Brain-state dependent astrocytic Ca2+ signals are coupled to both positive and negative BOLD-fMRI signals

Significance The role of astrocytes on brain function is controversial in many aspects. It remains challenging to specify the in vivo functional impact of astrocytic calcium signal when mediating vasodilation/constriction at varied physiological or pathophysiological conditions. Here, we applied simultaneous fMRI and GCaMP-mediated Ca2+ optical fiber recording to detect distinct astrocytic Ca2+ signals (evoked vs. intrinsic) coupled to positive and negative blood-oxygen-level-dependent signals, respectively and concurrently, with unique spatial and temporal patterns. Not only did we demonstrate the distinct neurovascular coupling events coupled to the evoked and intrinsic astrocytic calcium signals, but also revealed the thalamic regulation mechanism underlying the astrocytic calcium-mediated brain state switch. This astrocytic-relevant regulatory mechanism could underlie numerous brain disorder and injury models relevant to gliovascular disruption. Astrocytic Ca2+-mediated gliovascular interactions regulate the neurovascular network in situ and in vivo. However, it is difficult to measure directly both the astrocytic activity and fMRI to relate the various forms of blood-oxygen-level-dependent (BOLD) signaling to brain states under normal and pathological conditions. In this study, fMRI and GCaMP-mediated Ca2+ optical fiber recordings revealed distinct evoked astrocytic Ca2+ signals that were coupled with positive BOLD signals and intrinsic astrocytic Ca2+ signals that were coupled with negative BOLD signals. Both evoked and intrinsic astrocytic calcium signal could occur concurrently or respectively during stimulation. The intrinsic astrocytic calcium signal can be detected globally in multiple cortical sites in contrast to the evoked astrocytic calcium signal only detected at the activated cortical region. Unlike propagating Ca2+ waves in spreading depolarization/depression, the intrinsic Ca2+ spikes occurred simultaneously in both hemispheres and were initiated upon the activation of the central thalamus and midbrain reticular formation. The occurrence of the intrinsic astrocytic calcium signal is strongly coincident with an increased EEG power level of the brain resting-state fluctuation. These results demonstrate highly correlated astrocytic Ca2+ spikes with bidirectional fMRI signals based on the thalamic regulation of cortical states, depicting a brain-state dependency of both astrocytic Ca2+ and BOLD fMRI signals.