Optogenetics

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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.

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.

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