Five years back, a group of scientists led by Karl Deisseroth of Stanford University came up with a way to precisely control neurons simply by shining light on them. They did so by introducing an algal gene for a light-activated protein into the nerve cells.
Such techniques that combine optics with genetics have resulted in the fast-growing field of optogenetics, creating powerful new tools to understand how myriad nerve cells communicate with one another in the hugely complex circuitry that is the brain.
For Dr. Deisseroth, who is also a practising psychiatrist, these methods offer a window into why his patients exhibit problems with some of the brain's most advanced functions. Moreover, discovering where and how the brain's circuitry is malfunctioning holds the promise of more effective treatment for mental disorders.
“Despite the noble efforts of clinicians and researchers, our limited insight into the roots of psychiatric disease hinders the search for cures and contributes to the stigmatization of this enormous problem, the leading cause worldwide of years lost to death or disability,” he pointed out in an article that has just been published in Scientific American . Dr. Deisseroth was in Thiruvananthapuram recently to receive the first Nakasone Award of the Human Frontier Science Programme, an international effort to promote novel, interdisciplinary research in the life sciences. The award was in recognition of his “pioneering work on the development and application of optogenetic techniques for the study of the relationship between neural circuits and behaviour.”
Algae and microbes
While in the city, he spoke to this correspondent at length about his work.
Certain proteins found in some algae and microbes respond to light by regulating the movement of electrically charged atoms known as ions into and out of cells. In animals, neurons that are genetically modified to produce such proteins can then be controlled with light pulses.
It turned out that these proteins respond to light rapidly. Neurons communicate by generating small signals that last one-thousandth of a second or less. The precise timing of those signals is also very important. “If you don't operate at that level of precision, you are not speaking the language of the brain,” he said.
Such light-activated regulators of ion flow had been known for a long time. Although others had previously thought about using these proteins to control neurons, it was considered a very high-risk experiment, something that was very unlikely to work, Dr. Deisseroth remarked.
The sense of risk arose from a number of factors. For one thing it was not clear that these microbial proteins would work in animals with the precision that neurons demanded. Besides, it was assumed that these proteins needed other components to function. In that case, a complicated system might be required to get these proteins to work properly.
Finally, “it was considered reasonably likely that the whole process would be toxic.” These were, after all, proteins that sat in the membrane of cells and the membrane was a very fragile structure. If a cell produced too much of such a protein, its surface coating could break down and it would die.
But as he observed in his article in Scientific American , “Against all odds, the experiments worked shockingly well.” With pulses of light, the firing of nerve cells could be controlled with great precision.
“You don't just put the gene in,” he said during the interview. A small bit of DNA was also attached to it that dictated which nerve cells could make the protein. There were other tricks too to select the neurons that would be controlled with light.
Dr. Deisseroth and his colleagues have used these techniques to examine dopamine neurons that could play a role in depression. These neurons, which are found deep in the mid-brain with their long branches extending to other parts of the brain, have been associated with sensations of pleasure and reward.
In depression, what used to be enjoyable is no longer so, he observed. Depressed people can't get anything positive out of life and that contributes to worsening their depression.
Recordings of electrical activity in dopamine neurons had showed that they fire little bursts of signals when something unexpectedly good happens. But it was not known if those electrical signals produced the pleasurable feelings or had some other role.
To test that, certain dopamine neurons in mice were made sensitive to light. Pulses of light were sent down a fine optical fibre to induce electrical activity in the neurons of the freely moving mice.
The animals then acted as if they had been rewarded, choosing to spend more time in places where they had received the light pulses.
Interestingly, when the light pulses were given not as a burst but in a more spread out manner, there was no effect at all.
“So we think we understand now a little bit more about patterns of activity in specific cells that at least can trigger behavioural conditioning, reinforcement and perhaps reward.”
But that was only the first step. There was much more to do in understanding that process and how it may go wrong in depression, he said.
Using rats and mice, Dr. Deisseroth's team has employed optogenetic methods to study how electrical stimulation with electrodes implanted in the brain (known as deep brain stimulation) helps people with Parkinson's disease.
In people afflicted with this illness, progressive loss of dopamine neurons in one region of the brain results in slowness of movement, tremors and rigidity of the limbs.
Hundreds of labs
Apart from his own group, there are already hundreds of labs around the world employing these techniques. “We are working hard to make optogenetic systems easily used by others,” said Dr. Deisseroth.
“I think we will see optogenetics applied to a much broader range of questions beyond neuroscience.”
At its core, it is about controlling events in defined cells within complex tissues in animals, he pointed out.
