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Discovery: A New Brain Pathway for Stress

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In many individuals, a major stressor activates a critical and previously unknown pathway in the brain that regulates anxiety in response to traumatic events. The amygdala, which is the emotional center of the brain, reacts to the stressor by increasing production of the protein neuropsin. The release of neuropsin activates a series of chemical events  that further stimulate amygdala activity, which in turn activates a gene that determines the stress response at a cellular level. Due to this gene activation, these individuals develop long-term anxiety and a typical anxious response to real or perceived stressors.

A study just published in the journal Nature for the first time clarifies the mechanism whereby, in certain individuals and not in others, the extracellular proteolysis triggered by fear-associated responses facilitates neuronal plasticity at the neuron–matrix interface. This process centers around the activity of the serine protease neuropsin, which is critical for stress-related plasticity in the amygdala. Neuropsin determines the dynamics of the EphB2–NMDA-receptor interaction, the expression of the “anxiety gene” Fkbp5 and the triggering of anxiety-like behavior. When faced with a stressor, individuals who are neuropsin-deficient show a much less frequent expression of the Fkbp5 gene and low anxiety. On the other hand, the behavioral response to stress in individuals who are rich in neuropsin shows a more frequent expression of the Fkbp5 gene and much more significant anxiety-related behavior. The researchers, consisting of a team of neuroscientists at the University of Leicester, UK, in collaboration with researchers from Poland and Japan, conclude that their findings establish a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to the development of an anxiety-driven response to stress.

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

The study took four years to complete and it sought to examine the behavioral consequences of a series of cellular events caused by stress in the amygdala. They discovered that when certain proteins produced by the amygdala were blocked, either via medication or by gene therapy, the study subjects did not exhibit the highly anxious traits.

This is a significant discovery for the study and treatment of maladaptive stress responses that result in anxiety. By knowing which chemicals along the neuropsin pathway are present in the human brain at the moment of traumatic events, the researchers believe that it will be possible to design intervention therapies for controlling stress-induced behaviors and for the prevention and treatment of stress-related psychiatric disorders such as depression and posttraumatic stress disorder.