Wednesday, 2 June 2010

Illuminating the brain's bright future

In the 1920s Felix the Cat had a brilliant idea and a light bulb appeared over his head; thus was created the signature of an epiphany. But recent advances in neuroscience leave you wondering whether in the future we will be more familiar with light bulbs actually driving our thoughts and inspiration rather than just being a visual metaphor. Gero Miesenböck, currently Waynflete Professor of Physiology at Oxford University, has been pioneering work that uses light to control brain cells, a field known as optogenetics.

Our brain consists of approximately 100 billion neurons that, as Miesenböck lyrically describes, form “an intricate tapestry”. To understand how neuronal signalling drives our behaviour, he says, we need to tease apart the disparate contributions that each of the different populations of neurons make to our behaviour. Nobel laureate Francis Crick remarked in a famous article in 1979 that one thing scientists have dreamed about is a tool that would allow them to selectively activate or turn off certain groups of cells while leaving others unaffected. Twenty years later, he suggested how this might be achieved: with light and molecular engineering. And this is precisely what optogenetics does.

To understand this technique we have to go back to the 1990s when German biologist Peter Hegemann discovered that green algae, commonly found in ponds, respond to light by wagging their tail. This behaviour was intriguing because algae are unicellular creatures without eyes. Hegemann discovered that when light photons hit the protein coils packed in the algae’s cell membrane, a chemical reaction creates a tiny gap in the membrane, causing an ionic current to be produced and the algae’s tail to wag. The protein that allows this reaction with light is called channelrhodopsin and is comparable to rhodopsins found in our own eyes.

Meanwhile, Miesenböck and his colleagues, working in New York and later at Yale, wondered whether they could exploit a similar mechanism to control brain cells. They took light sensitive proteins like the photoreceptors of our eyes, transplanted them into neurons and, by simply shining a light on them, the team was able to activate the modified neurons, a first step towards neuronal control.

To exploit the full power of this method, however, the researchers needed to discover a way just to excite or inhibit selected populations of cells, and with genetic engineering they were able to achieve this. By harnessing the cunning of viruses or by creating genetically-modified mice and flies, it was possible to make expression of the rhodopsin-encoding gene specific to particular neurons, meaning that only those neurons would become active when illuminated.

The road to success for optogenetics was not easy. The first difficult step was to find out whether they were able to transplant the rhodopsin-containing photoreceptors of flies to other cells in a culture and activate them with a flash of light. Once they succeeded in doing this, the second, even more complicated challenge was to move from changing neuronal activity in a cell culture to changing the behaviour of a living being, in Miesenböck’s case the fruit fly. The promise became initially clear when Susana Lima, Miesenböck’s PhD student at the time, showed him the first baby steps taken by a fruit fly on command of light. Within 5 years, they had learned how to remote control a fly.

The technique is now so advanced there is a large volume of work looking at how brain cells control behaviour. Last year in Cell, Miesenböck and his team exposed the learning mechanisms of a fly by creating false memories (1). They placed a fly in a narrow chamber, half of which smelled of an old tennis shoe, the other half of sweet fruit. By observing how much time the fly spent on either side, the researchers were able to work out which was the fly’s preferred smell. When this location was later paired with a memorable, aversive signal – a painful electrical shock – the fly learned to avoid this location and spend more time on the opposite side of the chamber. From previous research, Miesenböck knew which neurons were involved in learning to associate the shock with an odour and could therefore directly target this system with optogenetics. By activating these cells with light when the fly was in the location of its preferred smell, Miesenböck’s team was able to provoke identical avoidance behaviour even though no electric shock was given. Thus, the fly learned from an experience it never had.

Might we be able to use this technique to control our minds in the future? Miesenböck thinks that it will be a while before optogenetics can be used in humans: “You would have to express a foreign gene in a targeted fashion and this is where the show-stopper currently lies”. While using this technique in humans may be a long way off, he does believe that optogenetic research in flies might nonetheless directly aid our understanding of the human brain because biology is generally conserved. “Nature rarely invents the wheel twice”.

For now, Miesenböck thinks the field should focus on blurring the boundaries between work in whole organisms and fine-scale research in cell cultures. They could make use of the fact that tissue in a cell culture can be treated as if it was still part of a functioning brain by activating the cells with flashes of light – a use of optogenetics that is currently underappreciated. “There will be room for brain-free neurobiology, where optogenetics provides the interface to allow researchers to really talk to and feed artificial information into neuronal systems”.

Miesenböck also advocates using light “to enable scientists to drive nervous systems outside their normal operating limits, because this is often where mechanisms reveal themselves”. Miesenböck’s team used this approach to investigate the origin of sex differences in flies. While male and female fly brains are very similar, they nonetheless display sex-specific courting behaviours. The gene that controls male courting behaviour is expressed in a very small number of neurons in the abdominal ganglia of the fly. By specifically targeting these cells with optogenetics and shining light onto this circuitry, Miesenböck’s team was able to produce male courting behaviour in all the flies, even the females (2). Thus, they were able to show that females possess a bisexual brain containing a motor programme necessary for male courtship behaviour, but do not activate it because the neuronal commands required for the behaviour are absent.

With the ability to dissect neuronal functioning in the healthy brain, optogenetics might also hold potential to help understand the exact mechanisms that cause neurological and psychiatric diseases such as depression and schizophrenia and even help treat them. For example, Karl Deisseroth and his team at Stanford University in California published a study in Science last year that used optogenetics in rats to investigate directly how deep brain stimulation might alleviate symptoms of Parkinson’s Disease, something that had previously been poorly understood (3).

Thus, despite the difficulties in applying the method to humans, Miesenböck is hopeful: “With optogenetics we can really identify the players that are responsible for particular behaviour and that may give us knowledge for targets of more conventional treatment. Then conventional treatment can become more effective and cleaner.

1. Claridge-Chang et al., 2009. Writing memories with light-addressable reinforcement circuitry. Cell 139:405- 415.
2. Dylan Clyne & Miesenböck, 2008. Sex-Specific Control and Tuning of the Pattern Generator for Courtship Song in Drosophila. Cell 133:354-363.
3. Gradinaru et al., 2009. Optical deconstruction of parkinsonian neural circuitry. Science 324:354-359.

This article appeared in 'Phenotype'. Here you can read the magazine its entirety.

A shorter, related post can be found on my blog here.

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