Optogenetics

Optogenetics is an emerging field combining optics and genetics to probe neural circuits, within intact mammals and other animals, at the high speeds (millisecond-timescale) needed to understand brain information processing.

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The term first appeared in 2006 (Deisseroth 2006) in the context of describing new high-speed optical methods for probing and controlling genetically targeted neurons within intact neural circuits, and has subsequently appeared in the pages of Science (Miller 2006) and Nature (Zhang 2007, Adamantidis 2007) describing applying these methods to behaving animals. The term connotes performing millisecond-scale genetics on the neural code in behaving animals, e.g. mammals, in genetically defined cell types (Gradinaru 2007, Adamantidis 2007, Aravanis 2007).

Traditional genetics generates “loss-of-function” or “gain of function” in specific genes or genetically defined cells within intact organisms, to probe how the genetic code controls organismal development and behavior. A new class of genetics may be needed to understand nervous system function and dysfunction, with gain-of-function and loss-of-function manipulations of the neural code that operate on the same temporal scale as the brain, with millisecond precision while maintaining cell-type resolution.

Optogenetics uses nontraditional tools to achieve this goal, generating “loss-of-function” or “gain-of-function” changes in the neural code, in genetically targeted cells (for example, trains of action potentials at specific frequencies in specific cell types). This can be achieved with fast light-gated microbial opsins , or ion channels engineered using compounds such as azobenzene. Among the microbial opsins which can be used to investigate the function of biological neural networks are Channelrhodopsin-2 (ChR2) to excite neurons, and Halorhodopsin (NpHR) to inhibit neurons. These probes allow cell-type-specific and temporally precise control of neural function within intact circuits and behaving animals including mammals.

Optogenetics also necessarily includes 1) the development of genetic targeting strategies such as cell-specific promoters to deliver the light-sensitive probes to specific populations of neurons in the brain of living animals (e.g. worms, fruit flies, mice), and 2) hardware (e.g. integrated fiberoptic and solid-state optical tools) to allow specific cell types, even deep within the brain, to be controlled in freely behaving animals including mammals. Optical fibers can deliver light deep into the brain region of interest, and for superficial brain areas such as the cerebral cortex, either optical fibers or LEDs can be directly mounted to the surface of the animal's brain. The microbial opsins (including ChR2 and NpHR) have the advantage that they can be functionally expressed in the mammalian brain without the addition of exogenous co-factors, although in invertebrates such as worms and fruit flies some amount of all-trans-retinal (ATR) need to be supplemented with food.

This new field of optogenetics now has allowed temporally-precise understanding of how specific brain cell types important in neuropsychiatric disease function within intact neural circuits in vivo (Adamantidis 2007, Arenkiel 2007, Huber 2007), effectively allowing neuroscientists to begin to conduct genetics on the neural code.

References

• Deisseroth K, Feng G, Majewska AK, Miesenbock G, Ting A, Schnitzer MJ. Next-generation optical technologies for illuminating genetically targeted brain circuits. J Neurosci. 2006 Oct 11; 26(41):10380-6. PMID 17035522
• Miller G. Optogenetics. Shining new light on neural circuits. Science. 2006 Dec 15;314(5806):1674-6. PMID 17170269
• Zhang F, Aravanis AM, Adamantidis A, de Lecea L, Deisseroth K. Circuit-breakers: optical technologies for probing neural signals and systems. Nat Rev Neurosci. 2007 Aug;8(8):577-81. PMID 17643087
• Aravanis A, Wang LP, Zhang F, Meltzer L, Mogri M, Schneider MB, Deisseroth K. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J. Neural Eng. 2007 Sept; 4:S143-S156. PMID 17873414
• Gradinaru V, Thompson KR, Zhang F, Mogri M, Kay K, Schneider MB, Deisseroth K. Targeting and readout strategies for fast optical neural control in vitro and in vivo. J Neurosci. 2007 Dec 26;27(52):14231-8. PMID 18160630
• Airan RD, Hu ES, Vijaykumar R, Roy M, Meltzer LA, Deisseroth K. Integration of light-controlled neuronal firing and fast circuit imaging. Curr Opin Neurobiol. 2007 Dec 17. PMID 18093822
• Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature. 2007 Nov 15;450(7168):420-4. Epub 2007 Oct 17. PMID 17943086
• Arenkiel BR, Peca J, Davison IG, Feliciano C, Deisseroth K, Augustine GJ, Ehlers MD, Feng G. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron. 2007 Apr 19;54(2):205-18. PMID 17442243
• Huber D, Petreanu L, Ghitani N, Ranade S, Hromádka T, Mainen Z, Svoboda K. Sparse optical microstimulation in barrel cortex drives learned behaviour in freely moving mice. Nature. 2008 Jan 3;451(7174):61-4. PMID: 18094685
• Wang H, Peca J, Matsuzaki M, Matsuzaki K, Noguchi J, Qiu L, Wang D, Zhang F, Boyden E, Deisseroth K, Kasai H, Hall WC, Feng G, Augustine GJ. High-speed mapping of synaptic connectivity using photostimulation in Channelrhodopsin-2 transgenic mice. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8143-8. PMID 17483470
• Zhang F, Wang LP, Brauner M, Liewald JF, Kay K, Watzke N, Wood PH, Bamberg E, Nagel G, Gottschalk A, Deisseroth K. Multimodal fast optical interrogation of neural circuitry. Nature. 2007 Apr 5;446:633-39. PMID 17410168
• Zhang F, Wang LP, Boyden ES, Deisseroth K. Channelrhodopsin-2 and optical control of excitable cells. Nat Methods. 2006 Oct; 3(10):785-92. PMID 16990810
• Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci. 2005 Sep;8(9):1263-8. PMID 16116447
• Wang S, Szobota S, Wang Y, Volgraf M, Liu Z, Sun C, Trauner D, Isacoff EY, Zhang X. All optical interface for parallel, remote, and spatiotemporal control of neuronal activity. Nano Lett. 2007 Dec;7(12):3859-63. Epub 2007 Nov 23. PMID 18034506
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• Han X, Boyden ES. Multiple-color optical activation, silencing, and desynchronization of neural activity, with single-spike temporal resolution. PLoS ONE. 2007 Mar 21;2(3):e299. PMID 17375185