The effect of the delta sleep-inducing peptide on the development of toxic brain edema-swelling]

Antiedematic effects of the drugs are connected with their action on the mediator systems. DSIP has a wide range of modulatory effects on the brain mediator systems. DSIP antiedematic effect was studied on the toxic brain edema-swelling (BES) model. Physical characteristics of the nervous tissue such as thickness and wetness were used as evaluation criteria. According to the findings, the doses of 75-100 micrograms/kg DSIP were optimal. It is suggested that DSIP effect on BES is multicomponent and rather complicated. Inhibition of serotonin, noradrenaline and histamine systems and activation of GABA-ergic system by DSIP act as a possible antiedematic mechanism.     

Control of aerobic glycolysis in the brain in vitro

Protoveratrine-(5 M) stimulated aerobic glycolysis of incubated rat brain cortex slices that accompanies the enhanced neuronal influx of Na⁺ is blocked by tetrodotoxin (3 M) and the local anesthetics, cocaine (0.1 mM) and lidocaine (0.5 mM). On the other hand, high [K⁺]-stimulated aerobic glycolysis that accompanies the acetylcholine-sensitive enhanced glial uptakes of Na⁺ and water is unaffected by acetylcholine (2 mM). Experiments done under a variety of metabolic conditions show that there exists a better correlation between diminished ATP content of the tissue and enhanced aerobic glycolysis than between tissue ATP and the ATP-dependent synthesis of glutamine. Whereas malonate (2 mM) and amino oxyacetate (5 mM) suppress ATP content and O₂ uptake, stimulate lactate formation, but have little effect on glutamine levels, fluoroacetate (3 mM) suppresses glutamine synthesis in glia, presumably by suppressing the operation of the citric acid cycle, with little effect on ATP content, O₂ uptake, and lactate formation. Exogenous citrate (5 mM), which may be transported and metabolized in glia but not in neurons, inhibits lactate formation by cell free acetone-dried powder extracts of brain cortex but not by brain cortex slices. These results suggest that the neuron is the major site of stimulated aerobic glycolysis in the brain, and that under our experimental conditions glycolysis in glia is under lesser stringent metabolic control than that in the neuron. Stimulation of aerobic glycolysis by protoveratrine occurs due to diminution of the energy charge of the neuron as a result of stimulation of the sodium pump following tetrodotoxin-sensitive influx of Na⁺; stimulation by high [K⁺, NH₄ ⁺, or Ca²⁺ deprivation occurs partly by direct stimulation of key enzymes of glycolysis and partly by a fall in the tissue ATP concentration.     

The problem of using correlation methods in brain function]

In a series of publications, the author used the correlation hypothesis to explain the main mechanisms of functioning of bat and dolphin echo locators. A good fit of calculated parameters to experimental data was shown. In this work, by the example of generalization of the recognition problem, the use by the brain of correlation methods for solving more general problems independently on the modality of sensor signals was analyzed. In favor of the hypothesis that correlation methods are widely used in brain functioning are the data presented in the paper, which prove that an associative neuron is a suitable analog computer. It is suited for rapid "computation" of the intercorrelation function of discrete input and reference signals. The set of weighting coefficients of neuron synaptic inputs serve as such signals. The pool of associative neurons determines the values on the correlation function in the required range by changing the "numbers" of inputs from neuron to neuron at which discrete signals arrive.     

Real neuron assemblies forming during screen structure activities of the brain

The assembly organization of neuron reactions is a specific peculiarity of the screen structures of which the projection fields of the higher parts of the brain are composed. Such an organization is characterized by the local synergism of the responses of neuron groups in-teracting antagonistically, in contrast to the global neuron synergism of the nuclear segmental structures and the individual neuron antagonism of diffuse unspecific structures. Another characteristic feature of assembly organization is the presumable participation of neurons in the reaction of the assembly which warrants the flexibility and reliability of the realization of central functions. Of interest is the phylogenetic decrease in size and increase in number of working assemblies per unit area of projection field which enhances the resolving power of the analyzer. In different analyzer fields under the action of different stimuli a constant relationship of the reactions is found, i.e., two excited neurons to one inhibited neuron. Apparently, this proportion underlies the organization of balanced assemblies. The inadequacy of the stimuli and the deterioration of the functional state of the brain favor the "spreading" of assemblies; they increase in size, but at the same time the close correlation is lost between the impulse currents of the incoming neurons.Rostov-on-DonState University. Translated from Neirofiziologiya, Vol. 1, No. 2, pp. 123–129, September–October, 1969.     

Immunolocalisation of crustacean-SIFamide in the median brain and eyestalk neuropils of the marbled crayfish

Crustacean-SIFamide (GYRKPPFNGSIFamide) is a novel neuropeptide that was recently isolated from crayfish nervous tissue. We mapped the localisation of this peptide in the median brain and eyestalk neuropils of the marbled crayfish (Marmorkrebs), a parthenogenetic crustacean. Our experiments showed that crustacean-SIFamide is strongly expressed in all major compartments of the crayfish brain, including all three optic neuropils, the lateral protocerebrum with the hemiellipsoid body, and the medial protocerebrum with the central complex. These findings imply a role of this peptide in visual processing already at the level of the lamina but also at the level of the deeper relay stations. Immunolabelling is particularly strong in the accessory lobes and the deutocerebral olfactory lobes that receive a chemosensory input from the first antennae. Most cells of the olfactory globular tract, a projection neuron pathway that links deuto- and protocerebrum, are labelled. This pathway plays a central role in conveying tactile and olfactory stimuli to the lateral protocerebrum, where this input converges with optic information. Weak labelling is also present in the tritocerebrum that is associated with the mechanosensory second antennae. Taken together, we suggest an important role of crustacean-SIFamidergic neurons in processing high-order, multimodal input in the crayfish brain.     

Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood

Background

Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors.

Results

Distinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes.

Conclusions

This study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities.     

Mapping behavioural evolution onto brain evolution: the strategic roles of conserved organization in individuals and species

The pattern of individual variation in brain component structure in pigs, minks and laboratory mice is very similar to variation across species in the same components, at a reduced scale. This conserved pattern of allometric scaling resembles robotic architectures designed to be robust to changes in computing power and task demands, and may reflect the mechanism by which both growing and evolving brains defend basic sensory, motor and homeostatic functions at multiple scales. Conserved scaling rules also have implications for species-specific sensory and social communication systems, motor competencies and cognitive abilities. The role of relative changes in neuron number in the central nervous system in producing species-specific behaviour is thus highly constrained, while changes in the sensory and motor periphery, and in motivational and attentional systems increase in probability as the principal loci producing important changes in functional neuroanatomy between species. By their nature, these loci require renewed attention to development and life history in the initial organization and production of species-specific behavioural abilities.     

Effects of Atorvastatin on Pathological Changes in Brain Tissue and Plasma MMP-9 in Rats with Intracerebral Hemorrhage

To explore the effects of atorvastatin on hydrocephalus, neurocyte apoptosis, and the level of plasma matrix metalloproteinase-9 (MMP-9) after intracerebral hemorrhage (ICH) in rats. A rat model of ICH was established by intracerebral injection of collagenase. The brain water content was determined by the wet/dry weight ratio, ultrastructural changes in brain tissue were observed by electron microscopy, and the level of plasma MMP-9 was quantified by ELISA. Atorvastatin showed significant effects in reducing the brain water content, blocking neuron apoptosis, and decreasing plasma MMP-9 in rats with ICH. There was a positive linear correlation between plasma MMP-9 and the brain water content. Atorvastatin can significantly relieve brain edema, decrease the brain injury caused by MMP-9 and protect neurons in rats with ICH.     

Distribution and release of adenosine triphosphate in rat brain

The steady-state level of brain ATP was measured after the tissue had been treated with a focused microwave irradiation system. The brain ATP content (1.50 nmol/mg tissue) obtained by microwave fixation is similar to that observed by others using fast-freezing and microwave fixation techniques. The concentrations of ATP in different brain regions show a rather uniform distribution, ranging from 1.918±0.059 (brainstem) to 2.393±0.19 (caudate) nmol/mg tissue; however, insufficient microwave fixation time seems to produce a greater regional variation of ATP. Release of ATP was investigated by placing a cup on the sensory-motor cortex. The rate for basal release of ATP is 1.43±0.14 femtomole/min/mm². A 30-fold increase in ATP release was obtained by direct stimulation of the cortex with 5 mA pulses of 0.2 msec duration at a rate of 20/sec over a period of 10 min. These results, in conjunction with others describing the potent pharmacological action of the nucleotide, seem to suggest that ATP could be a mediator in a purinergic system in the CNS.     

The high frequency properties of brain tissue

Computer modeling is becoming increasingly important in the realm of brain biomechanics and injury. New computer simulations range from modeling of brain surgery, a low frequency, high strain event, to predicting injury as a result of an impact to the head, a high frequency event with varying strain magnitudes. This range of modeling efforts requires characterization of the tissue over as wide a frequency and strain range as possible. Research done to date has concentrated on the low frequency properties of the tissue. Complex compression and complex shear moduli have been measured at frequencies up to 350 Hz. Impact modeling requires use of frequency data at significantly higher frequencies than these. The "wave-in-a-tube" ultrasonic method was applied to brain tissue to determine mechanical properties at frequencies between 100 kHz and 10 MHz. Of these properties, only complex bulk modulus |K*| is fairly invariant (2133 MPa) with respect to frequency. Complex shear and complex Young's moduli vary with frequency and approach an asymptotic upper limit. Some variation in complex Poisson's ratio was also observed.     

Morphometric characteristics of neuron-glial relations in brain edema caused by stimulation of hypothalamic nuclei

Morphologic characteristics and certain changes in cell composition of the cortex and the white substance of the brain have been studied at experimentally produced brain edema by stimulation of the lateral hypothalamic field, the indefinite zone, Forel's fields H1 and H2. It has been stated that diffuse edema of the white substance and perivascular edema dominate in histopathological changes. Morphometrical analysis of the structural changes had demonstrated a certain increase in the cortex thickness, decreased density in the arrangement of the neurons and increased volume of their nuclei at more moderate enlargement of their body volumes, as well as increased volume of the nuclei in the cortical glial cells and the white substance cells. In the cortex cells is observed, that is accompanied with increased glial index and average number of perineuronal gliocytes per one neuron. Simultaneously, in both hemispheres, the character in the arrangement of the perineuronal glia as regards the neuron changes. At the same time, in the white substance, the density of the glial arrangement sharply decreases. The changes have demonstrated that wider perivascular spaces predominate in small vessels. All the changes mentioned are more pronounced in the contralateral hemisphere.     

An update on the role of brain glutamine synthesis and its relation to cell-specific energy metabolism in the hyperammonemic brain: further studies using NMR spectroscopy

Ammonia is a neurotoxin that is implicated in the pathogenesis of hepatic encephalopathy due to acute and chronic liver failure. However, its relation to neurological damage and brain edema is poorly understood. During the last decades, it has been the prevailing hypothesis that an osmotic disturbance induced by the astrocytic accumulation of glutamine leads to brain edema. However, various findings are at variance with this hypothesis. The present review will discuss: (a) correlation of ammonia with encephalopathy and brain edema in HE; (b) glutamine synthesis and astrocyte swelling; (c) glutamine synthesis and the glutamine-cycle: relation to brain energy metabolism; (d) glutamine synthesis and the glutamate-glutamine cycle and its relation to anaplerotic activity; (e) evidence favouring the "glutamine hypothesis"; (f) evidence contradicting the "glutamine hypothesis"; (g) glutamine synthesis and osmoregulation; (h) glutamine synthesis in chronic liver failure; (i) impaired brain energy metabolism in acute liver failure (ALF) and its relation to astrocytic glutamine synthesis. Taken together, the precise role of glutamine in the development of brain edema in ALF remains unclear. Astrocytic changes due to glutamine accumulation may lead secondarily to effects on brain energy metabolism. However, the relation between impaired energy metabolism and glutamine accumulation has not been well established. It is noteworthy that no single biochemical factor appears to be responsible for the many symptoms of HE. For example, brain glutamine accumulation and low-grade brain edema occur in chronic liver failure (CLF) suggesting common mechanisms are responsible for the neurological dysfunction in CLF and ALF. Recent NMR spectroscopic studies have provided considerably new information in this area. Future NMR studies using the stable isotope 13C may be useful in the study of the dynamics of brain metabolism in patients with ALF so as to better elucidate the precise role of glutamine accumulation and of glutamine-independent components to brain edema in ALF.     

Effect of nootropil and contvykal on the structural changes in the central nervous system in hypoxic brain edema]

The brain cortex of rabbits exposed to 15-minute ishemia in the presence of monitored hypotonia was studied in 27 experiments in order to verify the efficacy of nootropil and contrykal as agents intended for the treatment of posthypoxic edema of the brain. The therapeutic efficacy was assessed on the basis of the evidence obtained with the aid of light and electron microscopy. It was found that nootropil exerts a favourable action on the ultrastructure of intracellular organella of the neuron: mitochondria, lysosomes, ribosomal apparatus, nuclear envelope, etc. Under the effect of nootropil and contrykal the posthypoxic microcirculatory changes showed signs of compensation and proved reversible. Manifestations of posthypoxic edema of the brain were less pronounced. It is suggested that the efficacy of the treatment regimen offered is related to the normalizing effect of nootropil on metabolic and repair processes in neurons and cellular elements pertaining to the microcirculatory system as well as with a direct action of contrykal on the local factors of capillary permeability.     

Dopamine is necessary to endogenous morphine formation in mammalian brain in vivo

Morphine, the most used compound among narcotic analgesics, has been shown to be endogenously present in different mammalian/invertebrate normal tissues. In this study, we used mice that cannot make dopamine due to a genetic deletion of tyrosine hydroxylase specifically in dopaminergic neurons, to test the hypothesis that endogenous dopamine is necessary to endogenous morphine formation in vivo in mammalian brain. When dopamine was lacking in brain neurons, endogenous morphine was missing in brain mouse whereas it could be detected in brain from wild type rodent at a picogram range. Our data prove for the first time that endogenous dopamine is necessary to endogenous morphine formation in normal mammalian brain. Morphine synthesis appears to be originated from dopamine through L-tyrosine in normal brain tissue. Morphine synthesis is not considered to occur inside the same neuron in normal tissue; released dopamine might be transported into morphinergic neuron and further transformed into morphine. A physiological role for endogenous morphine is suggested considering that dopamine could modulate thermal threshold through endogenous morphine formation in vivo. Thus, dopamine and endogenous opiates/opioid peptides may be interconnected in the physiological processes; yet, endogenous morphine may represent a basic link of this chain.     

Mechanics of the brain: perspectives,challenges, and opportunities

The human brain is the continuous subject of extensive investigation aimed at understanding its behavior and function. Despite a clear evidence that mechanical factors play an important role in regulating brain activity, current research efforts focus mainly on the biochemical or electrophysiological activity of the brain. Here, we show that classical mechanical concepts including deformations, stretch, strain, strain rate, pressure, and stress play a crucial role in modulating both brain form and brain function. This opinion piece synthesizes expertise in applied mathematics, solid and fluid mechanics, biomechanics, experimentation, material sciences, neuropathology, and neurosurgery to address today’s open questions at the forefront of neuromechanics. We critically review the current literature and discuss challenges related to neurodevelopment, cerebral edema, lissencephaly, polymicrogyria, hydrocephaly, craniectomy, spinal cord injury, tumor growth, traumatic brain injury, and shaken baby syndrome. The multi-disciplinary analysis of these various phenomena and pathologies presents new opportunities and suggests that mechanical modeling is a central tool to bridge the scales by synthesizing information from the molecular via the cellular and tissue all the way to the organ level.     

The effects of trifluoperazine on brain edema,aquaporin-4 expression and metabolic markers during the acute phase of stroke using photothrombotic mouse model

Stroke is the second leading cause of death and the third leading cause of disability globally. Edema is a hallmark of stroke resulting from dysregulation of water homeostasis in the central nervous system (CNS) and plays the major role in stroke-associated morbidity and mortality. The overlap between cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema. Water balance in the brain is tightly regulated, primarily by aquaporin 4 (AQP4) channels, which are mainly expressed in perivascular astrocytic end-feet. Targeting AQP4 could be a useful therapeutic approach for treating brain edema; however, there is no approved drug for stroke treatment that can directly block AQP4. In this study, we demonstrate that the FDA-approved drug trifluoperazine (TFP) effectively reduces cerebral edema during the early acute phase in post-stroke mice using a photothrombotic stroke model. This effect was combined with an inhibition of AQP4 expression at gene and protein levels. Importantly, TFP does not appear to induce any deleterious changes on brain electrolytes or metabolic markers, including total protein or lipid levels. Our results support a possible role for TFP in providing a beneficial extra-osmotic effect on brain energy metabolism, as indicated by the increase of glycogen levels. We propose that targeting AQP4-mediated brain edema using TFP is a viable therapeutic strategy during the early and acute phase of stroke that can be further investigated during later stages to help in developing novel CNS edema therapies.     

Cholesterol metabolism in the brain

The central nervous system accounts for only 2% of the whole body mass but contains almost a quarter of the unesterified cholesterol present in the whole individual. This sterol is largely present in two pools comprised of the cholesterol in the plasma membranes of glial cells and neurons and the cholesterol present in the specialized membranes of myelin. From 0.02% (human) to 0.4% (mouse) of the cholesterol in these pools turns over each day so that the absolute flux of sterol across the brain is only approximately 0.9% as rapid as the turnover of cholesterol in the whole body of these respective species. The input of cholesterol into the central nervous system comes almost entirely from in situ synthesis, and there is currently little evidence for the net transfer of sterol from the plasma into the brain of the fetus, newborn or adult. In the steady state in the adult, an equivalent amount of cholesterol must move out of the brain and this output is partly accounted for by the formation and excretion of 24S-hydroxycholesterol. This cholesterol turnover across the brain is increased in neurodegenerative disorders such as Alzheimer's disease and Niemann-Pick type C disease. Indirect evidence suggests that large amounts of cholesterol also turn over among the glial cells and neurons within the central nervous system during brain growth and neuron repair and remodelling. This internal recycling of sterol may involve ligands such as apolipoproteins E and AI, and one or more membrane transport proteins such as members of the low density lipoprotein receptor family. Changes in cholesterol balance across the whole body may, in some way, cause alterations in sterol recycling and apolipoprotein E expression within the central nervous system, which, in turn, may affect neuron and myelin integrity. Further elucidation of the processes controlling these events is very important to understand a variety of neurodegenerative disorders.     

Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.     

Immunolocalization of choline acetyltransferase of common type in the central brain mass of Octopus vulgaris

Acetylcholine, the first neurotransmitter to be identified in the vertebrate frog, is widely distributed among the animal kingdom. The presence of a large amount of acetylcholine in the nervous system of cephalopods is well known from several biochemical and physiological studies. However, little is known about the precise distribution of cholinergic structures due to a lack of a suitable histochemical technique for detecting acetylcholine. The most reliable method to visualize the cholinergic neurons is the immunohistochemical localization of the enzyme choline acetyltransferase, the synthetic enzyme of acetylcholine. Following our previous study on the distribution patterns of cholinergic neurons in the Octopus vulgaris visual system, using a novel antibody that recognizes choline acetyltransferase of the common type (cChAT), now we extend our investigation on the octopus central brain mass. When applied on sections of octopus central ganglia, immunoreactivity for cChAT was detected in cell bodies of all central brain mass lobes with the notable exception of the subfrontal and subvertical lobes. Positive varicosed nerves fibers where observed in the neuropil of all central brain mass lobes.Key words: invertebrate, cephalopod, choline acetyltransferase, neuron, immunohistochemistry.