Optogenetics

Optogenetics
Neuropsychology
 
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Optogenetics is the combination of genetic and optical methods to control specific events in targeted cells of living tissue, even within freely moving mammals and other animals, with the temporal precision (millisecond-timescale) needed to keep pace with functioning intact biological systems.

In 2010, optogenetics was chosen as the Method of the Year (MOTY) across all fields of science and engineering by the interdisciplinary research journal Nature Methods (MOTY primer, MOTY editorial, MOTY commentary). At the same time, optogenetics was highlighted in the article on “Breakthroughs of the Decade” in the scientific research journal Science BotD; these journals also referenced recent public-access general-interest video MOTY video and textual SciAm summaries of optogenetics.

Contents

History

The theoretical utility of selectively controlling precise neural activity (action potential) patterns within subtypes of cells in the brain (for example, using light to control optically-sensitized neurons) had been articulated by Francis Crick in his Kuffler Lectures at the University of California in San Diego (Crick 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 photostimulation method was demonstrated by Gero Miesenbock, who employed Drosophila multiple-protein cascades initiated by G protein-coupled rhodopsin photoreceptors for controlling neural activity in cultured neurons. Miesenbock later employed a combination chemical-and-G-protein coupled receptor method to modulate the behavior of fruit flies with light, and the Kramer and Isacoff groups likewise employed synthesized organic photoswitches or “caged” compounds that could interact with genetically-introduced ion channels (Zemelman 2002, Zemelman 2003, Banghart 2004, Lima 2005).

In 2005, the first of many studies using mammals, instead of invertebrates, was initiated by Karl Deisseroth's group at Stanford University (2005)). They brought the first single-component optogenetic system to neurobiology (beginning with channelrhodopsin, a single-component light-activated cation channel from unicellular 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 the channelrhodopsin (ChR) by the vertebrate tissues. The surprising experimental utility of this single-component “microbial opsin” approach was quickly proven with many additional microbial opsin classes and in a variety of animal models ranging from behaving mammals to classical model organisms such as flies, worms, and zebrafish. The “optogenetic” terminology was coined in 2006 (Deisseroth 2006), and since 2005 hundreds of laboratories around the world have employed microbial opsins to study complex biological systems (references below).

In 2010 Finnish company Valkee bring into market Bright light headset for severe seasonal symptoms experienced during long winter due the lack of light.Bright light has shown efficacy in various mood swings from PMS to job stress, and is a widely-accepted de-facto treatment for winter blues.[1] In clinical trials, 9 of 10 people with severe seasonal symptoms experienced total relief within 4 weeks. [2]

Description

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. 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 (gain of function). For loss of function, 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, including in freely-moving mammals (Witten 2010).

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 (Kim 2005), 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 (Airan 2009). 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 (Levskaya 2009, Wu 2009, Yazawa 2009, Stierl 2011, Ryu 2010). 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 (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. 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 (Cardin 2009, Gradinaru 2009, Sohal 2009, Tsai 2009, Witten 2010).

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).

References

  1. ^ "Benefits of Valkee brain stimulation headset". http://www.valkee.com/uk.+2011-11-22. http://www.valkee.com/uk/valkee-benefits.html#navigation. Retrieved 2011-11-22. 
  2. ^ "Science & research". http://www.valkee.com/uk.+2011-11-22. http://www.valkee.com/fi/tiede.html. Retrieved 2011-11-22. 

References

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