Astrovascular decoupling in awake 5×FAD mice is associated with reduced astrocytic calcium

Abstract

INTRODUCTION: Evidence points to dysregulated Ca2+ in neurons and astrocytes in models of amyloidosis. While most of these data were obtained in vitro or in vivo under anesthesia, less work has investigated these variables in awake ambulating mice. METHODS: Astrocytic Ca2+ fluctuations (GCaMP8f) were imaged concomitantly with vasoreactivity in S1 on a two-photon microscope during rest and ambulation. Single-cell resolution variables were extracted using continuous wavelet transform and traditional ΔF/F measures. RESULTS: Along with increases in amyloid beta (Aβ) accumulation, we found significant reductions in measures of astrocyte functional connectivity, pairwise correlations, and network synchronicity in older 5×FAD mice, with greater decreases in females. Results align with altered gait and reduced astrovascular coupling. DISCUSSION: The results provided here are novel and demonstrate that age and sex are major risk factors for AD; however, central astrovascular dysregulations appear to exist in response to reduced, rather than elevated astrocyte Ca2+ transients. Highlights: Gait analyses reveal older 5×FAD animals display shorter stride length while ambulating. While resting astrocytic calcium activity is increased with age, sex, and genotypes, these results do not explain changes in astrovascular coupling. Only small changes in astrocyte calcium transients and vessel morphology are seen, while the astrocyte-to-vessel correlations (astrovascular coupling) are significantly reduced. Astrocyte network analysis reveals significant reductions in measures of astrocytic communication and activity which are associated with reduced functional vasoreactivity in awake ambulating animals.