Dysregulation of cortical astrocytes in models of Alzheimer's Disease

PROJECT SUMMARY: Disruption of astrocytes, a cell type that plays key roles in inflammatory responses and synaptic function in the brain, is a key hallmark of advanced Alzheimer's Disease (AD). Astrocytes exhibit robust state-dependent modulation via noradrenergic signaling. Loss of neuromodulatory inputs to the cerebral cortex in AD contributes to dysregulation of attention, arousal, and cognition, processes that are robustly modulated by release of norepinephrine (NE). Functional dysregulation of the coupling between neuromodulatory systems and astrocytic function likely precedes late-stage loss of neurons and contributes to early cognitive symptoms. However, despite extensive anatomical evidence, there is little functional data on astrocytic or neuromodulatory signaling across stages of pathology. In addition, technical limitations have precluded longitudinal measurements of astrocytic or neuromodulatory signaling in genetic models of disease. To address this gap, we propose to combine novel imaging approaches, including wide-field `mesoscopic' imaging of astrocytic, neural, and NE signaling 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 astrocytic signaling. (2) AD pathology causes a progressive loss of coupling between noradrenergic signaling and astrocyte activity. 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 brain systems throughout the lifetime in models of Alzheimer's Disease and provide a novel framework for future evaluation of therapeutic approaches.