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Contact: University of Leicester Press Office
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University of Leicester

Neuroscientists discover new 'chemical pathway' in the brain for stress

Breakthrough study offers hope for targeted treatment of stress-related disorders

IMAGE: Nerve cells (red) reach out and communicate with each other at junctions called synapses (green) that release chemicals to promote anxiety.

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A team of neuroscientists at the University of Leicester, UK, in collaboration with researchers from Poland and Japan, has announced a breakthrough in the understanding of the 'brain chemistry' that triggers our response to highly stressful and traumatic events.

The discovery of a critical and previously unknown pathway in the brain that is linked to our response to stress is announced today in the journal Nature. The advance offers new hope for targeted treatment, or even prevention, of stress-related psychiatric disorders.

About 20% of the population experience some form of anxiety disorder at least once in their lives. The cumulative lifetime prevalence of all stress-related disorders is difficult to estimate but is probably higher than 30%.

Dr Robert Pawlak, from the University of Leicester who led the UK team, said: "Stress-related disorders affect a large percentage of the population and generate an enormous personal, social and economic impact. It was previously known that certain individuals are more susceptible to detrimental effects of stress than others. Although the majority of us experience traumatic events, only some develop stress-associated psychiatric disorders such as depression, anxiety or posttraumatic stress disorder. The reasons for this were not clear."

Dr Pawlak added that a lack of correspondence between the commonness of exposure to psychological trauma and the development of pathological anxiety prompted the researchers to look for factors that may make some individuals more vulnerable to stress than others.

"We asked: What is the molecular basis of anxiety in response to noxious stimuli? How are stress-related environmental signals translated into proper behavioural responses? To investigate these problems we used a combination of genetic, molecular, electrophysiological and behavioural approaches. This resulted in the discovery of a critical, previously unknown pathway mediating anxiety in response to stress."

The study found that the emotional centre of the brain the amygdala reacts to stress by increasing production of a protein called neuropsin. This triggers a series of chemical events which in turn cause the amygdala to increase its activity. As a consequence, a gene is turned on that determines the stress response at a cellular level.

IMAGE: Newly discovered neurochemical cascade promoting stress-induced anxiety. Neuropsin interacts with cell membrane proteins NMDA and EphB2 to induce expression of the Fkbp5 gene.

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"We then examined behavioural consequences of the above series of cellular events caused by stress in the amygdala," said Dr Pawlak. "Studies in mice revealed that upon feeling stressed, they stayed away from zones in a maze where they felt unsafe. These were open and illuminated spaces they avoid when they are anxious."

"However when the proteins produced by the amygdala were blocked either pharmacologically or by gene therapy the mice did not exhibit the same traits. The behavioural consequences of stress were no longer present. We conclude that the activity of neuropsin and its partners may determine vulnerability to stress."

Neuropsin was previously discovered by Professor Sadao Shiosaka, a co-author of the paper. This research, for which the bioinformatics modelling was done by Professor Ryszard Przewlocki and his team, has for the first time characterized its mechanism of action in controlling anxiety in the amygdala.

The study took four years to complete, during which scientists from the Department of Cell Physiology and Pharmacology collaborated with colleagues from the Medical Research Council Toxicology Unit at the University of Leicester, the Department of Molecular Neuropharmacology, Polish Academy of Sciences in Krakow, Poland and Nara Institute of Science and Technology in Japan. The work was supported by the European Union, the Medical Research Council and Medisearch the Leicestershire Medical Research Foundation. The first author, Benjamin Attwood, sponsored by Medisearch, took 3 years off from his medical studies curriculum to complete the necessary experiments. He commented: "It has been a thoroughly absorbing project to uncover how our experiences can change the way we behave. Hopefully this will lead to help for people that have to live with the damaging consequences of traumatic experiences."

Dr Pawlak added: "We are tremendously excited about these findings. We know that all members of the neuropsin pathway are present in the human brain. They may play a similar role in humans and further research will be necessary to examine the potential of intervention therapies for controlling stress-induced behaviours."

"Although research is now needed to translate our findings to the clinical situation, our discovery opens new possibilities for prevention and treatment of stress-related psychiatric disorders such as depression and posttraumatic stress disorder."

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Notes to Editors:

Dr Pawlak is available via e-mail. Please contact the University of Leicester press office: 0116 252 2415 email pressoffice@le.ac.uk

Details of the paper are as follows:

Neuropsin cleaves EphB2 in the amygdala to control anxiety

DOI: 10.1038/nature09938

Benjamin Attwood1, Julie-Myrtille Bourgognon1, Satyam Patel1, Mariusz Mucha1, Emanuele Schiavon1, Anna E. Skrzypiec1, Kenneth W. Young2, Sadao Shiosaka3, Michal Korostynski4, Marcin Piechota4, Ryszard Przewlocki4, Robert Pawlak1

1 Department of Cell Physiology and Pharmacology, University of Leicester, University Road, LE1 9HN, Leicester, UK
2 Medical Research Council Toxicology Unit, Lancaster Road, LE1 9HN, Leicester, UK
3 Division of Structural Cell Biology, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
4 Department of Molecular Neuropharmacology, Institute of Pharmacology, 12 Smetna Street 31-343 Krakow, Poland

The following funding acknowledgements from the authors appear at the end of the paper:

This work was supported by Medical Research Council Project Grant (G0500231/73852), and a Marie Curie Excellence Grant (MEXT-CT-2006-042265 from European Commission) to Robert Pawlak, Medisearch Fellowship to Benjamin Attwood, the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid, # 20300128) and Japan Science and Technology Agency (CREST program) to Sadao Shiosaka, GENADDICT (LSHM-CT-005166 from the European Commission) to Ryszard Przewlocki and NN405 274137 from MNiSZW to Michal Korostynski.

ABOUT THE MRC:

For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk.

About the EU Marie Curie award

A total of 50,000 researchers have been supported by the 'Marie Curie Actions' since 1996.

Support is available for researchers moving within Europe as well as to other parts of the world. Individual fellowships are also open to top researchers from outside the EU who want to carry out research in Europe.

Applications are evaluated by an independent panel of renowned European and international scientists. The evaluation is based on the scientific quality of the project and its likely impact on European competitiveness, as well as on the excellence of the host institute and the researcher.

Due to the high number of applicants, only the best projects are funded.

The EU will allocate more than 4.5 billion under the Marie Curie scheme between 2007 and 2013.

Medisearch The Leicestershire Medical Research Foundation

Medisearch was set up in the 1970's as a charitable trust to support research within the Leicestershire Teaching Hospitals and The University of Leicester Medical School. The Trust maintains independence from the NHS and University, but is administered on a day to day basis by staff within the University of Leicester College of Medicine, Biological sciences and Psychology, on behalf of the Trustees.

By supporting and funding medical research and equipment across Leicestershire, Rutland and Northamptonshire, Medisearch aims to develop new treatments and promote a wider understanding of some of the most severe conditions. Through this research, the charity is bringing hope to future generations.

http://www.le.ac.uk/medisearch/



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