The Brain: Now You See It, Soon You Won’t

A post mortem brain is a white, fatty, opaque, three-pound mass. Traditionally scientists have looked inside it by cutting the brain into thin slices, but the relationships and connections of the tens of billions of neurons are then almost impossible to reconstruct.   What if we could strip away the fat and study the details of the wiring and the location of specific proteins, in three dimensions? An NIH funded team at Stanford University has done just that, developing a breakthrough method for unmasking the brain.

Using a chemical cocktail, they infuse the brain with a hydrogel that locks in the brain’s form and structure in a type of matrix. Then the fatty layer that coats each nerve cell is stripped away, leaving a transparent brain (check out the transparent mouse brain below). The hydrogel prevents the brain from disintegrating into a puddle once the fat is gone.

Photo on the left shows an opaque mouse brain. Photo on the right (after CLARITY) shows a nearly transparent mouse brain.

Caption: CLARITY transforms a mouse brain at left into a transparent but still intact brain at right. Shown superimposed over a quote from the great Spanish neuroanatomist Ramon y Cajal.
Credit: Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

The new technique, cleverly but mind-bendingly named Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue Hydrogel─or CLARITY─will undoubtedly advance the BRAIN Initiative that President Obama announced just last week at the White House . In fact, Karl Deisseroth, leader of the CLARITY project, was in the East Room that morning, and has been chosen as a member of the NIH BRAIN working group.

Using CLARITY, the authors follow an individual neuron as its snakes through the brain of an autistic individual. They’ve stained the transparent brain in multicolored fluorescent hues to highlight the activity of individual genes, cells, neurotransmitters, and proteins.

A photo showing a 3D appearance of colored dots and swirls

Caption: This is the hippocampus, a structure important for learning, memory, and emotion.
Each color represents a different molecular label; this labeling can happen after the brain is
CLARIFied but still fully intact.
Credit: Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

In another extraordinary technical feat, they’ve imaged the transparent mouse brain with a light microscope, revealing a forest of neurons that glow like bioluminescent trees (below).

Photo of green blobs with long tails leading downward

Caption: A yellow fluorescent protein reveals mostly projection (Thy1) neurons in an entire intact mouse brain.
Credit: Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

CLARITY is powerful. It will enable researchers to study neurological diseases and disorders, focusing on diseased or damaged structures without losing a global perspective. That’s something we’ve never before been able to do in three dimensions.

Video: take a fantastic voyage through a mouse brain

Reference: Structural and molecular interrogation of intact biological systems. Kwanghun Chung, Jenelle Wallace, Sung-Yon Kim, Sandhiya Kalyanasundaram, Aaron S. Andalman,
Thomas J. Davidson, Julie J. Mirzabekov, Kelly A. Zalocusky, Joanna Mattis, Aleksandra K. Denisin, Sally Pak, Hannah Bernstein, Charu Ramakrishnan, Logan Grosenick, Viviana Gradinaru & Karl Deisseroth. Nature.Published online 10 April 2013

For more information: NIH BRAIN Initiative

NIH support: NIH Director’s Transformative Research (TR01) Award (Common Fund; National Institute of Mental Health); National Institute on Drug Abuse; National Institute of General Medical Sciences (Medical Scientist Training Program)

5 thoughts on “The Brain: Now You See It, Soon You Won’t

  1. Cool concept and AWESOME video! Can someone in-the-know help me wrap my brain around this…

    Is it accurate to say hydrogel monomers are introduced to the tissue, cross-linked with biomolecules (except lipids), and then thermally polymerized into a matrix, which will maintain spacial information when unbound material (lipids) are removed?

    I can see how the removal of tightly packed lipids allow photos to penetrate deeper into the tissue allowing for the insane images shown, but isn’t the imaging depth still somewhat limited by the ‘piles’ of molecules that remain or is there enough empty space to see to the center of an organ such as the brain? I guess I didn’t expect the fatless brain to be as transparent as the photo above.

  2. In my country, there are no such studies, but I’d love to know more about this new research. Can you point me to how I can keep track of this research?

Comments are closed.