Mapping neural connections within the brain has always been one of the most complex and slowest scientific tasks in neuroscience. In traditional methods, researchers had to slice brain tissue into very thin sections, photograph them section by section using microscopy, then trace the path of each neuron in a very complex and very slow way, before manually reassembling the neural pathways as if they were a three-dimensional puzzle being assembled piece by piece.
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“Electron microscopy requires high technical skills,” explains Boxuan Zhao, a professor of cell biology and development at the University of Illinois at Urbana-Champaign in the United States. “Imaging even a cubic millimeter of brain tissue can take months, and results in huge petabyte-sized datasets, in addition to the need for large teams of analysts or advanced artificial intelligence systems to track neurons throughout the tissue.”
To address this deficiency, Zhao’s team developed an advanced and efficient technique for accurately mapping neural connections within the brain by labeling neurons using what are known as “molecular barcodes,” which are unique sequences of ribonucleic acid (RNA) that act as an identification fingerprint for each neuron.
"Thanks to this technology, brain mapping can be transformed from a slow imaging task into a problem that can be solved using fast and scalable sequencing techniques compared to traditional methods," says Zhao.
He adds "this transformation allows for the study of a much larger number of nerve cells in multiple brains and under more diverse experimental conditions than was previously possible, especially in the brains of large mammals."
Communications map
According to a study recently published in the journal Nature Methods, researchers have developed a new platform called "Connectom-Sec," a term that refers to the integration of a "connectom"—that is, a map of neural connections—with "genetic sequencing."
According to Zhao, who led the study, this technique relies on providing each neuron with a unique RNA barcode, similar to a molecular identification tag that can be read using modern DNA sequencing techniques, which can analyze billions of molecules in parallel and at a low cost.
Next, specialized proteins designed by the researchers capture these "barcodes" from the neuron cell body and transport them to the synapse—the precise functional point of contact that allows a neuron to transmit electrical or chemical signals to another cell—where they are attached. One protein works on the transmitting side and the other on the receiving side.
In the third step, researchers divide brain tissue into millions of intact synaptic connections known as synaptic strands, and then sequence the barcodes within each strand. The appearance of two different barcodes within the same synapse indicates an actual connection between the two neurons. Simultaneously, the sequences of the neuronal cell bodies themselves are analyzed to identify each cell and its gene expression pattern.
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