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 2ϩ 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 2ϩ in a manner that is independent of phasic, neuronal-evoked vasodilation.

Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression—Evoked cerebral oligemia

“…Cerebral COX-1 is expressed primarily in neurons, glia and endothelial cells [35][36][37] and has been suggested to play a role in maintaining resting vascular tone. 30,38 Constitutive expression of cerebral COX-2, however, is limited to excitatory neurons where, unlike COX-1, it is thought to mediate neurovascular coupling. 31,32,39 The reliance on COX-1 metabolites for the transformation of the hyperemic response to oligemia following CSD suggests that despite their massive depolarization, excitatory cortical neurons which primarily express COX-2, 40,41 are unlikely to contribute.…”

“…[47][48][49] Such dilution could potentially explain why in our study epidural SC-560 treatment (at 500 mM) did not reduce resting CBF while previous studies noted decreased resting CBF and cerebral vasoconstriction following parenchymal superfusion of this inhibitor at concentrations !10 mM. 30,38,50 Because SC-560, as well naproxen, affected CBF only during the oligemic stage, it is also tempting to speculate that these COX inhibitors are more efficient in blocking the synthesis of vasoconstricting prostanoids that mediate the post-CSD oligemia than inhibiting the formation of vasodilating prostanoids that control basal CBF. Nonetheless, given the uncertainty about the precise parenchymal concentration of the inhibitors in our study, the effects elicited by these agents should be interpreted with caution given the possibility that the inhibition was only partial.…”

“…Throughout the experiment, the level of anesthesia was verified by testing for lack of reflexive responses to pinching of the hind paw. Core body temperature was maintained at [37][38] C, using a temperature-controlled heating pad. A silicone catheter (PE10), filled with heparinized saline, was placed in the left femoral artery to monitor mean arterial pressure (MAP, TA-100 blood pressure monitor, CWE Inc., Ardmore PA, USA).…”

The Bimodal Nature of Neurovascular Coupling: Slow Tonic and Rapid Phasic Responses are Separately Controlled by Specific Astrocyte Metabotropic and Ionotropic Glutamate Receptors

“…The bimodal nature of neurovascular coupling In brain, it has been observed that there are two types of NVC that control changes in CBF [3]. One type is rapid [phasic] in response to increased glutamatergic neuron synaptic activity and characterized by release of nitric oxide (NO) generated by neuron nitric oxide synthase (nNOS) [4] and liberation of K + and free glutamate (Glu) to extracellular fluid (ECF).…”

Interpreting BOLD: towards a dialogue between cognitive and cellular neuroscience

“…Rather than triggering a rapid vascular response, synaptic activity-evoked astrocyte calcium increases have been proposed to mediate sustained vascular responses to prolonged stimulation [40,43,44]. Furthermore, astrocytes also appear to play a role in maintaining the resting tone of the vasculature [45][46][47], which could affect the size of the blood flow response following neuronal activity [48].…”