Generating Nanometric Resolution Of The Entire Brain 1,000x Faster Than Other Methods

  • A new technique can rapidly visualize large areas of brain tissue in remarkable details.
  • It utilizes two newly developed technologies: expansion microscopy and lattice light sheet.
  • This data-intensive approach allows researchers to trace particular proteins through the brain.

The human brain is perhaps the most complex structure that we know of in the entire universe. Despite its compact size, it contains over 80 billion neurons and a more or less equal number of other cells. These neurons connect through about 7,000 synapses each in an immensely complex network.

The foundation of modern neuroscience was laid by a pathologist Santiago Ramón y Cajal in the late 19th century, when he created thousands of in-depth illustrations that revealed the complexity of neurons and their networks.

During the 20th century, the understanding of neurons and their functions became increasingly accurate and molecular. This is the time when scientists began to understand the transmission of electrical signals in neurons of the giant axon of a squid, collectively known as action potentials.

Today, we have the technology to visualize brain tissues at unprecedented levels. We’ve figured out what makes neurons form new connections with other neurons and how individual proteins affect neuronal structure and function.

However, despite recent advances, scientists haven’t been able to achieve subcellular resolution of large samples that can help construct an entire brain in remarkable details without consuming a lot of time.

Now, researchers at MIT and Harvard University have developed a technique that can visualize large areas of brain tissue in high-resolution at speeds up to 1,000 times faster than existing methods.

This new technique is built by utilizing two newly developed technologies: expansion microscopy and lattice light sheet. It has the potential to image a large section of mouse cortex at nanometric resolution, in only a few days. This may help scientists explore the ultrafine architecture of neural networks, better understand diseases in the brain, and develop better artificial intelligence for decision-making.

How It Works?

The method enlarges tissue samples so that subcellular details can be studied easily with traditional optical microscopes. This is done by infusing tiny specimens with swellable gels. All tissue molecules get tightly attached to the gel scaffold, thus their relative 3D positions do not change even after expansion.

After expansion, the volume of a sample increases dramatically. The size becomes large enough to be captured by a high-speed, high-resolution microscope. However, the microscope must not photo-bleach (photochemical alteration of a dye) or otherwise it would completely distort the tissue sample before imaging.

Reference: ScienceMag | doi: 10.1126/science.aau8302 | The Harvard Gazette

To make sure it doesn’t happen, researchers developed a lattice light-sheet microscopy that sweeps an ultrathin light sheet through a sample and illuminates only the Plane of Focus (that represents the microscope’s theoretical plane of sharpest focus and lies in the depth of field).

In this way, samples can be imaged at subcellular resolutions without damaging tissues. This new technique yields crystal-clear pictures at extremely fast speeds (compared to existing methods) over massive volumes.


The researchers applied their technique on mouse brain tissues: it rapidly revealed complex subcellular details, including dendritic spines (tiny membranous protrusion from a dendrite of neurons that usually receives signals from a single axon at the synapse).

Nanometric Resolution Of Entire BrainDopaminergic neurons and synaptic proteins within the fruit fly brain | Courtesy of researchers 

It’s a data-intensive method. For instance, to visualize the entire brain of a fruit fly that has a volume of 20,000,000 µm³, researchers had to image over 51,000 three-dimensional portions of the brain, which represents approximately 200 terabytes of data.

The team developed several algorithms to examine the data and produce immersive clips, showing detailed insights of the brain. They analyzed over 1,500 dendritic spines and counted almost 40,000,000 synapses across the whole fly brain.

Read: The First Brain-to-Brain Interface Lets 3 People Share Thoughts Directly To Each Other’s Head

The technique also allows researchers to trace particular proteins through the brain. Moreover, it has the potential to visualize other biological systems and various diseases, such as cancer.

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