Dependence of oxygen delivery on blood flow in rat brain: a 7 tesla nuclear magnetic resonance study.
ABSTRACT Magnetic resonance imaging (MRI) and spectroscopy (MRS) were used at a magnetic field strength of 7 T to measure CBF and CMRO2 in the sensorimotor cortex of mature rats at different levels of cortical activity. In rats maintained on morphine anesthesia, transitions to lower activity and higher activity states were produced by administration of pentobarbital and nicotine, respectively. Under basal conditions of morphine sulfate anesthesia, CBF was 0.75 +/- 0.09 mL x g(-1) x min(-1) and CMRO2 was 3.15 +/- 0.18 micromol x g(-1) x min(-1). Administration of sodium pentobarbital reduced CBF and CMRO2 by 66% +/- 16% and 61% +/- 6%, respectively (i.e., "deactivation"). In contrast, administration of nicotine hydrogen tartrate increased CBF and CMRO2 by 41% +/- 5% and 30% +/- 3%, respectively (i.e., "activation"). The resting values of CBF and CMRO2 for alpha-chloralose anesthetized rats were 0.40 +/- 0.09 mL x g(-1) x min(-1) and 1.51 +/- 0.06 micromol x g(-1) x min(-1), respectively. Upon forepaw stimulation, CBF and CMRO2 were focally increased by 34% +/- 10% and 26% +/- 12%, respectively, above the resting nonanesthetized values (i.e., "activation"). Incremental changes in CBF and CMRO2, when expressed as a percentage change for "deactivation" and "activation" from the respective control conditions, were linear (R2 = 0.997) over the entire range examined with the global and local perturbations. This tight correlation for cerebral oxygen delivery in vivo is supported by a recent model where the consequence of a changing effective diffusivity of the capillary bed for oxygen, D, has been hypothetically shown to be linked to alterations in CMRO2 and CBF. This assumed functional characteristic of the capillary bed can be theoretically assessed by the ratio of fractional changes in D with respect to changes in CBF, signified by omega. A value 0.81 +/- 0.23 was calculated for omega with the in vivo data presented here, which in turn corresponds to a supposition that the effective oxygen diffusivity of the capillary bed is not constant but presumably varies to meet local requirements in oxygen demand in a similar manner with both "deactivation" and "activation."
SourceAvailable from: nature.com[Show abstract] [Hide abstract]
ABSTRACT: The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO2). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO2. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply.Journal of Cerebral Blood Flow & Metabolism advance online publication, 23 October 2013; doi:10.1038/jcbfm.2013.181.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 10/2013; DOI:10.1038/jcbfm.2013.181 · 5.34 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Introduction Nicotine, the major addictive component of tobacco, exerts several CNS-mediated effects on human and animal behaviours . Nicotine's central activity is mediated by ligand-gated ion channel receptors that belong to the large nicotinic acetylcholine receptor family . Pre-synaptic nicotinic receptors are known to modulate the release of several neurotransmitters involved in the reinforcement and reward pathway . However, little is known about nicotine's effects on neuronal activity at a system level. Here we have applied phMRI methods to map for the first time the rCBV response to nicotine in the anesthetized rat. Moreover, we have investigated the effects of pre-treatment with the nicotinic receptor antagonist mecamylamine on nicotine-induced brain activity. Methods All experiments were carried out in accordance with Italian regulations governing animal welfare and protection and internal ethical review. Sprague-Dawley rats (250-350g) were scanned under halothane anaesthesia (induction 2.0%, maintenance level 0.8%). During the fMRI experiment, the animals were mechanically ventilated under neuromuscular blocker (d-Tubocurarine 0.25 mg/kg in bolus followed by a continuous infusion at 0.25 mg/kg. hr). Arterial blood pressure was measured throughout the experiments and blood gas levels were sampled at several time-points. MRI data were acquired using a Bruker Biospec 4.7T system, a 72-mm birdcage resonator for RF transmit and a quadrature surface receive coil (Bruker, Ettlingen, Germany). The time series experiment comprised 90 time points using the RARE sequence: matrix 128x128; FOV 40mm; RARE factor 32; slice thickness 2mm; 8 contiguous coronal slices; TE eff =110ms; TR=2700ms; δt=40s. A 2.67 ml/kg dose of Endorem blood pool contrast agent (Guerbet, France) was administered i.v. following 5 reference image frames, to sensitise the acquisition to changes in CBV. Three studies were performed: (1) acute i.v. nicotine challenge at two doses (1mg/kg [n=6] or 0.3mg/kg [n=7]) vs. vehicle (saline [n=6]). (2) i.p. mecamylamine challenge (1mg/kg [n=6], vs. vehicle (saline [n=3]). (3) pre-treatment with either mecamylamine (1mg/kg i.p., [n=7]) or vehicle (saline [n=9]) 30 minutes prior to i.v. nicotine challenge (1mg/kg, 30 min after i..p. injection). To rule out potential confounds arising from peripheral blood pressure changes elicited by nicotine, we have performed additional experiments with norepinephrine, a potent non-brain-penetrant vasopressor, at a dose that mimics the nicotine cardiovascular response (0.5 µg/kg,, i.v, [n=4]). Image analysis comprised co-registration of the image data from all animals to the same subject, masking out of non-brain tissue, conversion of time series' to rCBV. The nicotine response was quantified by pixel-wise multiple linear regression. Group comparisons were performed by t-tests between appropriate groups of contrast images. The statistical threshold of effect was determined using the Benjamini-Hochberg procedure with a false discovery rate (FDR) of q=0.05. RCBV time courses were extracted a posteriori for specific regions of interest (ROIs) based on correspondence between the anatomical images and an anatomical atlas. Results Acute infusion of nicotine (1 mg/kg) induced significant rCBV increases in the amygdala, the caudal-ventral hippocampus, endopyriform nucleus, and several cortical structures (cingulate, medial prefrontal, insular, rhinal cortices, Figure 1). The lower dose of nicotine (0.3 mg/kg) did not produce a statistically significant rCBV response. Analysis of the time-course profile of activation (Figure 2) showed a fast increase in rCBV peaking approximately 2 min after injection, followed by a gradual return to pre-injection baseline values (ca. 10 minutes post injection). Prior treatment of rats with the non-competitive nicotinic acetylcholine receptor antagonist mecamylamine (1 mg/kg, i.p.) strongly attenuated nicotine-induced rCBV response (Figure 2). Mecamylamine alone (1 mg/kg i.p.) did not show detectable effects on rCBV. Nicotine injection induced only a slight and transient increase in arterial blood pressure, which was significant only 1 minute post injection (+27 %, p<0.01). Pre-treatment with mecamylamine did not affect amplitude and duration of peripheral blood pressure changes. Acute administration of norepinephrine (0.5 µg/kg, i.v.) gave rise to a blood pressure increase similar to that observed with by 1 mg/kg nicotine (p>0.01, all time-points). Animals challenged with norepinephrine did not exhibit detectable rCBV changes, thus ruling out potential confounding peripheral effects.
[Show abstract] [Hide abstract]
ABSTRACT: Systemic effects of anesthesia on the dynamics of the apnea-induced Blood Oxygen Level Dependent (BOLD) signal is still not clear. In the present study, the dynamics of the fMRI-BOLD signal and blood flow using laser Doppler flowmetry (LDF) was studied in rats in response to apnea. Two anesthetics namely pentobarbital and urethane, hypothesized to have distinct effects on the mean arterial blood pressure (MAP) were used. During normoxic baseline conditions, MAP decreased in response to apnea in rats anesthetized with pentobarbital but increased with urethane. However, MAP did not change significantly in response to apnea during hyperoxic or hypercapnic baseline conditions with both anesthetics. LDF increased in response to apnea during normoxia, hyperoxia or hypercapnia and was influenced by MAP during normoxia. Apnea-induced BOLD signal dynamics was similar with both anesthetics, dominated by an alteration in arterial blood oxygenation and independent of changes in MAP. Our results suggest that anesthesia-dependent MAP change modulates the apnea-induced cerebral blood flow (CBF) response but has a minimal effect on the fMRI-BOLD signal probably due to uncoupling of CBF and oxygen consumption.Brain Research 06/2004; 1011(2):141-147. DOI:10.1016/S0006-8993(04)00380-4 · 2.83 Impact Factor