BRAIN AND ANXIETY · Neural mechanisms of fear and anxiety: Interactions between proteases and extra-cellular Milieu

Final Activity Report Summary - BRAIN AND ANXIETY (Neural Mechanisms of Fear and Anxiety: Interactions between Proteases and Extracellular Milieu)

Understanding neural bases of stress, fear and anxiety is of an immense importance to modern society. Anxiety disorders affect about 25% of adults at least once in their lives, and make a huge social, family and welfare impact. The most dramatic form, posttraumatic stress disorder (PTSD) is characterised by cognitive impairment, depression, fear, anxiety, and may eventually lead to suicide. Understanding of the neural mechanisms of PTSD and other anxiety disorders could reduce the personal and societal impact through development of more efficient therapies. How is fear and anxiety formed in the brain? Fear memories are encoded as changes in strength of synaptic connections, a process called plasticity. Extracellular proteolysis provides an attractive mechanism underlying neuronal plasticity. Precisely orchestrated exocytosis of a protease could help remodel synaptic connections by degrading extracellular matrix proteins, interacting with membrane receptors or activating latent growth factors. This monosite four-year project based in Leicester was designed to study the molecular mechanisms of stress-induced plasticity, fear and anxiety. Guided by our previous research we focused on the role of extracellular proteases and their interactions with membrane receptors or extracellular matrix components. To elucidate mechanisms of fear and anxiety we identified protease-regulated genes in the amygdala and examined their roles in various models of stress using a combination of genetic, cell biological, pharmacological, electrophysiological and behavioural approaches. Our experiments demonstrated a critical role of limbic proteases, their receptors and molecular partners in conditioned and innate fear, alcohol addiction and certain forms of neuronal death. Thus, during the lifetime of the project we achieved the following objectives: We identified protease-activated receptor 1 (PAR-1) as novel mediator of stress-related plasticity in the amygdala. We found a novel stress-related pathway in the amygdala linking Klk8-mediated proteolysis to activity-driven transcription of anxiety-related genes. We have identified ephrins and their receptors Ephs as novel modulators of fear and anxiety in the limbic system. We identified the activation of the tissue/plasminogen activator/plasmin system as a new, critical mechanism of neuronal death associated with alcohol abuse. Together with our collaborators from the Rockefeller University we discovered that certain forms of excitotoxic neuronal death are mediated by toxic laminin degradation products. We contributed to the discovery and characterisation of the M3-muscarinic receptor-mediated facilitation of fear. We identified lipocalin-2 as a major stress-related gene in the limbic system and characterised its effect on stress-induced neuronal plasticity and anxiety-like behaviour. We found that integrins are important mediators of unconditioned but not conditioned fear in the amygdala.

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