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A new brain process responsible for the delayed stress response and the long-term effects of stress has been identified in the framework of an international cooperation of researchers of Semmelweis University of Budapest, the Swedish Karolinska Institute, the American Yale University and the Medical University of Vienna. In the mechanism mediated by brain fluid, the brain area responsible for stress responses and behavioural formation is triggered with a delay of several tens of minutes after the danger occurs. The results may open up new perspectives to understand post-traumatic stress syndrome, chronic stress and the nervous processes of burnout.

To date, two major brain stress mechanisms have been known, both triggered by a well-defined group of neurons in the hypothalamus. One of the processes is a hormonal pathway that ultimately releases hormones through the bloodstream from the adrenal glands within seconds following stress. The second process involves an even faster nerve path, during which a direct neural link is formed under the fraction of a second towards the so-called prefrontal cortex, a region of the brain that is associated with moderating our behaviour.

The research led by Alán Alpár (Budapest), Tamás Horváth (New York), Tomas Hökfelt (Stockholm) and Tibor Harkany (Vienna) found that these same neurons are able to trigger a third type of stress reaction that appears much later and has long-lasting effects. The newly described mechanism occurs in the brain fluid. In this process, a molecule that plays an important part in the development and maintenance of the nervous system, the so-called ciliary neurotrophic factor (CNTF), reaches the stress centre by circulating through brain fluid. Since this mechanism is diffused through brain fluid, it is much slower than the process through the bloodstream; material thins more slowly in brain fluid and therefore it can prolong its effect. The molecules in brain fluid continuously bombard the stress centre’s neurons that keep the prefrontal cortex constantly alert, resulting in a more alert and responsive nervous system.

According to Dr. Alán Alpár, it is very likely that all three mechanisms are activated in the event of stress, but in the development of the delayed and lasting effect of stress, this third type of process they have identified plays an important part.

The areas of the brain that are responsible for the rapid response to the external stress stimulus have been described by Dr. János Selye, world-renowned Hungarian stress researcher. He also described what happens in a situation of stress, how the hypothalamus activates the pituitary, which then activates the adrenal cortex, explains Dr. Tomas Hökfelt. Stress, however, is a protracted process, the potential for environmental threats may, for example, persist, which requires not only immediate but also sustained attention from the human body. The researchers wanted to understand this process when they began to map the molecular biological background of the limbic system’s function and dysfunction. The mechanism through brain fluid described above has been detected not only in animal experiments but also in human specimens.

The discovery can be a new perspective for understanding the formation of post-traumatic stress disorder. The persistence of acute and chronic stress, as well as burnout are some of the major challenges that people face in today’s society, and understanding the nervous process leading to this can later provide an opportunity to treat these neuropsychiatric diseases, says Dr. Tibor Harkany. During the research, several molecular mechanisms were introduced, which can later be drug targets for pharmacologists.

The research was supported by the Hungarian Brain Research Program (Alán Alpár) and the European Research Council (Tibor Harkany). The results of the research have recently been published in the European Molecular Biology Organization (EMBO) Journal.


Pálma Dobozi
Photo: Attila Kovács – Semmelweis University
Translation: Diána Módos, Faye Gillespie