Serotonin is one of the most important neurotransmitters in the brain, helping to regulate our mood and playing a crucial role in depression. Thanks to new research from Aarhus University and others, it is now possible to monitor the serotonin circuitry in the brain – while it happens.

2021.01.04 | Ib Salomon

The brain is constantly sending signals. Some of them are electrical, others chemical. Among the chemical signals, serotonin plays an extremely important role. It is a chemical neurotransmitter which conveys signals from nerve cell to nerve cell, and the amount of serotonin present helps to define our mood. Serotonin has shown itself to be crucial in connection with depression and it plays a key role in the chemistry of the brain in general.

"However, a fundamental issue has been that it’s difficult to directly follow how serotonin is released, exchanged and reabsorbed in the brain cells. Serotonin molecules are so small that they can’t be seen under a microscope, so various indirect methods have been developed, but these aren’t that precise," explains Steffen Sinning, associate professor at the Department of Forensic Medicine at Aarhus University. He is one of the researchers behind an extensive research project which has just published its results in the journal Cell.

Can accelerate treatment of depression

Thanks to a method that Steffen Sinning has helped develop, it is now possible to very precisely follow the serotonin system in the brain – and do so all the way down to the cellular level – while the system is actually working. Steffen Sinning predicts that this will help to accelerate the treatment of depressions, among others.

The researchers have discovered that they can infuse the brain with a specially designed protein that binds onto the serotonin and has been engineered to be fluorescent when there is more serotonin present – in other words, it emits light and these light signals can then be measured in microscopes and other ways.

"Now we can measure the activity all the way inside the cells and do this as it’s actually taking place. It’s really quite incredible," says Steffen Sinning. The research project is both international and multidisciplinary, and Steffen Sinning has contributed by helping to modify the protein that literally causes the serotonin processes to emit fluorescent light, as well as by helping to show that the new tool can be used to study the transport of serotonin in and out of the nerve cells. The fluorescent protein that forms part of the basis material for the newly developed serotonin sensor was originally discovered by a Japanese researcher – in a jellyfish!

Now possible with extremely high temporal resolution

The researchers have conducted a wide range of experiments using the new method. Some took place on slices of still living brain tissue from mice, others on living mice who were exposed to events that cause the brain to release serotonin – and in both cases, the researchers were able to follow the signal path between the brain cells and measure the amount of serotonin. Mice are used because their size makes them easy to handle, and partly because the processes in the brains of mice are very similar to the processes in the human brain.

"We’ve also examined how serotonin is released in the different sleep cycles in mice and we can see that the largest amount is released when the mouse is awake and at the smallest when it’s in REM sleep, i.e. dreaming. This is an area that was previously very difficult to study with the same extremely high temporal resolution as we can now using our newly developed serotonin sensor," says Steffen Sinning. He summarises the new method thus:

"It gives us an opportunity to study brain processes involved in basic behaviour and psychiatric disorders much more directly and in unprecedented detail, which again gives us the opportunity to better understand both the healthy and diseased brain, and thus in the long term develop better treatment of e.g. depression."

The research results – more information

The research is basic research.

Partners: This is an international and multidisciplinary project involving, among other things, the University of California and the Janelia Research Campus in the USA.

Funding: Primarily via American foundations, in particular the Howard Hughes Foundation. Steffen Sinning's contribution is financed via appointments at Yale University and the Department of Forensic Medicine, Aarhus University.

Link to the article in Cell.

Contact

Associate professor Steffen Sinning
Aarhus University, Department of Forensic Medicine
(+45) 4076 8836
stsi@forens.au.dk