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Zebrafish brains open doors to all brains

By: Krishna Ramanujan,  Cornell Chronicle
Mon, 11/16/2015

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While studies have shown that humans may have an innate fear of snakes, such trepidation appears to have eluded Joe Fetcho, a Cornell neurobiologist.

Fetcho’s childhood fascination for understanding snake locomotion eventually led him to his calling: using zebrafish to answer questions of how neuronal circuits in vertebrate brains produce behaviors.

Though Fetcho began graduate school intent on solving the puzzle of how snakes move, he quickly learned the task was incredibly complicated.

“I said, if I am going to make headway on a problem in a reasonable period of time, I have to tackle something that is not that complex,” he said.

By switching to the study of the circuits of zebrafish, whose transparency make them ideal for researchers to look anywhere into the brain and spinal cord, Fetcho aimed to uncover how brains produce behaviors and movements.

By having the blueprint for basic brain function, “it is a foundation for figuring out how behaviors go awry,” he said.

Fetcho’s work has relevance today, as the Obama administration has launched the BRAIN Initiative, an effort to understand how the brain works, and to treat diseases and disorders such as Alzheimer’s, autism and traumatic brain injury.

“One of the goals of that initiative is to monitor the activity of every neuron in the nervous system in a human while a human is behaving,” said Fetcho, professor and associate chair of the Department of Neurobiology and Behavior in the College of Arts and Sciences, and co-director of the new Cornell Neurotech initiative. Thanks partly to Fetcho, the zebrafish is the only organism where extensive real-time mapping of neuronal activity has been achieved.

“The core approaches were used to do that were ones that we pioneered in my lab,” Fetcho said of the work that lays the groundwork for achieving this feat in humans.

What zebrafish tell us about vertebrate brains

Since imaging is the best way to see how brains produce behaviors, it made sense to pick an animal that lent itself most easily to being viewed, which led Fetcho to the almost transparent zebrafish, a species that has served as a model for experimentation in development for decades.

“Once you start asking what the differences are between what a human can do and what other animals can do, 99 percent is the same,” Fetcho said.

Of course, humans have special abilities, such as higher consciousness, but neurologic disorders are related to circuits that are much more fundamental, he said. All the core movements in vertebrates are pretty much universal and ancient in how they are controlled, he added.

“I can predict whether a cell type is critical for a typical behavior based on our work in zebrafish, and then the people who work on much more difficult-to-study nervous systems can test my idea in a mammal,” Fetcho said, adding that studying and imaging the brains of mice, for example, is so complex that researchers often don’t know where to start. Fetcho’s work offers a guide, a flashlight in the darkness.

 

This diagram reveals the evolutionary development and diversification of vertebrate brains. The major regions are mostly similar, but with degrees of elaboration, Fetcho says. Credit: The Central Nervous System of Vertebrates, Rudolf Nieuwenhuys et al.,  1998, Springer-Verlag Berlin Heidelberg.

Lab work

In his lab, Fetcho seeks to understand the golden rules for building circuits that might be shared across different behaviors and animals.

It turns out, the nervous system builds components early in life, which are then mixed and matched, like a builder might use parts from a catalog. There are neuron types for producing coarse, big movements, and smaller, more specialized cells for controlling refined, slower or weaker movements. In this way, the brain selects parts and combines them to produce behaviors such as moving an arm or an eye, or breathing.

“People thought there would be a fundamentally different way to build a circuit for eye movements than limb movements, but it turns out, that’s not the case,” he said. “It’s a parts catalog approach to building circuits.”

Gadgets that connect the dots

“I love gadgets, I’m a gadget freak,” Fetcho said. That enthusiasm led him and physics postdoctoral researcher Matt Farrar to build from scratch their own “light sheet microscope” last summer for imaging every neuron in the zebrafish brain.

The microscope takes advantage of a technology first demonstrated in the Fetcho lab: an engineered zebrafish whose neurons fluoresce when electrically activated. The neurons light up due to a sensor that detects the flood of calcium ions when the cells are active.

 The light sheet microscope, which sits on a large table and looks like a tinkerer’s elaborate erector set, is one of two such devices in the country to image the neuronal activity of live zebrafish brains. The microscope collects the activity of fluorescing brain neurons and stores the data in a 120-terabyte server. Fetcho wrote the software that allows him to image the neurons on a screen in 3-D, take cross-sections, analyze the intensity of a neuron’s response, and compare its activity patterns with other nerve cells.

“You can click on any neuron you want and say, find me every other cell that has a similar pattern, and you can see that often they are clustered,” he said. In this way, Fetcho has started to connect which neurons might be associated with certain movements, such as gill movements in a fish. He can go to the region of the brain that is known to control breathing, click on a neuron lit up on the screen, and see every other neuron with a similar activity pattern.

“It points out all the other cells that are controlling the gills that have a similar pattern that we couldn’t otherwise find very easily,” he said.

This image shows the brain and spinal cord of an intact living zebrafish. Nerve cells have been labeled using fluorescent proteins of different colors.  Most of the nerve cells are labeled in green and appear as green dots.  Others are labeled in orange, yellow, and purple in a way that fills the entire cell, so the processes of each cell are visible in the brain and spinal cord. Credit: Fetcho Lab

The big picture

By inventing new ways to look at zebrafish, Fetcho is creating a model for how to collect and analyze data, which may then be applied to humans. And while his interest in snakes – and science – was sparked by pure curiosity, that inquisitiveness has led him to ask fundamental questions about motor circuits that all animals have in common and to develop the tools to answer those questions.

“If you can look at things in a way that no one has ever done before, that’s how discoveries are made,” he said.

This article originally appeared in the Cornell Chronicle. Video produced by Jason Koski and Krishna Ramanujan.

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