Microscopy technique records near-whole brain activity with high temporal, spatial resolution

Scientists at the Research Institute of Molecular Pathology (IMP), the Max Perutz Laboratories (MFPL), and the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna in Austria have developed a high-speed imaging technique with high temporal and spatial resolution. The technique is based on their ability to “sculpt” the three-dimensional  distribution of light in the sample, enabling them to record the activity of 70% of the nerve cells in a worm’s (C. elegans) head.

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Researchers have so far focused on studying the activity of single neurons and small networks in the worm, but have not been able to establish a functional map of the entire nervous system. This is mainly due to limitations in the imaging techniques: the activity of single cells can be resolved with high precision, but simultaneously looking at the function of all neurons that comprise entire brains has been a major challenge. So there has always a trade-off between spatial or temporal accuracy and the size of brain regions that could be studied.

"Previously, we would have to scan the focused light by the microscope in all three dimensions," says quantum physicist Robert Prevedel, who a is senior postdoc in the lab of Alipasha Vaziri, an IMP-MFPL Group Leader heading the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna, where the new technique was developed. "That takes far too long to record the activity of all neurons at the same time. The trick we invented tinkers with the light waves in a way that allows us to generate 'discs' of light in the sample. Therefore, we only have to scan in one dimension to get the information we need. We end up with three-dimensional videos that show the simultaneous activities of a large number of neurons and how they change over time."

Frontal part of a nematode seen through a microscope
Frontal part of a nematode seen through a microscope. The neurons of the worm’s "brain" are colored in green. Above are the discs of light generated by the WF-TeFo microscope, scanning the brain area and recording the activity of certain neurons (artist’s interpretation). (Image courtesy of IMP)

However, the new microscopy technique is only half the story. Visualizing the neurons requires tagging them with a fluorescent protein that lights up when it binds to calcium, signaling the nerve cells’ activity. "The neurons in a worm’s head are so densely packed that we could not distinguish them on our first images," explains neurobiologist Tina Schrödel, a doctoral student in the lab of IMP group leader Manuel Zimmer and co-first author of the study. "Our solution was to insert the calcium sensor into the nuclei rather than the entire cells, thereby sharpening the image so we could identify single neurons."

The new technique has great potential beyond studies in worms, the researchers say, and will lead to experiments that were previously not possible. One of the questions that will be addressed is how the brain processes sensory information to "plan" specific movements and then executes them. This ambitious project will require further refinement of both the microscopy methods and computational methods in order to study freely moving animals. The research team is set to achieve this goal in the next two years.

Their work has been published in the journal Nature Methods; for more information, please visit http://dx.doi.org/10.1038/nmeth.2637.

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