In the late 19th century, the Spanish anatomist Santiago Ramón y Cajal laid the foundation for modern neuroscience with a microscope, a pen, and some paper. Applying a cell-staining technique to samples of brain tissue, he produced thousands of detailed illustrations that revealed for the first time the intricate complexity of neurons and neuronal networks. Based on his observations, Ramón y Cajal proposed that the neuron was the basic functional unit of the nervous system, a hypothesis confirmed when the electron microscope was invented in the 1950s.
In the decades since, microscopy has remained central to efforts to understand the brain in health and disease. Scientists today can visualize brain tissues in remarkable detail, down to the level of the individual proteins responsible for neuronal structure and function. Despite technological advances, however, challenges remain. Attempts to achieve that level of resolution for large samples can lead to tissue damage or be prohibitively time-consuming — imaging a single whole fruit fly brain with an electron microscope, for example, can require years or even decades of work.
Now, researchers at Howard Hughes Medical Institute’s Janelia Research Campus, the Massachusetts Institute of Technology, and Harvard Medical School have developed a method that yields high-resolution visualizations of large volumes of brain tissue at speeds roughly 1,000 times faster than other methods. Combining two recently developed technologies — expansion microscopy and lattice light-sheet microscopy — enabled them to image an entire fruit fly brain, as well as large sections of mouse cortex, in subcellular detail in only a few days.
The work — led by HHMI investigators Eric Betzig of Janelia and Edward Boyden of MIT, and carried out in collaboration with Srigokul Upadhyayula, HMS assistant professor of pediatrics at Boston Children’s Hospital, and Tomas Kirchhausen, HMS professor of cell biology in the Blavatnik Institute at HMS — was detailed in a study published online in Science on Jan. 17.
“The greatest scientific challenge of the 21st century is the brain, perhaps the most complex structure that we know of in the universe,” said Upadhyayula, who is co-first author of the study. “This new method can potentially usher in a new era for neuroscience, as we explore the ultrafine architecture of neurons and neural circuits across the brain, at scales and resolutions that were previously unattainable.”
Rapidly imaging large volumes of brain tissue at high resolution could lead to detailed maps of the activity and wiring of the brain, the authors said, which may help scientists better understand diseases of the brain, build better artificial intelligence, or even explain the molecular drivers of behavior, decision-making, and more.