Mapping the brain's serotonin pathways increases knowledge of our emotions

Fear and curiosity are emotions that determine how adventurous or cautious we are. But how are our emotions controlled by biological factors in the brain's nerve cells? New research shows that clearly defined serotonin pathways in the brain and their connections to for example amygdala and hypothalamus affect how we feel and act.

Iskra följer forskare som jobbar med mikroskop
Postdoc Joseph Clerke prepares tissue samples for analysis together with group leader Iskra Pollak Dorocic. Photo: Jens Olof Lasthein/Stockholm University

"We have found that there are six different molecular types of serotonin neurons, not just one as we originally thought. We have also been able to determine where in the brain tissue the different types are located and how they are organised, says Iskra Pollak Dorocic.


Neuronal circuits in focus

Iskra Pollak Dorocic leads a research group that, on a neurological level, looks at so-called neural circuits in the brain using different biological methods. Through them, you can learn more about how the brain works. Both behaviour and emotional states can be better understood by studying how neural circuits communicate with each other.

The main research focus is on serotonin in the brain and how it affects us. Serotonin neurons are not randomly distributed throughout the brain. They are concentrated in a few, relative to their importance, small areas deep inside the brain. The serotonin neurons are then connected to the rest of the brain through a complex system of neural circuits.

"In particular, we want to learn more about three different neural connections: those between serotonin and the amygdala, the part of the brain that controls emotions; the hypothalamus, the part that controls body temperature and sleep; and the VTA (ventral tegmental area), the part that controls the reward system and the tendency to develop addiction," says Iskra Pollak Dorocic.

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Postdoc Joseph Clerke and group leader Iskra Pollak Dorocic study serotonin-producing neurons on a microscopic image of the brain. The serotonin neurons are shown in green. Photo: Jens Olof Lasthein/Stockholm University

Studying both normal and pathological conditions

Iskra Pollak Dorocic and her research team focus both on understanding how the brain works in a so-called normal state and when normal functions no longer work, such as in severe anxiety and depression. Anxiety is actually a normal emotion, but in some situations, it can become so-called pathogenic, that is, manifest as a medical condition. Whether anxiety is at a normal level or not is determined by how much it affects daily life. The way serotonin neurons send their signals in the brain affects which side of the line anxiety levels are on.

"We don't know exactly the full range of functions of serotonin in the brain, but we know that it is extremely important for a large range of biological beings. The challenge is to functionally define what serotonin does and how different types of serotonin circuits affect functions and behaviours. One type is linked to motivation, another to anxiety. Previous studies have shown that the release of serotonin in the amygdala affects how the brain responds to situations that create fear and anxiety. Those who have less serotonin activity linked to the amygdala react more strongly to anxious situations," says Iskra Pollak Dorocic.

The brain at cellular level

There are many ways to study the brain: genetically, at the molecular and cellular level, and at the psychological and behavioural level. How much impact serotonin has, whether or not it is the main cause of problems like anxiety, is a matter of debate within research. Through experiments using the latest technology, known as 'in vivo', that is, behavioural studies linked to biological analyses of neural activity in living beings, the research team is contributing new knowledge about how serotonin works.

"The brain is an area that, until now, we have lacked in-depth knowledge of, particularly in the case of serotonin-based neuropsychiatric disorders. There has been a lack of knowledge about what causes these conditions. There are many hypotheses, of course, but they are often quite old and lack conclusive evidence," says Iskra Pollak Dorocic.

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Map of the parts of the brain. Photo: Jens Olof Lasthein/Stockholm University

Part of a revolutionary development

For example, treatment with drugs, known as antidepressants, is based on affecting the entire serotonin system, not specifically the neurons and circuits that affect the symptoms of depression. Iskra Pollak Dorocic's research team is trying to remedy this.

"The last 10-15 years have brought about a revolution in brain research in terms of methods and technological advances, " says Iskra Pollak Dorocic.

Cutting-edge technology provides new opportunities

At a time when brain research has made enormous strides, her lab at SciLifeLab is in the eye of the storm. To help them, they have advanced technologies, such as the sequencing method spatial transcriptomics, developed at SciLifeLab. With spatial transcriptomics, it is possible to map the serotonin in the brain, analyse the expression of the genes and link the expression to specific locations in the brain.

Other methods can be used in vivo, i.e. in living organisms. Such a method is called calcium imaging:

"We can label neurons in the brain with a biological label, which means we can measure the activity of specific serotonin neurons and circuits during different types of behaviour. We can also turn functions and connections off and on temporarily to see how this affects behaviour," says Iskra Pollak Dorocic.


What do you hope to achieve with your studies?

1. To increase the basic understanding of brain functions, a fundamental research mission where we study serotonin. We want to understand in more depth what serotonin does in the brain in a so-called normal state. A large volume of literature over the last few decades has resulted in some contradictory findings that show the complexity of the serotonin system and show that there is much more to be discovered about the function of serotonin.

2. With a better understanding of serotonin and how distinct the different groups of serotonin neurons are, creating better conditions for developing drugs that can more accurately treat different types of mental disorders. The treatments available now are outdated and treat the whole nervous system, not the part you actually want to treat. So, in the longer term, we want to increase the possibility of finding therapies that treat the nervous system in a more targeted way, not the whole system like now. Current drugs target the entire serotonin system in the whole brain, and are not very specific.

3. To get a better understanding of how antidepressants affect us.

Iskra Pollak med sin forskargrupp i labbet
Group discussion in the lab. From left to right, PhD student Charlotta Henningson, group leader Iskra Pollak Dorocic, postdocs Joseph Clerke and Jakub Mlost and research assistant Jesper Shiapan. Photo: Jens Olof Lasthein/Stockholm University

Research project: Mapping of the serotonin system

  • Mapping the spatial molecular serotonin system in the brain, by performing RNA sequencing in brain tissue.
  • In addition, the lab studies the effect at the molecular level of so-called antidepressants on the different serotonin populations. SSRIs are the most common antidepressant medication. Between 2010 and 2020, the amount of SSRIs prescribed doubled and is now taken by about 10% of the population.

"In particular, we are interested in how SSRIs affect us at the molecular level in serotonin neurons. A fundamental effect is that it blocks the natural reuptake (absorption) of serotonin in the brain so that it stays longer in the tissue. We want to know how SSRIs affect gene expression during short-term and long-term treatment. What happens after one dose? After several days? Or weeks? The study is not yet complete, but we have found, among other things, patterns of gene expression that explain how anxiety and depression levels can rise at the beginning of treatment and then go down after several weeks of treatment."

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Tissue to be examined. Photo: Jens Olof Lasthein/Stockholm University

Research project: The serotonin system and our behaviour

  • The second project focuses on our behaviours and is done on living individuals, so called 'in vivo'. The aim of the project is to record the neural activity of different serotonin neurons during behavioural tasks.
  • Neurons in living mice have been tagged with genetic markers, which can then be imaged in different colours depending on which group of serotonins is selected. This allows researchers to see where different types of serotonin are located in the tissue and measure their activity during behaviour. By studying the behaviour of the mice, the team can then see how the different types of serotonin neurons and circuits affect emotional states such as fear, curiosity and anxiety.

"We can see in real time how the activity of serotonin neurons and the release of the neurotransmitter affect behaviour. During an experiment, mice are given access to four corridors with different levels of safety and challenge. By studying what they choose, we can see whether it is curiosity or fear that drives their choices. The mice in the study are allowed to explore new environments with varying levels of risk. We then measure the serotonin levels of different connections in the brain, to determine in which area of the brain serotonin release plays a role in this exploratory behaviour. In another set of experiments, we can turn on and off selected serotonin neurons and see if that manipulation has an effect on the behaviour of the mouse. Then, for example, we look at how much serotonin signalling occurs in the brain when they were risk-prone or more fearful. What we clearly see is that the serotonin level is high when the mice are more adventurous."


Facts and further reading


  • Serotonins in the brain were discovered in the 1950s, but have so far been considered a single system. The place in the brain where serotonin neurons are found is called the dorsal raphe nucleus (DR). It is located in the centre of the back of the brain.
  • Serotonin is both a signalling substance (neurotransmitter) - a molecule that transmits a nerve signal by chemical means from one nerve cell to another in the nervous system, and a chemical messenger (neuromodulator) - a substance released by a nerve in the brain that affects networks in the brain, either closely or remotely, with a dampening or activating effect. 
  • There are many different neurotransmitters in the brain, but most are involved in rapid signalling through small electrical currents and have either driving or inhibiting effects on emotions. Serotonin is a slower-acting neurochemical substance, and can have both an excitatory, inhibitory or regulatory effect. Neurons in the dorsal raphe nucleus produce serotonin, and these neurons send long projections through the brain where serotonin is then released.
  • Serotonin neurons are unique in their highly complex and extensive connections throughout the brain, and in their central role in many different brain functions.


Read more about Iskra Pollak Dorocic’s research (SciLifeLab)

Read more about the research on neuronal circuits at Stockholm University