Optogenetics: Better research in a flash
By Mark Wanner
A flash of light can do the most amazing things.
Recent news stories have covered how light flashes can be used to implant false memories. In another study they were used to stimulate neurons in specific regions of the brain to turn on—and off— behaviors related with obsessive-compulsive disorder. Light is also being used at the single-gene level to rapidly start and stop the expression of a targeted gene. It essentially creates a genetic on-off switch that will make it much easier to figure out the roles of particular genes.
What sounds like science fiction is actually some of the progress being made using an exciting new technology in neuroscience called optogenetics. Don’t reach for the dark sunglasses and aluminum foil just yet, however. The research is being done in mice at this time. And while The Jackson Laboratory didn't discover or implement it up front, it’s now a leader in making the tools and techniques more and more useful. In fact, the work JAX does for optogenetics illustrates its vital role in biomedical research, even in areas outside the original research being done by its own faculty.
Image courtesy McGovern Institute
From far-fetched to practical
Optogenetics is barely a decade old. The seemingly far-fetched idea of using light to selectively control neural activity was originally proposed in the late 1990s. Less than a decade later, in 2005, a group at Stanford University led by Karl Deisseroth published a practical way to actually accomplish the feat.
The key components for the technique come from unlikely sources—algae and bacteria—but optogenetics is allowing researchers to study mammalian neuron function with far more precision than previously possible. In basic terms, optogenetics uses a family of proteins called opsins, which have light-sensitive regions connected with regions that act as tiny ion pumps across cell membranes. Therefore, light allows the flow of ions across membranes for a defined interval of time. Because the nervous system functions through electrical conductivity such as that created by the ion flow, it’s possible to use opsins to turn neurons "on" or "off"—activate or inhibit them—with light. And with advanced genetics techniques, it’s currently possible to make the opsins functional only in a very specific region of the brain in mice.
"Researchers are able to turn up or turn down certain parts of the brain and see what happens," says Michael Sasner, Ph.D., who works with the optogenetic mouse models in his role as the associate director, bioinformatics & model development in Genetic Resource Science at JAX. "You can induce or repress defined behaviors just by shining light. Being able to manipulate the system in such precise ways—you can turn off a specific neural circuit for 10 milliseconds, for example—provides a very sophisticated, non-invasive way to look at neural function."
Interest in the work has increased even more with the launch of the federal BRAIN (Brain Research through Advancing Innovative Neurotechologies) initiative, a key part of President Obama’s focus on significantly improving our understanding of the human brain. Optogenetics will contribute greatly to meeting the project’s mission to "accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought."
Putting the pieces together
The impressively rapid progression of optogenetics from concept to valuable research tool has several components. First there had to be a commitment to sharing and open access. Innovators Deisseroth, Ed Boyden (now at MIT) and Feng Zhang (now at the Broad Institute) set the tone from the beginning, freely providing resources and expertise. Others have continued the culture of open access, and JAX now serves as a crucial resource hub as the field progresses and expands.
"Optogenetics is one of the most powerful research tools available to illustrate the mechanisms of brain function and the composition of brain circuitry," says Hongkui Zeng, Ph.D., of the Allen Institute for Brain Science (AIBS), a current leader in developing and expanding the use of optogenetic techniques. Zeng is in charge of generating mouse genetic tools and related public datasets to fuel neuroscience discovery at AIBS. "We work closely with JAX and donate the optogenetics mouse strains we generate even before we publish the papers documenting them. We are rapidly developing these tools for our own use and for the larger research community, and we count on JAX to rapidly disseminate them."
Sasner sees JAX’s role as tying the pieces together to accelerate research.
"It takes one to two years to make these mice, so having a repository of the available strains saves a huge amount of time," says Sasner. "A researcher can come to us and see which strains are already available, what data has been curated in our databases, what resources we can offer to improve their research with these models, and more. We integrate the resources needed for good neuroscience. Everyone has the same toolbox, so previous experiments can be replicated and confirmed, and new experiments can be quickly and easily generated to build upon earlier work."
Thinking BRAIN and beyond
The advisory committee for the BRAIN initiative recently released a summary of nine priorities for the project moving forward in 2014. The first six involve basic science in model organisms, and it doesn’t take a scientist to see how at least four in particular—create structural maps of the brain; develop new large-scale network recording capabilities; develop a suite of tools for circuit manipulation; and link neuronal activity to behavior—will benefit from the new optogenetic tools and techniques.
Of course, these basic research efforts are building toward contributions to human health and medicine. Says Zeng, "Optogenetics isn’t directly translatable to humans yet, but understanding the mechanisms of how brain circuitry works will provide insight into how human brains work and how to treat human diseases. It is a key first step to developing therapies."
And the technique is so powerful that, in the future, Sasner sees even broader uses.
"There’s no reason this has to be restricted to the brain," says Sasner. "Cardiomyocytes that control the beating of the heart function through electrical stimulus, so perhaps someday we could see a pacemaker controlled by light. Simply put, optogenetics is a technological leap that provides tools that allow a much greater understanding of biology than was previously possible."