Project Summary/Abstract Alzheimer’s Disease (AD) is a devastating disease with enormous unmet medical need. It is likely necessary to understand, detect, and treat Alzheimer’s Disease earlier in disease development. Patients often exhibit aberrant neural activity even before pathology or cognitive decline. Amyloid-beta (Ab) and tau can perturb neural activity, and activity can affect their levels, thus aberrant neural activity may be both a symptom and cause of Ab and tau, forming a vicious cycle. This project will investigate the hypothesis that aberrant neural activity is a primary driver of and tractable therapeutic target for Alzheimer’s Disease, and that targeting it can rescue cognitive deficits. There is a lack of direct evidence on the causative role of aberrant neural activity in Alzheimer’s Disease, let alone the mechanisms, a significant gap in our understanding. Human imaging methods have low resolution, and human studies cannot use precise perturbations to test direct cause and effect. Yet, stimulation therapies are used on patients, using limited data to inform protocols, resulting in promising but inconclusive results. This project will use cutting-edge systems neuroscience techniques to conduct single-cell resolution examination and perturbation of the brain to determine the mechanistic role of aberrant neural activity in cognitive decline in Alzheimer’s Disease mice, and to reverse it. To identify aberrant single-neuron and network dynamics, 2-photon Ca2+ imaging will be used in Alzheimer’s Disease mice during cognitive tasks over disease progression. This will be the first longitudinal study of single-neuron activity in Alzheimer’s Disease mice during cognitive tasks, and the first lifelong study of neural activity. To discover activity-based anatomical connectivity changes, activity- dependent neuron projection labeling will be used to label neurons activated during learning and recall. Tissue- clearing will enable imaging of projections across the entire brain in 3D, along with Ab and tau, over disease progression. This will discover specific brain regions, circuits, and cells that change in parallel to Ab and tau and correlate with cognition. These will be the first brain-wide, activity-dependent projection tracing experiments, and the first longitudinal study of anatomical connectivity changes in Alzheimer’s Disease. To test the functional role of aberrant activity and to restore cognition, single-cell optogenetics will be used to recapitulate or reverse the activity patterns changed in Alzheimer’s Disease, and circuits will be modulated to correct connectivity. Optogenetics will be used in AD mice to determine if AD therapies improve cognition through effects on neural activity. The investigator will receive technical, conceptual, and career development training from a mentoring team of leading experts in world-class labs at Stanford University in preparation for transition to a faculty position. This work will discover fu...