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

Contents

History

The term “optogenetics” was initially coined in 2006 (Deisseroth 2006) to refer to this rapidly adapted approach of using new high-speed optical methods for probing and controlling genetically targeted neurons within intact neural circuits. Over the next year, the term used to describe this new technique was featured in the pages of Science and Nature, in a series of general-interest (Miller 2006) and scientific/technical (Zhang 2007a, Adamantidis 2007) reports, and is now widely used.

The hallmark of optogenetics is introduction of light-activated channels and enzymes that allow manipulation of neural activity with millisecond precision while maintaining cell-type resolution through the use of specific targeting mechanisms.

Description

Because the brain is a high-speed system, millisecond-scale temporal precision is central to the concept of optogenetics, which allows probing the causal role of specific action potential patterns in defined cells. By analogy, traditional genetics is used to probe the causal role of specific proteins within cells, via “loss-of-function” or “gain of function” changes in these proteins, to probe how the genetic code controls organismal development and behavior. Correspondingly, to probe the neural code, optogenetics by definition must allow addition or deletion of precise activity patterns within specific cells in the brains of intact animals, including mammals.

The temporal precision of traditional genetic manipulations is rather slow, from hours or days to months. The hallmark of optogenetics is introduction of light-activated channels and enzymes that allow manipulation of neural activity with millisecond precision while maintaining cell-type resolution through the use of specific targeting mechanisms. As a result, trains of action potentials at specific frequencies can be induced in specific cell types within the brains of behaving animals. The potential importance of selectively controlling precise action potential patterns within subtypes of cells in the brain (for example, using light to control optically-sensitized neurons), was best articulated by Francis Crick beginning with a Scientific American Article in 1979. Several photostimulation methods were developed between 2002 and 2005 beginning with the Miesenbock group and later the Kramer and Isacoff groups; for a variety of technical reasons, while achieving photonic modulation of excitation, these methods do not allow control of defined action potential patterns in behaving mammals(Zemelman 2002, Banghart 2004). In 2005, the Deisseroth group (Ed Boyden, Feng Zhang et al., Boyden 2005) at Stanford University brought the first of several microbial opsins to neurobiology (Channelrhodopsin-2, a single-component light-activated cation channel from algae), which allowed millisecond-scale temporal control in mammals, required only one gene to be expressed in order to work, and responded to visible-spectrum light with a chromophore (retinal) that was already present and supplied to ChR2 by the mammalian brain tissue. The experimental utility of ChR2 was quickly proven in a variety of animal models ranging from behaving mammals to classical model organisms such as flies, worms, and zebrafish, and since 2005 hundreds of groups have employed ChR2 and related microbial proteins to study neural circuits.

Among the microbial opsins which can be used to investigate the function of biological neural networks are the Channelrhodopsins ChR2 and VChR1 to excite neurons, and Halorhodopsin (NpHR) to inhibit neurons. Moreover, by fusing vertebrate opsins to specific G-protein coupled receptors, chimeric photosensors have been created that allow researchers to manipulate the concentration of defined intracellular messengers such as cGMP, cAMP and IP3 in individual cells (Airan 2009) within behaving mammals. This emerging repertoire of optogenetic probes now allows cell-type-specific and temporally precise control of multiple axes of neural 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 (Aravanis et al., 2007; Adamantidis et al., 2007; Gradinaru et al., 2007). 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. A key advantage of microbial opsins (including ChR2, VChR1 and NpHR) as noted above is that they are fully functional in the mammalian brain without the addition of exogenous co-factors. In invertebrates such as worms and fruit flies some amount of all-trans-retinal (ATR) needs to be supplemented with food.

The new field of optogenetics has furthered our understanding of how specific neuronal cell types contribute to the function of neural circuits in vivo (Adamantidis 2007, Alilain 2008, Aravanis 2007, Arenkiel 2007, Atasoy 2008, Ayling 2009, Bernstein 2008, Bi 2006, Cardin 2009, Douglass 2008, Gradinaru 2009, Han 2009, Hira 2009, Huber 2008, Hwang 2007, Kuhlman 2008, Ligali 2008, Lima 2009, Li 2005, Liewald 2008, Lin 2008, Liu 2009, Nagel 2005, Sohal 2009, Toni 2008, Tsai 2009, Wang 2007, Zhang 2007, Zhang 2008). On the clinical side, patients with Parkinson's disease and other neurological and psychiatric disorders may benefit from insights arising in the course of optogenetics-driven research. Indeed, optogenetics papers in 2009 have provided insight into neural codes relevant to Parkinson’s Disease, autism, schizophrenia, drug abuse, and depression (Cardin 2009, Gradinaru 2009, Sohal 2009, Tsai 2009).

References

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