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Brain’s circuits shown with new CLARITY

BioPhotonics
Jul 2013

STANFORD, Calif. – Replacing the fatty tissue of a postmortem mouse’s brain with a hydrogel has rendered the gray matter transparent, enabling scientists to trace individual neuron connections with unprecedented detail.

Traditionally, imaging organs such as the brain has involved a slicing or sectioning method, which destroys long-distance neural connections.


Intact adult mouse brain before and after the two-day CLARITY process developed in the lab of Dr. Karl Deisseroth of Stanford University. In the image on the right, the fine brain structures can be seen faintly as the areas of blurriness above the words “number,” “unexplored,” “continent” and “stretches.” Courtesy of the Deisseroth Lab.


Now the brain’s circuits can be seen with CLARITY (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging/Immunostaining/In situ hybridization-compatible Tissue-hYdrogel). The technique, developed by Dr. Karl Deisseroth and a multidisciplinary team at Stanford University, yields a 3-D transparent brain, with all of its important structures – neurons, axons, dendrites, synapses, proteins, nucleic acids, etc. – intact and in place.

“We drew upon chemical engineering to transform biological tissue into a new state that is intact but optically transparent and permeable to macromolecules,” said postdoctoral scholar Kwanghun Chung.


A 3-D rendering of clarified brain imaged from below (ventral half).


The method works by replacing the brain’s fatty tissues, called lipids, with a hydrogel, which is built from within the brain itself in a process conceptually similar to petrification. The intact postmortem brain is immersed in a hydrogel solution and heated slightly to form a mesh that congeals everything in place except the fatty parts, which are removed through a process called electrophoresis.

“We thought that if we could remove the lipids nondestructively, we might be able to get both light and macromolecules to penetrate deep into tissue, allowing not only 3-D imaging, but also 3-D molecular analysis of the intact brain,” Deisseroth said.

Fluorescent antibodies were used to trace neural circuits through the entire brain, enabling the researchers to explore deeply into the nuances of local circuit wiring. Relationships between cells and subcellular structures also can be investigated.


A 3-D view of stained hippocampus showing fluorescence-expressing neurons (green), connecting interneurons (red) and supporting glia (blue).


“Of particular interest for future study are intrasystem relationships, not only in the mammalian brain, but also in other tissues or diseases for which full understanding is only possible when thorough analysis of single, intact systems can be conducted,” he said. “CLARITY may be applicable to any biological system, and it will be interesting to see how other branches of biology may put it to use.”

The process – performed primarily on a mouse brain, but also used to image zebra fish brains and preserved human brain samples – was described in Nature (doi: 10.1038/nature12107).


GLOSSARY
electrophoresis
The movement of particles or ions in a solution toward the electrode having the opposite sign because of the application of an electrical field.
optogenetics
A discipline that combines optics and genetics to enable the use of light to stimulate and control cells in living tissue, typically neurons, which have been genetically modified to respond to light. Only the cells that have been modified to include light-sensitive proteins will be under control of the light. The ability to selectively target cells gives researchers precise control. Using light to control the excitation, inhibition and signaling pathways of specific cells or groups of cells...
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