For Stanford University associate professor Karl Deisseroth, the exploration of natural diversity has led to the development of a plethora of novel neuroscience tools. Deisseroth, along with graduate student Feng Zhang, has used light-sensitive molecules from a variety of species to develop ways to control neurons using only light. The approach—termed optogenetics—took center stage Monday afternoon at the 39th Annual Society for Neuroscience meeting in Chicago, Illinois, when Deisseroth, Zhang, and several other investigators presented the latest developments in optogenetics and discussed how the field is poised to answer fundamental questions in neural biology.
Optogenetics involves the use of proteins called opsins, which are light-sensitive molecules that can be found in a vast array of species. When coupled with neural cells, many of these molecules can influence activity after being exposed to specific wavelengths of light. Though the field is relatively nascent, the applications of this technology have shown promise. Zhang described recent efforts to identify new opsin proteins to expand upon the current range of options when it comes to the optical control of neurons. “We have been mining the diversity of microorganisms in extreme conditions,” said Zhang. He described two new opsins from chlorophytes and cryptophytes, which have excitatory and inhibitory functions when exposed to certain wavelengths and which can be expressed in specific subsets of neurons in the brain.
As Deisseroth and Zhang continue to work on the tools for an increased range of light sensitivity and cell-specific expression, other researchers are starting to pick up these approaches in an effort to understand basic neurological processes. Michael Häusser of University College London spoke about his group’s recent work exploring memory recall using optical stimulation. Häusser is interested in trying to reactivate specific subsets of neurons involved in memory formation and then determine how few neurons are needed to trigger recall. Häusser described a recent experiment wherein he created a plasmid linking the c-fos promoter (involved with synaptic plasticity in the brain) to the light-sensitive channelrhodopsin-2 optogenetic protein and green fluorescent protein. This was then injected into mice. The mice underwent classical delay fear conditioning, where an auditory tone was followed by a foot shock, but without optical stimulation. Following conditioning, Häusser exposed the mice to light of the required wavelength to activate channelrhodopsin and found that such light activation was sufficient to reproduce the fear response without the need for the auditory tone. According to Häusser, this indicates that light alone is capable of reproducing learned behaviors in this system. A further surprise came when Häusser analyzed transfected tissues to discover that fewer than 100 cells in a specific region of the brain were necessary to cause the effect.
The optogenetic toolkit is growing and researchers are responding with a rapidly growing number of increasingly complex experiments that are revealing new details about the circuitry and function of the brain. Though light-sensitive molecules coupled to brain activity seems like an unlikely pairing, Deisseroth expressed his continued surprise at how far optogenetics has come and how much the diversity of these molecules in nature has revealed about the inner workings of the brain. “Who would have predicted such a connection?” he said.