Humble Organism Points Way to Future of MH Research

The next great arena for neuroscientific research has its origins in light-sensitive proteins derived from algae found in ponds—hardly the first place to look for new ways to understand and maybe someday treat depression or epilepsy.

The new science of optogenetics, barely a decade old, not only expands the researcher's tool kit but offers some important insights into the nature of science itself, one of its leading practitioners said in a lecture at APA's annual meeting in New Orleans in May.

Credit: David Hathcox

“You couldn't predict the impact of algae on Parkinson's disease,” said Karl Deisseroth, M.D., Ph.D., an associate professor of bioengineering and psychiatry at Stanford University.

Bench and bedside are not far apart for Deisseroth, perhaps one of the few bioengineers who also works as a clinical psychiatrist, seeing patients one day a week.

His research is largely based on channelrhodopsin-2, a protein found in the multicellular chlorophyte alga Volvox carteri that regulates the conductance of ions into cells, including neurons. When activated by blue light, channelrhodopsin-2 allows sodium ions to enter the neuron, increasing its positive charge and thus its activity. When the light is turned off, the channel closes, and neuronal activity decreases.

Another protein, called halorhodopsin and discovered in a different microorganism living in a salt lake in Egypt, responds to yellow light. Halorhodopsin transfers chloride ions into the neuron, increasing its negative charge and reducing its activity.

Several other proteins are also in the optogeneticist's library or under development and are likely to broaden the constellation of optical controls, said Deisseroth.

Scientists can insert the proteins into cells or use transgenic mice bred to express them in their brains.

Firing different-colored light down an optical fiber thin enough to plug into a single neuron triggers or suppresses the neuron's action.

Timing of the light impulse can be controlled to the millisecond, and the experimental rodents can roam freely throughout their cages while they are being studied.

Flexible, lightweight, implanted fiber optics have several advantages over the metal electrodes used in research and in treatment interventions like deep brain stimulation, said Deisseroth.

Electrical inputs can stimulate surrounding cells, not just the ones targeted for investigation. Those adjacent cells may fire along with the target, making it difficult to tell just what the target cell is doing when stimulated.

Also, the neuron's output is electrical and can be masked by the electrode's input. Because the fiber-optic procedure uses light as an input, it does not obscure the neuron's electrical output.

Deisseroth demonstrated the effects of the optogenetic system in a short video. A mouse with an optical fiber embedded in its brain wandered randomly about its cage. When the blue light was turned on, it began to walk in a counterclockwise circle. When the light was switched off, it resumed its undirected ramble.

The information provided by the process is not limited to a single cell, said Deisseroth. Researchers can follow the neuron's signal throughout the neural circuits to which it belongs.

“Using fMRI, we can see the global maps and local signals causally driven by defined cells,” he said. “We can not only evoke spikes, but also put neurons into an excitable state and let the native signals work.”

The field is changing so fast that the technology has outstripped researchers' understanding of what it can do, Deisseroth noted. “But we are still going forward at top speed.”

He concluded with two observations that went beyond the promise of optogenetics in comprehending the brain and its workings. “There's a lesson here about preserving ecological niches,” he said, referring to extreme locations where the microbes that stimulated his research were found. “And it shows the value of pure, undirected basic science.”

Information about Deisseroth's work is posted at <www.stanford.edu/group/dlab/about_pi.html>.