Astrocytes Integrate Behavioral State and Vascular Signals during Functional Hyperemia

Abstract

Dynamic changes in astrocyte free Ca 2+ regulate synaptic signaling and local blood flow. Although astrocytes are poised to integrate signals from synapses and the vasculature to perform their functional roles, it remains unclear what dictates astrocyte responses during neurovascular coupling under realistic conditions. We examined peri-arteriole and peri-capillary astrocytes in the barrel cortex of active mice in response to sensory stimulation or volitional behaviors. We observed an AMPA and NMDA receptor-dependent elevation in astrocyte endfoot Ca 2+ that followed functional hyperemia onset. This delayed astrocyte Ca 2+ signal was dependent on the animal's action at the time of measurement as well as a neurovascular pathway that linked to endothelial-derived nitric oxide. A similar elevation in endfoot Ca 2+ was evoked using vascular chemogenetics or optogenetics, and opto-stimulated dilation recruited the same nitric oxide pathway as functional hyperemia. These data show that behavioral state and microvasculature influence astrocyte Ca 2+ in active mice.

Ca2+signaling in astrocytes is sleep-wake state specific and modulates sleep

“…Previously it was unclear whether physiological sensory input uncoupled from locomotion and startle elicits Ca 2+ signaling in rodent cortical astrocytes. Notably, Ca 2+ responses were only detected in barrel cortex astrocytes after high-velocity (90 Hz) whisker deflections or when the stimulus occurred together with volitional locomotion, but not during natural whisking alone (Stobart et al, 2018;Tran et al, 2018). Our demonstration of a robust astrocytic Ca 2+ response to spontaneous whisking in resting animals likely relies on the use of our sensitive activity-based analytical tool.…”

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…To date, despite the indication that astrocyte endfeet lining the cerebrovasculature are modified as a result of stress disorder in humans (Rajkowska et al, 2013) as well as in rodent models (Di Benedetto et al, 2016), evidence for dysfunction at the vascular interface is sparse. Under physiological conditions astrocytes integrate synaptic, behavioral and vascular information to mediate an appropriate blood vessel response (Tran, Peringod, & Gordon, 2018). As there is strong evidence for stress influencing both synaptic transmission and behavioral state (Füzesi, Daviu, Wamsteeker Cusulin, Bonin, & Bains, 2016;Sterley et al, 2018), stress-induced modification of neurovascular coupling is expected.…”

Seizures cause sustained microvascular constriction associated with astrocytic and vascular smooth muscle Ca2+ recruitment

“…However, examining Ca 2+ signals in astrocyte endfeet and VSMCs in awake mice, rather than in brain slices or in vivo preparations utilizing anesthesia or sedation, is important because signaling pathways involving neurons, astrocytes and microvascular can crosstalk in a realistic manner. Thus, imaging behaving mice is important to prevent misrepresentation of the relationships between hypersynchronous neural activity, astrocyte and VSMC Ca 2+ , and hemodynamics (Tran & Gordon, 2015b, 2015aTran, Peringod, & Gordon, 2018). Here we performed in vivo two-photon imaging on awake head restrained mice to examine the Ca 2+ activity patterns of cortical astrocytes and VSMCs during ictal and postictal periods to gain insight into the cellular underpinnings of seizure induced hypoperfusion/hypoxia.…”