New 3-D Imaging Technology Promises Breakthroughs in Brain Research

Karl Deisseroth, M.D., Ph.D., Expert on optogenetics, CLARITY, depression, autism
Karl Deisseroth, M.D., Ph.D.

Brain & Behavior Research Foundation Scientific Council Member and NARSAD Grantee, Karl Deisseroth, M.D., Ph.D., led a team at Stanford in developing a new experimental method they are calling "CLARITY," that enables researchers for the first time to obtain high-resolution three-dimensional imagery of the brain. The new method, as reported today in Nature, renders the brain essentially transparent, making it possible to see in detail its complex fine wiring and essential features underpinning the functioning of the brain while also offering a global perspective of brain structure.

Prior to CLARITY, creating a 3-D image of the brain required carving its tissue into hundreds or thousands of hair-thin slices, scanning images of the slices in microscopic detail, and then painstakingly realigning the sections. Now a 3-D view of all the complex circuitry in the brain is possible while all of the important structures of the brain remain intact and in place (neurons, axons, dendrites, synapses, proteins, nucleic acids, etc.). By replacing the brain’s fat with a clear gel, CLARITY turns the opaque and impenetrable brain transparent and permeable. The hydrogel also importantly holds the brain’s anatomy intact and because it is permeable, the brain can be stained to localize proteins, neurotransmitters and genes at a high resolution (as in video below).

CLARITY provided this 3D view showing a thick slice of a mouse brain’s memory hub, or hippocampus. It reveals a few different types of cells: projecting neurons (green), connecting interneurons (red), and layers of support cells, or glia (blue). Conventional 2D methods require that brain tissue be thinly sliced, sacrificing the ability to analyze such intact components in relation to each other. CLARITY permits such typing of molecular and cellular components to be performed repeatedly in the same brain. Source: Kwanghun Chung, Ph.D., and Karl Deisseroth, M.D., Ph.D., Stanford University

“Studying intact systems with this sort of molecular resolution and global scope—to be able to see the fine detail and the big picture at the same time—has been a major unmet goal in biology, and a goal that CLARITY begins to address,” says Dr. Deisseroth, Professor of Bioengineering and of Psychiatry and Behavioral Sciences. The new imaging technology can be used to make any organ transparent, but it was the challenges of imaging the brain that motivated Dr. Deisseroth, who hopes to dissect psychiatric disorders such as schizophrenia, depression and autism.
The research in this study was performed primarily on a mouse brain, but Dr. Deisseroth and team have used CLARITY on zebrafish and on preserved human brain samples. When the team used CLARITY to study human post-mortem clinical samples from an autistic patient, the images revealed an unusual pattern of bridging connections from a particular class of inhibitory cells in the brain. The findings demonstrate how this new high resolution 3-D imaging method can clarify structural and molecular features of intact brains under normal as well as disease conditions. 
“If CLARITY is a predictor, the next few years could be a period of rapid new insights into brain structure and function,” says Dr. Tom Insel, Director of the National Institute of Mental Health. “One can barely begin to imagine how tools like CLARITY will change our concepts of how the brain works in health and disease.”