Undressing The Brain With Scale

And it appears that they are on their way to undressing the brain. A study published in Nature Neuroscience in 2011 details how a newly-developed urea-containing reagent called Scale renders mouse brains transparent, giving neuroscientists a great view into the brain's complexities.

Making the brain transparent not only provides a more straightforward way to visualize the brain circuitry but also enables neuroscientists to look into the brain at depths which were recently unattainable.

Visualizing the brain is in itself nothing new. Using fluorescence labeling, the Brainbow mouse project by Havard Medical School distinguished and mapped individual neurons of the mouse brain. However, the method is labor-intensive and time-consuming. Because fluorescence is lost due to scattering of light (caused by density of the tissue), fluorescence-labeled particles situated deep in a brain tissue cannot be properly visualized by microscopy. To circumvent this obstacle, ultra-thin brain tissue slices have to be peeled and sequentially imaged. The high-resolution snapshots are then computer-reassembled to form 3D representations of the brain's circuitry.

With Scale however, there is no need for all this cutting and reassembling. By treating a mouse brain in Scale for two weeks, researchers turned the brain transparent (great pictures of a transparent mouse brain and a transparent embryo at reference 1-subscription required). With the fluorescent signals no longer being lost, they were able to dwell seriously deep into the mouse brain. The researchers were able to image it to depths of 2 mm, roughly three times deeper than what could previously be achieved. And when they used a special objective lens, the researchers were able to penetrate even deeper at 4 mm working distance.

Importantly, the Scale treatment is fully reversible with recovered samples undistinguishable from untreated ones. This indicates that the brain tissues are not (or at the very least are only minimally) disrupted by the treatment. The reversibility of the treatment has another exciting advantage. Coupling Scale's ability to provide global 3D reconstruction of the brain's circuitry with neuronal and synaptic structures obtained from immunohistochemistry performed later on the recovered tissues, researchers will be able to zoom out and zoom in brain tissues.

Although current works with Scale have been targeted to mice investigations, other species such as primates may be next in line in the near future. In a more distant future, we may even look at the application of "live Scale" which would render live tissues transparent.

Dreaming you're naked in front of a crowd may not be pleasant but undressing the brain for neuroscientists is swell, isn't it?

Image credit: Ed Mitchell (from flickr)

References:

1. Hama, H. et al. Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain. Nature Neuroscience 14, 1481-1488 (2011).
2. Gundersen, B. Seeing more clearly with Scale. Nature Neuroscience 14, 1362 (2011).