Frontal Cerebral Cortex Research Articles

Necrotizing Meningoencephalitis in a Cow

An 18-month-old Charolais cow developed depression and drooling and was submitted for necropsy after euthanasia. The cow was 1 of 50 moved between 2 farms approximately 5 days before the onset of clinical disease. Gross findings included swollen and hemorrhagic areas of malacia in the frontal, temporal, and parietal lobes of the cerebral cortex. Microscopically there was a necrotizing meningoencephalitis with intranuclear astrocytic and neuronal eosinophilic viral inclusions in the frontal, temporal, and parietal cerebral cortex as well as in the basal nuclei and thalamus. The gross and microscopic findings were consistent with necrotizing meningoencephalitis caused by bovine herpesvirus (BHV-1 or BHV-5), and the diagnosis was confirmed by detection of bovine herpesviral antigen on fresh samples of brain via fluorescent antibody test using a monoclonal antibody against BHV-1 glycoprotein C.

Not Lost in Translation: Neural Responses Shared Across Languages

How similar are the brains of listeners who hear the same content expressed in different languages? We directly compared the fMRI response time courses of English speakers and Russian speakers who listened to a real-life Russian narrative and its English translation. In the translation, we tried to preserve the content of the narrative while reducing the structural similarities across languages. The story evoked similar brain responses, invariant to the structural changes across languages, beginning just outside early auditory areas and extending through temporal, parietal, and frontal cerebral cortices. The similarity of responses across languages was nearly equal to the similarity of responses within each language group. The present results demonstrate that the human brain processes real-life information in a manner that is largely insensitive to the language in which that information is conveyed. The methods introduced here can potentially be used to quantify the transmission of meaning across cultural and linguistic boundaries.

Effect of CDP-choline on age-dependent modifications of energy- and glutamate-linked enzyme activities in synaptic and non-synaptic mitochondria from rat cerebral cortex

The effect of aging and CDP-choline treatment (20mgkg−1 body weight i.p. for 28days) on the maximal rates (Vmax) of representative mitochondrial enzyme activities related to Krebs’ cycle (citrate synthase, α-ketoglutarate dehydrogenase, malate dehydrogenase), glutamate and related amino acid metabolism (glutamate dehydrogenase, glutamate–oxaloacetate- and glutamate–pyruvate transaminases) were evaluated in non-synaptic and intra-synaptic “light” and “heavy” mitochondria from frontal cerebral cortex of male Wistar rats aged 4, 12, 18 and 24months.During aging, enzyme activities vary in a complex way respect to the type of mitochondria, i.e. non-synaptic and intra-synaptic. This micro-heterogeneity is an important factor, because energy-related mitochondrial enzyme catalytic properties cause metabolic modifications of physiopathological significance in cerebral tissue in vivo, also discriminating pre- and post-synaptic sites of action for drugs and affecting tissue responsiveness to noxious stimuli.Results show that CDP-choline in vivo treatment enhances cerebral energy metabolism selectively at 18months, specifically modifying enzyme catalytic activities in non-synaptic and intra-synaptic “light” mitochondrial sub-populations. This confirms that the observed changes in enzyme catalytic activities during aging reflect the bioenergetic state at each single age and the corresponding energy requirements, further proving that in vivo drug treatment is able to interfere with the neuronal energy metabolism.

Low-Dose Sarin Exposure Produces Long Term Changes in Brain Neurochemistry of Mice

Sarin is a toxic organophosphorus (OP) nerve agent that has been reported to cause long-term alterations in behavioral and neuropsychological processes. The present study was designed to investigate the effect of low dose sarin exposure on the monoamine neurotransmitter systems in various brain regions of mice. The rationale was to expand our knowledge about the noncholinergic neurochemical alterations associated with low dose exposure to this cholinesterase inhibitor. We analyzed the levels of monoamines and their metabolites in different brain areas after exposure of male C57BL/6 mice to a subclinical dose of sarin (0.4 LD50). Mice did not show any signs of cholinergic toxicity or pathological changes in brain tissue. At 1, 4 and 8 weeks post-sarin exposure brains were collected for neurochemical analysis. A significant decrease in the dopamine (DA) turnover, as measured by the metabolite to parent ratio, was observed in the frontal cerebral cortex (FC) at all time points tested. DA turnover was significantly increased in the amygdala at 4 weeks but not at 1 or 8 weeks after exposure. The caudate nucleus displayed a decrease in DA turnover at 1 week but no significant change was observed at 4 and 8 weeks suggesting a reversible effect. In addition to this, serotonin (5-HT) levels were transiently altered at various time points in all the brain regions studied (increase in FC, caudate nucleus and decrease in amygdala). Since there were no signs of cholinergic toxicity or cell death after sarin exposure, different non-cholinergic mechanisms may be involved in regulating these effects. Our results demonstrate that non-symptomatic dose of OP nerve agent sarin has potent long-term, region-specific effects on the monoaminergic neurotransmitter systems. Data also suggests differential effects of sarin on the various DA projections. These neurochemical alterations could be associated with long term behavioral and neuropsychological changes associated with low dose OP exposure.

Modulation of cerebral blood flow parameters in humans following consumption of nitrate-rich beetroot juice

Nitrate, abundant in beetroot, has been shown to reduce blood pressure and the oxygen cost of sub-maximal exercise; improve endothelial function and modulate regional perfusion in the brain. In this randomised, placebo-controlled, double-blind, crossover study, 16 physically active healthy young adult males received either 450 ml of beetroot juice (∼5.5 mmol nitrate) or a fruit flavoured placebo drink. Following a 90-min absorption period participants performed Stroop and Rapid Visual Information Processing tasks (9-min each) at rest, and during cycling at 50% and 70% VO2max and finally following exercise. Pre-frontal cerebral haemodynamics, as indexed by concentration changes in oxygenated and deoxygenated haemoglobin, were assessed throughout using Near Infrared Spectroscopy. Dietary nitrate modulated the haemodynamic response to task performance/exercise, with a significant interaction effect revealing lower cerebral deoxygenated haemoglobin relative to placebo during each task within each of the four post-intervention assessments. Dietary nitrate also significantly reduced systolic blood pressure post-exercise and time to limit of tolerance during 90% VO2max was significantly increased. Cognitive performance was unaffected. These data support previous reports of modulation of blood pressure and lowered deoxygenated haemoglobin in muscle following dietary nitrate and demonstrate that this effect on deoxygenated haemoglobin extends to the frontal cerebral cortex. Taken together these findings suggest a decrease in oxygen extraction during mental and physical performance with no resultant detrimental effects on cognitive performance and a positive effect on physical performance, suggesting a decrease in oxygen cost.

Altered serotonin, dopamine and norepinepherine levels in 15q duplication and Angelman syndrome mouse models.

Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally deleted and is associated with autism when maternally duplicated has recently been shown to regulate monoamine synthesis in the Drosophila brain. Therefore, we examined monoamine levels in striatum, ventral midbrain, frontal cerebral cortex, cerebellar cortex and hippocampus in Ube3a deficient and Ube3a duplication animals. We found that serotonin (5HT), a monoamine affected in autism, was elevated in the striatum and cortex of AS mice. Dopamine levels were almost uniformly elevated compared to control littermates in the striatum, midbrain and frontal cortex regardless of genotype in Ube3a deficient and Ube3a duplication animals. In the duplication 15q autism mouse model, paternal but not maternal duplication animals showed a decrease in 5HT levels when compared to their wild type littermates, in accordance with previously published data. However, maternal duplication animals show no significant changes in 5HT levels throughout the brain. These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain.

Identification and characterization of Huntington related pathology: An in vivo DKI imaging study

An important focus of Huntington Disease (HD) research is the identification of symptom-independent biomarkers of HD neuropathology. There is an urgent need for reproducible, sensitive and specific outcome measures, which can be used to track disease onset as well as progression. Neuroimaging studies, in particular diffusion-based MRI methods, are powerful probes for characterizing the effects of disease and aging on tissue microstructure. We report novel diffusional kurtosis imaging (DKI) findings in aged transgenic HD rats. We demonstrate altered diffusion metrics in the (pre)frontal cerebral cortex, external capsule and striatum. Presence of increased diffusion complexity and restriction in the striatum is confirmed by an increased fiber dispersion in this region. Immunostaining of the same specimens reveals decreased number of microglia in the (pre)frontal cortex, and increased numbers of oligodendrocytes in the striatum. We conclude that DKI allows sensitive and specific characterization of altered tissue integrity in this HD rat model, indicating a promising potential for diagnostic imaging of gray and white matter pathology.

Heterogeneous sensitivity of cerebral and muscle tissues to acute normobaric hyperoxia at rest

The purpose was to investigate the effects of acute normobaric hyperoxia at rest on cerebral, respiratory and leg muscle oxygenation. Ten healthy men were studied twice in a single-blinded counterbalanced crossover study protocol. On one occasion they breathed air and on the other 100% normobaric O2 for a 2-hour time period. Oxygenated (Δ[O2Hb]), deoxygenated (Δ[HHb]) and total (Δ[tHb]) hemoglobin in the cerebral frontal cortex, and in the intercostal and vastus lateralis muscles were simultaneously monitored with near-infrared spectroscopy. The hyperoxic stimulus promptly increased Δ[O2Hb] (~2μM) and decreased Δ[HHb] (~3.6μM) in the frontal cortex. These cerebral responses were directly and fully countered by resumption of normoxic air breathing. In contrast, Δ[HHb] significantly decreased due to the acute hyperoxic stimulus in both intercostal and vastus lateralis muscles. The temporal changes in muscle oxygenation were slower compared to those in the cerebral area; and they only partially recovered during the 15-min normoxic-recovery period. Acute supplementation of normobaric O2 at rest influences cerebral, leg and respiratory muscle oxygenation of healthy individuals, but not in the same manner. Namely, the frontal cortex seems to be more sensitive to hyperoxia than are the skeletal muscle regions.

Cerebral cortex oxygen delivery and exercise limitation in patients with COPD

In healthy humans, cerebral oxygen desaturation during exercise affects motor unit recruitment, while oxygen supplementation enhances cerebral oxygenation and work capacity. It remains unknown whether in patients with chronic obstructive pulmonary disease (COPD), the well-documented improvement in exercise tolerance with oxygen supplementation may also be partly due to the increase in cerebral oxygenation. Using near infrared spectroscopy, we measured both frontal cerebral cortex blood flow (CBF) using indocyanine green dye and cerebrovascular oxygen saturation (S(t,O(2))) in 12 COPD patients during constant-load exercise to exhaustion at 75% of peak capacity. Subjects exercised while breathing air, 100% oxygen or normoxic heliox, the latter two in balanced order. Time to exhaustion while breathing air was less than for either oxygen or heliox (mean±sem 394±35 versus 670±43 and 637±46 s, respectively). Under each condition, CBF increased from rest to exhaustion. At exhaustion, CBF was higher while breathing air and heliox than oxygen (30.9±2.3 and 31.3±3.5 versus 26.6±3.2 mL·min(-1) per 100 g, respectively), compensating for the lower arterial oxygen content (C(a,O(2))) in air and heliox, and leading to similar cerebral cortex oxygen delivery (CQ(O(2)) for air was 5.3±0.4, for oxygen was 5.5±0.6 and for heliox was 5.6±1.0 mL O(2) per min per 100 g). In contrast, end-exercise S(t,O(2)) was greater while breathing oxygen compared with air or heliox (67±4 versus 57±3 and 53±3%, respectively), reflecting C(a,O(2)) rather than CQ(O(2)). Prolonged time to exhaustion by breathing oxygen and heliox, despite these having a similar CQ(O(2)) to air, a lower S(t,O(2)) with heliox than oxygen, and yet similar endurance time and similar S(t,O(2)) in air and heliox despite greater endurance with heliox, do not support the hypothesis that an improvement in cerebral cortex oxygen availability plays a contributing role in increasing exercise capacity with oxygen or heliox in patients with COPD.

Frontal cerebral cortex blood flow, oxygen delivery and oxygenation during normoxic and hypoxic exercise in athletes

During maximal hypoxic exercise, a reduction in cerebral oxygen delivery may constitute a signal to the central nervous system to terminate exercise. We investigated whether the rate of increase in frontal cerebral cortex oxygen delivery is limited in hypoxic compared to normoxic exercise. We assessed frontal cerebral cortex blood flow using near-infrared spectroscopy and the light-absorbing tracer indocyanine green dye, as well as frontal cortex oxygen saturation (S(tO2)%) in 11 trained cyclists during graded incremental exercise to the limit of tolerance (maximal work rate, WRmax) in normoxia and acute hypoxia (inspired O2 fraction (F(IO2)), 0.12). In normoxia, frontal cortex blood flow and oxygen delivery increased (P < 0.05) from baseline to sub-maximal exercise, reaching peak values at near-maximal exercise (80% WRmax: 287 ± 9 W; 81 ± 23% and 75 ± 22% increase relative to baseline, respectively), both leveling off thereafter up to WRmax (382 ± 10 W). Frontal cortex S(tO2)% did not change from baseline (66 ± 3%) throughout graded exercise. During hypoxic exercise, frontal cortex blood flow increased (P = 0.016) from baseline to sub-maximal exercise, peaking at 80% WRmax (213 ± 6 W; 60 ± 15% relative increase) before declining towards baseline at WRmax (289 ± 5 W). Despite this, frontal cortex oxygen delivery remained unchanged from baseline throughout graded exercise, being at WRmax lower than at comparable loads (287 ± 9 W) in normoxia (by 58 ± 12%; P = 0.01). Frontal cortex S(tO2)% fell from baseline (58 ± 2%) on light and moderate exercise in parallel with arterial oxygen saturation, but then remained unchanged to exhaustion (47 ± 1%). Thus, during maximal, but not light to moderate, exercise frontal cortex oxygen delivery is limited in hypoxia compared to normoxia. This limitation could potentially constitute the signal to limit maximal exercise capacity in hypoxia.

Acute administration of vinpocetine, a phosphodiesterase type 1 inhibitor, ameliorates hyperactivity in a mice model of fetal alcohol spectrum disorder

BackgroundMaternal alcohol use during pregnancy causes a continuum of long-lasting disabilities in the offspring, commonly referred to as fetal alcohol spectrum disorder (FASD). Attention-deficit/hyperactivity disorder (ADHD) is possibly the most common behavioral problem in children with FASD and devising strategies that ameliorate this condition has great clinical relevance. Studies in rodent models of ADHD and FASD suggest that impairments in the cAMP signaling cascade contribute to the hyperactivity phenotype. In this work, we investigated whether the cAMP levels are affected in a long-lasting manner by ethanol exposure during the third trimester equivalent period of human gestation and whether the acute administration of the PDE1 inhibitor vinpocetine ameliorates the ethanol-induced hyperactivity. MethodsFrom postnatal day (P) 2 to P8, Swiss mice either received ethanol (5g/kg i.p.) or saline every other day. At P30, the animals either received vinpocetine (20mg/kg or 10mg/kg i.p.) or vehicle 4h before being tested in the open field. After the test, frontal cerebral cortices and hippocampi were dissected and collected for assessment of cAMP levels. ResultsEarly alcohol exposure significantly increased locomotor activity in the open field and reduced cAMP levels in the hippocampus. The acute treatment of ethanol-exposed animals with 20mg/kg of vinpocetine restored both their locomotor activity and cAMP levels to control levels. ConclusionsThese data lend support to the idea that cAMP signaling system contribute to the hyperactivity induced by developmental alcohol exposure and provide evidence for the potential therapeutic use of vinpocetine in FASD.

The hemorrhage caused by sporadic‐type cerebral amyloid angiopathy occurs primarily in the cerebral sulci

We examined a solitary hematoma in a patient with sporadic cerebral amyloid angiopathy (CAA). The hematoma affected the middle frontal sulcus, cerebral cortex (CC) and subcortical frontal white matter (sfWM). We embedded the hematoma in four paraffin blocks, each of which was cut serially into 6-µm-thick sections. The first section and every 18th section from each block were subjected to Elastica-Goldner (E-G) staining, and the distribution and diameter of the ruptured blood vessels (rBVs) were examined. The rBVs were then marked on diagrams representing each E-G-stained section. The present study yielded the following important findings: (i), early- and recently ruptured Aβ-positive arteries were present mainly in the intrasulcal hematoma (ISH), rather than in the CC; (ii) many early-ruptured arteries in the ISH were larger in diameter than those in the CC; and (iii) ruptures of the cortical arteries, even near the cortical surface, did not occur so frequently and the ruptured vessels were small in size. We concluded that in patients with subcortical hematoma caused by sporadic-type CAA, successive rupturse of the meningeal vessels, mainly arteries, occur in the cerebral sulcus initially, followed by formation of an ISH and development of a fresh hemorrhagic or anemic infarct in the CC surrounding the ISH, the latter in most cases then extending into the brain parenchyma through the necrotic CC at the depth of the sulcus, finally creating a secondary hematoma in the subcortical white matter.

CT and MRI of Wernicke’s encephalopathy

The purpose of this pictorial essay is to present the computed tomography (CT) and magnetic resonance imaging (MRI) findings of Wernicke's encephalopathy, a rare, severe, acute neurological syndrome due to thiamine (vitamin B1) deficiency, associated with high morbidity and mortality. The classical clinical triad, which includes ocular signs, altered consciousness and ataxia, can be found in only one-third of patients. Although chronic alcoholic patients are the most commonly affected, Wernicke's encephalopathy may complicate malnutrition conditions in nonalcoholic patients, in whom it is greatly underestimated. CT and above all MRI of the brain play a fundamental role in diagnosing the condition and ruling out other diseases. MRI is the most sensitive technique and is required in all patients with a clinical suspicion of Wernicke's encephalopathy. Medial thalami, mamillary bodies, tegmentum, periaqueductal region, and tectal plate are typical sites of abnormal MRI signal. The dorsal medulla, red nuclei, cranial nerve nuclei, cerebellum, corpus callosum, frontal and parietal cerebral cortex are less common sites of involvement although they are more frequently affected in nonalcoholic patients. Paramagnetic contrast material may help to identify lesions not otherwise visible.

Estradiol replacement evokes a wide range of transcriptional changes in the frontal cerebral cortex of middle-aged, ovariectomized rats

Event Abstract Back to Event Estradiol replacement evokes a wide range of transcriptional changes in the frontal cerebral cortex of middle-aged, ovariectomized rats M. Sárvári1*, I. Kalló2, E. Hrabovszky1, N. Solymosi3, K. Tóth4, I. Likó5, B. Molnár6, K. Tihanyi5 and Z. Liposits1 1 Hungarian Academy of Sciences, Institute of Experimental Medicine, Hungary 2 Pázmány Péter Catholic University, Faculty of Information Technology, Hungary 3 Eötvös Loránd University, Department of the Physics of Complex Systems, Hungary 4 Semmelweis University, Second Department of Medicine, Hungary 5 Gedeon Richter Plc., Hungary 6 Hungarian Academy of Sciences, Molecular Medicine Research Unit, Hungary Estradiol (E2) plays an important role in the maintenance of cortical functions. Around menopause, the incidence of cognitive disturbances and mood fluctuations increases. The symptoms can be counterbalanced by hormone replacement supporting the idea that estrogens help to maintain the function of the frontal cortex. We used middle-aged, ovariectomized rats and E2 replacement for 4 weeks to dissect the role of the genomic effects of E2 in the maintenance of the function of the frontal cortex. The expression level of 28,000 transcripts was determined by oligonucleotide microarray resulting in the identification of ten E2-regulated functions: neurotransmission (Adora2a, Drd1a, Drd2, Cartpt, Nts, Tac1), signal transduction (Igf2, Igfbp2, Igfbp6), transcription (Etv4, Irf7), transport (Abca1, Hba-a2), extracellular matrix (Col1a2), immunity (C3, CD74), metabolism (Acer2, Osbpl3), miscellaneous and unknown functions. After selection of 39 genes for validation, 74 percent of the changes were confirmed by quantitative real-time PCR. The genomic effects of E2 alter elements of dopaminergic and peptidergic neurotransmission, adenosine and IGF signaling and immune surveillance. These results suggest that the genomic effects of estrogens may play a significant role in the maintenance of cortical functions during hormone replacement in postmenopausal women. Acknowledgements Supported by the Hungarian Scientific Research Fund (OTKA K69127 and T73002) and the EU Seventh Framework Programme (FP7/2007-2013). Keywords: Neuroendocrinology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neuroendocrinology Citation: Sárvári M, Kalló I, Hrabovszky E, Solymosi N, Tóth K, Likó I, Molnár B, Tihanyi K and Liposits Z (2011). Estradiol replacement evokes a wide range of transcriptional changes in the frontal cerebral cortex of middle-aged, ovariectomized rats. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00028 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. M. Sárvári, Hungarian Academy of Sciences, Institute of Experimental Medicine, Budapest, Hungary, sarvari@koki.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers M. Sárvári I. Kalló E. Hrabovszky N. Solymosi K. Tóth I. Likó B. Molnár K. Tihanyi Z. Liposits Google M. Sárvári I. Kalló E. Hrabovszky N. Solymosi K. Tóth I. Likó B. Molnár K. Tihanyi Z. Liposits Google Scholar M. Sárvári I. Kalló E. Hrabovszky N. Solymosi K. Tóth I. Likó B. Molnár K. Tihanyi Z. Liposits PubMed M. Sárvári I. Kalló E. Hrabovszky N. Solymosi K. Tóth I. Likó B. Molnár K. Tihanyi Z. Liposits Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Effect of Chronic Antipsychotic Treatment on Brain Structure: A Serial Magnetic Resonance Imaging Study with Ex Vivo and Postmortem Confirmation

There is increasing evidence that antipsychotic (APD) may affect brain structure directly. To examine this, we developed a rodent model that uses clinically relevant doses and serial magnetic resonance imaging (MRI), followed by postmortem histopathological analysis to study the effects of APD on brain structures. Antipsychotic , haloperidol, and olanzapine were continuously administered to rats via osmotic minipumps to maintain clinic-like steady state levels for 8 weeks. Longitudinal in vivo MRI scanning (T₂-weighted) was carried out at baseline, 4 weeks, and 8 weeks, after which animals were perfused and their brains preserved for ex vivo MRI scanning. Region of interest analyses were performed on magnetic resonance images (both in vivo as well as ex vivo) along with postmortem stereology using the Cavalieri estimator probe. Chronic (8 weeks) exposure to both haloperidol and olanzapine resulted in significant decreases in whole-brain volume (6% to 8%) compared with vehicle-treated control subjects, driven mainly by a decrease in frontal cerebral cortex volume (8% to 12%). Hippocampal, corpus striatum, lateral ventricles, and corpus callosum volumes were not significantly different from control subjects, suggesting a differential effect of APD on the cortex. These results were corroborated by ex vivo MRI scans and decreased cortical volume was confirmed postmortem by stereology. This is the first systematic whole-brain MRI study of the effects of APD, which highlights significant effects on the cortex. Although caution needs to be exerted when extrapolating results from animals to patients, the approach provides a tractable method for linking in vivo MRI findings to their histopathological origins.

Novel Insight into Cholinergic Factors Associated with Schizophrenia and Autoimmunity

Schizophrenia affects 1% of the world`s population, but its cause remains obscure. Numerous theories have been proposed regarding the etiology of schizophrenia, ranging from neurodegenerative, autoimmune processes, neurotransmitter abnormalities to inflammation. Here, we propose an integrative view of autoimmune processes and neurotransmitter dysregulation in schizophrenia. We focus on the role of serum autoantibodies against cerebral muscarinic cholinergic receptors (mAChR) as a neuroimmune factor in the etiology of schizophrenia. We describe the presence of circulating antibodies from patients with paranoid schizophrenia, that interact with mAChRs of cerebral frontal cortex neural and glial cells. The antibodies can inhibit irreversible binding of the specific mAChR radioligand. We have demonstrated with synthetic peptides that these autoantibodies react against the second extracellular loop of human neural M1 mAChR and glial M2 mAChR. Also, the corresponding affinity-purified anti-peptide antibody displays an agonisticlike activity that is associated with specific M1 and M2 receptor activation. We have established that anti-mAChR autoantibodies appear to interpose in crosstalk between neurons and glia, and therefore, could be involved in negative/positive symptoms or inflammatory abnormalities associated with schizophrenia. M1 or M2 mAChR activation by autoantibodies can give conflicting messages. Chronic autoantibody fixation on postsynaptic neuronal M1 mAChR results in receptor downregulation, uncoupled to Gq protein, which stabilizes phospholipase C activity, and interferes with cognitive function (including attention, learning and memory) and alters neuronal plasticity, which causes negative symptoms. On the contrary, the antibody fixation on. presynaptic glia M2 mAChR inhibits the agonist action determined that the glia loss the negative control on excitatory neurotransmitter release (dopamine and glutamate). Therefore, the antibodies could induce loss of glial physiological buffering function, which causes differential exposure to positive symptoms. Furthermore, the antibody with agonistic activity on glial M1 mAChR contributes to neuro-inflammatory activity, which triggers the production of NO (Nitric Oxide), PGE2 (Prostaglandin E2) and MMP-3 (Metalloproteinase-3) via induction of COX-1(Ciclooxygenase-1) and iNOS(inducible Nitric oxide syntase) gene expression and activity. We have evidence that supports the hypothesis that alteration of the immune system is involved in the pathogenesis of schizophrenia, and that muscarinic receptors could represent promising novel targets for the treatment of the disease. Keywords: Cholinergic system, autoantibodies, schizophrenia disease, muscarinic receptor, cerebral frontal cortex, biological effects, ELISA assay, binding assay.

Distribuição do vírus rábico no sistema nervoso central em ruminantes naturalmente infectados

Com o objetivo de identificar a distribuição das lesões do vírus rábico no sistema nervoso central de casos espontâneos de raiva em ruminantes e comparar as técnicas de imunofluorescência direta (IFD), inoculação em camundongos (ICC) e presença de corpúsculos de Negri para o diagnóstico da doença foram analisados materiais proveniente de 48 casos de raiva, incluindo amostras de córtex frontal, temporal, parietal e occipital, hipocampo, tálamo, colículo rostral e caudal, cerebelo, ponte, medula oblonga, núcleo da base e porções da medula cervical, torácica e lombar. De 48 amostras analisadas, todas foram positivas na IFD e na ICC e em 30 (62,5%) foram encontrados corpúsculo de Negri (CN). No entanto, houve diferenças importantes no resultados dos três testes nas diferentes regiões do SNC avaliadas. Nos cortes de córtex cerebral, em 38 bovinos, a presença de corpúsculos de inclusão foi baixa (11%-37%) assim como a positividade para IFD e ICC (60-80%). Pelo contrário, todas as amostras de ponte, tálamo e medula testados foram positivas para IFD e ICC. Em outras regiões do tronco encefálico e também no cerebelo a positividade para ICC e IFD foi de 60% a 96,7%. No cerebelo foi encontrada a maior frequência (88,2%) de corpúsculos de inclusão. Em oito ovinos as provas de ICC e IFD foram positivas em todos os cortes e foram observados corpúsculos de inclusão em três animais. Foram analisados somente dois casos de caprinos encontrando-se corpúsculos de inclusão em um e ambos foram positivos para IFD e ICC. Os resultados obtidos nesse trabalho sugerem que a conduta recomendada pelo Manual Técnico de Controle da Raiva dos Herbívoros (MTCRH) permite o diagnóstico de raiva associando o estudo histológico aos testes de IFD e ICC que incluem cerebelo, tálamo e tronco encefálico que apresentam alta positividade para as provas de IFD e ICC. No entanto, a melhor conduta é a de incluir metade do encéfalo cortado longitudinalmente e amostras de medula. Isto permite examinar por IFD e ICC uma ou mais regiões onde essas provas apresentam maior positividade e, posteriormente, se essas provas fossem negativas, retornar ao material original e examinar outras regiões. Por outro lado, a coleta de amostras dos locais recomendados pela MTCRH, assim com a coleta de metade do encéfalo, podem prejudicar o diagnóstico de outras doenças para o qual é necessário o estudo de todo o encéfalo após a fixação em formaldeído, para constatar a simetria e a distribuição das lesões. Nestes casos, com base nos resultados obtidos neste trabalho, pode ser recomendado para diagnóstico laboratorial de raiva o envio exclusivo de porções da medula cervical, dorsal e lombar, já que as três porções apresentaram 100% de positividade nas provas de IFD e ICC. Além disso, o estudo histológico de todas as porções do cérebro incluídas neste trabalho permitirá complementar o diagnóstico.

Hyperactive mice show elevated D2High receptors, a model for schizophrenia: Calcium/calmodulin‐dependent kinase II alpha knockouts

The cerebral frontal cortex of patients who had schizophrenia shows elevated levels of RNA for calcium/calmodulin-dependent protein kinase II beta (CaMKIIbeta). In addition, recent research shows that animal models for schizophrenia, such as amphetamine-sensitized rats, consistently show elevated levels of D2 receptors in their high-affinity state (D2(High)), the major target for antipsychotic medication. The present study was done, therefore, to examine whether an alteration in the levels of CaMKIIbeta could lead to altered levels of D2(High) receptors. We found that the CaMKII inhibitor, KN-93, markedly reduced D2(High) states in rat striatum. In addition, we studied heterozygous CaMKIIalpha knock-out mice that show features analogous to schizophrenia. The striata of these mice revealed a 2.8-fold increase in D2(High) receptors. In frontal cortex of the heterozygous CaMKIIalpha knock-out mice, CaMKIIalpha mRNA levels were reduced by 50%, while CaMKIIbeta mRNA levels were unaltered. In striatum, CaMKIIbeta mRNA levels were increased by 29%, suggesting the presence of a new CaMKIIbeta regulatory pathway not previously described. The elevated levels of CaMKIIbeta mRNA in the striatum suggest that this enzyme may increase D2(High) in animals and possibly in schizophrenia itself.

Estradiol Replacement Alters Expression of Genes Related to Neurotransmission and Immune Surveillance in the Frontal Cortex of Middle-Aged, Ovariectomized Rats

Estradiol (E2) modulates a wide range of functions of the frontal cerebral cortex. From the onset of menopause, declining levels of E2 can cause cognitive disturbances and changes in behavior that can be counterbalanced by hormone replacement. To study the effect of E2 replacement on the cortical transcriptome in a rodent model with low serum E2 level, we treated middle-aged, ovariectomized rats with E2 or vehicle using osmotic minipumps for 4 wk. Six animals for each group were selected, and samples of their frontal cortex were subjected to expression profiling using oligonucleotide microarrays. The explored E2-regulated genes were related to neurotransmission (Adora2a, Cartpt, Drd1a, Drd2, Gjb2, Nts, and Tac1), immunity (C3, C4b, Cd74, Fcgr2b, Mpeg1, and RT1-Aw2), signal transduction (Igf2, Igfbp2, Igfbp6, Rgs9, and Sncg), transport (Abca1, Hba-a2, Slc13a3, and Slc22a8), extracellular matrix (Col1a2, Col3a1, Fmod, and Lum), and transcription (Irf7 and Nupr1). Seventy-four percent of the transcriptional changes identified by microarray were confirmed by quantitative real-time PCR. The genes identified by expression profiling indicated that chronic E2 replacement significantly altered the transcriptome of the frontal cortex. The genomic effects of E2 influenced dopaminergic and peptidergic neurotransmission, immune surveillance, adenosine and insulin-like growth factor signaling and transport processes, among other functions. Identification of these novel E2-regulated mechanisms highlights the wide range of genomic responses of the aging female frontal cerebral cortex subjected to hormone replacement. Some of the genomic effects identified in this study may underlie the beneficial effects of E2 on cognition, behavior, and neuroprotection.

Near infrared spectroscopy in children at high risk of low perfusion

Tissue oximetry has been suggested as a noninvasive tool to continuously monitor and detect states of low body perfusion. This review summarizes recent developments and available data on the use of near infrared spectroscopy (NIRS) in children at risk for low perfusion. During states of low cardiac output, cerebral blood flow and thus cerebral NIRS may be better preserved than in somatic tissue sites. Consequently, sites other than the frontal cerebral cortex have been investigated for a possible correlation with invasive measures of systemic perfusion and oxygenation (e.g. abdomen, flank, and muscle). The abdominal site seems preferable to the flank site NIRS (kidney region) application. In order to increase the sensitivity, specificity, and positive predictive value of tissue oximetry to detect systemic hypoperfusion, multisite NIRS such as a combination of cerebral and somatic site NIRS has been suggested. NIRS has also been used to assess systemic perfusion in patients undergoing first-stage palliation for hypoplastic left heart syndrome. Despite shortcomings in the ability of NIRS technology to accurately reflect validated and directly measured parameters of systemic oxygen delivery and blood flow, NIRS can certainly assist in the detection of low-flow states (low cardiac output). Large, randomized, prospective studies with well defined outcome parameters are still missing and warranted in order to clearly define the role of NIRS in children at risk for low perfusion.