Multiscale imaging of context-dependent decision-making

PROJECT SUMMARY/ABSTRACT Real-life decisions are often context-dependent. For example, a motorist may decide to slow down at a yellow traffic light if a police car is nearby or accelerate if the intersection is empty. The ability to use contextual information to flexibly guide decisions is a critical component of higher-order cognition that is often impaired in psychiatric conditions like schizophrenia. To facilitate the identification of potential therapies for these disorders, scientists have investigated the brain bases of context-dependent decision-making in humans and animal models. Whole-brain functional magnetic resonance imaging (fMRI) studies in humans have identified areas in the frontal and parietal cortices that appear to maintain contextual information so it can be used to guide subsequent decisions. However, fMRI alone cannot reveal the causal and cellular-level roles of these areas in context-dependent decision-making, and this level of understanding is critical for the development of novel therapeutics. As such, studying the neurobiology of context maintenance and other higher-order cognitive processes in mice will be crucial for guiding research on new therapies for human disorders. However, it is still unclear (1) what areas across the mouse brain contribute to the maintenance of contextual information and (2) how activity in these areas shapes activity in decision-making regions and behavior. The aims of this proposal leverage the global coverage of fMRI and the extensive genetic toolkit available in mice to answer these questions. Aim 1 uses a novel platform for behaving mouse fMRI to image mice as they complete a task that requires them to maintain contextual information in order to receive rewards. Comparing brain activity during this task to activity in a nearly identical task that does not rely on contextual information will identify areas that are involved in the maintenance of contextual information across the brain. Aim 2 uses optogenetics and two-photon microscopy to silence activity in one of these potential context maintenance areas to determine how it causally contributes to cellular-level activity in a decision-making area and task performance. Together, these experiments will unveil new neural substrates of context-dependent decision- making and suggest potential treatment targets for future pre-clinical studies of psychiatric illness. This proposal was tailored to both exploit my existing expertise in whole-brain imaging and facilitate my acquisition of new technical skills and professional competencies that will advance me towards my goal of becoming an independent physician-scientist. Dr. Michael Shadlen, an expert in perceptual decision-making, and Dr. Itamar Kahn, an expert in behaving mouse fMRI, are the ideal pair of sponsors for this project, and the vibrant scientific and clinical communities at Columbia make this the ideal place for me to pursue this training.