Optogenetics: A New Frontier

by Jen Guidera

Neuroscientists often try to correlate observable behavior with activity in the brain. This is a grand undertaking, with the human brain containing an estimated 86 billion neurons and 100 trillion synapses (9)(10). Given the size and complexity of the brain, you may be surprised to learn that one of the most fruitful fields in neurobiology, that of electrophysiology, focuses on establishing correlations between brain activity and behavior at the level of single cells. Correlating brain activity to behavior at such a small level is attractive because of its innately higher resolution, with single cells offering potentially more information than entire brain regions.

A new technique called optogenetics is revolutionizing how we study the brain at the level of single neurons. In this news brief, we will explain how optogenetics works, tell the short story of its birth, and finally present a few of the current applications to which optogenetics has been applied.

At its simplest, optogenetics involves firing neurons with light (3). Normally, neurons fire when they receive a burst of positive charge from one or more upstream neurons. This burst of positive charge causes protein channels embedded in the membrane of the receiving neuron to open. Importantly, these channels are specially designed to allow positive charge to flow into the cell when opened, so that the resulting influx of positive charge sends another burst of positive charge to the next neuron.

Optogenetics uses protein channels that both mimic and differ from the cell’s own protein channels. Like the cell’s own protein channels, channels used in optogenetics also allow positive charge to flow into the cell when open, generating a signal sent to other neurons. However, unlike the cell’s own protein channels, channels used in optogenetics open in response to light (2).

Furthermore, drawing on techniques from genetics, scientists can express these light-responsive protein channels in specific populations of neurons, allowing one to fire only certain neuron types. The consequence of both of these differences—response to light and expression in certain cell populations—gives neuroscientists new and exciting control over neurons: when neurons fire, and which neurons fire.

Optogenetics has a fairly recent history. The inspiration for optogenetics can be traced back to a tiny light-sensitive protein channel, discovered in 2002 in a species of single-celled green algae (1). The protein, called “channel rhodopsin-1”, is elegant in its simplicity: it is an ion channel that opens in response to light. When opened, the channel allows positive ions to flow into the algae, allowing the algae to pinpoint where it must swim to receive more light, an important input for photosynthesis.

A few years after the discovery of channelrhodopsin, scientists had the idea to insert the channel into the membrane of neurons (2). The thinking was that channelrhodopsin could be genetically engineered into only certain populations of neurons. Then, acting in the same way as native mammalian ion channels, these light-sensitive ion channels could be opened by shining light on the neurons, allowing positive ions to rush into the neurons and generating the electrical signal that neurons use to communicate.

Although conceptually simple, putting this idea into practice could be potentially very messy, recalled the pioneering optogeneticist and MIT professor Ed Boyden in his account of the field’s birth and early history (2). Would an ion channel, which had evolved over hundreds of thousands of years in a single-celled organism, be compatible with mammalian neurons, which evolved separately over hundreds of thousands of years? And, would the channels be powerful enough to depolarize the relatively larger mammalian neurons? However, despite possible complications, in 2005, just three years after the discovery of the light-gated ion channel, scientists genetically engineered channelrhodopsin into hippocampal neurons (3).

Since the discovery of channelrhodopsin-1, many more light-sensitive ion channels have been discovered, differing in the wavelength of light they respond to, how long they remain open, and what type of ions they allow into the cell (3). The discovery of these channels opens up new possibilities for the temporal and population-specific control of neurons.

In the last decade since its birth, optogenetics has been used to study basic neural circuits, including the innate escape response (4) and the proboscis extension reflex in butterflies (5). The technique has also been applied to study more complex circuits, such as those involved in anxiety (6). Beyond the discovery of the neural underpinnings of certain behaviors, optogenetics has the potential to be incorporated into novel therapies for currently untreatable conditions, including depression and drug addiction. For example, optogenetic simulation of medial prefrontal cortex neurons in a mouse model of depression has been shown to relieve symptoms of depression (7). In the case of drug addiction, optogenetic stimulation of a distinct population of neurons projecting to the nucleus accumbens has been shown to reverse the neural and behavioral effects of cocaine addiction in mice (8).

Only ten years old, optogenetics is a burgeoning field with a bright future.

References

1. Channelrhodopsin-1: a light-gated proton channel in green algae. G. Nagel, D. Ollig, M. Fuhrmann, S. Kateriya, A. M. Musti, E. Bamberg, P. Hegemann. Science. 296, 2395-8 (2002).
2. A history of optogenetics: the development of tools for controlling brain circuits with light. Boyden. F1000 Biol Reports. 3 (2011).
3. The development and application of optogenetics. L. Fenno, O. Yizhar, K. Deisseroth. Annu. Rev. Neurosci. 32, 389-412 (2011).
4. Manipulation of an innate escape response in drosophila: photoexcitation of acj6 neurons induces the escape response. G. Zimmerman, L. Wang, A. G. Vaughan, D. S. Manoli, F. Zhang, K. Deisseroth. PLOS one. 4, 1-10 (2009).
5. Motor control in a Drosophila taste circuit. M. D. Gordon, K. Scott. Neuron. 61, 373-384 (2009).
6. Diverging neural pathways assemble a behavioral state from separable features in anxiety. S. Kim et al. Nature. 496, 219-223 (2013).
7. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. H. E. Covington et al. The Journal of Neuroscience. 30, 16082-16090 (2010).
8. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behavior. Pascoli. Nature. 481, 71-75(2011)
9. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. F. A. Azevedo et al. J Comp Neurol. 513, 532-41 (2009).
10. Synapses and dendritic spines as pathogenic targets in Alzheimer’s disease. W. Yu and B. L. Neural Plast. 2012, 1-8 (2011).