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When Fish “Play,” Dr. Takashi Kawashima Sees How Neurons Work

A unique fish meets a unique research method to reveal a deep-brain system

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Can tiny zebrafish play video games? Dr. Takashi Kawashima, a new scientist in the Weizmann Institute of Science’s Neurobiology Department, is building a virtual reality system meant for fish in which, as they “play,” he will be able to see inside their heads. Combining this system with microscopy and analytical methods that can track the activities of all the neurons in the fishes’ brains, he intends to uncover the workings of a primitive, yet crucial system – the serotonin system – in the brain. In doing so, he will shed light, among other things on the ways that mood-altering drugs work in our brains – something that is still poorly understood.

The virtual reality “game” is based on a simulation of moving water. Immersed in this virtual reality will be immature zebrafish, which are transparent – including their brains – so every one of their neurons can be observed with an optical microscope. In this system, the fishes’ heads are immobilized inside the microscope, and the movement of their tails controls the simulation, giving them the illusion of swimming. Just as humans engaged in a virtual reality world forget the real one beneath their feet, the illusion is convincing enough to the fish, so that they respond to changes induced in their environments in a natural, realistic way.

The fish make the "water" go by faster or slower by flicking their tails

Kawashima helped develop the system together with his colleagues at the Janelia Research Campus of the Howard Hughes Medical Institute as a postdoctoral fellow there.  A zebrafish brain is the size of the tip of a toothpick, but it has some 100,000 neurons,” says Kawashima. “So over a few days, we can amass a terabytes of data. My area of expertise is both the collection of this data and the computer analysis that will help us unravel it.” In a study recently described in Science, Kawashima and his colleagues further improved this system so as to track the firing of neurons at a millisecond precision, a feat that involved adding entire dimensions to the data.

Kawashima’s intent, in his Weizmann Institute lab, is to probe the serotonin system – a group of specialized nerve cells in the brain that can be found in practically every organism with a nervous system. In results he published in Cell, he found that serotonin neurons control fish’s swimming behaviors. Surprisingly, these neurons work in the same way for many animals, even when the observable behaviors are different.

We still don’t know how serotonin neurons process information and how they interact with other brain regions

In our own nervous systems, serotonin is a neurotransmitter that is linked to regulating our moods, among other things, and this is why selective serotonin reuptake inhibitors (SSRIs) like Prozac are often effective. They use the body’s own serotonin, recirculating it in the brain. But researchers are divided on the mechanisms by which these drugs work and quite a few open questions remain: What causes these neurotransmitters to be produced? What is the connection between the serotonin system and such disorders as depression, anxiety and anorexia? And why do the drugs only work for some people, and when they do, why do they require several weeks to take effect? “To answer such questions,” says Kawashima, “we need to know their basic mode of actions first.”

One of the reasons that the serotonin system is still poorly understood is that it is located so deep inside the brain that it is very hard to observe. We still don’t know how serotonin neurons process information and how they interact with other brain regions. Using zebrafish is thus a way to observe this system in detail.  “We currently study this during fish’s swimming. We will eventually extend this to more relevant contexts, including as the stress response, in this virtual reality,” he says.

The fishes' transparent bodies enable the researchers to track every neuron

Along with building a new version of the “virtual reality” microscope for observing fishes’ neurons, Kawashima is working on developing the markers to specifically reveal the activities of the serotonin system. And since fish can respond to stress in ways that are quite similar to human behaviors – refraining from eating or refusing to explore their surroundings, for example – he expects his research to shed light on such disorders as depression, anorexia and PTSD.


Two neuroscientists in the family

Takashi is married to another neuroscientist, Mio, “though we work in very different areas,” he says. It was, in fact, Mio’s area of interest that eventually led the two to the Weizmann Institute of Science. “She attended a conference in her area, and I went along as the ‘babysitter.’ Our older daughter was then around a year old and still nursing, so I attended the conference to help. Among other things, the conference organizers arranged one-on-one lunch dates between established and young researchers, and instead of signing up, I went along with Mio. Her lunch date turned out to be Prof. Alon Chen – who is currently the Institute’s President elect. He started to ask me about my work, as well, and I ended up sending him my CV. The next day, he and his colleagues invited me to interview at the Weizmann Institute.”

Mio, who has been researching another region of the brain – the amygdala – is a senior intern in the lab of Prof. Orly Reiner. Both Takashi and Mio have lived in the US/Europe as well as Japan, and even with the difficulties of culture and language, they are already beginning to feel at home in Israel. “The weather and food are great, the childcare is excellent (the couple have two daughters, aged three years and three months), and people here have a culture of helping one another,” he says. “I also appreciate that people here tend to speak their minds. People are surprised to find that my disposition is rather ‘Israeli’ when it comes to saying what I’m thinking, but I believe it will help me get along here at the Institute.”

Dr. Takashi Kawashima's research is supported by the Birnbach Family Career Development Chair.

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