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Mental disorders through permanent stress

The link between stress and the immune system

by Meike Drießen  

November 3, 2014


Activated through permanent stress, immune cells will have a damaging effect on and cause changes to the brain. This might result in mental disorders.

Stress affects every aspect of lifeAstrid Friebe and her colleague view an object slide with a brain slice.Under the microscope, it becomes apparent what kind of activities different immune cells have been performing in the brain.Using very thin brain slices, the researchers study in detail the processes underlying mental disorders.By conducting long-term laboratory work, Astrid Friebe is striving to figure out what exactly may cause the activity of microglial cells to have a harmful effect on neural cells.In order to learn about the consequences of stress, the researchers are focusing on the cellular level.Prep work for setting up a cell culture.Box with pipette tips.

The search for causes of mental disorders has been keeping researchers busy for a long time. Various hypotheses have been postulated; in the 1960s, for example, scientists assumed the underlying cause to be a chemical imbalance in the brain. Is the balance of messenger substances disrupted? Do hormones play a key role?

Later, researchers discovered the so-called neuroplasticity, the brain's ability to adapt. Contact points between neurons, namely synapses, can be regrown, but they can also disappear, new neurons form, but they also die. Such processes occur during learning and training and are perfectly normal. But they also play a role in mental disorders. As it turned out, therapies had a demonstrable impact on those processes.

A small and very recent research field is so-called psychoneuroimmunology. It focuses on the immune system’s significance in the evolution of mental disorders, and strives to use all previous approaches in combination with each other.

Fig. 1

Using very thin brain slices, the researchers study in detail the processes underlying mental disorders. © RUBIN, photo: Nelle

"Originally, the brain and the immune system were considered two separate systems," explains Prof Dr Georg Juckel, Medical Director at the RUB's LWL university clinic for psychiatry, psychotherapy and preventive medicine. "It was assumed that the brain operates independently from the immune system and has hardly anything to do with it. This, however, is not true." Direct neural connections from the brain to organs of the immune system, such as the spleen, do exist. And vice versa, immune cells migrate to the brain, and local immune cells carry out various tasks there, including disposing of damaged synapses. There is yet more evidence supporting the theory that the immune system is involved in brain processes: in patients suffering from certain mental conditions, the immune parameters present characteristic mutations. A treatment with immune system mediators such as Interferon alpha, which is deployed in e.g. hepatitis C treatment, leads to depressions in 20 to 30 per cent of the patients.

Dr Astrid Friebe's work group in the LWL clinic lab researches into the mechanisms involved in these processes (fig. 1). The researchers are mainly interested in microglial cells. These immune-competent cells, which belong to the phagocyte family, are typically responsible for repairing synaptic links, removing damaged synapses and encouraging the growth of new neurons in the brain. Moreover, they carry out various metabolic processes, some of which have not yet been fully understood. In case of a threat, microglial cells are activated and switch into the destructive mode. In this active mode, they trigger inflammation and release messengers that damage nerve cells. "We see this very clearly in patients suffering from multiple sclerosis or Alzheimer's. The brain areas affected by inflammation or neurodegeneration are surrounded by a circle of microglial cells," describes Georg Juckel. In schizophrenia patients, the number of microglial cells is considerably higher than in healthy individuals. Here, the cells cause synaptic links between neurons to degenerate. Those links form the so-called grey matter, which in schizophrenia patients is significantly decreased.

Fig. 2

Under the microscope, it becomes apparent what kind of activities different immune cells have been performing in the brain. © RUBIN, photo: Nelle

Microglial cells can also be activated via the peripheral immune system, i.e. outside the brain. This is where stress comes into play: it is an important factor affecting the immune system. Acute stress stimulates the immune system. "That makes sense," explains Astrid Friebe: "In stress situations, the body readies itself for fight or flight, prepares itself for potential injuries, too." But what happens under permanent stress? "What is certain is that microglial cells adapt to the new conditions, in a way. The more frequently they get triggered due to stress, the more they are inclined to remain in that mode. This is when microglial cells start to pose a danger to the brain." Permanent stress is thus a relevant risk factor in the development of mental disorders.

Why will some people develop a mental condition under permanent stress while others won't? "We suspect that the origins of a schizophrenia predisposition go back to the embryonic phase," says Georg Juckel. This assumption is backed by a large US study conducted in the 1950s. It showed that children born of mothers who contracted true viral influenza during pregnancy were seven times as likely to suffer schizophrenia later in life. The researchers from Bochum confirmed this result in animal models. They also discovered that particularly high numbers of activated microglial cells are found in the brains of young adults, which is the age bracket where schizophrenia most commonly breaks out. "We don't know what exactly happens in the embryo when his or her mother contracts influenza," says Astrid Friebe. "But the embryo undergoes some kind of immune response which has far-reaching consequences and presumably shapes the future immune system."

Fig. 3

Using very thin brain slices, the researchers study in detail the processes underlying mental disorders. © RUBIN, photo: Nelle

Currently, the work group is studying the damaging effects of activated microglial cells in detail (fig. 2). What kind of molecules do they release that are harmful to nerve cells? "We suspect this has something to do with nitrogen monoxide, because we have found evidence that more enzymes are formed that produce nitrogen-monoxide bonds," says Astrid Friebe. In the next step, the researchers will have to substantiate this hypothesis in cell cultures.

At the same time, the scientists used the animal model to investigate depressions. Looking into this condition, the immune and stress effects can be expressly brought together. "Depressions can – in mice and in humans – be triggered not only through the addition of immune system mediators such as Interferon alpha, but also through stress itself. In both cases, microglial cells are activated," explains Astrid Friebe. Currently, the research question is: in which brain regions exactly do the cells have a damaging effect (fig. 3). "In conclusion one can say: stress is a risk factor for activating a predisposed immune system," says Georg Juckel.


Schizophrenia is a severe mental disorder that occurs quite frequently. The likelihood for developing this condition at some point in one's life is one per cent. Multiple relapses typically characterise the course of this disorder, which most commonly breaks out in young adults. Typical symptoms include exaggeration of and delusions regarding everyday experiences, up to and including hallucinations (positive symptoms), lack of motivation, cognitive and motor deficits (negative symptoms).

Contact faculty

Prof Dr med Georg Juckel
LWL University Clinic for Psychiatry, Psychotherapy and Preventive Medicine
Alexandrinenstr. 1-3
44791 Bochum, Germany
Phone: +49/234/5077-1100

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