PROJECT SUMMARY: Degeneration of neuromodulatory neurons, such as cholinergic neurons in the basal forebrain and noradrenergic neurons in the Locus Coeruleus, is a key hallmark of advanced Alzheimer’s Disease (AD). Loss of neuromodulatory inputs to the cerebral cortex contributes to dysregulation of attention, arousal, and cognition, processes that are robustly modulated by release of acetylcholine (ACh) and norepinephrine (NE). Functional dysregulation of these neuromodulatory systems likely precedes late-stage loss of projection neurons and contributes to early cognitive symptoms. However, despite extensive anatomical evidence, there is little functional data on neuromodulatory signaling across stages of pathology. In addition, technical limitations have precluded longitudinal measurements of neuromodulatory signaling in genetic models of disease. To address this gap, we propose to combine novel imaging approaches, including wide-field ‘mesoscopic’ imaging of ACh and NE signaling and neuronal activity across the entire cortex in awake behaving animals. Using two genetic models of AD, we will test the following hypotheses: (1) The initial consequence of pathology is early loss of state-dependent spatiotemporal dynamics of ACh and NE signaling. (2) AD pathology causes a progressive loss of coupling between neuromodulators and cortical activity and between ACh and NE. Importantly, we will longitudinally track changes over time within each animal and also compare across models to identify convergent signatures of disease-related dysregulation. Our results will provide an unprecedented level of insight into the disruption of key neuromodulatory systems throughout the lifetime in models of Alzheimer’s Disease and provide a novel framework for future evaluation of therapeutic approaches.