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Researchers Turn Brains Transparent By Sucking Out the Fat

By turning brains clear and applying colored dyes, connections between neuron networks can now be examined in 3D at unprecedented levels of detail

A new technique renders a mouse brain (opaque, at left) entirely transparent (at right) for easier imaging. Image by Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

The human brain is one of the most complex objects in the known universe. Packed into just 3 pounds of flesh (on average) is an assembly of roughly 86 billion interconnected neurons, forming countless intricate networks that make up the essence of your personality.

A preserved brain on an examination table, though, conveys none of this complexity: It looks, more or less, like a pile of grey meat, because we can’t see through the outer cells’ membranes to see the individual neurons inside.

This problem is the motivation behind a new technique, developed a Stanford team led by Kwanghun Chung and Karl Deisseroth, to make preserved brains entirely transparent to light. By doing so, and then using specialized chemical markers that attach to certain kinds of cells, they created a way to see whole brains in all their complex, interconnected splendor. Such complexity is readily seen in the mouse brain imaged below, in which certain types of neurons have been labeled with a florescent green dye:

A transparent mouse brain injected with a green dye that attaches to neuron cells. Image by Kwanghun Chung and Karl Deisseroth, Howard Hughes Medical Institute/Stanford University

The scientists say their technique, which was announced in a paper published today in Nature, works for preserved human brains as well as those of mice, and can be applied to many other types of organs as well. The method takes advantage of the fact that organs’ color—and hence the reason they’re not clear—is entirely due to the fat molecules that make up each cell’s membrane.

In a living brain, these molecules preserve the organ’s structural integrity. But in a preserved brain, they obscure the internal structure from view. To address this issue, the researchers filled the experimental mouse brains with hydrogels—which bind to the functional elements of the cells (proteins and DNA) but not the fat molecules—and form a jelly-like mesh that preserves the original structure. Then, they cleared away the fat molecules with a detergent, rendering the organ completely transparent.

Producing a fully intact, transparent mouse brain (as shown in the image at top) creates all sorts of interesting imaging opportunities. With the fat molecules flushed out, the elements of experimental or clinical interest (neuron networks or genes, for example) are no longer obscured by cell membranes. (In much the same way, zebrafish, with their transparent embryos, are heavily used in many fields of biological research.)

To see the aspects clearly, the researchers added colored chemical markers that specifically attach to certain kinds of molecules. Once this is done, scientists can examine them with a conventional light microscope, or combine multiple images from digital microscopes to create a 3-D rendering.

As a proof-of-concept, in addition to the mouse brain, the research team performed the procedure on small pieces of a deceased autistic person’s brain that had been in storage for 6 years. With specialized chemical markers, they were able to trace individual neurons across large swaths of tissue. They also found atypical ladder-like neuron structures that have also been seen in the brains of animals with autism-like symptoms.

This sort of detailed analysis has previously only been possible by laboriously examining tiny slices of brain with a microscope to infer a full three-dimensional picture. But now, interconnections between different parts of the brain can be seen on a broader level.

The fact that the technique works on all sorts of tissues could open up many new avenues of research: analysis of an organ’s signaling molecule pathways, clinical diagnosis of disease in a biopsy sample, and, of course, a more detailed examination of the neuron relationships and networks that make up the human brain. For more, watch the video below, courtesy of Nature Video:


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