New Brain Process Responsible for Long Term Stress Identified

Summary: Researchers have identified a new neural mechanism that contributes to long term stress and PTSD. The study reports the mechanism is mediated by brain fluid in areas associated with stress response.

Source: Semmelweis University.

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 researcher
Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress image is credited to Semmelweis University.

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.

About this neuroscience research article

Funding: 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.

Source: Pálma Dobozi – Semmelweis University
Publisher: Organized by
Image Source: image is credited to Semmelweis University.
Original Research: Abstract for “Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress” by Alán Alpár, Péter Zahola, János Hanics, Zsófia Hevesi, Solomiia Korchynska, Marco Benevento, Christian Pifl, Gergely Zachar, Jessica Perugini, Ilenia Severi, Patrick Leitgeb, Joanne Bakker, Andras G Miklosi, Evgenii Tretiakov, Erik Keimpema, Gloria Arque, Ramon O Tasan, Günther Sperk, Katarzyna Malenczyk, Zoltán Máté, Ferenc Erdélyi, Gábor Szabó, Gert Lubec, Miklós Palkovits, Antonio Giordano, Tomas GM Hökfelt, Roman A Romanov, Tamas L Horvath,and Tibor Harkany in EMBO Journal. Published September 12 2018.

Cite This Article

[cbtabs][cbtab title=”MLA”]Semmelweis University”New Brain Process Responsible for Long Term Stress Identified.” NeuroscienceNews. NeuroscienceNews, 13 September 2018.
<>.[/cbtab][cbtab title=”APA”]Semmelweis University(2018, September 13). New Brain Process Responsible for Long Term Stress Identified. NeuroscienceNews. Retrieved September 13, 2018 from[/cbtab][cbtab title=”Chicago”]Semmelweis University”New Brain Process Responsible for Long Term Stress Identified.” (accessed September 13, 2018).[/cbtab][/cbtabs]


Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

Stress‐induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin‐releasing hormone‐releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain’s aqueductal system. CNTF binding to its cognate receptors on norepinephrinergic neurons in the locus coeruleus then initiates sequential phosphorylation of extracellular signal‐regulated kinase 1 and tyrosine hydroxylase with the Ca2+‐sensor secretagogin ensuring activity dependence in both rodent and human brains. Both CNTF and secretagogin ablation occlude stress‐induced cortical norepinephrine synthesis, ensuing neuronal excitation and behavioral stereotypes. Cumulatively, we identify a multimodal pathway that is rate‐limited by CNTF volume transmission and poised to directly convert hypothalamic activation into long‐lasting cortical excitability following acute stress.

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