The role of genes and life experience in the neural modulation of threat sensitivity

The ability to appropriately respond to threats is crucial for survival and requires precise calibration - too little sensitivity leaves individuals vulnerable to danger, while excessive reactions to harmless situations can lead to social isolation and impair quality of life. Individuals show natural variation in threat sensitivity, shaped by both genetic background and lifetime experiences, with disrupted threat processing underlying psychiatric conditions including anxiety and post-traumatic stress disorders. This project investigates how genetic variation and experience shape neural circuits to set threat sensitivity, comparing different mouse subspecies with distinct threat sensitivities while tracking individual behaviour and neural activity over extended periods. Using escape from imminent threats as a model system and focusing on a spatially restricted midbrain circuit, we will identify the algorithmic principles by which the superior colliculus and periaqueductal gray transform sensory stimuli into escape decisions, and how these computations are modified by experience and genetic background. We will determine the cellular and circuit mechanisms implementing these changes and identify key genes regulated through evolution and experience to control threat sensitivity. This research will identify key neural mechanisms regulating threat sensitivity and advance our understanding of individual variations in threat processing. Keywords: threat, escape, midbrain, mouse, experience, genes