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Stress and anxiety are normal: They evolved to help us deal with daily threats to our existence. But the stress response – pounding heart, tensed muscles, sweating palms – is meant to shut down after the threat has passed. People who have a hard time “turning off” their stress response, often as a result of psychological trauma, can develop post-traumatic stress syndrome, as well as anorexia, anxiety disorders or depression.
How does the body recover from its response to shock or acute stress? This question is at the heart of research conducted by Dr. Alon Chen of the Institute’s Neurobiology Department. The response begins in the brain, and Chen concentrates on a family of proteins that play a prominent role in regulating this mechanism. One protein in the family – CRF – is known to initiate a chain of events that occurs when we cope with pressure, and scientists have hypothesized that other members of the family are involved in shutting down that chain. In research that appeared in the Proceedings of the National Academy of Sciences (PNAS), Chen and his team have now, for the first time, provided sound evidence that three family members known as urocortin 1, 2 and 3 – are responsible for turning off the stress response.
The research group, including Adi Neufeld Cohen, Dr. Michael Tsoory, Dmitriy Getselter and Shosh Gil, created genetically engineered mice that don’t produce the three urocortin proteins. Before they were exposed to stress, these mice acted just like the control mice, showing no unusual anxiety. When the scientists stressed the mice, both groups reacted in the same way, showing clear signs of distress. Differences between the groups appeared only when they were checked 24 hours after the stressful episode: While the control mice had returned to their normal behavior, appearing to have recovered completely from the shock, the engineered mice were still showing the same levels of anxiety the scientists had observed immediately following their exposure to the stress.
Clearly, the urocortin proteins are crucial for returning the body to normal, but how, exactly, do they do this? To identify the mechanism for the proteins’ activity, Chen and his team tested both groups of mice for expression levels of a number of genes known to be involved in the stress response. They found that gene expression levels remained constant both during and after stress in the engineered mice. In contrast, patterns of gene expression in the control mice showed quite a bit of change 24 hours after the event. In other words, without the urocortin system, the “return to normal” program couldn’t be activated, and the stress genes continued to function.
Chen: “Our findings imply that the urocortin system plays a central role in regulating stress responses, and this may have implications for anxiety disorders, depression, anorexia and other conditions. The genetically engineered mice we created could be effective research models for these diseases.”
Dr. Alon Chen's research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Nella and Leon Benoziyo Center for Neurological Diseases; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Irwin Green Alzheimer's Research Fund; the Mark Besen and the Pratt Foundation, Australia; Roberto and Renata Ruhman, Brazil; and Martine Turcotte, Canada. Dr. Chen is the incumbent of the Philip Harris and Gerald Ronson Career Development Chair.
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