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New Imaging Method Could be Used to Study Human Brain Disorders

A new technique devised by researchers at Cornell University enables imaging the brain of a zebrafish at all stages of development. The technique could apply to the study of human brain disorders, such as autism.

Image Credit: Gorodenkoff/

Young zebrafish are translucent, which makes them ideal models for live imaging. However, they turn opaque when they age, which has made it difficult for researchers to view a live adult brain.

At present, an interdisciplinary team of researchers from Cornell Neurotech has designed a microscopy tool engineered with calcium sensors to image adult zebrafish. The sensors light up to show when neurons are triggered.

All vertebrate brains are analogous by nature, thereby enabling researchers to use their technique to understand basic principles of the structure and function of brain that apply to all vertebrates, including humans.

All vertebrate brains are, to a first approximation, the same, with nearly all brain regions [present] in nearly every vertebrate. This is not surprising because they all, even the simplest ones, have to do the same things to survive and reproduce.

Joseph Fetcho, Professor of Neurobiology and Behavior and Director, Cornell Neurotech, College of Arts and Sciences, Cornell University

Fetcho is a co-senior author of the study titled “Deep Three-Photon Imaging of the Brain in Intact Adult Zebrafish,” published in the April 27th issue of Nature Methods. The other senior author of the study is Chris Xu, professor of applied engineering and physics in the College of Engineering and the Mong Family Foundation Director of Cornell Neurotech-Engineering.

Upon being activated, nerve cells tend to get flooded with calcium. The fish used in Fetcho’s studies were designed with a protein that attaches itself to the calcium in nerve cells. Moreover, the protein fluoresces upon excitation with a laser light of 480-nm wavelength, enabling the fluorescing cells to be imaged using a microscope.

However, there is a problem: When the light pulse is delivered, a single 480-nm photon aimed via the top of the fish’s head will activate other fluorescent proteins in the path of the beam, leading to image blurring. In the new technique, photons of 1400-nm wavelength are delivered to a focal point in the brain.

Thus, each individual photon includes a wavelength too long to activate intermediary proteins. However, three photons in combination will carry sufficient energy to activate a fluorescent protein when light is focused at the focal point.

Then, the laser repeatedly scans along a line in the brain, and the repeated imaging causes parallel lines to add up to a two-dimensional cross-section of a brain region. Repeating the process at various depths would enable researchers to achieve a three-dimensional image of brain structures.

According to Fetcho, using the new tool, researchers can now use fish that are designed to create a model of autism and other disorders, and observe how the disease advances with the aging of the fish. These fish models could also be employed to test prospective treatments to see whether they enhance function, and how the structure and function of brain change with the improvement in condition.

This is a step ... toward cures for some of the devastating brain disorders faced by humans.

Joseph Fetcho, Professor of Neurobiology and Behavior and Director, Cornell Neurotech, College of Arts and Sciences, Cornell University

The imaging technology was developed at Xu’s lab, while Fetcho’s lab worked on the behavioral and neurobiology aspects of the research. Co-author Andrew Bass, the Horace White Professor of Neurobiology and Behavior in A&S, also offered a different fish model that is under development, for a smaller relative of zebrafish, known as Danionella dracula, which would be simpler to image.

This study was supported by grants from the National Institutes of Health and the National Science Foundation.

Journal Reference:

Chow, D. M., et al. (2020) Deep three-photon imaging of the brain in intact adult zebrafish. Nature Methods.

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