Elucidating the Neural Computations Underlying Spatial Learning, Decision-Making and Generalization in Virtually-Navigating Monkeys

Project Summary/Abstract Patients with Alzheimer’s disease and Alzheimer’s disease-related dementias exhibit symptoms that include deficits in spatial navigation, and in forming/using cognitive maps of space to guide decision-making, especially in new environmental situations. These deficits are linked to disease-related perturbation of medial temporal lobe and frontal lobe brain structures, but surprisingly little is known about the underlying computations that go awry. Spatial navigation is believed to be dependent on populations of neurons in the hippocampus with “place-cell” like representations. Decision-making in novel situations is dependent on representations of latent features that are shared across examples or experiences, as observed in prefrontal cortex. Finally, the output of these computations must reach the motor cortex where neural activity is coupled to immediate behavior. However, studies to determine whether/how neural computations across these brain regions contribute to decisions based on spatial location, especially in novel situations have not been conducted. Furthermore, whether symptoms of Alzheimer’s disease and related dementias can be treated by modulating these computations is not known. To address this gap, I created an innovative new virtual reality paradigm and trained monkeys to make decisions about which objects to collect based on learned spatial rules. I will combine this with high-channel- count electrophysiology in trained monkeys to determine if/how population-level representations in the HPC- PFC-PMd support decision-making based on spatial rules. Then, I will elucidate if and how population activity in the HPC-PFC-PMd circuit supports generalization in novel situations. In my independent laboratory, I will use this model system as a platform for elucidating the neural mechanism of an emerging treatment for Alzheimer’s disease and Alzheimer’s disease-related dementias. These contributions are significant because they will provide new insights into the neural mechanisms of some of our most adaptive cognitive capacities, while also creating a new platform for discovering and testing new treatments where I systematically test the effects of neural perturbations on neural circuit function and behavior. This project will facilitate my training as an independent researcher through new experience in high-channel count, multi-area recordings, training in the etiology and treatment of Alzheimer’s disease and related dementias, and in running a monkey electrophysiology lab at the intersection of basic and translational neuroscience. This project will result in direct interactions between experimental neurophysiologists, theoretical neuroscientists, and clinician-scientists. This award will help me achieve my long-term career goal to run an independent research laboratory at an academic institution with a medical school, where I will operate a monkey electrophysiology lab at the nexus of 1) elucidating neural mechanisms of learning and decision-making, and 2) developing/testing novel therapeutics for disorders of memory and decision-making, including Alzheimer’s disease and Alzheimer’s disease related dementias.