A groundbreaking nanoscale project has catapulted our understanding of the human brain forward, with a team of scientists reconstructing a cubic millimeter of brain tissue in unprecedented detail. This minuscule segment, just a millimeter on each side, contains an astonishing 57,000 cells, 150 million synapses, and 230 millimeters of ultrafine blood vessels, packed within its microscopic space.

The project, nearly a decade in the making, stands as the most detailed and extensive reproduction of the human brain to date. The data generated amounts to over 1.4 petabytes, showcasing the resolution of synapses—structures that facilitate neuron communication. “The word ‘fragment’ is ironic,” remarks neuroscientist Jeff Lichtman of Harvard University. “A terabyte is, for most people, gigantic, yet a fragment of a human brain – just a miniscule, teeny-weeny little bit of human brain – is still thousands of terabytes.”

The human brain, with its billions of neurons and trillions of synapses, is exceptionally intricate. This complexity has made detailed studies of synaptic circuitry incredibly challenging. A deeper understanding of the brain’s operations promises profound benefits for research into brain function and disorders, ranging from injuries to mental illnesses and dementia.

Lichtman and his team aim to create a “connectome”—a comprehensive map of the brain’s wiring. Their current project focuses on reconstructing an entire mouse brain, but similar techniques applied to human brain segments are accelerating knowledge acquisition.

The team’s reconstruction efforts were based on a human brain sample from an epilepsy patient, obtained during surgery to access an underlying lesion. This sample was meticulously prepared: fixed, stained with heavy metals, embedded in resin, and sectioned into 5,019 ultra-thin slices, each with an average thickness of 33.9 nanometers. Using high-throughput serial section electron microscopy, the researchers imaged the tissue in exquisite detail, generating 1.4 petabytes of data.

This massive dataset was analyzed with specialized techniques and algorithms, resulting in “a 3D reconstruction of nearly every cell and process in the aligned volume.” The reconstruction, named H01, has already unveiled previously unseen details about the human brain. For instance, glial cells were found to outnumber neurons 2:1, and oligodendrocytes—the cells that coat axons with protective myelin—were identified as the most common cell type.

The reconstruction also revealed that while each neuron had thousands of relatively weak connections, rare, powerful axonal connections were found, linked by up to 50 synapses. Additionally, some axons were arranged in unusual, extensive whorls. Given that the sample was from an epilepsy patient, it remains unclear whether these features are typical of the human brain or specific to the disorder.

The team’s next focus is understanding the formation of the mouse hippocampus, a critical region for learning and memory. Lichtman envisions a future where whole-brain reconstructions in animal models of various neurological conditions become routine, providing unprecedented insights into brain function and disorders.

“There is this level of understanding about brains that presently doesn’t exist,” Lichtman explained to The Harvard Gazette. “We know about the outward manifestations of behavior. We know about some of the molecules that are perturbed. But in between the wiring diagrams, until now, there was no way to see them. Now, there is a way.”

The research has been published in Science, and the data along with the H01 reconstruction have been made freely available on a dedicated website, offering an invaluable resource for further exploration and study in the field of neuroscience.

By Impact Lab