NORAD

Animals improve decision efficiency and reduce uncertainty by being flexible and by exploring and collecting information. Altered control of exploratory decisions can lead to obsessive or disorganized behaviours as in OCD or schizophrenia. One critical issue is to understand how the brain regulates exploration under uncertainty. In NORAD, our hypothesis is that the locus coeruleus (LC)/noradrenaline (NA) system drives specific medial frontal cortical (mFC) dynamics to enable directed exploratory behaviours. Using advanced electrophysiology, chemogenetics and optogenetics in an unprecedented series of experiments in rats and monkeys, we will test whether NA inputs to the mFC influence behavioural flexibility, i) selective and regional perturbations of LC/NA cortical inputs enable specific cortical dynamics and impact the regulation of exploration, and ii) time selective perturbations of LC/NA inputs to prefrontal regions can interferes with precise aspects of exploration and decision making. The project is planned along 7 tasks that will set and develop appropriate behavioural quantifications, evaluate the impact of global LC/NA stimulation on exploration, test the functional selectivity of LC to mFC inputs, evaluate the causal role of LC/NA inputs on frontal cortical dynamics, and test the temporal specificity of LC influence on mFC during flexible behaviours. We propose to use advanced chemogenetic approaches to understand the functional relevance of the LC-PFC pathways. Such approaches are a revolution for neuroscience, allowing the testing of hypotheses impossible to address otherwise. The increased use and development of these methods for primates will benefit research well beyond the scope of the present project. We also propose an innovative approach to develop vectors carrying material for non-invasive means of validating transfections in animal models but also potentially in humans for applications with gene therapies. As a result, the multi-species and innovative methodological approaches of our project will provide unprecedented knowledge with wide scientific implications.