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.

Grant Number: 1R21AG087186-01A1
NIH Institute/Center: NIH
Principal Investigator: JESSICA CARDIN