Karl Deisseroth is a pioneer in optogenetics, the technology that has taken neuroscience by storm by enabling the use of optical and genetic methods to precisely control the switching on and off of individual neurons and brain circuits.
Deisseroth and his team at Stanford have now come up with an entirely new method to explore the brain that U.S. National Institute of Mental Health director Thomas Insel told Nature represents "probably one of the most important advances for doing neuroanatomy in decades."
As its name suggests, it is a means of making the post-mortem brain of a mouse or human transparent, a boon to researchers who wish to literally get a clearer picture of the mess of wiring in neural tissue without having to digitally stack images of tiny brain slices in a computer. The paper in our sister publication Nature went live on April 10 so Scientific American decided to talk with Deisseroth about the advance.
What is CLARITY?
Clarity is the process of exchanging natural tissue components for components from outside the body to achieve new visibility, access, or function. For example, the CLARITY method described in the Nature paper involves exchanging native lipids for an artificial hydrogel, that provides transparency, firmness, and the ability to label tissues.
How do you get it to work?
We first build in-place, and from within the tissue, a new firm hydrogel infrastructure that retains proteins and nucleic acids but excludes lipids, which can then be vigorously removed with ionic detergents and electrophoresis
What will be the benefit for brain and other researchers?
This enables researchers to study complex biological systems with high resolution without taking them apart. This not only saves a great deal of time and effort but serves useful scientific purposes as well, by allowing assessment of joint relationships among the different elements within a complex system-- for example, brainwide connection patterns coupled with panels of molecular labels.
How does it fit with your other work on techniques to understand neural circuits (optogenetics)?
It's independent from our optogenetics technology, but the two could work together. For example, one could clarify a brain from an animal in which optogenetic control had been delivered (over neurons expressing an opsin fused to a fluorescent protein as we usually have it configured) and which had resulted in a known behavioral change (a mouse that stops feeding after receiving an electrical shock, for instance). One could thereby map the local and global connectivity of those same neurons in the same animal known to cause behavioral change to a known extent.
Do you think you'll ever be able to do something like this in a live animal?
The CLARITY method described in the Nature paper is not compatible with life since the lipids are essential for life, but other CLARITY approaches could be.
Image Source: Kwanghu Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University