BRAIN Initiative: developing technology to catalyse neuroscience discovery. Philos. Trans. R. Soc. Lond B Biol. Sci. 370 (2015).
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.
Lee, S. H. et al. Activation of specific interneurons improves V1 feature selectivity and visual perception. Nature 488, 379–383 (2012).
Iyer, S. M. et al. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. Nat. Biotech. 32, 274–278 (2014).
Warden, M. R. et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492, 428–432 (2012).
Chaudhury, D. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013).
Felix-Ortiz, A. C. & Tye, K. M. Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. J. Neurosci. 34, 586–595 (2014).
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).
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).
Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013).
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).
Touriño, C., Eban-Rothschild, A. & de Lecea, L. Optogenetics in psychiatric diseases. Curr. Opin. Neurobiol. 23, 430–435 (2013).
Felix-Ortiz, A. C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013).
Anthony, T. E. et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156, 522–536 (2014).
Kim, S. Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013).
Tye, K. M. et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471, 358–362 (2011).
Jennings, J. H. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013).
Redondo, R. L. et al. Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513, 426–430 (2014).
Bero, A. W. et al. Early remodeling of the neocortex upon episodic memory encoding. Proc. Natl Acad. Sci. USA 111, 11852–11857 (2014).
Ramirez, S., Tonegawa, S. & Liu, X. Identification and optogenetic manipulation of memory engrams in the hippocampus. Front. Behav. Neurosci. 7, 226 (2013).
Miyazaki, K. W. et al. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards. Curr. Biol. 24, 2033–2040 (2014).
Irmak, S. O. & de Lecea. L. Basal forebrain cholinergic modulation of sleep transitions. Sleep 37, 1941–1951 (2014).
Lerner, T. N. et al. Intact-brain analyses reveal distinct information carried by SNc dopamine subcircuits. Cell 162, 635–647 (2015).
Deisseroth, K., Etkin, A. & Malenka, R. C. Optogenetics and the circuit dynamics of psychiatric disease. JAMA 313, 2019–2020 (2015).
Luthi, A. & Luscher, C. Pathological circuit function underlying addiction and anxiety disorders. Nat. Neurosci. 17, 1635–1643 (2014).
Salzman, C. D. & Fusi, S. Emotion, cognition, and mental state representation in amygdala and prefrontal cortex. Annu. Rev. Neurosci. 33, 173–202 (2010).
Dolan, R. J. Emotion, cognition, and behavior. Science 298, 1191–1194 (2002).
Bressler, S. L. & Menon, V. Large-scale brain networks in cognition: emerging methods and principles. Trends Cogn. Sci. 14, 277–290 (2010).
Varela, F., Lachaux, J. P., Rodriguez, E. & Martinerie, J. The brainweb: phase synchronization and large-scale integration. Nat. Rev. Neurosci. 2, 229–239 (2001).
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).
Doudna, J. A. & Charpentier, E. Genome editing. The new frontier of genome engineering with CRISPR–Cas9. Science 346, 1258096 (2014).
Maggio, I. & Goncalves, M. A. Genome editing at the crossroads of delivery, specificity, and fidelity. Trends Biotechnol. 33, 280–291 (2015).
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).
Ding, Q. et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ. Res. 115, 488–492 (2014).
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).
Konermann, S. et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500, 472–476 (2013).
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).
Noebels, J. Pathway-driven discovery of epilepsy genes. Nat. Neurosci. 18, 344–350 (2015).
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).
Abrahams, B. S. & Geschwind, D. H. Connecting genes to brain in the autism spectrum disorders. Arch. Neurol. 67, 395–399 (2010).
Lotharius, J. & Brundin, P. Pathogenesis of Parkinson's disease: dopamine, vesicles and α-synuclein. Nat. Rev. Neurosci. 3, 932–942 (2002).
Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).
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).
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).
Barbeau, A. L-dopa therapy in Parkinson's disease: a critical review of nine years' experience. Can. Med. Assoc. J. 101, 59–68 (1969).
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).
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).
Jenner, P. Dopamine agonists in Parkinson's disease — focus on non-motor symptoms. Eur. J. Neurol. 15 (Suppl. 2), 1 (2008).
Noyes, K., Liu, H. & Holloway, R. G. What is the risk of developing parkinsonism following neuroleptic use? Neurology 66, 941–943 (2006).
Hall, R. A., Jackson, R. B. & Swain, J. M. Neurotoxic reactions resulting from chlorpromazine administration. J. Am. Med. Assoc. 161, 214–218 (1956).
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).
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).
Trivedi, M. H. et al. Medication augmentation after the failure of SSRIs for depression. N. Engl. J. Med. 354, 1243–1252 (2006).
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).
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).
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).
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).
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).
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).
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).
Williams, R. H. et al. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J. Neurosci. 34, 6023–6029 (2014).
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).
Dobolyi, A. et al. Receptors of peptides as therapeutic targets in epilepsy research. Curr. Med. Chem. 21, 764–787 (2014).
Schone, C. et al. Optogenetic probing of fast glutamatergic transmission from hypocretin/orexin to histamine neurons in situ. J. Neurosci. 32, 12437–12443 (2012).
Carter, M. E., Han, S. & Palmiter, R. D. Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. J. Neurosci. 35, 4582–4586 (2015).
Carter, M. E. et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533 (2010).
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).
Adamantidis, A. & Carter, M. C. & de Lecea, L. Optogenetic deconstruction of sleep–wake circuitry in the brain. Front. Mol. Neurosci. 2, 31 (2010).
Carter, M. E. et al. Mechanism for hypocretin-mediated sleep-to-wake transitions. Proc. Natl Acad. Sci. USA 109, E2635–E2644 (2012).
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).
Saper, C. B., Chou, T. C. & Scammell, T. E. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 24, 726–731 (2001).
Shan, L., Bao, A. M. & Swaab, D. F. The human histaminergic system in neuropsychiatric disorders. Trends Neurosci. 38, 167–177 (2015).
Coppen, A. The biochemistry of affective disorders. Br. J. Psychiatry 113, 1237–1264 (1967).
Liu, Z. et al. Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron 81, 1360–1374 (2014).
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).
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).
Dugue, G. P. et al. Optogenetic recruitment of dorsal raphe serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice. PLoS ONE 9, e105941 (2014).
Alford, S. C., Wu, J., Zhao, Y., Campbell, R. E. & Knopfel, T. Optogenetic reporters. Biol. Cell 105, 14–29 (2013).
Prigge, M., Rosler, A. & Hegemann, P. Fast, repetitive light-activation of CaV3.2 using channelrhodopsin 2. Channels (Austin.) 4, 241–247 (2010).
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).
Esch, E. W., Bahinski, A. & Huh, D. Organs-on-chips at the frontiers of drug discovery. Nat. Rev. Drug Discov. 14, 248–260 (2015).
Birmingham, K. et al. Bioelectronic medicines: a research roadmap. Nat. Rev. Drug Discov. 13, 399–400 (2014).
Okun, M. S. Deep-brain stimulation — entering the era of human neural-network modulation. N. Engl. J. Med. 371, 1369–1373 (2014).
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).
Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).
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).
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).
Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).
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).
Valjent, E. et al. Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol. Neuropsychopharmacology 35, 401–415 (2010).
Pascoli, V. et al. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509, 459–464 (2014).
Pascoli, V., Turiault, M. & Luscher, C. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71–75 (2012).
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).
Sulzer, D. et al. Dopamine neurons make glutamatergic synapses in vitro. J. Neurosci. 18, 4588–4602 (1998).
Trudeau, L. E. et al. The multilingual nature of dopamine neurons. Prog. Brain Res. 211, 141–164 (2014).
Trudeau, L. E. Glutamate co-transmission as an emerging concept in monoamine neuron function. J. Psychiatry Neurosci. 29, 296–310 (2004).
Perucca, P. & Gilliam, F. G. Adverse effects of antiepileptic drugs. Lancet Neurol. 11, 792–802 (2012).
Krook-Magnuson, E. & Soltesz, I. Beyond the hammer and the scalpel: selective circuit control for the epilepsies. Nat. Neurosci. 18, 331–338 (2015).
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).
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).
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).
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).
Grosenick, L., Marshel, J. H. & Deisseroth, K. Closed-loop and activity-guided optogenetic control. Neuron 86, 106–139 (2015).
Barrett, J. M., Berlinguer-Palmini, R. & Degenaar, P. Optogenetic approaches to retinal prosthesis. Vis. Neurosci. 31, 345–354 (2014).
Picaud, S. & Sahel, J. A. Retinal prostheses: clinical results and future challenges. C. R. Biol. 337, 214–222 (2014).
Pearson, R. A. et al. Restoration of vision after transplantation of photoreceptors. Nature 485, 99–103 (2012).
Bi, A. et al. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron 50, 23–33 (2006).
Busskamp, V. et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 329, 413–417 (2010).
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).
Alilain, W. J. et al. Light-induced rescue of breathing after spinal cord injury. J. Neurosci. 28, 11862–11870 (2008).
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).
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).
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).
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).
Stroh, A. et al. Tracking stem cell differentiation in the setting of automated optogenetic stimulation. Stem Cells 29, 78–88 (2010).
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).
Deisseroth, K. et al. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42, 535–552 (2004).
Famm, K., Litt, B., Tracey, K. J., Boyden, E. S. & Slaoui, M. Drug discovery: a jump-start for electroceuticals. Nature 496, 159–161 (2013).
Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).
Mattis, J. et al. Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. Nat. Methods 9, 159–172 (2012).
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).
Fishell, G. & Heintz, N. The neuron identity problem: form meets function. Neuron 80, 602–612 (2013).
Warden, M. R., Cardin, J. A. & Deisseroth, K. Optical neural interfaces. Annu. Rev. Biomed. Eng. 16, 103–129 (2014).
Rossi, M. A. et al. A wirelessly controlled implantable LED system for deep brain optogenetic stimulation. Front. Integr. Neurosci. 9, 8 (2015).
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).
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.
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).
Izpisua Belmonte, J. C. et al. Brains, genes, and primates. Neuron 86, 617–631 (2015).
Diester, I. et al. An optogenetic toolbox designed for primates. Nat. Neurosci. 14, 387–397 (2011).
Dai, J. et al. Modified toolbox for optogenetics in the nonhuman primate. Neurophotonics 2, 031202 (2015).
Zhang, F. et al. The microbial opsin family of optogenetic tools. Cell 147, 1446–1457 (2011).
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).
Hochbaum, D. R. et al. All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. Nat. Methods 11, 825–833 (2014).
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).
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).
Vogt, C. C. et al. Systemic gene transfer enables optogenetic pacing of mouse hearts. Cardiovasc. Res. 106, 338–343 (2015).
Bruegmann, T. et al. Optogenetic control of heart muscle in vitro and in vivo. Nat. Methods 7, 897–900 (2010).
Ambrosi, C. M., Klimas, A., Yu, J. & Entcheva, E. Cardiac applications of optogenetics. Prog. Biophys. Mol. Biol. 115, 294–304 (2014).
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).
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).
Nagel, G. et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl Acad. Sci. USA 100, 13940–13945 (2003).
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).
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).
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).
Broussard, G. J., Liang, R. & Tian, L. Monitoring activity in neural circuits with genetically encoded indicators. Front. Mol. Neurosci. 7, 97 (2014).
Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).
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).
Rose, T., Goltstein, P. M., Portugues, R. & Griesbeck, O. Putting a finishing touch on GECIs. Front. Mol. Neurosci. 7, 88 (2014).
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.
The authors declare no competing financial interests.
- 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.
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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