Abu Dhabi scientists shine a light on how the brain works

Scientists at New York University Abu Dhabi have created a way to study how serotonin works by literally shining a light on it.

Dr Timothy Dore is doing research in to the role of serotonin as a neurotransmitter chemical at NYU Abu Dhabi. Dolores Johnson / The National
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There is no organ in the biological world more complex than the human brain. And although some machines may have greater computing power, none comes close to matching the human mind when its myriad abilities are considered together.

Scientists are still a long way off fully understanding how it works – but it is clear that one chemical plays a crucial role at the heart of many of its activities.

That chemical is serotonin. A neurotransmitter, serotonin is the key chemical that passes information from one nerve cell to another.

It manages things as diverse as mood, learning, memory, appetite and pain. And beyond that it has other, more surprising functions. It regulates the movements of the intestine, for example.

In some of these roles, serotonin stimulates neural systems, while in others it has an inhibitory effect, and in yet more it functions as a hormone. But how, exactly, it works is, in many cases, more mysterious.

To help unravel that mystery, scientists at New York University Abu Dhabi (NYUAD) have created a way of working out what serotonin is up to – by literally shining a light on it.

In work published in the journal Chemistry & Biology, Dr Timothy Dore, an associate professor of chemistry at NYUAD, created a form of serotonin that only does its thing when lit up.

They did this by putting it in a chemical cage that is only broken by a flash of light that “uncages” the chemical within. Aptly enough, Dr Dore describes the cage as “a switch – like turning on the light”.

Being able to switch the serotonin on makes it much easier to work out what it’s doing. You can inject the caged serotonin into a sample of tissue or even a whole animal, and observe it with the serotonin inactive. Then flash the sample with light to switch the serotonin on, and see what happens.

“We want to mimic the natural release [of serotonin in organisms], but in a controlled way so we can control serotonin-mediated processes when we want to,” said Dr Dore.

It’s not the first time scientists have created light-activated serotonin, but the compounds Dr Dore’s group are using are much more sensitive to light than those used previously.

That is a big advantage when you are trying to work with real animals, which are often opaque. It means you can “flash” the cages, unlocking the serotonin, with far less light. As Dr Dore puts it, “one doesn’t want to give the biological preparation sunburn, so to speak”.

In their recent study, the researchers microinjected caged serotonin into the larvae of zebrafish (a species widely used by scientists, and so one whose biology is already very well known). When they flashed the light, nerve activity in the fish rose – showing that the cages had indeed been broken and the serotonin was active. The same thing happened in mice.

In further work, tadpoles of Xenopus frogs – another model species – were injected with inactive serotonin, which was then uncaged by light.

And it turned out that the timing of that uncaging was crucial. A key stage during the early development is the establishment of symmetry – the properties that make your left half broadly similar to your right half. But also important is the establishment of asymmetry – the fact that while similar, your left is not identical to your right, in a number of crucial respects. Your heart, for example, is on the left – your intestines also have a left-right-left winding structure that is very much asymmetrical.

When the serotonin was uncaged – and therefore activated – very early in development, when the embryo was no more than a blob of 16 cells, this left-right asymmetry got messed up, and the embryos developed with inverted hearts or stomachs. But these problems weren’t seen when the serotonin was uncaged later.

This result, and soon-to-be-published follow-up work by two of Dr Dore’s co-authors, Laura Vandenberg and Michael Levin of Tufts University, Massachusetts, shows left-right asymmetry is established very early in embryonic development – and that serotonin is crucial to its establishment.

So far, the caged serotonin studies have been done in relatively simple animal systems – mice, zebrafish larvae and tadpole embryos.

But eventually they could be extended to help uncover the secrets of how the chemical functions in other biological systems – including the human mind.

“Being able to activate neural circuits dependent on serotonin for their activation or inhibition is valuable for studying the role serotonin plays for transmitting signals in the brain,” said Dr Dore.

Even work on a model animal such as zebrafish could, for example, improve the understanding of the brain pathways that lead to epileptic seizures, in which serotonin is believed to have some as-yet-unclear role.

Light-activated serotonin could also be used to study depression. Higher levels of serotonin in the brain are believed to improve mood – hence the popularity of drugs known as selective serotonin reuptake inhibitors such as Prozac. They prevent tissues taking up serotonin, meaning more is left to promote the transmission of signals between nerve cells in the brain – and so a better mood.

It also demonstrates how useful the light-activated serotonin can be to scientists.

“[They] have been able to take this [serotonin] tool and answer fundamental questions about embryonic development,” said Dr Dore. “For me that’s the most satisfying thing – to build this tool, and to have this tool [used] to learn something that we would never be able to learn without it.”

Dr Dore, a chemist, is now focused on tinkering with the chemistry of the serotonin cages, to make them more sensitive still to light.

He is also interested in developing similar “caged” forms of other neurotransmitters and substances that regulate complex processes such as the way genes are expressed. That means “caged” molecules of various forms could prove crucial to the understanding of an even wider range of biological activity, even beyond the mysteries of the human mind.