Optogenetics: Shedding light on the brain's secrets

The history of optogenetics

In a 1979 article, Francis Crick explained how he believed the greatest challenge facing neuroscientists was the need to control one type of brain cell whilst the others are left unchanged.

Electrical stimulation is not able to do this, because it stimulates all nearby cells without discrimination. Drugs are too slow to act in comparison to the millisecond timeframe of events in the brain.

Crick later suggested that using light might be able to solve this issue, as it can be turned on and off very quickly. However, a way to make brain cells sensitive to light was not known at the time.

In 2005, Karl Deisseroth and colleagues, published their seminal paper "Millisecond-timescale, genetically targeted optical control of neural activity" (not as catchy as optogenetics, right?). Published in the journal Nature, this was the first research paper to fully describe optogenetics as a strategy that made neurons sensitive to light and then used light to stimulate them. The paper showed how, by combining optical technologies and breakthroughs in genetics, it is possible for researchers to excite or inhibit specific neurons within the brain and study the outputs.

How does it work?

The story of how optogenetics works begins with the humble green algae Chlamydomonas Reinhardtii.

This simple organism uses photosynthesis in order to create the energy it needs to live. To make this process as efficient as possible it has an eyespot. This light-sensitive part of the cell tells an unassuming single-celled alga which direction light is coming from so it can move into a better position.

In order to activate the eyespot, C. Reinhardtii moves ions across a membrane through ion channels. When light of the correct wavelength hits these channels it causes a change in their shape; opening them so that ions can flow across the membrane. The most commonly used ion channel for stimulation in optogenetics is Channelrhodopsin-2.

Image credit: Karl Deisseroth

Neurons are triggered in the same way (by moving ions from outside the cell to the inside). Once a certain number of positive ions have crossed the cell membrane, a threshold is reached which causes the neuron to fire.

Researchers used genetics to express the light-activated ion channels on neurons within the brain. When light hits these ion channels, they open and ions enter the cells and cause them to fire.

In order to get the ion channels expressed within the brain, a genetically modified virus was made. This virus, when injected into an area of the brain, is able to recombine its DNA with the DNA of the host cells. Once recombined, all of the cell dynamics and machinery necessary to express the ion channel gene is available, and the cell will begin expressing the channels on its cell membrane.

Different types of brain cells express a slightly different group of genes, which is how they differentiate from each other. Most genes have a promoter region and if this is active in the cell then it will cause the gene to be expressed. By using the promoter specific to a certain type of cell within your transgenic virus, it is possible to express the light sensitive ion channels in just those cells.

Why is optogenetics transforming neuroscience?

Optogenetics gives neuroscientists an unprecedented level of control in neurons.

• Illuminating only certain regions of the brain enables manipulation to be targeted to a specific space (with lasers, this region can be minuscule).
• Using pulses of light allows the modulation to be targeted to specific times, giving high temporal resolution.
• Limiting the genetic modification to specific cell types makes it possible to study functions associated with only those cells.

In the 13 years since Karl Deisseroth and his team described how to carry out optogenetics, the technique has been used to study brain many areas of brain function, examples include:

• Next-generation optogenetic molecules control single neurons
• Brighter prospects for chronic pain
• Midbrain 'start neurons' control whether we walk or run

Another area where optogenetics may have potential uses is in the clinic. Currently, deep brain stimulation is a successful treatment for Parkinson's disease. This is the implant of electrodes into the brain that can be turned on and off to help relieve symptoms. An alternative treatment could be to implant LEDs into the brain instead of electrodes and use them to stimulate only the neurons that are affected by the disease. Read more about this here.

Halorhodopsin, an ion channel from Archaebacteria, was used to inhibit neuronal activity shortly after the discovery of channelrhodopsin-2. Halorhodopsin is activated by a different wavelength of light to channelrhodopsin-2 and so both channels can be used to independently activate and inhibit neuronal activity, but in the same organism and/or cells.

Recently, work has been done to create even more light-sensitive ion channels that can be implanted into different cell types. Ed Boyden, a member of the team who published the 2005 paper, has been trying to create ion channels that are sensitive to red light. Red light travels further through biological tissue than blue or yellow light (the colours that activate channelrhodopsin-2 and halorhodopsin respectively). This means external light sources can be used to stimulate or inhibit neurons deeper into the brain.

More infomation about optogenetics

• #LabHacks: Choosing the best opsin for your optogenetics experiments
• Recent advances in optogenetics research
• First human test of optogenetics highlights its clinical potential
• The potential of optogenetic cochlear implants
• Optogenetics: Lighting the way for the future

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