Local Uncoupling of the Cerebrovascular and Metabolic Responses to Somatosensory Stimulation after Neuronal Nitric Oxide Synthase Inhibition

Abstract

It has recently been shown, using either genetically engineered mutant mice (nitric oxide synthase [NOS] knockout) or specific pharmacological tools, that type I NOS (neuronal isoform of NOS, [nNOS]) participates in coupling cerebral blood flow to functional activation. However, it has not been clearly established whether the associated metabolic response was preserved under nNOS inhibition and whether this action was exerted homogeneously within the brain. To address these issues, we analyzed the combined circulatory and metabolic consequences of inhibiting the nNOS both at rest and during functional activation in the rat anesthetized with alpha-chloralose. Cerebral blood flow and cerebral glucose use (CGU) were measured autoradiographically using [14C]iodoantipyrine and [14C]2-deoxyglucose during trigeminal activation induced by unilateral whiskers stimulation in vehicle- and 7-nitroindazole-treated rats. Our data show that inhibition of nNOS globally decreased CBF without altering CGU, indicating that NO-releasing neurons play a significant role in maintaining a resting cerebrovascular tone in the whole brain. During whisker stimulation, nNOS inhibition totally abolished the cerebrovascular response only in the second order relay stations (thalamus and somatosensory cortex) of the trigeminal relay without altering the metabolic response. These findings provide evidence that the involvement of neurally-derived NO in coupling flow to somatosensory activation is region-dependent, and that under nNOS inhibition, CBF and CGU may vary independently during neuronal activation.

Metabolic demands of neural-hemodynamic associated and disassociated areas in brain

“…22 Earlier CBF responses recorded using iodoantipyrene autoradiography showed similar increase in CBF to sensory stimulation at both thalamus and whisker barrel cortex. 29 Even in humans similar CBF responses in cortical and thalamic areas are observed. 40 Similar studies performed earlier in relation to neurovascular couplings in rat whisker barrel cortex and VPM.…”

“…Previous studies using 131 Iiodoantipyrine autoradiography observed similar CBF changes in thalamus as compared with whisker barrel cortex. 29 In other words, the CBF-CBV relationship, given by Grubb's equation below, is significantly different in S1 FL and VPL,…”

“…Our observation of comparable CMR O2 changes in VPL and S1 FL (Figure 3) are consistent with previous studies that have reported significant glucose metabolic (CMR glc ) changes in both cortical and thalamic regions in the anesthetized rat. 29,30 Relation between neurophysiological and neuroimaging responses…”

In vivo quantification of localized neuronal activation and inhibition in the rat brain using a dedicated high temporal-resolution β + -sensitive microprobe

“…First, local metabolic decreases observed after local mitochondrial blockade were investigated in individual rat striata after unilateral intrastriatal injection of the mitochondrial complex II inhibitor, malonate. Second, the ability of the probe to measure modest increases (5-10%) in somatosensory cortex metabolic rates in response to physiological sensory stimulation was evaluated in the well established whisker-stimulation model (13,14). In addition, the present studies show that in comparison with small-animal PET imaging, the ␤-MICROPROBE allows absolute quantitative studies of local cerebral kinetics and, by using compartmental modeling approaches, the determination of kinetic rate constants for any radiolabeled positron-emitting probe.…”

NMDA-Dependent Mechanisms Only Affect the BOLD Response in the Rat Dentate Gyrus by Modifying Local Signal Processing

“…Thus, an fMRI signal depends on neuronal-triggered mechanisms that control the vascular system. This so-called neurovascular coupling is thought to be mediated by vasoactive factors, such as nitric oxide or arachidonic acid derivates (Cholet et al, 1997;Lecrux et al, 2011;Pepicelli et al, 2005;Stefanovic et al, 2006Stefanovic et al, , 2007 and specific transmitter systems, such as dopamine, GABA, or glutamate (Busija et al, 2007;Cauli et al, 2004;Choi et al, 2006;Kocharyan et al, 2008). The main problem in the study of the particular role of a transmitter system in the generation of a BOLD response is that the applied receptor agonists or antagonists may have diverse points of action.…”