Controlling the brain with light: Where are we at with optogenetics?

Optogenetics has had a blockbuster billing. This remarkable neuroscience tool has been lauded to have the potential to illuminate the inner workings of the brain and allow us to understand and treat neurological diseases. But how far off are we from these goals and what have we achieved thus far?

Optogenetics has been explained before on this blog and elsewhere and is explained excellently in the video below.

Briefly, in order to understand the way the brain works we need to be able to investigate how circuits of cells communicate with each other. Previously, we have used electrodes to record what is going on inside the brain. By presenting a stimulus and recording the brain’s response, we can try and interpret what this response means. The true test of our understanding, however, relies on us being able to produce the required behavioural response by stimulating the brain.

Using electrodes, we can record the response of a nerve cell when a mouse wants to turn right. Then we can replay this response back to the mouse’s brain and see whether he turns right. The problem with this is that we will not only stimulate the nerve cells we want, but all of their neighbours as well. The brain is precisely organised and neighbouring cells may carry out completely different roles so this will commonly be a large interference.

What optogenetics allows us to do is insert a light-sensitive ion channel into the cells that we want to activate. This channel will open when we flash a burst of light onto it, in turn activating our cell. This technology thus allows us look at the actions of specific population of cells without the interference that comes with using electrodes.

From http://neurobyn.blogspot.se/2011/01/controlling-brain-with-lasers.html
From http://neurobyn.blogspot.se/2011/01/controlling-brain-with-lasers.html

So in just over a decade since optogenetics was first described, what have we managed to do? I’ve split my summary into two main headings. The first highlights basic research that increases our understanding of the brain. The second, the possibilities for understanding and treating disease.

Basic research

Top row shows the behavioural set-up. Mice detect whether the pole is in the right (right) or wrong (left) position and are trained to either lick (right) to receive a water reward or not lick (left). Bottom row shows the optogenetic intervention.  When a laser beam is crossed (red dot), the cortex is stimulated. Mice were fooled into licking in the left condition, even though their whisker hadn’t touched a pole. From O’Connor et al. (2013).
Top row shows the behavioural set-up. Mice detect whether the pole is in the right (right) or wrong (left) position and are trained to either lick (right) to receive a water reward or not lick (left). Bottom row shows the optogenetic intervention. When a laser beam is crossed (red dot), the cortex is stimulated. Mice were fooled into licking in the left condition, even though their whisker hadn’t touched a pole. From O’Connor et al. (2013).

Optogenetics has been used successfully to understand more about perception and the senses. Karel Svoboda’s group at the Janelia Farm Research Campus in the US have been able to create what they call ‘illusory touch’ in the brain of awake, behaving mice. Mice were trained to detect the position of a vertical pole, presented near to their whiskers. When the mice sensed that the pole was in the right position, they were trained to expect a drink of water and would lick (see left). When the pole was in a wrong position, they were trained to do nothing. Once trained, mice were able to give the correct response 75% of the time.

The researchers suspected they knew the area of the brain that was telling the mouse when their whiskers touched the pole, a part of the cerebral cortex. To test this, they injected an optogenetic channel into this area and replaced the pole with a laser beam and detector. The detector was linked to a light on the skull so that when the whisker passed through the laser light beam, a signal was sent to shine light onto the cerebral cortex and activate the specific cells they were interested in. They found that by activating the cortex when the whisker passed through the beam, the mouse would lick even though the whisker hadn’t touched a pole. They had created an illusion in the mouse’s brain that his whisker had touched a pole!

Another optogenetics study that hit the headlines recently looked into memory formation in the hippocampus. Susumu Tonegawa and his team from the RIKEN-MIT Center for Neural Circuit Genetics in the USA were interested in proving the crucial role of the hippocampus in memory formation. They inserted optogenetic channels into the hippocampus of mice in such a way that when new memories were formed, the cells that were connected by this memory would also contain these light-sensitive channels.

By placing mice in an arena and allowing them to explore, the mice would form spatial memories of the arena within their hippocampus. The new cells and connections generated would form a circuit that could be stimulated with light. The next day, the researchers placed the mice in a new arena that the mouse had no knowledge of. The researchers shone a light on the head of the mouse to activate the cells formed the previous day. They simultaneously gave the mouse an electric shock. Now, when placed back in the first arena, the mouse froze. It had associated the memory of the first arena with an electric shock, even though the mouse had never been shocked in the first arena! The researchers described this as creating a false memory within the brain.

 

Treating disease

Perhaps the most exciting aspect of optogenetics is its potential to treat disease, with the fantastic Karl Deisseroth leading the way. Arguably, the most natural place to start when talking about the therapeutic options of light-responsive channels is with blindness.

A collaborative group led by Botond Roska at the Friedrich Miescher Institute for Biomedical Research in Switzerland has looked into retinitis pigmentosa, a form of blindness caused by degeneration of the retina at the back of the eye. Using two animal models, they have been able to restore vision by inserting a light-sensitive channel into the retina. This therapy worked well enough to allow the previously blind mice to be able to carry out visually guided behaviours.

eyeA further use of therapeutic optogenetics has been mooted for the treatment of Parkinson’s disease. In Parkinson’s, a region of the brain called the basal ganglia degenerates, leading to an inability of the patient to co-ordinate movement. Increasing the activity of this region has been shown to have therapeutic benefit and the lab of Anatol Kreitzer at the University of California, US have shown potential in an optogenetic approach. They were able to mould the activity of the basal ganglia in such a way to create Parkinsonian-like symptoms in mice and also to reduce Parkinsonian-like symptoms in a mouse model of Parkinson’s.

So has optogenetics lived up to the hype so far? Well despite its application in humans lacking somewhat at this point, it appears that optogenetics has already answered some vital questions we have. The challenge now is to develop the technology further so that we have more accurate and controllable tools for when we’d like to start using them in humans. The excitement surrounding optogenetics is still widespread and there is no evidence yet that the bubble is set to burst anytime soon.

Post by: Oliver Freeman @ojfreeman

Papers Referenced:

Sensory Perception – O’Connor et al. Nature Neuroscience (2013)

Memory Formation – Ramirez et al. Science (2013)

Blindness – Busskamp et al. Science (2010)

Parkinson’s Disease – Kravitz et al. Nature (2010)

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