Harvard Team Maps Over 70,000 Neuronal Connections Using Advanced Silicon Chip

Harvard researchers have made significant strides in neuronal recording technology, mapping and cataloguing more than 70,000 synaptic connections from approximately 2,000 rat neurons. This achievement, detailed in Nature Biomedical Engineering, represents a major advance in the field and brings scientists closer to creating a comprehensive synaptic connection map of the brain.

The team, led by Donhee Ham, developed an array of 4,096 microhole electrodes on a silicon chip capable of performing massively parallel intracellular recording of cultured rat neurons. This new design builds upon their 2020 breakthrough device, which used vertical nanoneedle electrodes and could extract about 300 synaptic connections.

Co-lead authors Jun Wang and Woo-Bin Jung spearheaded the design and fabrication of the microhole electrode array. The microhole design, similar to a patch-clamp electrode, proved more effective than the previous nanoneedle approach. Wang explained, "Not only do microhole electrodes better couple to the interiors of neurons than the vertical nanoneedle electrodes, but they are also much easier to fabricate."

The new chip exceeded expectations, with over 90% of the electrodes successfully coupling to neurons. This resulted in the extraction of 70,000 plausible synaptic connections, a significant increase from their previous work. The improved data quality also allowed for categorization of synaptic connections based on characteristics and strengths.

The integrated electronics in the silicon chip plays as equally an important role as the microhole electrode, providing gentle currents in an elaborate way to obtain intracellular access, and recording at the same time the intracellular signals,” said Jung.

One of the biggest challenges, after we succeeded in the massively parallel intracellular recording, was how to analyze the overwhelming amount of data,” Professor Ham said. “We have since come a long way to gain insight into synaptic connections from them. We are now working toward a newer design that can be deployed in a live brain."