Pharmacological Uncoupling of Activation Induced Increases in CBF and CMRO₂

Abstract

Neurovascular coupling provides the basis for many functional neuroimaging techniques. Nitric oxide (NO), adenosine, cyclooxygenase, CYP450 epoxygenase, and potassium are involved in dilating arterioles during neuronal activation. We combined inhibition of NO synthase, cyclooxygenase, adenosine receptors, CYP450 epoxygenase, and inward rectifier potassium (Kir) channels to test whether these pathways could explain the blood flow response to neuronal activation. Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)) of the somatosensory cortex were measured during forepaw stimulation in 24 rats using a laser Doppler/spectroscopy probe through a cranial window. Combined inhibition reduced CBF responses by two-thirds, somatosensory evoked potentials and activation-induced CMRO(2) increases remained unchanged, and deoxy-hemoglobin (deoxy-Hb) response was abrogated. This shows that in the rat somatosensory cortex, one-third of the physiological blood flow increase is sufficient to prevent microcirculatory increase of deoxy-Hb concentration during neuronal activity. The large physiological CBF response is not necessary to support small changes in CMRO(2). We speculate that the CBF response safeguards substrate delivery during functional activation with a considerable 'safety factor'. Reduction of the CBF response in pathological states may abolish the BOLD-fMRI signal, without affecting underlying neuronal activity.

The Oxygen Paradox of Neurovascular Coupling

“…109 In the cerebellum, Offenhauser et al 11 found larger initial decreases of tissue pO 2 during inhibition of CBF responses. Mathiesen et al 102 demonstrated initially unaffected CMRO 2 responses during pharmacologically reduced CBF responses after climbing fiber stimulation in the cerebellum.…”

Functional Hyperemia and Mechanisms of Neurovascular Coupling in the Retinal Vasculature

“…A similar phenomenon is seen in the brain, where a number of neurovascular coupling mechanisms are believed to operate concurrently to produce functional hyperemia. 45 However, recent studies suggest that one particular neurovascular coupling mechanism, the feedforward mechanism where glial cells release vasodilatory PGE 2 and EETs, is a principal and perhaps dominant mechanism mediating functional hyperemia in the retina. Determining the relative importance of this and other neurovascular coupling mechanisms awaits further experimentation.…”

“…Recent work has demonstrated, however, that some of these signals do not mediate neurovascular coupling. Specifically, functional hyperemia can occur in the absence of a drop in oxygen [45][46][47] or glucose 48 levels or acidification of the parenchyma, 49,50 demonstrating that O 2 , glucose, and CO 2 do not function as the neurovascular coupling signal. Still, neurovascular coupling could be mediated, at least in part, by adenosine or lactate metabolic signals.…”

Activity-dependent Increases in Local Oxygen Consumption Correlate with Postsynaptic Currents in the Mouse CerebellumIn Vivo

“…4 A, D,E), suggesting that the muscimol effect required specific interaction with GABA A receptors. Previous studies have indicated that the stimulation-evoked rises in CBF can be reduced by 80 -90% without concomitant reductions in the evoked electrophysiological signal (Offenhauser et al, 2005;Caesar et al, 2008b;Leithner et al, 2010). CF stimulation evokes large rises in lactate that are coupled to rises in synaptic activity and spike rate (Caesar et al, 2008a).…”