Heterogeneity of Sensory-Induced Astrocytic Ca2+ Dynamics During Functional Hyperemia

Abstract

Astrocytic Ca2+ fluctuations associated with functional hyperemia have typically been measured from large cellular compartments such as the soma, the whole arbor and the endfoot. The most prominent Ca2+ event is a large magnitude, delayed signal that follows vasodilation. However, previous work has provided little information about the spatio-temporal properties of such Ca2+ transients or their heterogeneity. Here, using an awake, in vivo two-photon fluorescence-imaging model, we performed detailed profiling of delayed astrocytic Ca2+ signals across astrocytes or within individual astrocyte compartments using small regions of interest next to penetrating arterioles and capillaries along with vasomotor responses to vibrissae stimulation. We demonstrated that while a 5-s air puff that stimulates all whiskers predominantly generated reproducible functional hyperemia in the presence or absence of astrocytic Ca2+ changes, whisker stimulation inconsistently produced astrocytic Ca2+ responses. More importantly, these Ca2+ responses were heterogeneous among subcellular structures of the astrocyte and across different astrocytes that resided within the same field of view. Furthermore, we found that whisker stimulation induced discrete Ca2+ “hot spots” that spread regionally within the endfoot. These data reveal that astrocytic Ca2+ dynamics associated with the microvasculature are more complex than previously thought, and highlight the importance of considering the heterogeneity of astrocytic Ca2+ activity to fully understanding neurovascular coupling.

Astrocytic Ca2+ signals partake in inhibitory neurovascular coupling in a brain state-dependent manner

“…Another explanation could be a combination effect, as stimulation of VGAT IN will release GABA and several neuropeptides, in contrast to PV IN releasing only GABA. These two stimulation paradigms reflect the complex interneuron-astrocyte interactions, which may explain the diversity of astrocytic Ca 2+ responses reported in the literature 5,8,48 . The GABAergic astrocytic Ca 2+ responses were immediate and transient but could spontaneously fluctuate under non-physiological conditions, such as in response to local puffing of GABA or after modulating the GABA A receptor activity.…”

Extracellular Calcium Influx Pathways in Astrocyte Calcium Microdomain Physiology

“…However, a fast, dynamic role for astrocytes in regulating vasodilation during neurovascular coupling remains controversial. Early studies in brain slices ex vivo linked astrocyte Ca 2+ to changes in vascular tone [12,[74][75][76][77], but this has not translated to in vivo experiments where astrocyte Ca 2+ events, particularly in endfeet microdomains, may [28,30,31] or may not [32,72,78] rapidly precede vasodilatory responses during neurovascular coupling. Several of these recent in vivo studies suggest astrocyte Ca 2+ events are not essential for vasodilation [32,72,79]; however, when astrocyte endfoot Ca 2+ signals are evoked by brief, local circuit activity, the magnitude of the hemodynamic response is enhanced [79].…”

Impaired Hippocampal Neurovascular Coupling in a Mouse Model of Alzheimer’s Disease

“…However, in the present study, the vascular tone does not seem to differ between WT and APP mice since the level of preconstriction induced by a thromboxane receptor agonist was the same in these groups ( Blanco et al, 2008 ). The link between spatiotemporal characteristics of astrocytic Ca 2+ increases and the amplitude and duration of the vascular response remains to be further investigated ( Sharma et al, 2020 ).…”