What do neuroscientists think of depression

News portal - Ruhr University Bochum

Statistically speaking, one in five people will suffer from a depression or anxiety disorder at some point in their life. It is unclear in detail which mechanisms underlie these diseases. And this although researchers have been pursuing the hypothesis for more than 60 years that a change in the level of the messenger substance serotonin is one of the causes.

Serotonin system is difficult to understand

"Unfortunately for us it is incredibly difficult to understand how the serotonin system works," says Prof. Dr. Olivia Masseck, who has held the junior professorship for high-resolution fluorescence microscopy since the end of April 2016. She wants to elicit its secrets from the complex system. There are a total of 14 different receptors in the brain for the messenger substance serotonin, and they occur in different cell types. This makes it difficult to find out what functions the different receptors have in the different cell types.

In order to find out the task of such receptors, it has long been customary to activate or block them with pharmaceuticals and to observe which functions are impaired as a result. However, many substances do not only work on one receptor, but on several at the same time. In addition, through the use of pharmaceuticals, researchers cannot differentiate between receptors in the individual cell types. "So far, it has not been possible for us to investigate the serotonin signaling pathways with high spatial and temporal resolution," adds Masseck. Until optogenetics came along.

This method revolutionized neuroscience.

"This method has revolutionized the neurosciences," says the researcher, whose collaboration partner Prof. Dr. Stefan Herlitze was one of the pioneers in the field. Optogenetics allows the activity of certain nerve cells or receptors to be controlled with light. What sounds like science fiction is everyday life in the RUB's neuroscientific laboratories. Masseck: “Before we were passive observers and could only record cell activity; now we can influence them in a targeted manner. "

Find out the function of individual receptors

The Bochum researcher is particularly interested in the 5-HT receptors1A and 5-HT1B, the so-called autoreceptors of the serotonin system. They occur in serotonin-producing cells and regulate there how much of the messenger substance is released; that is, they determine how high the serotonin level is in the brain.

In a normal organism, 5-HT1A and 5-HT1B activated when a serotonin molecule binds to the receptor. The docking process triggers a chain of reactions in the cell. This signal cascade causes, among other things, that the activity of the nerve cell decreases and that it releases less of the messenger substance.

Visual pigments coupled to receptors

Olivia Masseck modified certain cells in the brains of mice to produce the 5-HT1A-Receptor was able to activate without serotonin. She combined it with a visual pigment from the retina - called opsin. More precisely, she used blue or red visual pigments from the cones, which are responsible for color vision. In this way she created a serotonin receptor that she could turn on with red or blue light. In this way, the RUB researcher can find out what role 5-HT1A-Receptor plays in anxiety and depression.

To do this, she introduced the combination protein made up of light-sensitive opsin and serotonin receptor into the brain of mice using a virus that had been rendered harmless. Like a shuttle, it transports the genetic information that contains the blueprint for the combination protein. Once injected into the brain tissue, the virus smuggles the gene for the light-activated receptor into certain nerve cells. There it is read and the light-activated receptor is built into the cell membrane.

Switch off fear with light

Using light, the researcher was now able to switch the receptors in the living mouse on and off at will. She analyzed the influence this manipulation had on the behavior of the animals in an anxiety test, the open field test. She put individual mice in a large, empty Plexiglas box.

Usually the animals do not like to be in the brightly lit center of the box because there is no cover there. Instead, they spend most of their time near the walls. Olivia Masseck switched the receptor 5-HT1A with the light on, the behavior of the mice changed. They were less anxious and spent more time in the middle of the plexiglass box.

These results were confirmed in a further test. Here Olivia Masseck measured the time it took the mice to eat a food pellet in the middle of a large Plexiglas box. Normal animals waited six to seven minutes before they dared go to the center to eat. Mice with the serotonin receptor switched on ate after just one to two minutes. “This is an important indication for us that the 5-HT1AReceptor signaling pathway in the serotonin system has something to do with fear, ”concludes Masseck.

Olivia Masseck (center) and two students look at cells that contain a serotonin sensor under a special microscope. Later, the strength of the glow should show how much serotonin was released.
© Damian Gorczany

Next, the researcher would like to find out how the activation of 5-HT1AReceptor affects depressive behavior. "When the animals are exposed to chronic stress, they can develop symptoms similar to those of people with depression," says Masseck. "For example, you withdraw from social interactions."

However, this only applies to some of the mice - as is the case with humans. "Not every person who is chronically stressed or experiences bad situations develops depression," says Masseck. So what happens in the serotonin system of animals prone to depression compared to that of animals that do not develop symptoms of depression? The researcher would like to find out; on the one hand with the optogenetic methods described above, on the other hand she is currently working on a special serotonin sensor.

Real-time sensor for serotonin levels

In order to gain the most detailed insight possible into how anxiety and depression arise, Olivia Masseck is continuously looking for new methods. For example, she is working with her students on a sensor that can display the serotonin level in the brain in real time. One idea is to integrate a modified form of a green fluorescent protein into a serotonin receptor.

This protein only glows green if it is present in a certain spatial structure. When a serotonin molecule binds to a receptor, it changes its three-dimensional conformation. The aim is to incorporate the fluorescent protein into the receptor in such a way that its spatial structure changes together with that of the receptor when a serotonin molecule binds - in such a way that the protein begins to glow. Researchers are already using similar principles to measure calcium signals in cells.

Olivia Masseck assumes that her findings on the circuits and molecular mechanisms of anxiety and depression can be transferred to humans. Because mice have similar cell functions and their nervous system is structured similarly. The brain researcher even expects that optogenetics will make the leap to application in humans.

I am firmly convinced that optogenetics will also be used in humans in the next few decades.

"Genetically manipulating cells so that they can be controlled with light may sound like science fiction," she says, "but I firmly believe that optogenetics will also be used in humans in the next few decades." could, for example, replace deep brain stimulation in Parkinson's patients because it allows a much more targeted activation of the desired signal pathways. And ultimately with fewer side effects.

We need to have a discussion about what we want to use these techniques for and what not.

“First of all, optogenetics will probably be used for diseases of the retina,” says Olivia Masseck. There are already experiments in which researchers have been able to restore the visual performance of blind mice.

Olivia Masseck is well aware that her research also raises ethical questions. “We need to have a discussion about what we want to use these techniques for and what not,” she says. Her research shows how quickly the lines between science fiction films and scientific reality can blur.

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