Regional differences in cerebral vascular response to PaCO2 changes in humans measured by positron emission tomography.

Hypercapnia and hypocapnia produce cerebral vasodilation and vasoconstriction, respectively. However, regional differences in the vascular response to changes in Paco2 in the human brain are not pronounced. In the current study, these regional differences were evaluated. In each of the 11 healthy subjects, cerebral blood flow (CBF) was measured using 15O-water and positron emission tomography at rest and during hypercapnia and hypocapnia. All CBF images were globally normalized for CBF and transformed into the standard brain anatomy. t values between rest and hypercapnia or hypocapnia conditions were calculated on a pixel-by-pixel basis. In the pons, cerebellum, thalamus, and putamen, significant relative hyperperfusion during hypercapnia was observed, indicating a large capacity for vasodilatation. In the pons and putamen, a significant relative hypoperfusion during hypocapnia, that is, a large capacity for vasoconstriction, was also observed, indicating marked vascular responsiveness. In the temporal, temporo-occipital, and occipital cortices, significant relative hypoperfusion during hypercapnia and significant relative hypoperfusion during hypocapnia were observed, indicating that cerebral vascular tone at rest might incline toward vasodilatation. Such regional heterogeneity of the cerebral vascular response should be considered in the assessment of cerebral perfusion reserve by hypercapnia and in the correction of CBF measurements for variations in subjects' resting Paco2.     

Ectopic impulse generation in demyelinated axons: effects of PaCO2, pH, and disodium edetate

Demyelinating lesions in the trigeminal root were produced by chronic implantation of chromic suture in 12 cats. Two types of abnormal repetitive action potential generation were recorded from demyelinated fibers: reflected spikes and afterdischarge. Both types of abnormal impulse generation were increased by hypocalcemia induced by disodium edetate infusion, hypocapnia produced by hyperventilation, and, to a lesser extent, alkalosis secondary to sodium bicarbonate administration. This hyperexcitability of fibers could be inhibited by hypoventilation with elevation of PaCO2 or by calcium chloride administration. These results may help explain the pathophysiological basis of paroxysmal symptoms in multiple sclerosis and other disorders in which demyelination is a prominent feature.     

Focal cerebral ischemia in the rat: topography of hemodynamic and histopathological changes

We studied local cerebral blood flow, as measured by autoradiography with digital image processing and by tissue morphology, in six rats 4 hours after occlusion of the proximal middle cerebral artery. A consistent, three-dimensional pattern of graded reductions in local cerebral blood flow involved the affected hemisphere, with a densely ischemic zone (local cerebral blood flow less than 3 ml/100 gm/min) in the dorsolateral caudate putamen and the adjacent frontoparietal cortex. In the frontoparietal cortex, the normal laminar pattern of local cerebral blood flow was disrupted, and there was a transcortical gradient in flow, with pronounced ischemia in deeper layers and relatively preserved superficial flow. Comparisons of autoradiographic findings with histopathological abnormalities in adjacent frozen sections showed that the region of ischemic damage corresponded closely with the area of greatest reduction in blood flow. Although around this region local cerebral blood flow increased centrifugally, a striking finding was that flow density changed abruptly (a tenfold variation in flow within a 1 to 2 mm interval) at the edge of the pathological lesion. Penumbral conditions may therefore exist in only a very narrow zone 4 hours after onset of focal ischemia. After occlusion of a major cerebral artery, the pattern of local cerebral blood flow changes appears to depend on interactions among vascular architecture, reductions in perfusion pressure, alterations in metabolic demands, and variations in local vascular resistance.     

Regional changes in adrenaline of rat brain during development

The changes of adrenaline during development were studied in several regions of rat brain. Adrenaline is present in hypothalamus, medulla oblongata-pons, midbrain, and cerebellum. Adult levels are attained between 15 and 30 days, depending on the region. These adult levels are attained earlier in the caudal regions than in the rostral regions. In cerebellum and medulla oblongata-pons, the adrenaline content reaches a maximum at 15 days which is close to the time in which the levels of phenylethanolamine-N-methyltransferase (PNMT) reach their maximum. In midbrain and hypothalamus, there is a lag between the adult levels of adrenaline and the activity of PNMT. Adrenaline reaches adult levels at 25 days in midbrain and at 30 days in hypothalamus, while PNMT activity adult levels are attained at 15 days.     

Regional, reversible ultrastructural changes in rat brain with chronic neuroleptic treatment

Administration of the dopamine receptor antagonist (neuroleptic, antipsychotic), haloperidol, resulting in an increase in the number of dopamine binding sites in the striatum and nucleus accumbens, has been well established. These increases disappear following withdrawal of treatment. Ultrastructurally, we found an increase in the number of synapses containing perforated postsynaptic densities (PSDs) following haloperidol administration within the caudate nucleus but not within the nucleus accumbens. The effect in the caudate reversed following cessation of treatment. We speculate that the terminals undergoing the change are not dopaminergic but may originate from the cerebral cortex. This reversible morphological increase associated with dopamine antagonist drug therapy may be reflective of the tolerance developed to neuroleptic drug-induced extrapyramidal syndromes and/or may be associated with abnormal motor movements of tardive dyskinesia that occur following long-term treatment.     

Regional changes in phenylethanolamine-N-Methyltransferase of rat brain during development

The changes of phenylethanolamine-N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme that catalyzes the final step in the biosynthesis of adrenaline, were studied during the development of several regions of rat brain. PNMT is present in medulla oblongata-pons, hypothalamus, cerebellum, and midbrain five days before birth, and a progressive increase in the enzyme activity is observed during development. The adult levels are attained between 15 and 20 days, depending on the region. The increases in PNMT activity in the rostral regions are higher than in the caudal regions. PNMT attains adult levels earlier than tyrosine hydroxylase and dopamine-β-hydroxylase. The apparatus for adrenaline synthesis seems to be mature at three weeks after birth in the medulla oblongata-pons, which contains the cell bodies of adrenaline-containing neurons. In the other regions the adult levels of enzyme activity are attained at 15 days after birth.     

Regional changes in monoamines and metabolites following defensive aggression in the rat

Pharmacological studies have demonstrated that shock-induced defensive fighting is modulated by manipulations of the serotonergic, noradrenergic and dopaminergic neurotransmitter systems. In the present study, regional changes in 5-hydroxytryptamine, norepinephrine, dopamine and their metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylethylene glycol and 3,4-dihydroxyphenylacetic acid were measured following shock-induced fighting using high performance liquid chromatography coupled with electrochemical detection. Fighting produced reductions in the serotonergic, noradrenergic and dopaminergic systems and elevations in the noradrenergic and dopaminergic systems within the brain stem, hypothalamus, hippocampus, caudate and amygdala relative to shocked or non-shocked controls. These data demonstrate that the activities of these neurotransmitters are involved in defensive aggression in rats. The changes in catecholamines may indicate adaptive responses to stress, while the changes in serotonin may indicate a permissive function for serotonin depletion in defensive fighting.     

Regional brain sodium, potassium, and water changes in the rat middle cerebral artery occlusion model of ischemia

Middle cerebral artery occlusions (MCAo) in rats produce infarcts in the pyriform and frontoparietal cortex, extending into the lateral basal ganglia and parasagittal cortex. We estimated tissue H2O concentrations from wet and dry weight measurements and determined Na and K concentrations by atomic absorption spectroscopy in these areas of rat brains. Tissue samples were analyzed at 2, 4, and 24 hours after MCAo and sham MCAo, compared with normal values measured in unoperated rats. In the pyriform and frontoparietal areas, H2O concentrations increased to 34 and 7% greater than normal by 2 hours, and 89 and 94% by 24 hours after MCAo. Na concentrations rose in these areas to 73 and 37% greater than normal by 2 hours, and 281 and 330% by 24 hours. K concentrations did not change until 4 hours, but fell to 62 and 34% of normal in these areas by 24 hours. Such large ion shifts indicate severe tissue destruction. In the parasagittal cortex and basal ganglia areas, the ion and water changes were smaller and did not become significant until 24 hours after MCAo. Rates of Na entry into the infarct site were greatest at 0-2 hours, while the rates of K loss peaked later, between 2 and 4 hours. The difference in Na influx and K efflux resulted in net ion shifts that correlated highly with water entry, yielding a correlation coefficient of 0.992 (p less than 0.001) and a slope indicating that 1 ml of water entered the tissue with each 145 mumoles of ions. These findings strongly suggest that net ion shifts cause the early edema of regional brain ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxygen extraction fraction and cerebrovascular reactivity to PaCO2 changes in ischemic brain measured by positron emission tomography

Interrelations between oxygen extraction (OEF) and cerebrovascular reactivity to PaCO2 change (VRCO2) in ischemic brain were measured by the 15O gases steady state method and the H215O autoradiographic method using a positron emission tomography. OEF at rest and VRCO2 for hypercapnia and hypocapnia were assessed successively in five cross sections of 10 mm image resolution. With each study correlation coefficients between OEF and VRCO2 were calculated using 30 to 40 regions of interest. In hypercapnic measurements those which had a larger ischemic region resulted in a higher incident of a negative correlation. Fifteen of 19 studies (79%) showed the negative correlation. From the regression lines which showed significant correlation a mean OEF at VRCO2 =0 was 0.54 +/- 0.09, which might indicate the point at the maximal dilatation of the resistance vessels. On the other hand, in hypocapnic studies only five of 18 (28%) showed apositive correlation, and the other measurements showed diffusely negative VRCO2 over the whole regions in the brain.     

Regional peripheral and CNS hemodynamic effects of intrathecal administration of a substance P receptor agonist

Regional CNS and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P receptor agonist, [pGlu5,MePhe8,MeGly9]-substance P5-11 ([DiMe]-SP), were studied in anesthetized rats with the radioactive microsphere technique. It was previously shown that [DiMe]-SP caused a sympathetically mediated increase in mean arterial pressure (MAP) by an action within the spinal cord. In this study, [DiMe]-SP (5 and 33 nmol, i.t.) increased MAP. The 5 nmol dose increased resistance in cutaneous, renal, splanchnic, and adrenal vascular beds but decreased resistance, and increased blood flow in some skeletal muscle beds. Total peripheral resistance was unchanged. The 33 nmol dose increased resistance in each peripheral vascular bed analyzed and increased total peripheral resistance. Whereas each dose increased heart rate, stroke volume and cardiac output were unchanged with the 5 nmol dose and were reduced with the 33 nmol dose. Neither dose of [DiMe]-SP significantly altered regional brain or spinal cord blood flows. These data show that the i.t. administration of the SP agonist, [DiMe]-SP, increased vascular tone to most peripheral vascular beds whereas the low dose caused a vasodilation of skeletal muscle. These effects are consistent with the notion of a dose-related activation of SP receptors in the spinal cord affecting sympathetic outflow to the adrenals and to the vasculature.     

Regional changes in neuropeptide levels after 5,7-dihydroxytryptamine-induced serotonin depletion in the rat brain

Summary The levels of five neuropeptides (substance-P, somatostatin, cholecystokinin octapeptide, methionin-enkephalin and dynorphin) were examined in the brain and the spinal cord of rats 2 weeks after intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT). 5,7-DHT injection caused a significant reduction of the serotonin level in all regions of the brain. The level of each neuropeptide except dynorphin significantly increased in specific regions of the brain after 5,7-DHT treatment without any decrease in their levels in any region. Since, coexistence and interaction between classical neurotransmitters and neuropeptides in the same neurons have been reported, both are indispensable for evaluating pathophysiological state of the brain function associated with abnormal neural transmission. The present findings together with previous reports suggest that neuropeptides act as neurotransmitters and compensate for the impaired function of the serotonergic systems.     

Regional analysis of developmental changes in the extent of GluR6 mRNA editing in rat brain

The extent of mRNA editing of the kainate receptor subunit GluR6 was evaluated in the cortex, hippocampus and cerebellum of embryonic brains at days 14 and 19 of gestation, in brains of animals aged 4, 25 days, or 3 months, and in hippocampal neurons isolated from embryonic brains at day 19 of gestation and held in tissue culture for 2 or 8 days. Total RNA was isolated and reverse transcribed into cDNA, which was used as template for PCR across the edited base A in TMII of GluR6. The extent of editing was evaluated by restriction digest of PCR products with Bbv 1, gel electrophoresis and image analysis of bands. In all brain structures studied the extent of editing was significantly upregulated during development (P < 0.001). The most pronounced increase in the extent of editing was observed between embryonic days 14 and 19. Highest levels were reached 4 days (94 ± 1.3%) or 3 months after birth (95 ± 1.7%) in the cortex and hippocampus, respectively. Notably, in hippocampal neurons held in tissue culture editing was sharply reduced to 67 ± 3.1% and 29 ± 3.1% after 2 or 8 days in culture (P < 0.001 vs. the embryonic and adult state). The results illustrate that moderate but significant regional differences exist in the regulation of GluR6 mRNA editing during development (cortex vs. hippocampus and cerebellum). Comparing developmental changes in the extent of editing of AMPA/kainate receptor subunits in vivo and in vitro may help to elucidate the molecular mechanisms of the editing process.     

Regional changes in cerebral glucose utilization associated with amygdaloid kindling and electroshock in the rat

A method using [³H]2-deoxyglucose was used to identify brain areas activated during partial and generalized amygdaloid kindled seizures and generalized seizures following electro-convulsive shock in rats. The amygdala, hippocampus, septal nuclei and hypothalamus were bilaterally activated in kindled convulsions. Electroshock caused a more widespread involvement including the thalamus, striatum, reticular formation and cerebellum. Changes in the amygdala and hippocampus but not hypothalamus, were found after partial kindling.     

Regional changes in monoamine content and uptake of the rat brain during postnatal development.

Regional norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) contents in the developing rat brain were estimated. The rate of increase in NE content was the highest in diencephalon, followed by the lower brain stem, limbic-striatum, neocortex and cerebellum. With postnatal aging, DA concentration increased markedly in limbic-striatum, slightly in the neocortex and negligibly in other regions. In each region except cerebellum, 5-HT content increased gradually but the rate of increase in diencephalon was relatively high. Comparison of the kinetics of high affinity uptake of L-[3H]NE and [3H]5-HT between the neonatal and the adult brain indicated that Km values of L-[3H]NE and [3H]5-HT uptake were 2.9 X 10(-7) M and 1.7 X 10(-7) M respectively in neocortex, diencephalon and lower brain stem and 4.3 X 10(-7) M and 2.3 X 10(-7) M in limbic-striatum in the neonate as well as in the adult. Vmax values of both amines uptake differed regionally and the values in the neonate were lower than those in the adult in all regions. Limbic-striatum showed a higher Vmax value than other regions in uptake of both amines. These results suggested that innervation of monoaminergic neurons in the brain progressed with increasing age, that projections of both NE and 5-HT neurons were relatively high into hypothalamus and limbic-striatum and that DA neuron projections concentrated at striatum. Although the brain, except for limbic-striatum, showed neither regional nor developmental differences in affinity of L-[3H]NE and [3H]5-HT to synaptosomes, the density of nerve terminal of both monoaminergic neurons increased in all regions of the brain during postnatal development. In limbic-striatum, higher Km and Vmax values of both amines, uptake suggest the existence of both amines' uptake into DA terminal to some extent.     

Regional and time-sequential changes in amino acid neurotransmitters after focal cerebral ischemia in the rat

Focal brain lesion is known to induce changes of blood flow and glucose metabolism in the areas other than the lesioned part itself. A well known example of this remote effect is so called diaschisis. To clarify the role of neurotransmitters in this phenomenon, amino acid neurotransmitters were measured in rat basal ganglia after middle cerebral artery occlusion. In the same ischemia model, blood flow and glucose metabolism have been reported to increase in the ipsilateral substantia nigra and globus pallidus in the postischemia period. Our results showed that GABA and aspartate were reduced in ipsilateral substantia nigra and globus pallidus from the 3rd day on, with glutamate level showing no significant change. In the contralateral substantia nigra, GABA increased significantly from the 1st day through the 28th day, whereas glutamate or aspartate showed no significant change. The same, although less pronounced, tendency was observed in the contralateral globus pallidus. In contralateral striatum, GABA increased only during the 1st week. These results may be interpreted as follows. GABA and aspartate were reduced in ipsilateral substantia nigra and globus pallidus due to the afferent pathway interruption caused by focal ischemia. The reduction of inhibitory GABA probably set neurons in these nuclei in a relatively activated state, resulting in the elevation of glucose metabolism and blood flow. Increment of GABA in contralateral substantia nigra and globus pallidus can be attributed to a compensation for the reduction inn ipsilateral nuclei, because the increment was observed even in a chronic phase. This hitherto unknown phenomenon will raise an interesting problem as to the plasticity of the damaged brain.