I am a neuroscientist who uses advanced microscopy techniques to understand the basic mechanisms of Parkinson’s disease. Throughout my career, I have always been interested in imaging and microscopy as a way to answer essential biological questions. That’s why I (along with many other neuroscientists) am so excited about a new technique that creates fully intact, optically clear brains, allowing scientists to study how brain cells connect and communicate with each other in a completely revolutionary way.
The CLARITY technique, designed by Kwanghun Chung and Karl Deisseroth at Stanford University and detailed last month in a study in the journal Nature, makes brains clear by removing lipid (fat) molecules, which are the number one substance that interferes with the ability of light to penetrate through biological tissue. Lipids are the major component of all cellular membranes, a structure that acts as the bag that holds everything together inside of a cell. The trick to CLARITY is removing the bag, but keeping the rest of the cell from falling apart.
The authors do this by replacing all the lipids with a chemically engineered hydrogel substance. The hydrogel serves the purpose of holding all the cellular structures in place, but it does not interfere with the passage of light as lipids do. CLARITY gives researchers access to all of the DNA, proteins, and other components of the cell as they would normally exist in the brain, without the lipids getting in the way. Better yet, the hydrogel is porous enough to allow the infusion of multiple fluorescent molecules that bind to specific cellular components. That color codes the nervous system in a comprehensive pattern.
In addition to producing stunningly beautiful pictures, the CLARITY technique revolutionizes our ability to track how neurons connect to one another across large spans of brain volume. In the past, neuroscientists have had to cut preserved mouse brains into very thin slices using a specialized cutting machine, then try to track a single neuron through each of these adjacent slices, and finally reconstruct a 3D picture from the individual pieces. With CLARITY, no cutting is necessary – you can basically stick a specially prepared mouse brain under a microscope and look at the whole brain, perfectly intact.
The authors use CLARITY to create clear mouse brains, and also show that it can be applied to a small piece of human autopsy tissue. In one of the images from the paper, the authors trace a single neuron from a small block of human brain across the entire tissue section – about 1 centimeter, or the width of your fingernail. This may seem like a small distance. But to a neuroscientist who deals with structures that are 10,000 times smaller, that is huge!
The whole field is excited to see this technique repeated by other investigators and in other brain tissue. The hope is that eventually this method will become commonplace in research labs around the world.
With the breakthrough of CLARITY, we will be able to learn about whole-brain changes associated with various neurological disorders, including Parkinson’s disease, in a way that was never before possible. We will also greatly expand our knowledge of basic brain function, which is essential to progressing forward in neuroscience.
Kateri Spinelli, Ph.D.
Post doctoral fellow, Dept. of Neurology
OHSU Brain Institute