title: Tonic Local Brain Blood Flow Control by Astrocytes Independent of Phasic Neurovascular Coupling.
abstract: According to the current model of neurovascular coupling, blood flow is controlled regionally through phasic changes in the activity of neurons and astrocytes that signal to alter arteriole diameter. Absent in this model, however, is how brain blood flow is tonically regulated independent of regional changes in activity. This is important because a large fraction of brain blood flow is required to maintain basal metabolic needs. Using two-photon fluorescence imaging combined with patch-clamp in acute rat brain slices of sensory-motor cortex, we demonstrate that reducing resting Ca(2+) in astrocytes with intracellular BAPTA causes vasoconstriction in adjacent arterioles. BAPTA-induced vasoconstriction was eliminated by a general COX blocker and the effect is mimicked by a COX-1, but not COX-2, antagonist, suggesting that astrocytes provide tonic, steady-state vasodilation by releasing prostaglandin messengers. Tonic vasodilation was insensitive to TTX, as well as a variety of synaptic and extrasynaptic receptor antagonists, indicating that the phenomenon operates largely independent of neural activity. Using in vivo two-photon fluorescence imaging of the barrel cortex in fully awake mice, we reveal that acute COX-1 inhibition reduces resting arteriole diameter but fails to affect vasodilation in response to vibrissae stimulation. Our findings demonstrate that astrocytes provide tonic regulation of arterioles using resting intracellular Ca(2+) in a manner that is independent of phasic, neuronal-evoked vasodilation. Significance statement: The brain requires both phasic and tonic regulation of its blood supply to service energy needs over various temporal windows. While many mechanisms have been described for phasic blood flow regulation, how the brain accomplishes tonic control is largely unknown. Here we describe a way in which astrocytes contribute to the management of basal brain blood flow by providing steady-state vasodilation to arterioles via resting astrocyte Ca(2+) and the continuous release of prostaglandin messengers. This phenomenon may be important for understanding the declines in basal brain blood flow that occur in aging and dementia, as well as for the interpretation of fMRI data.
authors.affiliation: Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Rosenegger
authors.affiliation: Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Cam Ha T
authors.initials: CH
authors.lastname: Tran
authors.affiliation: Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Jackie I
authors.initials: JI
authors.lastname: Wamsteeker Cusulin
authors.affiliation: Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada gordong@ucalgary.ca.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Gordon
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology; D001253:Astrocytes / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009474:Neurons / Q000502:physiology; D000069336:Neurovascular Coupling / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013003:Somatosensory Cortex / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology; D014738:Vibrissae / Q000294:innervation
chemical_list: D002614:Chelating Agents; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D013779:Tetrodotoxin; D004533:Egtazic Acid; D051545:Cyclooxygenase 1; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
keywords: astrocytes; awake in vivo; calcium; neurovascular coupling; tonic blood flow; two photon