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Optogenetics (from the Greek optos, meaning "visible") is a neuromodulation technique employed in neuroscience that uses a combination of techniques from optics and genetics to control and monitor the activities of individual neurons in living tissue—even within freely-moving animals—and to precisely measure the effects of those manipulations in real-time. The key reagents used in optogenetics are light-sensitive proteins. Spatially-precise neuronal control is achieved using optogenetic actuators like channelrhodopsin, halorhodopsin, and archaerhodopsin, while temporally-precise recordings can be made with the help of optogenetic sensors like Clomeleon, Mermaid, and SuperClomeleon.
The earliest approaches were developed and applied in the lab of Gero Miesenböck, now Waynflete Professor of Physiology at the University of Oxford, and Richard Kramer and Ehud Isacoff at the University of California, Berkeley; these methods conferred light sensitivity but were never reported to be useful by other laboratories due to the multiple components these approaches required. A distinct single-component approach involving microbial opsin genes introduced in 2005 turned out to be widely applied, as described below. Optogenetics is known for the high spatial and temporal resolution that it provides in altering the activity of specific types of neurons within defined brain areas to control a subject's behavior.
In 2010 Karl Deisseroth at Stanford University was awarded the inaugural HFSP Nakasone Award "for his pioneering work on the development of optogenetic methods for studying the function of neuronal networks underlying behavior."
In 2010, optogenetics was chosen as the Method of the Year across all fields of science and engineering by the interdisciplinary research journal Nature Methods (Primer on Optogenetics, Editorial Commentary). At the same time, optogenetics was highlighted in the article on “Breakthroughs of the Decade” in the scientific research journal Science these journals also referenced recent public-access general-interest video Method of the year video and textual SciAm summaries of optogenetics.
In 2012 Gero Miesenböck was awarded the InBev-Baillet Latour International Health Prize for "pioneering optogenetic approaches to manipulate neuronal activity and to control animal behaviour."
In 2013 Ernst Bamberg, Ed Boyden, Karl Deisseroth, Peter Hegemann, Gero Miesenböck and Georg Nagel were awarded The Brain Prize for "their invention and refinement of optogenetics."
The "far-fetched" possibility of using light for selectively controlling precise neural activity (action potential) patterns within subtypes of cells in the brain was articulated by Francis Crick in his Kuffler Lectures at the University of California in San Diego in 1999. An early use of light to activate neurons was carried out by Richard Fork and later Rafael Yuste, who demonstrated laser activation of neurons within intact tissue, although not in a genetically-targeted manner. The earliest genetically targeted method, which used light to control genetically-sensitised neurons, was reported in January 2002 by Boris Zemelman (now at UT Austin) and Gero Miesenböck, who employed Drosophila rhodopsin photoreceptors for controlling neural activity in cultured mammalian neurons. In 2003 Zemelman and Miesenböck developed a second method for light-dependent activation of neurons in which single ionotropic channels TRPV1, TRPM8 and P2X2 were gated by caged ligands in response to light. Beginning in 2004, the Kramer and Isacoff groups developed organic photoswitches or "caged" compounds that could interact with genetically-introduced ion channels. However, these earlier approaches were not applied outside the original laboratories, likely because of technical challenges in delivering the multiple component parts required.
In April 2005, Susana Lima and Miesenböck reported the first use of genetically-targeted P2X2 photostimulation to control the behaviour of an animal. They showed that photostimulation of genetically circumscribed groups of neurons, such as those of the dopaminergic system, elicited characteristic behavioural changes in fruit flies. In August 2005, Karl Deisseroth's laboratory in the Bioengineering Department at Stanford including graduate students Ed Boyden and Feng Zhang (both now at MIT) published the first demonstration of a single-component optogenetic system, beginning in cultured mammalian neurons. using channelrhodopsin, a single-component light-activated cation channel from unicellular algae), whose molecular identity and principal properties rendering it useful for optogenetic studies had been first reported in November 2003 by the group of Georg Nagel. The groups of Gottschalk and Nagel were the first to extend the usability of Channelrhodopsin-2 for controlling neuronal activity to the intact animal by showing that motor patterns in the roundworm Caenorhabditis elegans could be evoked by targeted expression and stimulation of Channelrhodopsin-2 in selected neural circuits (published in December 2005).
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Millisecond-scale temporal precision is central to optogenetics, which allows the experimenter to keep pace with fast biological information processing (for example, in probing the causal role of specific action potential patterns in defined neurons). Indeed, to probe the neural code, optogenetics by definition must operate on the millisecond timescale to allow addition or deletion of precise activity patterns within specific cells in the brains of intact animals, including mammals (see Figure 1). By comparison, the temporal precision of traditional genetic manipulations (employed to probe the causal role of specific genes within cells, via "loss-of-function" or "gain of function" changes in these genes) is rather slow, from hours or days to months. It is important to also have fast readouts in optogenetics that can keep pace with the optical control. This can be done with electrical recordings ("optrodes") or with reporter proteins that are biosensors, where scientists have fused fluorescent proteins to detector proteins. An example of this is voltage-sensitive fluorescent protein (VSFP2).
The hallmark of optogenetics therefore is introduction of fast light-activated channels and enzymes that allow temporally precise manipulation of electrical and biochemical events while maintaining cell-type resolution through the use of specific targeting mechanisms. Among the microbial opsins which can be used to investigate the function of neural systems are the channelrhodopsins (ChR2, ChR1, VChR1, and SFOs) to excite neurons. For silencing, halorhodopsin (NpHR), enhanced halorhodopsins (eNpHR2.0 and eNpHR3.0), archaerhodopsin (Arch), Leptosphaeria maculans fungal opsins (Mac), and enhanced bacteriorhodopsin (eBR) have been employed to inhibit neurons (see Figure 2), including in freely-moving mammals.
Moreover, optogenetic control of well-defined biochemical events within behaving mammals is now also possible. Building on prior work fusing vertebrate opsins to specific G-protein coupled receptors  a family of chimeric single-component optogenetic tools was created that allowed researchers to manipulate within behaving mammals the concentration of defined intracellular messengers such as cAMP and IP3 in targeted cells  Other biochemical approaches to optogenetics (crucially, with tools that displayed low activity in the dark) followed soon thereafter, when optical control over small GTPases and adenylyl cyclases was achieved in cultured cells using novel strategies from several different laboratories. This emerging repertoire of optogenetic probes now allows cell-type-specific and temporally precise control of multiple axes of cellular function within intact animals.
Optogenetics also necessarily includes 1) the development of genetic targeting strategies such as cell-specific promoters or other customized conditionally-active viruses, to deliver the light-sensitive probes to specific populations of neurons in the brain of living animals (e.g. worms, fruit flies, mice, rats, and monkeys), and 2) hardware (e.g. integrated fiberoptic and solid-state light sources) to allow specific cell types, even deep within the brain, to be controlled in freely behaving animals. Most commonly, the latter is now achieved using the fiberoptic-coupled diode technology introduced in 2007, though to avoid use of implanted electrodes, researchers have engineered ways to inscribe a "window" made of zirconia that has been modified to be transparent and implanted in mice skulls, to allow optical waves to penetrate more deeply to stimulate or inhibit individual neurons.
To stimulate superficial brain areas such as the cerebral cortex, optical fibers or LEDs can be directly mounted to the skull of the animal. More deeply implanted optical fibers have been used to deliver light to deeper brain areas. Complementary to fiber-tethered approaches, completely wireless techniques have been developed utilizing wirelessly delivered power to headborne LEDs for unhindered study of complex behaviors in freely behaving vertebrates. In invertebrates such as worms and fruit flies some amount of retinal isomerase all-trans-retinal (ATR) is supplemented with food. A key advantage of microbial opsins as noted above is that they are fully functional without the addition of exogenous co-factors in vertebrates.
The field of optogenetics has furthered the fundamental scientific understanding of how specific cell types contribute to the function of biological tissues such as neural circuits in vivo (see references from the scientific literature below). Moreover, on the clinical side, optogenetics-driven research has led to insights into Parkinson's disease and other neurological and psychiatric disorders. Indeed, optogenetics papers in 2009 have also provided insight into neural codes relevant to autism, Schizophrenia, drug abuse, anxiety, and depression.
It has been pointed out that beyond its scientific impact, optogenetics also represents an important case study in the value of both ecological conservation (as many of the key tools of optogenetics arise from microbial organisms occupying specialized environmental niches), and in the importance of pure basic science (as these opsins were studied over decades for their own sake by biophysicists and microbiologists, without involving consideration of their potential value in delivering insights into neuroscience and neuropsychiatric disease).
In vivo optogenetic activation and/or silencing has been recorded in the following brain regions and cell-types.
The Deisseroth laboratory integrated optogenetics, freely moving mammalian behavior, in vivo electrophysiology, and slice physiology to probe the cholinergic interneurons of the nucleus accumbens by direct excitation or inhibition. Despite representing less than 1% of the total population of accumbal neurons, these cholinergic cells are able to control the activity of the dopaminergic terminals that innervate medium spiny neurons (MSNs) in the nucleus accumbens. These accumbal MSNs are known to be involved in the neural pathway through which cocaine exerts its effects, and because decreasing cocaine-induced changes in the activity of these neurons has been shown to inhibit cocaine conditioning. The few cholinergic neurons present in the nucleus accumbens may prove viable targets for pharmacotherapy in the treatment of cocaine dependence
In vivo and in vitro recordings (by the Cooper laboratory) of individual CAMKII AAV-ChR2 expressing pyramidal neurons within the prefrontal cortex demonstrated high fidelity action potential output with short pulses of blue light at 20 Hz (Figure 1). The same group recorded complete green light-induced silencing of spontaneous activity in the same prefrontal cortical neuronal population expressing an AAV-NpHR vector (Figure 2).
- ↑ (2006). Next-Generation Optical Technologies for Illuminating Genetically Targeted Brain Circuits. Journal of Neuroscience 26 (41): 10380–6.
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- ↑ Gero Miesenböck's Official Website. URL accessed on 29 May 2013.
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- ↑ The Brain Prize 2013. URL accessed on 3 October 2013.
- ↑ Crick, F. (December 1999). The impact of molecular biology on neuroscience. Philosophical Transactions of the Royal Society B 354 (1392): 2021–25.
- ↑ Fork, R. L. (March 1971). Laser stimulation of nerve cells in Aplysia. Science 171 (3974): 907–8.
- ↑ Yuste,, R., Nikolenko V; Poskanzer, K. E; (2007). Two-photon photostimulation and imaging of neural circuits. Nature Methods 4 (11): 943–950.
- ↑ (2003). Photochemical gating of heterologous ion channels: Remote control over genetically designated populations of neurons. PNAS 100: 1352–7.
- ↑ Banghart, M, Borges, K; Isacoff, E; Trauner, R. H. (21). Light-activated ion channels for remote control of neuronal firing. Nature Neuroscience 7 (12): 1381–1386.
- ↑ Volgraf,, M., Gorostiza, P.; Numano, R.; Kramer, R. H.; Isacoff, E. Y. (11). Allosteric control of an ionotropic glutamate receptor with an optical switch. Nature Chemical Biology 2 (1): 47–52.
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- ↑ Nagel,, G., Szellas, T.; Huhn, W.; Kateriya, S.; Adeishvili, N.; Berthold, P.; Ollig, D.; Hegemann, P.; Bamberg, E. (25). Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci U S A 100 (24): 13940–5.
- ↑ Nagel, G.; Brauner, M.; Liewald, J. F.; Adeishvili, N.; Bamberg, E.; Gottschalk, A. (December 2005). Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses. Curr. Biol. 15 (24): 2279–84.
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- ↑ (2005). Light-driven activation of beta 2-adrenergic receptor signaling by a chimeric rhodopsin containing the beta 2-adrenergic receptor cytoplasmic loops. Biochemistry 44 (7): 2284–92.
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- ↑ (October 2009). Spatiotemporal control of cell signalling using a light-switchable protein interaction. Nature 461 (7266): 997–1001.
- ↑ (September 2009). A genetically encoded photoactivatable Rac controls the motility of living cells. Nature 461 (7260): 104–8.. PMC 2766670. PMID 19693014
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- ↑ (January 2011). Light modulation of cellular cAMP by a small bacterial photoactivated adenylyl cyclase, bPAC, of the soil bacterium Beggiatoa. J. Biol. Chem. 286 (2): 1181–8.
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- ↑ (September 2007). An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng 4 (3): S143–56.. PMID 17873414
- ↑ (November 2007). Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450 (7168): 420–4.. PMID 17943086
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- <cite style="font-style:normal" >Zhang, F.; Aravanis, A. M.; Adamantidis, A.; de Lecea, L.; Deisseroth, K. (August 2007). Circuit-breakers: optical technologies for probing neural signals and systems. Nature Reviews Neuroscience. 8 (8): 577–81.</cite>
- <cite style="font-style:normal" >Zhang, Y. P.; Holbro, N.; Oertner, T. G. (August 2008). Optical induction of plasticity at single synapses reveals input-specific accumulation of alphaCaMKII. Proc. Natl. Acad. Sci. U.S.A. 105 (33): 12039–44.</cite>
- <cite style="font-style:normal" >Zhang, F. (June 2008). Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri. Nat. Neurosci. 11 (6): 631–3.</cite>
- <cite style="font-style:normal" id="Reference-Zhang-2010">Zhang, F., Gradinaru, V.; Adamantidis, A. R.; Durand, R.; Airan, R. D.; de Lecea, L.; Deisseroth, K. (2010). Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nature protocols 5 (3): 439–56.</cite>
- <cite style="font-style:normal" >Zhang, J., Laiwalla, F.; Kim, J. A.; Urabe, H.; Van Wagenen, R.; Song, Y. K.; Connors, B. W.; Zhang, F.; Deisseroth, K.; Nurmikko, A. V. (2009 Oct). Integrated device for optical stimulation and spatiotemporal electrical recording of neural activity in light-sensitized brain tissue. Journal of neural engineering 6 (5).</cite>
- <cite style="font-style:normal" >Zhu, P., Narita, Y.; Bundschuh, S. T.; Fajardo, O.; Schärer, Y. P.; Chattopadhyaya, B.; Bouldoires, E. A.; Stepien, A. E.; Deisseroth, K.; Arber, S.; Sprengel, R.; Rijli, F. M.; Friedrich, R. W. (2009-12-11). Optogenetic Dissection of Neuronal Circuits in Zebrafish using Viral Gene Transfer and the Tet System. Frontiers in neural circuits 3.</cite>
- <cite style="font-style:normal" id="Reference-Zimmermann-2009">Zimmermann, G., Wang, L. P.; Vaughan, A. G.; Manoli, D. S.; Zhang, F.; Deisseroth, K.; Baker, B. S.; Scott, M. P. (2009). Manipulation of an innate escape response in Drosophila: photoexcitation of acj6 neurons induces the escape response. PLoS ONE 4 (4): e5100.</cite>
- Optogenetics Resource Center, maintained by the Deisseroth lab.
- Synthetic Neurobiology Group, MIT, the portal of the Boyden lab.
- OpenOptogenetics.org, an optogenetics wiki, and its companion blog.
- Molecular Neurogenetics and Optophysiology Laboratory,"Optogenetic activation and silencing recordings of individual prefrontal cortical neurons in vivo and in vitro.
- Sohal lab portal
- Nurmikko lab portal
- Lab of Dr. Zhuo-Hua Pan
- Optophysiology at the Tyler lab
- Video: Ed Boyden on Optogenetics -- selective brain stimulation with light (SPIE Newsroom, April 2011)
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