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Sample records for mouse cerebral cortical

  1. Cerebral cortical hypoplasia with abnormal morphology of pyramidal neuron in growth-retarded mouse (grt/grt).

    PubMed

    Horiuchi-Hirose, Miwa; Saito, Shigeyoshi; Sato, Chika; Aoyama, Junya; Kobayashi, Tetsuya; Sawada, Kazuhiko

    2014-01-01

    The purpose of this study was to quantitatively characterize structural abnormalities of the cerebrum in a growth-retarded mouse (grt/grt) with a tyrosylprotein sulfotransferase 2 gene defect. Three-dimensional computed tomography (CT) images were obtained from fixed brains of male homogenous grt/grt (n=5) and heterozygous grt/+ (n=5) mice at 15 weeks of age, and volumes of representative cerebral regions were calculated on the basis of those images. Following CT measurements, cryosections of the brain were made, and immunohistochemistry for NeuN and SMI-32 was carried out. By CT-based volumetry, region-specific reductions in volumes were marked in the cerebral cortex and white matter, but not in other cerebral regions of grt/grt. When quantitatively evaluating the shape of the cerebral cortex, the frontooccipital length of the cortex was significantly smaller in grt/grt than in grt/+, whereas the cortical width was not altered in grt/grt. On the other hand, both cortical thickness and density of NeuN-immunopositive neurons in three distinctive cortical regions, i.e., the primary motor cortex, barrel field of primary somatosensory cortex and primary visual cortex, were not different between grt/grt and grt/+. By semi-quantitative immunohistochemical analysis, the intensity of SMI-32 immunostaining was significantly weaker in grt/grt than in grt/+ in the three cortical areas examined. SMI-32 staining was reduced, particularly in layer III pyramidal neurons in grt/grt, while it was sustained in multipolar neurons. The present results suggest that cerebral abnormalities in grt/grt mice are characterized by cortical hypoplasia at the frontooccipital axis with immature pyramidal neurons and insufficient development of callosal fibers.

  2. Junk DNA Used in Cerebral Cortical Evolution.

    PubMed

    Pratt, Thomas; Price, David J

    2016-06-15

    In this issue of Neuron, Rani et al. (2016) address important questions about the mechanisms of cerebral cortical evolution. They describe how a primate-specific long non-coding RNA titrates the levels of a microRNA that regulates an ancient signaling pathway controlling neuronal numbers. PMID:27311076

  3. Correlation of cerebral cortical morphology with behavior

    SciTech Connect

    Norton, S.

    1989-03-01

    Association between functional damage and damage to the central nervous system from toxic agents can be used to determine the value of behavioral tests as predictors of damage to the nervous system. Variability in data from behavioral tests may be caused, in part, by varying levels of structural differences in the nervous system. Stepwise multiple regression is one method for analyzing the relationship between variability in data resulting from linkage between functional and morphological or other parameters of the structure of the nervous system. As an example, the predictive value of four behavioral tests is assessed in detecting thinning of the cerebral cortex following gestational exposure of rats to ionizing radiation. In this analysis, there were seven independent variables for predicting cortical thickness. The sequence of number of times each variable was used in prediction, from most frequent to least frequent, was: angle of stride greater than negative geotaxis greater than continuous corridor greater than body weight greater than width of stride greater than length of stride greater than reflex suspension. The data support the concept that there are varying degrees of predictive associations between these functional and cortical parameters.

  4. Determination of cerebral cortical blood flow: a thermal technique.

    PubMed

    Hoehner, P J; Krause, G S; White, B C; Gadzinski, D S

    1983-01-01

    A mathematical model for tissue thermodilution was developed to study cerebral cortical perfusion before and after controlled perfusion arrest. Cerebral cortical perfusion rates are readily determined by this method. A thermistor was introduced into the subdural space and secured in direct contact with the frontal cortex in 12 dogs on ketamine and gallamine anesthesia. A 22-gauge angiocath was placed in the right superior thyroid artery and directed into the carotid artery on the same side as the thermistor. The dogs were placed on cardiac bypass using a circuit from the right atrium to the pulmonary artery and a second circuit from the left ventricular apex to the left femoral artery. Arterial pressure, central venous pressure (CVP), intracranial pressure (ICP), and left atrial pressure (LAP) were monitored directly. A heat exchanger was used to maintain a constant blood temperature of 37 C in the output of the left side bypass circuit. Thermal flow curves were generated in the cerebral cortex by injecting 2 to 4 cc of cold saline into the common carotid artery through the injection catheter. Preliminary evaluation of this flow method in comparison to radioactive microspheres indicates that this method can be used in a reliable and reproducible fashion to determine cerebral cortical blood flow.

  5. Effect of anxiety on cortical cerebral blood flow and metabolism

    SciTech Connect

    Gur, R.C.; Gur, R.E.; Resnick, S.M.; Skolnick, B.E.; Alavi, A.; Reivich, M.

    1987-04-01

    The relation between anxiety and cortical activity was compared in two samples of normal volunteers. One group was studied with the noninvasive xenon-133 inhalation technique for measuring cerebral blood flow (CBF) and the other with positron emission tomography (PET) using /sup 18/Flurodeoxyglucose (/sup 18/FDG) for measuring cerebral metabolic rates (CMR) for glucose. The inhalation technique produced less anxiety than the PET procedure, and for low anxiety subjects, there was a linear increase in CBF with anxiety. For higher anxiety subjects, however, there was a linear decrease in CBF with increased anxiety. The PET group manifested a linear decrease in CMR with increased anxiety. The results indicate that anxiety can have systematic effects on cortical activity, and this should be taken into consideration when comparing data from different procedures. They also suggest a physiologic explanation of a fundamental behavioral law that stipulates a curvilinear, inverted-U relationship between anxiety and performance.

  6. In Utero Electroporation: Assay System for Migration of Cerebral Cortical Neurons

    NASA Astrophysics Data System (ADS)

    Tabata, Hidenori; Nakajima, Kazunori

    During the development of the cerebral cortex, the majority of cortical neurons are generated in the ventricular zone (VZ) facing the lateral ventricle and then migrate toward the pial surface to form the highly organized 6-layered cerebral cortex. Detailed profiles of these processes and their molecular mechanisms had been largely unknown because of the absence of an efficient assay system. The in vivo electroporation system was initially devised for use within chick embryos (Funahashi et al., 1999; Itasaki et al., 1999; Momose et al., 1999; Muramatsu et al., 1997), and we and other groups have used that system as a basis for developing an in utero electroporation system, which allows plasmid DNA to be introduced into cortical progenitor cells in developing mouse embryos in the uterus (Fukuchi-Shimogori and Grove, 2001; Saito and Nakatsuji, 2001; Tabata and Nakajima, 2001; Takahashi et al., 2002). In utero electroporation of other sites in the brain, including the hippocampus (Navarro-Quiroga et al., 2007), cerebral basal ganglia (Borrell et al., 2005; Nakahira et al., 2006), cortical hem (Takiguchi-Hayashi et al., 2004), and dorsal thalamus (Bonnin et al., 2007), has recently been reported. Introducing green fluorescent protein (GFP) enables the entire processes of migration and layer formation to be visualized (Ajioka and Nakajima, 2005; Sasaki et al., 2008; Tabata and Nakajima, 2002, 2003), and the role of any gene involved in these processes can be easily assessed by overexpressing the proteins or their mutants (Ohshima et al., 2007), or by knocking down the genes by the RNA interference technique (Bai et al., 2003). Furthermore, the Tet-On/Off system and/or other plasmid- vector-based technologies will expand the potential of the analyses. In this section we review the principles and methods of gene transfer into the cortical wall of mouse embryos by means of the in utero electroporation system.

  7. Perinatal cortical infarction within middle cerebral artery trunks

    PubMed Central

    Govaert, P.; Matthys, E.; Zecic, A.; Roelens, F.; Oostra, A.; Vanzieleghem, B.

    2000-01-01

    AIM—To define neonatal pial middle cerebral artery infarction.
METHODS—A retrospective study was made of neonates in whom focal arterial infarction had been detected ultrasonographically. A detailed study was made of cortical middle cerebral artery infarction subtypes.
RESULTS—Forty infarctions, with the exception of those in a posterior cerebral artery, were detected ultrasonographically over a period of 10 years. Most were confirmed by computed tomography or magnetic resonance imaging. Factor V Leiden heterozygosity was documented in three. The onset was probably antepartum in three, and associated with fetal distress before labour in one. There were 19 cases of cortical middle cerebral artery stroke. The truncal type (n=13) was more common than complete (n = 5) middle cerebral artery infarction. Of six infarcts in the anterior trunk, four were in term infants and five affected the right hemisphere. Clinical seizures were part of the anterior truncal presentation in three. One of these infants, with involvement of the primary motor area, developed a severe motor hemisyndrome. The Bayley Mental Developmental Index was above 80 in all of three infants tested with anterior truncal infarction. Of seven patients with posterior truncal infarction, six were at or near term. Six of these lesions were left sided. Clinical seizures were observed in three. A mild motor hemisyndrome developed in at least three of these infants due to involvement of parieto-temporal non-primary cortex.
CONCLUSIONS—Inability to differentiate between truncal and complete middle cerebral artery stroke is one of the explanations for the reported different outcomes. Severe motor hemisyndrome can be predicted from neonatal ultrasonography on the basis of primary motor cortex involvement. Clinical seizures were recognised in less than half of the patients with truncal infarction; left sided presentation was present in the posterior, but not the anterior truncal type of infarction

  8. Cerebral cartography--a method for visualizing cortical structures.

    PubMed

    Holländer, I

    1995-01-01

    We present a method for visualizing the human cortex on one planar map. The data are taken from a 3D MRI study. Ray tracing with non-parallel rays is used to project the cortical relief onto a non-planar projection surface, which is in turn mapped onto the plane by cartographical projection. Two modifications of the method are proposed: the spherical mapping uses a sphere as the projection surface; the model-based mapping uses an analytically defined model of the scalp to generate the normal vectors. The cerebral cartography can be used for example for producing anatomical reference maps on which EEG measurement data can be superimposed.

  9. Cortical laminar necrosis related to migrainous cerebral infarction

    PubMed Central

    Arboix, Adrià; González-Peris, Sebastià; Grivé, Elisenda; Sánchez, María-José; Comes, Emili

    2013-01-01

    We present a 29-year-old woman with a long history of attacks of migraine with and without visual aura. She was a heavy smoker (20 cigarettes/d) and was currently taking oral contraceptives. During a typical migraine attack with aura, she developed dysarthria, left brachial hemiparesis and hemihypoesthesia and brief and autolimited left clonic facial movements. Four hours after onset, vascular headache and focal sensorimotor neurological deficit were the only persisting symptoms and, on seventh day, she was completely recovered. Brain magnetic resonance imaging on day 20 after onset showed a subacute ischemic lesion in the right temporo-parietal cortex compatible with cortical laminar necrosis (CLN). Extensive neurological work-up done to rule out other known causes of cerebral infarct with CLN was unrevealing. Only ten of 3.808 consecutive stroke patients included in our stroke registry over a 19-year period fulfilled the strictly defined International Headache Society criteria for migrainous stroke. The present case is the unique one in our stroke registry that presents CLN related to migrainous cerebral infarction. Migrainous infarction can result in CLN. PMID:24340278

  10. Toward a Genetic Dissection of Cortical Circuits in the Mouse

    PubMed Central

    Huang, Z. Josh

    2014-01-01

    The mammalian neocortex gives rise to a wide range of mental activities and consists of a constellation of interconnected areas that are built from a set of basic circuit templates. Major obstacles to understanding cortical architecture include the diversity of cell types, their highly recurrent local and global connectivity, dynamic circuit operations, and a convoluted developmental assembly process rooted in the genome. With our increasing knowledge of gene expression and developmental genetic principles, it is now feasible to launch a program of genetic dissection of cortical circuits through systematic targeting of cell types and fate-mapping of neural progenitors. Strategic design of even a modest number of mouse driver lines will facilitate efforts to compile a cell type parts list, build a Cortical Cell Atlas, establish experimental access to modern tools, and provide coordinates for tracing developmental trajectory from circuit assembly to functional operation. PMID:25233312

  11. [Preoperative direct cortical and sub-cortical electric stimulation during cerebral surgery in functional areas].

    PubMed

    Duffau, H; Capelle, L; Sichez, J P; Bitar, A; Faillot, T; Arthuis, F; Van Effenterre, R; Fohanno, D

    1999-09-01

    Indications of surgical treatment for lesions in functional cerebral areas depend on the ratio between the definitive neurological deficit and the beneficial effect of resection. Detection of eloquent cortex is difficult because of important individual variability. Peroperative direct cortical and subcortical electrical stimulations (DCS) provide the most precise and reliable method currently available allowing identification and preservation of neurons essential for motricity, sensitivity++ and language. We report our preliminary experience with DCS in surgery of intracerebral infiltrative tumors with a consecutive series of 15 patients operated from November 96 through September 97 in our institution. Presenting symptoms in the 15 patients (8 males, 7 females, mean age 43 years) were seizures in 11 cases (73%) and neurological deficit in 4 cases (27%). Clinical examination was normal in 11 patients and revealed hemiparesia in 4. Magnetic resonance imaging (MRI) with three-dimensional reconstruction showed a precentral tumor in 10 cases, central lesion in one patient, postcentral lesion in two cases, right insular tumor (non-dominant hemisphere) in one case. All patients underwent surgical resection using DCS with detection in 13 cases of motor cortex and subcortical pathways under genera anesthesia, in one case of somatosensory area under local anesthesia, and in one case of language areas also under local anesthesia. The tumor was recurrent in two patients had been operated earlier but without DCS. Resection, verified by postoperative MRI, was total in 12 cases (80%) and estimated at 80% in 3 patients. Histological examination revealed an infiltrative glioma in 12 cases (8 low grade astrocytomas, 3 low grade oligodendrogliomas, and one anaplastic oligodendroglioma), and metastases in 3 cases. Eight patients had no postoperative deficit, while the other 7 patients were impaired, with, in all cases except one, complete recovery in 15 days to 2 months. Direct

  12. Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model.

    PubMed

    Bischoff, Sabine J; Schmidt, Martin; Lehmann, Thomas; Irintchev, Andrey; Schubert, Harald; Jung, Christian; Schwab, Matthias; Huber, Otmar; Matziolis, Georg; Schiffner, René

    2016-09-01

    Serelaxin, recombinant human relaxin-2, modulates endothelial vasodilatory functionality and is under evaluation for treatment of acute heart failure. Little is known about acute effects on cerebral perfusion. We tested the hypothesis that Serelaxin might also have effects on the cerebral microcirculation in a sheep model, which resembles human brain structure quite well. We used laser Doppler flowmetry and sidestream dark-field (SDF) imaging techniques, which are reliable tools to continuously assess dynamic changes in cerebral perfusion. Laser Doppler flowmetry shows that bolus injection of 30 μg Serelaxin/kg body wt induces an increase (P = 0.006) to roughly 150% of cortical cerebral blood flow (CBF), whereas subcortical CBF remains unchanged (P = 0.688). The effects on area-dependent CBF were significantly different after the bolus injection (P = 0.042). Effects on cortical CBF were further confirmed by SDF imaging. The bolus injection of Serelaxin increased total vessel density to 127% (P = 0.00046), perfused vessel density to 145% (P = 0.024), and perfused capillary density to 153% (P = 0.024). Western blotting confirmed the expression of relaxin receptors RXFP1 and truncated RXFP2-variants in the respective brain regions, suggesting a possible contribution of RXFP1 on the effects of Serelaxin. In conclusion, the injection of a high dose of Serelaxin exerts quick effects on the cerebral microcirculation. Therefore, Serelaxin might be suitable to improve cortical microcirculation and exert neuroprotective effects in clinically relevant scenarios that involve cortical hypoperfusion. These findings need to be confirmed in relevant experimental settings involving cerebral cortical hypoperfusion and can possibly be translated into clinical practice. PMID:27402664

  13. A sharp cadherin-6 gene expression boundary in the developing mouse cortical plate demarcates the future functional areal border.

    PubMed

    Terakawa, Youhei W; Inoue, Yukiko U; Asami, Junko; Hoshino, Mikio; Inoue, Takayoshi

    2013-10-01

    The mammalian cerebral cortex can be tangentially subdivided into tens of functional areas with distinct cyto-architectures and neural circuitries; however, it remains elusive how these areal borders are genetically elaborated during development. Here we establish original bacterial artificial chromosome transgenic mouse lines that specifically recapitulate cadherin-6 (Cdh6) mRNA expression profiles in the layer IV of the somatosensory cortex and by detailing their cortical development, we show that a sharp Cdh6 gene expression boundary is formed at a mediolateral coordinate along the cortical layer IV as early as the postnatal day 5 (P5). By further applying mouse genetics that allows rigid cell fate tracing with CreERT2 expression, it is demonstrated that the Cdh6 gene expression boundary set at around P4 eventually demarcates the areal border between the somatosensory barrel and limb field at P20. In the P6 cortical cell pellet culture system, neurons with Cdh6 expression preferentially form aggregates in a manner dependent on Ca(2+) and electroporation-based Cdh6 overexpression limited to the postnatal stages perturbs area-specific cell organization in the barrel field. These results suggest that Cdh6 expression in the nascent cortical plate may serve solidification of the protomap for cortical functional areas. PMID:22875867

  14. Rab3A, a possible marker of cortical granules, participates in cortical granule exocytosis in mouse eggs.

    PubMed

    Bello, Oscar Daniel; Cappa, Andrea Isabel; de Paola, Matilde; Zanetti, María Natalia; Fukuda, Mitsunori; Fissore, Rafael A; Mayorga, Luis S; Michaut, Marcela A

    2016-09-10

    Fusion of cortical granules with the oocyte plasma membrane is the most significant event to prevent polyspermy. This particular exocytosis, also known as cortical reaction, is regulated by calcium and its molecular mechanism is still not known. Rab3A, a member of the small GTP-binding protein superfamily, has been implicated in calcium-dependent exocytosis and is not yet clear whether Rab3A participates in cortical granules exocytosis. Here, we examine the involvement of Rab3A in the physiology of cortical granules, particularly, in their distribution during oocyte maturation and activation, and their participation in membrane fusion during cortical granule exocytosis. Immunofluorescence and Western blot analysis showed that Rab3A and cortical granules have a similar migration pattern during oocyte maturation, and that Rab3A is no longer detected after cortical granule exocytosis. These results suggested that Rab3A might be a marker of cortical granules. Overexpression of EGFP-Rab3A colocalized with cortical granules with a Pearson correlation coefficient of +0.967, indicating that Rab3A and cortical granules have almost a perfect colocalization in the egg cortical region. Using a functional assay, we demonstrated that microinjection of recombinant, prenylated and active GST-Rab3A triggered cortical granule exocytosis, indicating that Rab3A has an active role in this secretory pathway. To confirm this active role, we inhibited the function of endogenous Rab3A by microinjecting a polyclonal antibody raised against Rab3A prior to parthenogenetic activation. Our results showed that Rab3A antibody microinjection abolished cortical granule exocytosis in parthenogenetically activated oocytes. Altogether, our findings confirm that Rab3A might function as a marker of cortical granules and participates in cortical granule exocytosis in mouse eggs. PMID:27423421

  15. Rab3A, a possible marker of cortical granules, participates in cortical granule exocytosis in mouse eggs.

    PubMed

    Bello, Oscar Daniel; Cappa, Andrea Isabel; de Paola, Matilde; Zanetti, María Natalia; Fukuda, Mitsunori; Fissore, Rafael A; Mayorga, Luis S; Michaut, Marcela A

    2016-09-10

    Fusion of cortical granules with the oocyte plasma membrane is the most significant event to prevent polyspermy. This particular exocytosis, also known as cortical reaction, is regulated by calcium and its molecular mechanism is still not known. Rab3A, a member of the small GTP-binding protein superfamily, has been implicated in calcium-dependent exocytosis and is not yet clear whether Rab3A participates in cortical granules exocytosis. Here, we examine the involvement of Rab3A in the physiology of cortical granules, particularly, in their distribution during oocyte maturation and activation, and their participation in membrane fusion during cortical granule exocytosis. Immunofluorescence and Western blot analysis showed that Rab3A and cortical granules have a similar migration pattern during oocyte maturation, and that Rab3A is no longer detected after cortical granule exocytosis. These results suggested that Rab3A might be a marker of cortical granules. Overexpression of EGFP-Rab3A colocalized with cortical granules with a Pearson correlation coefficient of +0.967, indicating that Rab3A and cortical granules have almost a perfect colocalization in the egg cortical region. Using a functional assay, we demonstrated that microinjection of recombinant, prenylated and active GST-Rab3A triggered cortical granule exocytosis, indicating that Rab3A has an active role in this secretory pathway. To confirm this active role, we inhibited the function of endogenous Rab3A by microinjecting a polyclonal antibody raised against Rab3A prior to parthenogenetic activation. Our results showed that Rab3A antibody microinjection abolished cortical granule exocytosis in parthenogenetically activated oocytes. Altogether, our findings confirm that Rab3A might function as a marker of cortical granules and participates in cortical granule exocytosis in mouse eggs.

  16. Foxp1 Regulates Cortical Radial Migration and Neuronal Morphogenesis in Developing Cerebral Cortex

    PubMed Central

    Li, Xue; Xiao, Jian; Fröhlich, Henning; Tu, Xiaomeng; Li, Lianlian; Xu, Yue; Cao, Huateng; Qu, Jia; Rappold, Gudrun A.; Chen, Jie-Guang

    2015-01-01

    FOXP1 is a member of FOXP subfamily transcription factors. Mutations in FOXP1 gene have been found in various development-related cognitive disorders. However, little is known about the etiology of these symptoms, and specifically the function of FOXP1 in neuronal development. Here, we report that suppression of Foxp1 expression in mouse cerebral cortex led to a neuronal migration defect, which was rescued by overexpression of Foxp1. Mice with Foxp1 knockdown exhibited ectopic neurons in deep layers of the cortex postnatally. The neuronal differentiation of Foxp1-downregulated cells was normal. However, morphological analysis showed that the neurons with Foxp1 deficiency had an inhibited axonal growth in vitro and a weakened transition from multipolar to bipolar in vivo. Moreover, we found that the expression of Foxp1 modulated the dendritic maturation of neurons at a late postnatal date. Our results demonstrate critical roles of Foxp1 in the radial migration and morphogenesis of cortical neurons during development. This study may shed light on the complex relationship between neuronal development and the related cognitive disorders. PMID:26010426

  17. A Survey of Parents of Children with Cortical or Cerebral Visual Impairment

    ERIC Educational Resources Information Center

    Jackel, Bernadette; Wilson, Michelle; Hartmann, Elizabeth

    2010-01-01

    Cortical or cerebral visual impairment (CVI) can result when the visual pathways and visual processing areas of the brain have been damaged. Children with CVI may have difficulty finding an object among other objects, viewing in the distance, orienting themselves in space, going from grass to pavement or other changes in surface, and copying…

  18. An Evo-Devo Approach to Thyroid Hormones in Cerebral and Cerebellar Cortical Development: Etiological Implications for Autism

    PubMed Central

    Berbel, Pere; Navarro, Daniela; Román, Gustavo C.

    2014-01-01

    The morphological alterations of cortical lamination observed in mouse models of developmental hypothyroidism prompted the recognition that these experimental changes resembled the brain lesions of children with autism; this led to recent studies showing that maternal thyroid hormone deficiency increases fourfold the risk of autism spectrum disorders (ASD), offering for the first time the possibility of prevention of some forms of ASD. For ethical reasons, the role of thyroid hormones on brain development is currently studied using animal models, usually mice and rats. Although mammals have in common many basic developmental principles regulating brain development, as well as fundamental basic mechanisms that are controlled by similar metabolic pathway activated genes, there are also important differences. For instance, the rodent cerebral cortex is basically a primary cortex, whereas the primary sensory areas in humans account for a very small surface in the cerebral cortex when compared to the associative and frontal areas that are more extensive. Associative and frontal areas in humans are involved in many neurological disorders, including ASD, attention deficit-hyperactive disorder, and dyslexia, among others. Therefore, an evo-devo approach to neocortical evolution among species is fundamental to understand not only the role of thyroid hormones and environmental thyroid disruptors on evolution, development, and organization of the cerebral cortex in mammals but also their role in neurological diseases associated to thyroid dysfunction. PMID:25250016

  19. An evo-devo approach to thyroid hormones in cerebral and cerebellar cortical development: etiological implications for autism.

    PubMed

    Berbel, Pere; Navarro, Daniela; Román, Gustavo C

    2014-01-01

    The morphological alterations of cortical lamination observed in mouse models of developmental hypothyroidism prompted the recognition that these experimental changes resembled the brain lesions of children with autism; this led to recent studies showing that maternal thyroid hormone deficiency increases fourfold the risk of autism spectrum disorders (ASD), offering for the first time the possibility of prevention of some forms of ASD. For ethical reasons, the role of thyroid hormones on brain development is currently studied using animal models, usually mice and rats. Although mammals have in common many basic developmental principles regulating brain development, as well as fundamental basic mechanisms that are controlled by similar metabolic pathway activated genes, there are also important differences. For instance, the rodent cerebral cortex is basically a primary cortex, whereas the primary sensory areas in humans account for a very small surface in the cerebral cortex when compared to the associative and frontal areas that are more extensive. Associative and frontal areas in humans are involved in many neurological disorders, including ASD, attention deficit-hyperactive disorder, and dyslexia, among others. Therefore, an evo-devo approach to neocortical evolution among species is fundamental to understand not only the role of thyroid hormones and environmental thyroid disruptors on evolution, development, and organization of the cerebral cortex in mammals but also their role in neurological diseases associated to thyroid dysfunction.

  20. Exercise increases mitochondrial glutamate oxidation in the mouse cerebral cortex.

    PubMed

    Herbst, Eric A F; Holloway, Graham P

    2016-07-01

    The present study investigated the impact of acute exercise on stimulating mitochondrial respiratory function in mouse cerebral cortex. Where pyruvate-stimulated respiration was not affected by acute exercise, glutamate respiration was enhanced following the exercise bout. Additional assessment revealed that this affect was dependent on the presence of malate and did not occur when substituting glutamine for glutamate. As such, our results suggest that glutamate oxidation is enhanced with acute exercise through activation of the malate-aspartate shuttle. PMID:27184881

  1. Anxiety and cerebral cortical metabolism in normal persons.

    PubMed

    Giordani, B; Boivin, M J; Berent, S; Betley, A T; Koeppe, R A; Rothley, J M; Modell, J G; Hichwa, R D; Kuhl, D E

    1990-04-01

    The State-Trait Anxiety Inventory (STAI) was administered to 43 normal volunteers immediately before and after a positron emission tomography (PET) procedure with [18F]-2-fluoro-2-deoxy-D-glucose (18F-FDG). High trait-anxious individuals had significantly higher state (situational) anxiety associated with the PET scan procedure than did low trait-anxious persons. State anxiety decreased significantly for all respondents following the PET scan procedure. No significant relationships between global or regional cortical metabolic rates and state anxiety were observed. The direct cortical metabolic effects of heightened anxiety in the scan setting, should they exist, are likely obscured in the normal variance of the 18F-FDG method. PMID:2367610

  2. Postnatal Erythropoietin Mitigates Impaired Cerebral Cortical Development Following Subplate Loss from Prenatal Hypoxia-Ischemia.

    PubMed

    Jantzie, Lauren L; Corbett, Christopher J; Firl, Daniel J; Robinson, Shenandoah

    2015-09-01

    Preterm birth impacts brain development and leads to chronic deficits including cognitive delay, behavioral problems, and epilepsy. Premature loss of the subplate, a transient subcortical layer that guides development of the cerebral cortex and axonal refinement, has been implicated in these neurological disorders. Subplate neurons influence postnatal upregulation of the potassium chloride co-transporter KCC2 and maturation of γ-amino-butyric acid A receptor (GABAAR) subunits. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) in Sprague-Dawley rats that mimic brain injury from extreme prematurity in humans would cause premature subplate loss and affect cortical layer IV development. Further, we predicted that the neuroprotective agent erythropoietin (EPO) could attenuate the injury. Prenatal TSHI induced subplate neuronal loss via apoptosis. TSHI impaired cortical layer IV postnatal upregulation of KCC2 and GABAAR subunits, and postnatal EPO treatment mitigated the loss (n ≥ 8). To specifically address how subplate loss affects cortical development, we used in vitro mechanical subplate ablation in slice cultures (n ≥ 3) and found EPO treatment attenuates KCC2 loss. Together, these results show that subplate loss contributes to impaired cerebral development, and EPO treatment diminishes the damage. Limitation of premature subplate loss and the resultant impaired cortical development may minimize cerebral deficits suffered by extremely preterm infants.

  3. Effects of 810 nm laser on mouse primary cortical neurons

    NASA Astrophysics Data System (ADS)

    Kharkwal, Gitika B.; Sharma, Sulbha K.; Huang, Ying-Ying; De Taboada, Luis; McCarthy, Thomas; Hamblin, Michael R.

    2011-03-01

    In the past four decades numerous studies have reported the efficacy of low level light (laser) therapy (LLLT) as a treatment for diverse diseases and injuries. Recent studies have shown that LLLT can biomodulate processes in the central nervous system and has been extensively studied as a stroke treatment. However there is still a lack of knowledge on the effects of LLLT at the cellular level in neurons. The present study aimed to study the effect of 810 nm laser on several cellular processes in primary cortical neurons cultured from mouse embryonic brains. Neurons were irradiated with light dose of 0.03, 0.3, 3, 10 and 30 J/cm2 and intracellular levels of reactive oxygen species, nitric oxide and calcium were measured. The changes in mitochondrial function in response to light were studied in terms of adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP). Light induced a significant increase in calcium, ATP and MMP at lower fluences and a decrease at higher fluence. ROS was induced significantly by light at all light doses. Nitric oxide levels also showed an increase on treatment with light. The results of the present study suggest that LLLT at lower fluences is capable of inducing mediators of cell signaling process which in turn may be responsible for the biomodulatory effects of the low level laser. At higher fluences beneficial mediators are reduced but potentially harmful mediators are increased thus offering an explanation for the biphasic dose response.

  4. Cognitive processes and cerebral cortical fundi: findings from positron-emission tomography studies.

    PubMed Central

    Markowitsch, H J; Tulving, E

    1994-01-01

    Positron-emission tomography (PET) studies of regional cerebral blood flow have provided evidence relevant to localization of cognitive functions. The critical loci identified in these studies are typically described in terms of macroanatomically labeled cortical and subcortical regions. We report the results of a meta-analysis of localization of changes in blood flow, based on nearly 1000 cerebral cortical peaks of activity obtained from groups of subjects in 30 PET studies. The results showed that, on average, 47% of these peaks were localized within the fundus regions of cortical sulci. This is an unexpectedly high proportion because fundal regions compose < 8% of the cortical mantle. Further analysis suggested a coarse correlation between the extent of fundal activation observed in different studies and the estimated cognitive complexity of the tasks used in the studies. These findings are potentially interesting because (i) the preponderance of fundal activation has implications for the interpretation of the PET data, (ii) they suggest that cortical sulcal and fundal regions may play a distinctive role in higher cognitive processing, or (iii) both of the above. PMID:7937984

  5. A Computational Model for Cerebral Cortical Dysfunction in Autism Spectrum Disorders

    PubMed Central

    Vattikuti, Shashaank; Chow, Carson C.

    2011-01-01

    Background Perturbations to the microscopic level balance between synaptic excitation and inhibition and neuron organization in the cerebral cortex are suggested to underlie autism spectrum disorder (ASD) traits. The mechanism linking these perturbations to cognitive behaviors in ASD is unknown. This study strives to bridge this gap by generating clinically testable diagnostic and pharmacological predictions based on the effect of synaptic imbalance and neuron distribution on a computational local circuit model of the cerebral cortex. Methods We use a computational microscopic model of the cerebral cortex that incorporates N-methyl-D-aspartate and gamma-aminobutyric acid synaptic kinetics. We employ the model circuit during model tasks similar to visually guided and gap oculomotor saccade tasks and interpret qualitative model predictions of saccade hypometria and dysmetria. We consider the effects of varying the excitatory to inhibitory synaptic balance, neuron density, and neuron clustering in this model. Results An increase of synaptic excitation over synaptic inhibition results in increased hypometria and dysmetria. Similar effects by either reduced inhibition or increased excitation suggest that a variety of pharmacological compounds can be used for both screening and medical management. On the other hand, any change to the microscopic neuron anatomy that increases the effective maximum distance between excitatory neurons decreases hypometria but has no affect on dysmetria. Conclusions Perturbations to a computational model of a local cerebral cortical circuit can account for saccade hypometria and dysmetria reported in ASD studies. This approach may provide a direct link between cerebral cortical function and ASD behaviors. PMID:19880095

  6. Ultrastructural characteristics of human adult and infant cerebral cortical neurons.

    PubMed Central

    Ong, W Y; Garey, L J

    1991-01-01

    Biopsy specimens of human cerebral cortex from three adults and two infants were studied by correlating their light microscopic features in semithin sections with their ultrastructural characteristics. There was good tissue preservation, due to a minimum delay between obtaining the specimens and fixation. Pyramidal cells had a prominent apical dendrite, fine heterochromatin clumps in the nucleus and generally small numbers of cytoplasmic organelles, except for numerous free ribosomes in some of the large pyramids of Layers III to VI. Non-pyramidal cells lacked an apical dendrite and were further classified, on size and ultrastructure, into small, medium and large types. Large numbers of asymmetrical and symmetrical synapses were present in the neuropil but very few axosomatic synapses were found in the human cerebral cortex compared with subhuman primates and other mammals. Some symmetrical synapses were characterised by the presence of wide pre- and postsynaptic densities. The same general features of the adult cortex were also encountered in the infant, with certain exceptions. Many of the infant neurons had less densely packed heterochromatin, but greater numbers of free ribosomes, compared with the adult, and lipofuscin was absent. There was a total absence of myelinated fibres from the infant cortex; more large diameter dendrites were present than in the adult and axosomatic synapses were commoner. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 PMID:2050578

  7. Emergence of Small-World and Limitations to Its Maximization in a Macaque Cerebral Cortical Network

    NASA Astrophysics Data System (ADS)

    Zhao, Qing-Bai; Liao, Meng-Jie; Chen, Qi-Cai

    2011-06-01

    We study both the emergence of small-world topology in a macaque cerebral cortical network and the limitations to maximization of small-worldness. The results show that the maximization of neural complexity leads to a small-world topology, but it also limits the maximization of small-worldness. It is suggested that the modular organization that corresponds to different functions may be a limitation. Additionally, the need for strong resilience against attacks may be another limitation.

  8. Diffuse optical correlation tomography of cerebral blood flow during cortical spreading depression in rat brain

    NASA Astrophysics Data System (ADS)

    Zhou, Chao; Yu, Guoqiang; Furuya, Daisuke; Greenberg, Joel; Yodh, Arjun; Durduran, Turgut

    2006-02-01

    Diffuse optical correlation methods were adapted for three-dimensional (3D) tomography of cerebral blood flow (CBF) in small animal models. The image reconstruction was optimized using a noise model for diffuse correlation tomography which enabled better data selection and regularization. The tomographic approach was demonstrated with simulated data and during in-vivo cortical spreading depression (CSD) in rat brain. Three-dimensional images of CBF were obtained through intact skull in tissues(~4mm) deep below the cortex.

  9. Cerebral cortical neurons with activity linked to central neurogenic spontaneous and evoked elevations in cerebral blood flow

    NASA Technical Reports Server (NTRS)

    Golanov, E. V.; Reis, D. J.

    1996-01-01

    We recorded neurons in rat cerebral cortex with activity relating to the neurogenic elevations in regional cerebral blood flow (rCBF) coupled to stereotyped bursts of EEG activity, burst-cerebrovascular wave complexes, appearing spontaneously or evoked by electrical stimulation of rostral ventrolateral medulla (RVL) or fastigial nucleus (FN). Of 333 spontaneously active neurons only 15 (5%), in layers 5-6, consistently (P < 0.05, chi-square) increased their activity during the earliest potential of the complex, approximately 1.3 s before the rise of rCBF, and during the minutes-long elevation of rCBF elicited by 10 s of stimulation of RVL or FN. The results indicate the presence of a small population of neurons in deep cortical laminae whose activity correlates with neurogenic elevations of rCBF. These neurons may function to transduce afferent neuronal signals into vasodilation.

  10. Cerebral cortical activity associated with non-experts' most accurate motor performance.

    PubMed

    Dyke, Ford; Godwin, Maurice M; Goel, Paras; Rehm, Jared; Rietschel, Jeremy C; Hunt, Carly A; Miller, Matthew W

    2014-10-01

    This study's specific aim was to determine if non-experts' most accurate motor performance is associated with verbal-analytic- and working memory-related cerebral cortical activity during motor preparation. To assess this, EEG was recorded from non-expert golfers executing putts; EEG spectral power and coherence were calculated for the epoch preceding putt execution; and spectral power and coherence for the five most accurate putts were contrasted with that for the five least accurate. Results revealed marked power in the theta frequency bandwidth at all cerebral cortical regions for the most accurate putts relative to the least accurate, and considerable power in the low-beta frequency bandwidth at the left temporal region for the most accurate compared to the least. As theta power is associated with working memory and low-beta power at the left temporal region with verbal analysis, results suggest non-experts' most accurate motor performance is associated with verbal-analytic- and working memory-related cerebral cortical activity during motor preparation. PMID:25058623

  11. Lipoic acid reduces inflammation in a mouse focal cortical experimental autoimmune encephalomyelitis model.

    PubMed

    Chaudhary, Priya; Marracci, Gail; Galipeau, Danielle; Pocius, Edvinas; Morris, Brooke; Bourdette, Dennis

    2015-12-15

    Cortical lesions are a crucial part of MS pathology and it is critical to determine that new MS therapies have the ability to alter cortical inflammatory lesions given the differences between white and gray matter lesions. We tested lipoic acid (LA) in a mouse focal cortical EAE model. Brain sections were stained with antibodies against CD4, CD11b and galectin-3. Compared with vehicle, treatment with LA significantly decreased CD4+ and galectin-3+ immune cells in the brain. LA treated mice had fewer galectin-3+ cells with no projections indicating decrease in the number of infiltrating monocytes. LA significantly reduces inflammation in a focal cortical model of MS. PMID:26616873

  12. Cortical reorganization induced by virtual reality therapy in a child with hemiparetic cerebral palsy.

    PubMed

    You, Sung H; Jang, Sung Ho; Kim, Yun-Hee; Kwon, Yong-Hyun; Barrow, Irene; Hallett, Mark

    2005-09-01

    Virtual reality (VR) therapy is a new, neurorehabilitation intervention aimed at enhancing motor performance in children with hemiparetic cerebral palsy (CP). This case report investigated the effects of VR therapy on cortical reorganization and associated motor function in an 8-year-old male with hemiparetic CP. Cortical activation and associated motor development were measured before and after VR therapy using functional magnetic resonance imaging (fMRI) and standardized motor tests. Before VR therapy, the bilateral primary sensorimotor cortices (SMCs) and ipsilateral supplementary motor area (SMA) were predominantly activated during affected elbow movement. After VR therapy, the altered activations disappeared and the contralateral SMC was activated. This neuroplastic change was associated with enhanced functional motor skills including reaching, self-feeding, and dressing. These functions were not possible before the intervention. To our knowledge, this is the first fMRI study in the literature that provides evidence for neuroplasticity after VR therapy in a child with hemiparetic CP. PMID:16138671

  13. Intraoperative imaging of cortical cerebral perfusion by time-resolved thermography and multivariate data analysis

    NASA Astrophysics Data System (ADS)

    Steiner, Gerald; Sobottka, Stephan B.; Koch, Edmund; Schackert, Gabriele; Kirsch, Matthias

    2011-01-01

    A new approach to cortical perfusion imaging is demonstrated using high-sensitivity thermography in conjunction with multivariate statistical data analysis. Local temperature changes caused by a cold bolus are imaged and transferred to a false color image. A cold bolus of 10 ml saline at ice temperature is injected systemically via a central venous access. During the injection, a sequence of 735 thermographic images are recorded within 2 min. The recorded data cube is subjected to a principal component analysis (PCA) to select slight changes of the cortical temperature caused by the cold bolus. PCA reveals that 11 s after injection the temperature of blood vessels is shortly decreased followed by an increase to the temperature before the cold bolus is injected. We demonstrate the potential of intraoperative thermography in combination with multivariate data analysis to image cortical cerebral perfusion without any markers. We provide the first in vivo application of multivariate thermographic imaging.

  14. Simultaneous imaging of intrinsic optical signals and cerebral vessel responses during cortical spreading depression in rats

    NASA Astrophysics Data System (ADS)

    Li, Pengcheng; Chen, Shangbin; Luo, Weihua; Luo, Qingming

    2003-12-01

    Cortical spreading depression (CSD) is an important disease model for migraine and cerebral ischemia. We investigated the spatio-temporal characteristics of the intrinsic optical signals (IOS) at 570 nm and the cerebral blood vessel responses during CSD simultaneously by optical reflectance imaging in vivo. The CSD were induced by pinprick in 10 α-chloralose/urethane anesthetized Sprague-Dawley rats. A four-phasic IOS response was observed at pial arteries and parenchymal sites in all experimental animals and an initial slight pial arteries dilation (21.5%+/-13.6%) and constriction (-4.2%+/-3.5%) precedes the dramatic dilation (69.2%+/-26.1%) of pial arterioles was recorded. Our experimental results show a high correlation (r = 0.89+/-0.025) between the IOS response and the diameter changes of the cerebral blood vessels during CSD in rats.

  15. Automatic localization of cerebral cortical malformations using fractal analysis

    NASA Astrophysics Data System (ADS)

    De Luca, A.; Arrigoni, F.; Romaniello, R.; Triulzi, F. M.; Peruzzo, D.; Bertoldo, A.

    2016-08-01

    Malformations of cortical development (MCDs) encompass a variety of brain disorders affecting the normal development and organization of the brain cortex. The relatively low incidence and the extreme heterogeneity of these disorders hamper the application of classical group level approaches for the detection of lesions. Here, we present a geometrical descriptor for a voxel level analysis based on fractal geometry, then define two similarity measures to detect the lesions at single subject level. The pipeline was applied to 15 normal children and nine pediatric patients affected by MCDs following two criteria, maximum accuracy (WACC) and minimization of false positives (FPR), and proved that our lesion detection algorithm is able to detect and locate abnormalities of the brain cortex with high specificity (WACC  =  85%, FPR  =  96%), sensitivity (WACC  =  83%, FPR  =  63%) and accuracy (WACC  =  85%, FPR  =  90%). The combination of global and local features proves to be effective, making the algorithm suitable for the detection of both focal and diffused malformations. Compared to other existing algorithms, this method shows higher accuracy and sensitivity.

  16. Automatic localization of cerebral cortical malformations using fractal analysis.

    PubMed

    De Luca, A; Arrigoni, F; Romaniello, R; Triulzi, F M; Peruzzo, D; Bertoldo, A

    2016-08-21

    Malformations of cortical development (MCDs) encompass a variety of brain disorders affecting the normal development and organization of the brain cortex. The relatively low incidence and the extreme heterogeneity of these disorders hamper the application of classical group level approaches for the detection of lesions. Here, we present a geometrical descriptor for a voxel level analysis based on fractal geometry, then define two similarity measures to detect the lesions at single subject level. The pipeline was applied to 15 normal children and nine pediatric patients affected by MCDs following two criteria, maximum accuracy (WACC) and minimization of false positives (FPR), and proved that our lesion detection algorithm is able to detect and locate abnormalities of the brain cortex with high specificity (WACC  =  85%, FPR  =  96%), sensitivity (WACC  =  83%, FPR  =  63%) and accuracy (WACC  =  85%, FPR  =  90%). The combination of global and local features proves to be effective, making the algorithm suitable for the detection of both focal and diffused malformations. Compared to other existing algorithms, this method shows higher accuracy and sensitivity. PMID:27444964

  17. Nicotinic agonists modulate basal forebrain control of cortical cerebral blood flow in anesthetized rats.

    PubMed

    Linville, D G; Williams, S; Raszkiewicz, J L; Arneric, S P

    1993-10-01

    Previous studies have indicated that electrical microstimulation of the cholinergic (basal forebrain, BF) elicits profound increases in cortical cerebral blood flow (CBF) that are selectively attenuated by nicotinic receptor antagonists. This study sought to determine whether nicotinic receptor agonists such as (-)-nicotine, and related agents, can enhance the increases in CBF elicited by electrical stimulation of the BF of urethane-anesthetized rats. The magnitude of cortical CBF responses, measured by laser-Doppler flowmetry, increased progressively with higher frequencies (range = 6.25-50 Hz) to a maximum of 248% of control. (-)-Nicotine and (-)-lobeline each further enhanced the responses to BF stimulation, with (-)-nicotine having the most potent effect (up to 350%). (+)-Nicotine and (-)-cotinine were without effect, suggesting stereoselectivity and that the effects were not mediated by the major metabolite of (-)-nicotine. In contrast, (-)-cystisine, another nicotinic receptor agonist, modestly inhibited the BF-elicited increase in CBF suggesting nicotinic receptor subtype selectivity in mediating the response. Arecoline, a potent muscarinic agonist, was without effect suggesting that muscarinic mechanisms are not involved in the mediation of this response. None of the nicotinic agents had overt effects on heart rate or blood pressure in the dose ranges examined. In experiments targeting the site of action of the nicotinically mediated enhancement, (-)-nicotine microinjections into the BF elicited profound increases in cortical CBF, whereas similar injections into the cerebral cortex were without effect suggesting that nicotine receptors mediating CBF increases are localized to the BF.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8229773

  18. An automated pipeline for cortical surface generation and registration of the cerebral cortex

    NASA Astrophysics Data System (ADS)

    Li, Wen; Ibanez, Luis; Gelas, Arnaud; Yeo, B. T. Thomas; Niethammer, Marc; Andreasen, Nancy C.; Magnotta, Vincent A.

    2011-03-01

    The human cerebral cortex is one of the most complicated structures in the body. It has a highly convoluted structure with much of the cortical sheet buried in sulci. Based on cytoarchitectural and functional imaging studies, it is possible to segment the cerebral cortex into several subregions. While it is only possible to differentiate the true anatomical subregions based on cytoarchitecture, the surface morphometry aligns closely with the underlying cytoarchitecture and provides features that allow the surface of the cortex to be parcellated based on the sulcal and gyral patterns that are readily visible on the MR images. We have developed a fully automated pipeline for the generation and registration of cortical surfaces in the spherical domain. The pipeline initiates with the BRAINS AutoWorkup pipeline. Subsequently, topology correction and surface generation is performed to generate a genus zero surface and mapped to a sphere. Several surface features are then calculated to drive the registration between the atlas surface and other datasets. A spherical diffeomorphic demons algorithm is used to co-register an atlas surface onto a subject surface. A lobar based atlas of the cerebral cortex was created from a manual parcellation of the cortex. The atlas surface was then co-registered to five additional subjects using a spherical diffeomorphic demons algorithm. The labels from the atlas surface were warped on the subject surface and compared to the manual raters. The average Dice overlap index was 0.89 across all regions.

  19. Differences in cerebral cortical anatomy of left- and right-handers.

    PubMed

    Guadalupe, Tulio; Willems, Roel M; Zwiers, Marcel P; Arias Vasquez, Alejandro; Hoogman, Martine; Hagoort, Peter; Fernandez, Guillen; Buitelaar, Jan; Franke, Barbara; Fisher, Simon E; Francks, Clyde

    2014-01-01

    The left and right sides of the human brain are specialized for different kinds of information processing, and much of our cognition is lateralized to an extent toward one side or the other. Handedness is a reflection of nervous system lateralization. Roughly ten percent of people are mixed- or left-handed, and they show an elevated rate of reductions or reversals of some cerebral functional asymmetries compared to right-handers. Brain anatomical correlates of left-handedness have also been suggested. However, the relationships of left-handedness to brain structure and function remain far from clear. We carried out a comprehensive analysis of cortical surface area differences between 106 left-handed subjects and 1960 right-handed subjects, measured using an automated method of regional parcellation (FreeSurfer, Destrieux atlas). This is the largest study sample that has so far been used in relation to this issue. No individual cortical region showed an association with left-handedness that survived statistical correction for multiple testing, although there was a nominally significant association with the surface area of a previously implicated region: the left precentral sulcus. Identifying brain structural correlates of handedness may prove useful for genetic studies of cerebral asymmetries, as well as providing new avenues for the study of relations between handedness, cerebral lateralization and cognition. PMID:24734025

  20. Differences in cerebral cortical anatomy of left- and right-handers

    PubMed Central

    Guadalupe, Tulio; Willems, Roel M.; Zwiers, Marcel P.; Arias Vasquez, Alejandro; Hoogman, Martine; Hagoort, Peter; Fernandez, Guillen; Buitelaar, Jan; Franke, Barbara; Fisher, Simon E.; Francks, Clyde

    2014-01-01

    The left and right sides of the human brain are specialized for different kinds of information processing, and much of our cognition is lateralized to an extent toward one side or the other. Handedness is a reflection of nervous system lateralization. Roughly ten percent of people are mixed- or left-handed, and they show an elevated rate of reductions or reversals of some cerebral functional asymmetries compared to right-handers. Brain anatomical correlates of left-handedness have also been suggested. However, the relationships of left-handedness to brain structure and function remain far from clear. We carried out a comprehensive analysis of cortical surface area differences between 106 left-handed subjects and 1960 right-handed subjects, measured using an automated method of regional parcellation (FreeSurfer, Destrieux atlas). This is the largest study sample that has so far been used in relation to this issue. No individual cortical region showed an association with left-handedness that survived statistical correction for multiple testing, although there was a nominally significant association with the surface area of a previously implicated region: the left precentral sulcus. Identifying brain structural correlates of handedness may prove useful for genetic studies of cerebral asymmetries, as well as providing new avenues for the study of relations between handedness, cerebral lateralization and cognition. PMID:24734025

  1. Relation between clinical findings and progression of cerebral cortical pathology in MM1-type sporadic Creutzfeldt-Jakob disease: proposed staging of cerebral cortical pathology.

    PubMed

    Iwasaki, Yasushi; Tatsumi, Shinsui; Mimuro, Maya; Kitamoto, Tetsuyuki; Hashizume, Yoshio; Yoshida, Mari

    2014-06-15

    In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.

  2. Cerebral hypoxia, missing cortical somatosensory evoked potentials and recovery of consciousness

    PubMed Central

    2014-01-01

    Background Bilaterally absent N20 components of the sensory evoked potentials (SEP) from the median nerve are regarded as accurately predicting poor outcome after cardiac arrest. Case presentation We are reporting on a patient, who regained consciousness despite this ominous finding. Early after cardiac arrest, MRI showed signal alterations in diffusion weighted imaging (DWI) bilaterally in the primary visual and sensorimotor cortex and in the basal ganglia. SEP were repeatedly absent. The patient survived shut out form sensory and visual experience and locked in for voluntary movements, but kept her verbal competence in several languages. Conclusion SEP inform about integrity only of a narrow cortical strip. It is unguarded, but common practice, to conclude from absent SEP, that a patient has suffered diffuse cortical damage after cardiac arrest. Cerebral MRI with DWI helps to avoid this prognostic error and furthers understanding of the sometimes very peculiar state of mind after cardiac arrest. PMID:24720818

  3. Aberrant synchrony in the somatosensory cortices predicts motor performance errors in children with cerebral palsy.

    PubMed

    Kurz, Max J; Heinrichs-Graham, Elizabeth; Arpin, David J; Becker, Katherine M; Wilson, Tony W

    2014-02-01

    Cerebral palsy (CP) results from a perinatal brain injury that often results in sensory impairments and greater errors in motor performance. Although these impairments have been well catalogued, the relationship between sensory processing networks and errors in motor performance has not been well explored. Children with CP and typically developing age-matched controls participated in this investigation. We used high-density magnetoencephalography to measure event-related oscillatory changes in the somatosensory cortices following tactile stimulation to the bottom of the foot. In addition, we quantified the amount of variability or errors in the isometric ankle joint torques as these children attempted to match a target. Our results showed that neural populations in the somatosensory cortices of children with CP were desynchronized by the tactile stimulus, whereas those of typically developing children were clearly synchronized. Such desynchronization suggests that children with CP were unable to fully integrate the external stimulus into ongoing sensorimotor computations. Our results also indicated that children with CP had a greater amount of errors in their motor output when they attempted to match the target force, and this amount of error was negatively correlated with the degree of synchronization present in the somatosensory cortices. These results are the first to show that the motor performance errors of children with CP are linked with neural synchronization within the somatosensory cortices.

  4. Effect of superfused insulin on cerebral cortical glucose utilization in awake goats

    SciTech Connect

    Pelligrino, D.A.; Miletich, D.J.; Albrecht, R.F. )

    1987-10-01

    The effect on cortical cerebral glucose utilization (CMR{sub glu}) of intracerebral insulin administration in awake goats was studied. The insulin was superfused in a mock cerebrospinal fluid (CSF) employing chronically implanted cranial windows. Two windows were implanted bilaterally: one window over an equivalent portion of each parietal cortex. With one window used to deliver insulin/CSF and the other used to simultaneously deliver CSF alone (control), changes in CMR{sub glu} were assessed using a modification of a sequential 2-({sup 3}H)- then 2({sup 14}C)deoxy-D-glucose (2DG) technique originally described by Altenau and Agranoff. Initial experiments employing {sup 125}I-insulin demonstrated that the superfusion procedure increased insulin levels only in the outer 1 mm of cortical tissue exposed to insulin containing perfusate. Additional preliminary evaluations, using conditions known to alter CMR{sub glu}, generally established that present methods were adequate to induce and detect CMR{sub glu} changes. However, it was also shown experimentally and using a mathematical model that 2-({sup 3}H)DG test/control tissue ratios could be influenced by subsequent changes in CMR{sub glu} and the dephosphorylation rate. Thus {sup 3}H ratios could not be used to establish preexperimental test/control CMR{sub glu} relationships as the originally devised model assumed but could be employed to indicate changes in dephosphorylation. The mathematical model allowed for improved estimates of CMR{sub glu} changes from 2({sup 14}C)DG/2-({sup 3}H)DG test over control tissue ratios. Even with these corrections, insulin was estimated to cause no more than an 8-15% increase in cortical CMR{sub glu}. A very limited role for insulin, at least in cerebral cortical metabolic regulation, is thus indicated.

  5. Application of in utero electroporation of G-protein coupled receptor (GPCR) genes, for subcellular localization of hardly identifiable GPCR in mouse cerebral cortex.

    PubMed

    Kim, Nam-Ho; Kim, Seunghyuk; Hong, Jae Seung; Jeon, Sung Ho; Huh, Sung-Oh

    2014-07-01

    Lysophosphatidic acid (LPA) is a lipid growth factor that exerts diverse biological effects through its cognate receptors (LPA1-LPA6). LPA1, which is predominantly expressed in the brain, plays a pivotal role in brain development. However, the role of LPA1 in neuronal migration has not yet been fully elucidated. Here, we delivered LPA1 to mouse cerebral cortex using in utero electroporation. We demonstrated that neuronal migration in the cerebral cortex was not affected by the overexpression of LPA1. Moreover, these results can be applied to the identification of the localization of LPA1. The subcellular localization of LPA1 was endogenously present in the perinuclear area, and overexpressed LPA1 was located in the plasma membrane. Furthermore, LPA1 in developing mouse cerebral cortex was mainly expressed in the ventricular zone and the cortical plate. In summary, the overexpression of LPA1 did not affect neuronal migration, and the protein expression of LPA1 was mainly located in the ventricular zone and cortical plate within the developing mouse cerebral cortex. These studies have provided information on the role of LPA1 in brain development and on the technical advantages of in utero electroporation. PMID:25078448

  6. Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons

    PubMed Central

    Bissonette, Gregory B.; Bae, Mihyun H.; Suresh, Tejas; Jaffe, David E.; Powell, Elizabeth M.

    2013-01-01

    Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition. PMID:24211452

  7. Sensorimotor and cognitive deficits after transient middle cerebral artery occlusion in the mouse.

    PubMed

    Bouët, Valentine; Freret, Thomas; Toutain, Jérôme; Divoux, Didier; Boulouard, Michel; Schumann-Bard, Pascale

    2007-02-01

    Whereas behavioral impairments after stroke are increasingly studied in the rat, little is known about the long-term functional consequences of focal ischemia in the mouse. To address this issue, Swiss mice underwent transient (60 min) intraluminal occlusion of the middle cerebral artery (MCAo) or sham surgery. Sensorimotor (chimney, accelerating rotarod, pole, corner, adhesive removal and staircase tests) and cognitive (passive avoidance and Morris water maze) performances were regularly assessed during 1 month, after which the final histological lesion was measured. Motor coordination and balance, assessed by the chimney and rotarod tests, were transiently altered by MCAo. Moreover, bradykinesia was evidenced by the pole test. The most striking and long-lasting (1 month) sensorimotor deficits were postural asymmetries on the corner test, bilateral skilled forepaw reaching deficits on the staircase test and a contralateral sensorimotor impairment on the adhesive removal test. MCAo animals showed normal spatial learning abilities on the Morris water maze test, but they displayed learning deficits measured by the passive avoidance test. This latter deficit was significantly correlated with both cortical and striatal damage. Our findings demonstrate the usefulness of three tests that had never been reported in the mouse after ischemia: the adhesive removal, staircase and pole tests, which showed deficits 1 month after ischemia and should therefore constitute meaningful tools in mice for assessing both neuroprotective and regenerative therapies in stroke preclinical studies.

  8. Altered Cortical GABAA Receptor Composition, Physiology, and Endocytosis in a Mouse Model of a Human Genetic Absence Epilepsy Syndrome*

    PubMed Central

    Zhou, Chengwen; Huang, Zhiling; Ding, Li; Deel, M. Elizabeth; Arain, Fazal M.; Murray, Clark R.; Patel, Ronak S.; Flanagan, Christopher D.; Gallagher, Martin J.

    2013-01-01

    Patients with generalized epilepsy exhibit cerebral cortical disinhibition. Likewise, mutations in the inhibitory ligand-gated ion channels, GABAA receptors (GABAARs), cause generalized epilepsy syndromes in humans. Recently, we demonstrated that heterozygous knock-out (Hetα1KO) of the human epilepsy gene, the GABAAR α1 subunit, produced absence epilepsy in mice. Here, we determined the effects of Hetα1KO on the expression and physiology of GABAARs in the mouse cortex. We found that Hetα1KO caused modest reductions in the total and surface expression of the β2 subunit but did not alter β1 or β3 subunit expression, results consistent with a small reduction of GABAARs. Cortices partially compensated for Hetα1KO by increasing the fraction of residual α1 subunit on the cell surface and by increasing total and surface expression of α3, but not α2, subunits. Co-immunoprecipitation experiments revealed that Hetα1KO increased the fraction of α1 subunits, and decreased the fraction of α3 subunits, that associated in hybrid α1α3βγ receptors. Patch clamp electrophysiology studies showed that Hetα1KO layer VI cortical neurons exhibited reduced inhibitory postsynaptic current peak amplitudes, prolonged current rise and decay times, and altered responses to benzodiazepine agonists. Finally, application of inhibitors of dynamin-mediated endocytosis revealed that Hetα1KO reduced base-line GABAAR endocytosis, an effect that probably contributes to the observed changes in GABAAR expression. These findings demonstrate that Hetα1KO exerts two principle disinhibitory effects on cortical GABAAR-mediated inhibitory neurotransmission: 1) a modest reduction of GABAAR number and 2) a partial compensation with GABAAR isoforms that possess physiological properties different from those of the otherwise predominant α1βγ GABAARs. PMID:23744069

  9. Optical coherence tomography reveals in vivo cortical structures of adult rats in response to cerebral ischemia injury

    NASA Astrophysics Data System (ADS)

    Ni, Yi-rong; Guo, Zhou-yi; Shu, So-yun; Bao, Xin-min

    2008-12-01

    Optical coherence tomography(OCT) is a high resolution imaging technique which uses light to directly image living tissue. we investigate the potential use of OCT for structural imaging of the ischemia injury mammalian cerebral cortex. And we examine models of middle cerebral artery occlusion (MCAO) in rats in vivo using OCT. In particular, we show that OCT can perform in vivo detection of cortex and differentiate normal and abnormal cortical anatomy. This OCT system in this study provided an axial resolution of 10~15μ m, the transverse resolution of the system is about 25 μm. OCT can provide cross-sectional images of cortical of adult rats in response to cerebral ischemia injury.We conclude that OCT represents an exciting new approach to visualize, in real-time, pathological changes in the cerebral cortex structures and may offer a new tool for Possible neuroscience clinical applications.

  10. Development of Cerebral Microbleeds in the APP23-Transgenic Mouse Model of Cerebral Amyloid Angiopathy—A 9.4 Tesla MRI Study

    PubMed Central

    Reuter, Björn; Venus, Alexander; Heiler, Patrick; Schad, Lothar; Ebert, Anne; Hennerici, Michael G.; Grudzenski, Saskia; Fatar, Marc

    2016-01-01

    Background: Cerebral amyloid angiopathy (CAA) is characterized by extracellular deposition of amyloid β (Aβ) around cerebral arteries and capillaries and leads to an increased risk for vascular dementia, spontaneous lobar hemorrhage, convexal subarachnoid hemorrhage, and transient focal neurological episodes, which might be an indicator of imminent spontaneous intracerebral hemorrhage. In CAA cerebral microbleeds (cMBs) with a cortical/juxtacortical distribution are frequently observed in standard magnetic resonance imaging (MRI). In vivo MRI of transgenic mouse models of CAA may serve as a useful tool to investigate translational aspects of the disease. Materials and Methods: APP23-transgenic mice demonstrate cerebrovascular Aβ deposition with subsequent neuropathological changes characteristic for CAA. We performed a 9.4 Tesla high field MRI study using T2, T2* and time of flight-magnetic resonance angiograpy (TOF-MRA) sequences in APP23-transgenic mice and wildtype (wt) littermates at the age of 8, 12, 16, 20 and 24 months, respectively. Numbers, size, and location of cMBs are reported. Results: T2* imaging demonstrated cMBs (diameter 50–300 μm) located in the neocortex and, to a lesser degree, in the thalamus. cMBs were detected at the earliest at 16 months of age. Numbers increased exponentially with age, with 2.5 ± 2 (median ± interquartilrange) at 16 months, 15 ± 6 at 20 months, and 31.5 ± 17 at 24 months of age, respectively. Conclusion: We report the temporal and spatial development of cMBs in the aging APP23-transgenic mouse model which develops characteristic pathological patterns known from human CAA. We expect this mouse model to serve as a useful tool to non-invasively monitor mid- and longterm translational aspects of CAA and to investigate experimental therapeutic strategies in longitudinal studies. PMID:27458375

  11. Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C.

    PubMed

    Hjerrild, Simon; Renvillard, Signe Groth; Leutscher, Peter; Sørensen, Leif Hougaard; Østergaard, Leif; Eskildsen, Simon Fristed; Videbech, Poul

    2016-04-01

    Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes. PMID:26530221

  12. Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

    PubMed Central

    Zhao, Yaqian; Huang, Guowei; Chen, Shuang; Gou, Yun; Dong, Zhiping; Zhang, Xumei

    2016-01-01

    Elevated homocysteine (Hcy) levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive) and hardly in astrocytes (GFAP-positive). 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA). Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level. PMID:27455253

  13. Cerebral vascular leak in a mouse model of amyloid neuropathology

    PubMed Central

    Tanifum, Eric A; Starosolski, Zbigniew A; Fowler, Stephanie W; Jankowsky, Joanna L; Annapragada, Ananth V

    2014-01-01

    In Alzheimer's disease (AD), there is increasing evidence of blood–brain barrier (BBB) compromise, usually observed as ‘microbleeds' correlated with amyloid plaque deposition and apoE-ɛ4 status, raising the possibility of nanotherapeutic delivery. Molecular probes have been used to study neurovascular leak, but this approach does not adequately estimate vascular permeability of nanoparticles. We therefore characterized cerebrovascular leaks in live APP+ transgenic animals using a long circulating ∼100 nm nanoparticle computed tomography (CT) contrast agent probe. Active leaks fell into four categories: (1) around the dorsomedial cerebellar artery (DMCA), (2) around other major vessels, (3) nodular leaks in the cerebral cortex, and (4) diffuse leaks. Cortical leaks were uniformly more frequent in the transgenic animals than in age-matched controls. Leaks around vessels other than the DMCA were more frequent in older transgenics compared with younger ones. All other leaks were equally prevalent across genotypes independent of age. Ten days after injection, 4 to 5 μg of the dose was estimated to be present in the brain, roughly a half of which was in locations other than the leaky choroid plexus, and associated with amyloid deposition in older animals. These results suggest that amyloid deposition and age increase delivery of nanoparticle-borne reagents to the brain, in therapeutically relevant amounts. PMID:25052555

  14. Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development

    PubMed Central

    Meechan, Daniel W.; Maynard, Thomas M.; Fernandez, Alejandra; Karpinski, Beverly A.; Rothblat, Lawrence A.; LaMantia, Anthony S.

    2015-01-01

    Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic “model” syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that “modeling a model”, in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development. PMID:25866365

  15. Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

    PubMed Central

    Meechan, Daniel W.; Tucker, Eric S.; Maynard, Thomas M.; LaMantia, Anthony-Samuel

    2009-01-01

    The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for “diseases of cortical connectivity” thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbumin-labeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism. PMID:19805316

  16. Adult Mouse Cortical Cell Taxonomy by Single Cell Transcriptomics

    PubMed Central

    Tasic, Bosiljka; Menon, Vilas; Nguyen, Thuc Nghi; Kim, Tae Kyung; Jarsky, Tim; Yao, Zizhen; Levi, Boaz; Gray, Lucas T.; Sorensen, Staci A.; Dolbeare, Tim; Bertagnolli, Darren; Goldy, Jeff; Shapovalova, Nadiya; Parry, Sheana; Lee, Changkyu; Smith, Kimberly; Bernard, Amy; Madisen, Linda; Sunkin, Susan M.; Hawrylycz, Michael; Koch, Christof; Zeng, Hongkui

    2016-01-01

    Nervous systems are composed of various cell types, but the extent of cell type diversity is poorly understood. Here, we construct a cellular taxonomy of one cortical region, primary visual cortex, in adult mice based on single cell RNA-sequencing. We identify 49 transcriptomic cell types including 23 GABAergic, 19 glutamatergic and seven non-neuronal types. We also analyze cell-type specific mRNA processing and characterize genetic access to these transcriptomic types by many transgenic Cre lines. Finally, we show that some of our transcriptomic cell types display specific and differential electrophysiological and axon projection properties, thereby confirming that the single cell transcriptomic signatures can be associated with specific cellular properties. PMID:26727548

  17. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics.

    PubMed

    Tasic, Bosiljka; Menon, Vilas; Nguyen, Thuc Nghi; Kim, Tae Kyung; Jarsky, Tim; Yao, Zizhen; Levi, Boaz; Gray, Lucas T; Sorensen, Staci A; Dolbeare, Tim; Bertagnolli, Darren; Goldy, Jeff; Shapovalova, Nadiya; Parry, Sheana; Lee, Changkyu; Smith, Kimberly; Bernard, Amy; Madisen, Linda; Sunkin, Susan M; Hawrylycz, Michael; Koch, Christof; Zeng, Hongkui

    2016-02-01

    Nervous systems are composed of various cell types, but the extent of cell type diversity is poorly understood. We constructed a cellular taxonomy of one cortical region, primary visual cortex, in adult mice on the basis of single-cell RNA sequencing. We identified 49 transcriptomic cell types, including 23 GABAergic, 19 glutamatergic and 7 non-neuronal types. We also analyzed cell type-specific mRNA processing and characterized genetic access to these transcriptomic types by many transgenic Cre lines. Finally, we found that some of our transcriptomic cell types displayed specific and differential electrophysiological and axon projection properties, thereby confirming that the single-cell transcriptomic signatures can be associated with specific cellular properties.

  18. Molecular cloning of the mouse CCK gene: expression in different brain regions and during cortical development.

    PubMed Central

    Vitale, M; Vashishtha, A; Linzer, E; Powell, D J; Friedman, J M

    1991-01-01

    In this paper we describe experiments that address specific issues concerning the regulation of the mouse cholecystokinin gene in brain and intestine. The mouse cholecystokinin gene was cloned and sequenced. Extensive homology among the mouse, man and rat genes was noted particularly in the three exons and the regions upstream of the RNA start site. RNAse protection assays for each of the three exons were used to demonstrate that CCK is expressed in only a subset of tissues and that the same cap site and splice choices are used in brain, intestine as well as in cerebellum, cortex, midbrain, hypothalamus and hippocampus. CCK RNA was also noted to be detectable in kidney. Thus the same gene using the same promoter is expressed in subsets of cells that differ in their biochemical, morphologic and functional characteristics. The level of expression of CCK was also monitored during mouse cortical development and the appearance of CCK RNA was compared to glutamate decarboxylase (GAD), enkephalin and somatostatin. It was noted that each of these cortical markers was first expressed at different times during cortical development. The appearance of CCK RNA during intestinal development was also measured and found to precede appearance in cortex by several days. Images PMID:2011497

  19. Brca1 is required for embryonic development of the mouse cerebral cortex to normal size by preventing apoptosis of early neural progenitors.

    PubMed

    Pulvers, Jeremy N; Huttner, Wieland B

    2009-06-01

    The extent of apoptosis of neural progenitors is known to influence the size of the cerebral cortex. Mouse embryos lacking Brca1, the ortholog of the human breast cancer susceptibility gene BRCA1, show apoptosis in the neural tube, but the consequences of this for brain development have not been studied. Here we investigated the role of Brca1 during mouse embryonic cortical development by deleting floxed Brca1 using Emx1-Cre, which leads to conditional gene ablation specifically in the dorsal telencephalon after embryonic day (E) 9.5. The postnatal Brca1-ablated cerebral cortex was substantially reduced in size with regard to both cortical thickness and surface area. Remarkably, although the thickness of the cortical layers (except for the upper-most layer) was decreased, cortical layering as such was essentially unperturbed. High levels of apoptosis were found at E11.5 and E13.5, but dropped to near-control levels by E16.5. The apoptosis at the early stage of neurogenesis occurred in both BrdU pulse-labeled neural progenitors and the neurons derived therefrom. No changes were observed in the mitotic index of apical (neuroepithelial, radial glial) progenitors and basal (intermediate) progenitors, indicating that Brca1 ablation did not affect cell cycle progression. Brca1 ablation did, however, result in the nuclear translocation of p53 in neural progenitors, suggesting that their apoptosis involved activation of the p53 pathway. Our results show that Brca1 is required for the cerebral cortex to develop to normal size by preventing the apoptosis of early cortical progenitors and their immediate progeny. PMID:19403657

  20. Analysing coupling architecture in the cortical EEG of a patient with unilateral cerebral palsy

    NASA Astrophysics Data System (ADS)

    Kornilov, Maksim V.; Baas, C. Marjolein; van Rijn, Clementina M.; Sysoev, Ilya V.

    2016-04-01

    The detection of coupling presence and direction between cortical areas from the EEG is a popular approach in neuroscience. Granger causality method is promising for this task, since it allows to operate with short time series and to detect nonlinear coupling or coupling between nonlinear systems. In this study EEG multichannel data from adolescent children, suffering from unilateral cerebral palsy were investigated. Signals, obtained in rest and during motor activity of affected and less affected hand, were analysed. The changes in inter-hemispheric and intra-hemispheric interactions were studied over time with an interval of two months. The obtained results of coupling were tested for significance using surrogate times series. In the present proceeding paper we report the data of one patient. The modified nonlinear Granger causality is indeed able to reveal couplings within the human brain.

  1. Characterization of rat cerebral cortical beta adrenoceptor subtypes using (-)-( sup 125 I)-iodocyanopindolol

    SciTech Connect

    Tiong, A.H.; Richardson, J.S. )

    1990-01-01

    (-)-(125I)-Iodocyanopindolol (-(ICYP)), used to characterize beta adrenoceptors on membrane preparations from rat cerebral cortex, was shown to have affinity for both beta adrenoceptors and serotonin receptors. Therefore, 10 microM serotonin was added to the assays to prevent (-)ICYP binding to serotonin receptors. Under these conditions, (-)ICYP binding to the cortical membrane preparation was reversible and saturable, and the association reaction was very slow. The dissociation reaction was also very slow, and revealed two affinity states corresponding to a high and a low affinity state. Scatchard analysis showed a single class of binding sites with an equilibrium dissociation constant (KD) of 20.7 pM, and a maximal density of binding sites (Bmax) of 95.1 fmol/mg membrane protein. Displacement binding analyses revealed a potency series of (-) isoproterenol greater than (-) epinephrine equal to (-) norepinephrine, suggesting a predominance of the beta 1 adrenoceptor subtype. Detailed competition ligand binding studies with the selective beta 1 adrenoceptor antagonist ICI-89406 and the selective beta 2 adrenoceptor antagonist ICI-118551, showed that about 70% of the beta adrenoceptor population in the rat cortex is of the beta 1 subtype with the remainder being of the beta 2 subtype. We conclude that since (-)ICYP binds to both beta adrenoceptors and serotonin receptors, it is important to prevent the binding of (-)ICYP to serotonin receptors by adding a suppressing ligand like excess cold serotonin when assaying beta adrenoceptors. We have presented the first such characterization of rat cerebral cortical beta adrenoceptors with (-)ICYP in this study.

  2. High Intracranial Pressure Effects on Cerebral Cortical Microvascular Flow in Rats

    PubMed Central

    Bush, Rachel C.; Müller, Wolfgang S.; Nemoto, Edwin M.

    2011-01-01

    Abstract To manage patients with high intracranial pressure (ICP), clinicians need to know the critical cerebral perfusion pressure (CPP) required to maintain cerebral blood flow (CBF). Historically, the critical CPP obtained by decreasing mean arterial pressure (MAP) to lower CPP was 60 mm Hg, which fell to 30 mm Hg when CPP was reduced by increasing ICP. We examined whether this decrease in critical CPP was due to a pathological shift from capillary (CAP) to high-velocity microvessel flow or thoroughfare channel (TFC) shunt flow. Cortical microvessel red blood cell velocity and NADH fluorescence were measured by in vivo two-photon laser scanning microscopy in rats at CPP of 70, 50, and 30 mm Hg by increasing ICP or decreasing MAP. Water content was measured by wet/dry weight, and cortical perfusion by laser Doppler flux. Reduction of CPP by raising ICP increased TFC shunt flow from 30.4±2.3% to 51.2±5.2% (mean±SEM, p<0.001), NADH increased by 20.3±6.8% and 58.1±8.2% (p<0.01), and brain water content from 72.9±0.47% to 77.8±2.42% (p<0.01). Decreasing CPP by MAP decreased TFC shunt flow with a smaller rise in NADH and no edema. Doppler flux decreased less with increasing ICP than decreasing MAP. The decrease seen in the critical CPP with increased ICP is likely due to a redistribution of microvascular flow from capillary to microvascular shunt flow or TFC shunt flow, resulting in a pathologically elevated CBF associated with tissue hypoxia and brain edema, characteristic of non-nutritive shunt flow. PMID:21395499

  3. Cerebral Cortical Thickness in Chronic Pain Due to Knee Osteoarthritis: The Effect of Pain Duration and Pain Sensitization

    PubMed Central

    2016-01-01

    Objective This study investigates associations between cortical thickness and pain duration, and central sensitization as markers of pain progression in painful knee osteoarthritis. Methods Whole brain cortical thickness and pressure pain thresholds were assessed in 70 participants; 40 patients with chronic painful knee osteoarthritis (age = 66.1± 8.5 years, 21 females, mean duration of pain = 8.5 years), and 30 healthy controls (age = 62.7± 7.4, 17 females). Results Cortical thickness negatively correlated with pain duration mainly in fronto-temporal areas outside of classical pain processing areas (p<0.05, age-controlled, FDR corrected). Pain sensitivity was unrelated to cortical thickness. Patients showed lower cortical thickness in the right anterior insula (p<0.001, uncorrected) with no changes surviving multiple test correction. Conclusion With increasing number of years of suffering from chronic arthritis pain we found increasing cortical thinning in extended cerebral cortical regions beyond recognised pain-processing areas. While the mechanisms of cortical thinning remain to be elucidated, we show that pain progression indexed by central sensitization does not play a major role. PMID:27658292

  4. Morphine enhances the release of /sup 3/H-purines from rat brain cerebral cortical prisms

    SciTech Connect

    Wu, P.H.; Phillis, J.W.; Yuen, H.

    1982-10-01

    In vitro experiments have shown that /sup 3/H-purines can be released from /sup 3/H-adenosine preloaded rat brain cortical prisms by a KCl-evoked depolarization. The KCl-evoked release of /sup 3/H-purines is dependent on the concentration of KCl present in the superfusate. At concentrations of 10(-7) approximately 10(-5)M morphine did not influence the basal release of /sup 3/H-purines from the prisms, although it enhanced the KCl-evoked release of /sup 3/H-purines. The enhancement of KCl-evoked /sup 3/H-purine release by morphine was concentration-dependent and was antagonized by naloxone, suggesting the involvement of opiate receptors. Uptake studies with rat brain cerebral cortical synaptosomes show that morphine is a very weak inhibitor of adenosine uptake. Comparisons with dipyridamole, a potent inhibitor of adenosine uptake, suggest that this low level of inhibition of the uptake did not contribute significantly to the release of /sup 3/H-purine by morphine seen in our experiments. It is therefore suggested that morphine enhances KCl-evoked /sup 3/H-purine release by an interaction with opiate receptors and that the resultant increase in extracellular purine (adenosine) levels may account for some of the actions of morphine.

  5. HIV-Associated Distal Neuropathic Pain is Associated with Smaller Total Cerebral Cortical Gray Matter

    PubMed Central

    Keltner, John R.; Fennema-Notestine, Christine; Vaida, Florin; Wang, Dongzhe; Franklin, Donald R.; Dworkin, Robert H.; Sanders, Chelsea; McCutchan, J. Allen; Archibald, Sarah L.; Miller, David J.; Kesidis, George; Cushman, Clint; Kim, Sung Min; Abramson, Ian; Taylor, Michael J.; Theilmann, Rebecca J.; Julaton, Michelle D.; Notestine, Randy J.; Corkran, Stephanie; Cherner, Mariana; Duarte, Nichole A.; Alexander, Terry; Robinson-Papp, Jessica; Gelman, Benjamin B.; Simpson, David M.; Collier, Ann C.; Marra, Christina M.; Morgello, Susan; Brown, Greg; Grant, Igor; Atkinson, J. Hampton; Jernigan, Terry L.; Ellis, Ronald J.

    2014-01-01

    Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance. PMID:24549970

  6. Optical coherence microscopy of mouse cortical vasculature surrounding implanted electrodes

    NASA Astrophysics Data System (ADS)

    Hammer, Daniel X.; Lozzi, Andrea; Abliz, Erkinay; Greenbaum, Noah; Turner, Kevin P.; Pfefer, T. Joshua; Agrawal, Anant; Krauthamer, Victor; Welle, Cristin G.

    2014-03-01

    Optical coherence microscopy (OCM) provides real-time, in-vivo, three-dimensional, isotropic micron-resolution structural and functional characterization of tissue, cells, and other biological targets. Optical coherence angiography (OCA) also provides visualization and quantification of vascular flow via speckle-based or phase-resolved techniques. Performance assessment of neuroprosthetic systems, which allow direct thought control of limb prostheses, may be aided by OCA. In particular, there is a need to examine the underlying mechanisms of chronic functional degradation of implanted electrodes. Angiogenesis, capillary network remodeling, and changes in flow velocity are potential indicators of tissue changes that may be associated with waning electrode performance. The overall goal of this investigation is to quantify longitudinal changes in vascular morphology and capillary flow around neural electrodes chronically implanted in mice. We built a 1315-nm OCM system to image vessels in neocortical tissue in a cohort of mice. An optical window was implanted on the skull over the primary motor cortex above a penetrating shank-style microelectrode array. The mice were imaged bi-weekly to generate vascular maps of the region surrounding the implanted microelectrode array. Acute effects of window and electrode implantation included vessel dilation and profusion of vessels in the superficial layer of the cortex (0-200 μm). In deeper layers surrounding the electrode, no qualitative differences were seen in this early phase. These measurements establish a baseline vascular tissue response from the cortical window preparation and lay the ground work for future longitudinal studies to test the hypothesis that vascular changes will be associated with chronic electrode degradation.

  7. Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse

    PubMed Central

    Joshi, Abhilasha; Viney, Tim J.; Kis, Viktor

    2015-01-01

    processes. During wakefulness and rapid eye movement sleep, the rhythmic firing of cortical GABAergic neurons plays a key role in governing network activity. We investigated subcortical GABAergic projections in the mouse that extend from the medial septum/diagonal band nuclei to GABAergic neurons in the hippocampus and related extrahippocampal cortical areas, including the medial entorhinal cortex. These areas contribute to navigation and show theta rhythmic activity. We found selective GABAergic targeting of different groups of cortical GABAergic neurons, immunoreactive for combinations of cell-type markers. As septal GABAergic neurons also fire rhythmically, their selective innervation of cortical GABAergic neurons suggests an oscillatory synchronization of neuronal activity across functionally related areas. PMID:26631464

  8. CEREBRAL CORTICAL MICROVASCULAR RAREFACTION IN METABOLIC SYNDROME IS DEPENDENT ON INSULIN RESISTANCE AND LOSS OF NITRIC OXIDE BIOAVAILABILITY

    PubMed Central

    Chantler, Paul D.; Shrader, Carl D.; Tabone, Lawrence E.; d’Audiffret, Alexandre C.; Huseynova, Khumara; Brooks, Steven D.; Branyan, Kayla W.; Grogg, Kristin A.; Frisbee, Jefferson C.

    2015-01-01

    Objective Chronic presentation of the metabolic syndrome (MS) is associated with an increased likelihood for stroke and poor stroke outcomes following occlusive cerebrovascular events. However, the physiological mechanisms contributing to compromised outcomes remain unclear, and the degree of cerebral cortical microvascular density (MVD) may represent a central determinant of stroke outcomes. Methods This study used the obese Zucker rat (OZR) model of MS and clinically-relevant, chronic interventions to determine the impact on cerebral cortical microvascular rarefaction via immunohistochemistry with a parallel determination of cerebrovascular function to identify putative mechanistic contributors. Results OZR exhibited a progressive rarefaction (to ~80% control MVD) of the cortical microvascular networks vs. lean Zucker rats. Chronic treatment with anti-hypertensive agents (captopril/hydralazine) had limited effectiveness in blunting rarefaction, although treatments improving glycemic control (metformin/rosiglitazone) were superior, maintaining ~94% control MVD. Chronic treatment with the antioxidant TEMPOL severely blunted rarefaction in OZR, although this ameliorative effect was prevented by concurrent NOS inhibition. Conclusions Further analyses revealed that the maintenance of glycemic control and vascular nitric oxide bioavailability were stronger predictors of cerebral cortical MVD in OZR than was prevention of hypertension, and this may have implications for chronic treatment of CVD risk under stroke-prone conditions. PMID:26014499

  9. A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.

    PubMed

    Nada, Shadia E; Tulsulkar, Jatin; Raghavan, Aparna; Hensley, Kenneth; Shah, Zahoor A

    2012-12-01

    Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LKE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti-inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LKE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in vivo studies showed that LKE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LKE pretreated mice, suggesting that LKE's neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP-1 and higher activity of SIRT-1 was also observed in LKE treated group suggesting its anti-apoptotic properties. Our results suggest that LKE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed to CRMP2 mediated action and PARP-1/SIRT-1 modulation. PMID:23036362

  10. A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.

    PubMed

    Nada, Shadia E; Tulsulkar, Jatin; Raghavan, Aparna; Hensley, Kenneth; Shah, Zahoor A

    2012-12-01

    Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LKE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti-inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LKE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in vivo studies showed that LKE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LKE pretreated mice, suggesting that LKE's neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP-1 and higher activity of SIRT-1 was also observed in LKE treated group suggesting its anti-apoptotic properties. Our results suggest that LKE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed to CRMP2 mediated action and PARP-1/SIRT-1 modulation.

  11. Layer-specific cholinergic control of human and mouse cortical synaptic plasticity.

    PubMed

    Verhoog, Matthijs B; Obermayer, Joshua; Kortleven, Christian A; Wilbers, René; Wester, Jordi; Baayen, Johannes C; De Kock, Christiaan P J; Meredith, Rhiannon M; Mansvelder, Huibert D

    2016-01-01

    Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans. PMID:27604129

  12. Predicting cortical bone adaptation to axial loading in the mouse tibia

    PubMed Central

    Pereira, A. F.; Javaheri, B.; Pitsillides, A. A.; Shefelbine, S. J.

    2015-01-01

    The development of predictive mathematical models can contribute to a deeper understanding of the specific stages of bone mechanobiology and the process by which bone adapts to mechanical forces. The objective of this work was to predict, with spatial accuracy, cortical bone adaptation to mechanical load, in order to better understand the mechanical cues that might be driving adaptation. The axial tibial loading model was used to trigger cortical bone adaptation in C57BL/6 mice and provide relevant biological and biomechanical information. A method for mapping cortical thickness in the mouse tibia diaphysis was developed, allowing for a thorough spatial description of where bone adaptation occurs. Poroelastic finite-element (FE) models were used to determine the structural response of the tibia upon axial loading and interstitial fluid velocity as the mechanical stimulus. FE models were coupled with mechanobiological governing equations, which accounted for non-static loads and assumed that bone responds instantly to local mechanical cues in an on–off manner. The presented formulation was able to simulate the areas of adaptation and accurately reproduce the distributions of cortical thickening observed in the experimental data with a statistically significant positive correlation (Kendall's τ rank coefficient τ = 0.51, p < 0.001). This work demonstrates that computational models can spatially predict cortical bone mechanoadaptation to a time variant stimulus. Such models could be used in the design of more efficient loading protocols and drug therapies that target the relevant physiological mechanisms. PMID:26311315

  13. Layer-specific cholinergic control of human and mouse cortical synaptic plasticity

    PubMed Central

    Verhoog, Matthijs B.; Obermayer, Joshua; Kortleven, Christian A.; Wilbers, René; Wester, Jordi; Baayen, Johannes C.; De Kock, Christiaan P. J.; Meredith, Rhiannon M.; Mansvelder, Huibert D.

    2016-01-01

    Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans. PMID:27604129

  14. A method for isolating high quality RNA from mouse cortical and cancellous bone.

    PubMed

    Kelly, Natalie H; Schimenti, John C; Patrick Ross, F; van der Meulen, Marjolein C H

    2014-11-01

    The high incidence of fragility fractures in cortico-cancellous bone locations, plus the fact that individual skeletal sites exhibit different responsiveness to load and disease, emphasizes the need to document separately gene expression in cortical and cancellous bone. A further confounding factor is marrow contamination since its high cellularity may effect gene expression measurements. We isolated RNA from cortical and cancellous bone of intact mouse tibiae, and also after marrow removal by flushing or centrifugation. RNA isolated from cancellous bone by each method was sufficient for gene expression analysis. Centrifugation removed contaminating cells more efficiently than flushing, as indexed by histology and decreased expression of Icam4, a highly expressed erythroid gene. In contrast, centrifuged cortical bone had 12- and 13- fold higher expression of the bone-related genes Col1a1 and Bglap, while levels in marrow-free cancellous bone were 30- and 31-fold higher when compared to bone where marrow was left intact. Furthermore, cortical bone had higher expression of Col1a1 and Bglap than cancellous bone. Thus, RNA isolated by this novel approach can reveal site-specific changes in gene expression in cortical and cancellous bone sites. PMID:25073031

  15. Lamin B1 protein is required for dendrite development in primary mouse cortical neurons

    PubMed Central

    Giacomini, Caterina; Mahajani, Sameehan; Ruffilli, Roberta; Marotta, Roberto; Gasparini, Laura

    2016-01-01

    Lamin B1, a key component of the nuclear lamina, plays an important role in brain development and function. A duplication of the human lamin B1 (LMNB1) gene has been linked to adult-onset autosomal dominant leukodystrophy, and mouse and human loss-of-function mutations in lamin B1 are susceptibility factors for neural tube defects. In the mouse, experimental ablation of endogenous lamin B1 (Lmnb1) severely impairs embryonic corticogenesis. Here we report that in primary mouse cortical neurons, LMNB1 overexpression reduces axonal outgrowth, whereas deficiency of endogenous Lmnb1 results in aberrant dendritic development. In the absence of Lmnb1, both the length and complexity of dendrites are reduced, and their growth is unresponsive to KCl stimulation. This defective dendritic outgrowth stems from impaired ERK signaling. In Lmnb1-null neurons, ERK is correctly phosphorylated, but phospho-ERK fails to translocate to the nucleus, possibly due to delocalization of nuclear pore complexes (NPCs) at the nuclear envelope. Taken together, these data highlight a previously unrecognized role of lamin B1 in dendrite development of mouse cortical neurons through regulation of nuclear shuttling of specific signaling molecules and NPC distribution. PMID:26510501

  16. Children with cerebral palsy have uncharacteristic somatosensory cortical oscillations after stimulation of the hand mechanoreceptors.

    PubMed

    Kurz, M J; Becker, K M; Heinrichs-Graham, E; Wilson, T W

    2015-10-01

    Numerous clinical investigations have reported that children with cerebral palsy (CP) have tactile discrimination deficits that likely limit their ability to plan and manipulate objects. Despite this clinical awareness, we still have a substantial knowledge gap in our understanding of the neurological basis for these tactile discrimination deficits. Previously, we have shown that children with CP have aberrant theta-alpha (4-14 Hz) oscillations in the somatosensory cortices following tactile stimulation of the foot. In this investigation, we evaluated if these aberrant theta-alpha oscillations also extend to the hand. Magnetoencephalography was used to evaluate event-related changes in the theta-alpha and beta (18-34 Hz) somatosensory cortical oscillations in groups of children with CP and typically developing (TD) children following tactile stimulation of their hands. Our results showed that the somatosensory theta-alpha oscillations were relatively intact in children with CP, which is in contrast to our previous results for foot tactile stimulations. We suspect that these inter-study differences may be related to the higher probability that the neural tracts serving the lower extremities are damaged in children with CP, compared to those serving the upper extremities. This inference is plausible since the participating children with CP had Manual Ability Classification System (MACS) levels between I and II. In contrast to the theta-alpha results, children with CP did exhibit a sharp increase in beta activity during the same time period, which was not observed in TD children. This suggests that children with CP still have deficits in the computational aspect of somatosensory processing.

  17. Upper Limb Function and Cortical Organization in Youth with Unilateral Cerebral Palsy

    PubMed Central

    Mackey, Anna; Stinear, Cathy; Stott, Susan; Byblow, Winston D.

    2014-01-01

    Aim: To explore the relationship between motor cortical and descending motor pathway reorganization, lesion type, and upper limb function in youth with unilateral cerebral palsy (CP). Methods: Twenty participants with unilateral CP (mean age 15 ± 3 years; 11 males) completed a range of upper limb functional measures. Structural MRI, diffusion-weighted, and functional MRI were conducted to determine type and extent of brain lesion, descending white matter integrity, and whole-brain activity during affected hand use. Single pulse transcranial magnetic stimulation (TMS) (n = 12) was used to examine functional integrity of the corticospinal pathway as well as primary motor cortex intracortical and interhemispheric inhibition from motor-evoked potentials and silent periods. Results: Fractional anisotropy measures within the posterior limb of the internal capsule were a predictor of upper limb function (R2 = 0.41, F = 11.3, p = 0.004). Participants with periventricular lesions tended to have better upper limb function [F(2, 17) = 42.48, p < 0.0001]. Five participants with evidence of cortical reorganization and functional ipsilateral projections to their affected hand had worse upper limb function. Deficits in intracortical and interhemispheric inhibitory mechanisms were found in participants with worse upper limb function (Melbourne Assessment of Unilateral Upper Limb Function: Mann Whitney p = 0.02). Conclusion: Neuroimaging and TMS can provide useful information related to hand function of individuals with unilateral CP and may have potential to assist as a predictive tool and/or guide rehabilitation. PMID:25071705

  18. Children with cerebral palsy have uncharacteristic somatosensory cortical oscillations after stimulation of the hand mechanoreceptors.

    PubMed

    Kurz, M J; Becker, K M; Heinrichs-Graham, E; Wilson, T W

    2015-10-01

    Numerous clinical investigations have reported that children with cerebral palsy (CP) have tactile discrimination deficits that likely limit their ability to plan and manipulate objects. Despite this clinical awareness, we still have a substantial knowledge gap in our understanding of the neurological basis for these tactile discrimination deficits. Previously, we have shown that children with CP have aberrant theta-alpha (4-14 Hz) oscillations in the somatosensory cortices following tactile stimulation of the foot. In this investigation, we evaluated if these aberrant theta-alpha oscillations also extend to the hand. Magnetoencephalography was used to evaluate event-related changes in the theta-alpha and beta (18-34 Hz) somatosensory cortical oscillations in groups of children with CP and typically developing (TD) children following tactile stimulation of their hands. Our results showed that the somatosensory theta-alpha oscillations were relatively intact in children with CP, which is in contrast to our previous results for foot tactile stimulations. We suspect that these inter-study differences may be related to the higher probability that the neural tracts serving the lower extremities are damaged in children with CP, compared to those serving the upper extremities. This inference is plausible since the participating children with CP had Manual Ability Classification System (MACS) levels between I and II. In contrast to the theta-alpha results, children with CP did exhibit a sharp increase in beta activity during the same time period, which was not observed in TD children. This suggests that children with CP still have deficits in the computational aspect of somatosensory processing. PMID:26235434

  19. Sanguinate's effect on pial arterioles in healthy rats and cerebral oxygen tension after controlled cortical impact.

    PubMed

    Mullah, Saad H; Abutarboush, Rania; Moon-Massat, Paula F; Saha, Biswajit K; Haque, Ashraful; Walker, Peter B; Auker, Charles R; Arnaud, Francoise G; McCarron, Richard M; Scultetus, Anke H

    2016-09-01

    Sanguinate, a polyethylene glycol-conjugated carboxyhemoglobin, was investigated for cerebral vasoactivity in healthy male Sprague-Dawley rats (Study 1) and for its ability to increase brain tissue oxygen pressure (PbtO2) after controlled cortical impact (CCI) - traumatic brain injury (TBI) (Study 2). In both studies ketamine-acepromazine anesthetized rats were ventilated with 40% O2. In Study 1, a cranial window was used to measure the diameters of medium - (50-100μm) and small-sized (<50μm) pial arterioles before and after four serial infusions of Sanguinate (8mL/kg/h, cumulative 16mL/kg IV), volume-matched Hextend, or normal saline. In Study 2, PbtO2 was measured using a phosphorescence quenching method before TBI, 15min after TBI (T15) and then every 10min thereafter for 155min. At T15, rats received either 8mL/kg IV Sanguinate (40mL/kg/h) or no treatment (saline, 4mL/kg/h). Results showed: 1) in healthy rats, percentage changes in pial arteriole diameter were the same among the groups, 2) in TBI rats, PbtO2 decreased from 36.5±3.9mmHg to 19.8±3.0mmHg at T15 in both groups after TBI and did not recover in either group for the rest of the study, and 3) MAP increased 16±4mmHg and 36±5mmHg after Sanguinate in healthy and TBI rats, respectively, while MAP was unchanged in control groups. In conclusion, Sanguinate did not cause vasoconstriction in the cerebral pial arterioles of healthy rats but it also did not acutely increase PbtO2 when administered after TBI. Sanguinate was associated with an increase in MAP in both studies.

  20. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication

    PubMed Central

    Jiang, Zhiwu; Gu, Liming; Chen, Yanxia

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  1. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication.

    PubMed

    Wang, Gefei; Li, Rui; Jiang, Zhiwu; Gu, Liming; Chen, Yanxia; Dai, Jianping; Li, Kangsheng

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  2. Visual cortical areas of the mouse: comparison of parcellation and network structure with primates

    PubMed Central

    Laramée, Marie-Eve; Boire, Denis

    2015-01-01

    Brains have evolved to optimize sensory processing. In primates, complex cognitive tasks must be executed and evolution led to the development of large brains with many cortical areas. Rodents do not accomplish cognitive tasks of the same level of complexity as primates and remain with small brains both in relative and absolute terms. But is a small brain necessarily a simple brain? In this review, several aspects of the visual cortical networks have been compared between rodents and primates. The visual system has been used as a model to evaluate the level of complexity of the cortical circuits at the anatomical and functional levels. The evolutionary constraints are first presented in order to appreciate the rules for the development of the brain and its underlying circuits. The organization of sensory pathways, with their parallel and cross-modal circuits, is also examined. Other features of brain networks, often considered as imposing constraints on the development of underlying circuitry, are also discussed and their effect on the complexity of the mouse and primate brain are inspected. In this review, we discuss the common features of cortical circuits in mice and primates and see how these can be useful in understanding visual processing in these animals. PMID:25620914

  3. Quantitative map of multiple auditory cortical regions with a stereotaxic fine-scale atlas of the mouse brain

    PubMed Central

    Tsukano, Hiroaki; Horie, Masao; Hishida, Ryuichi; Takahashi, Kuniyuki; Takebayashi, Hirohide; Shibuki, Katsuei

    2016-01-01

    Optical imaging studies have recently revealed the presence of multiple auditory cortical regions in the mouse brain. We have previously demonstrated, using flavoprotein fluorescence imaging, at least six regions in the mouse auditory cortex, including the anterior auditory field (AAF), primary auditory cortex (AI), the secondary auditory field (AII), dorsoanterior field (DA), dorsomedial field (DM), and dorsoposterior field (DP). While multiple regions in the visual cortex and somatosensory cortex have been annotated and consolidated in recent brain atlases, the multiple auditory cortical regions have not yet been presented from a coronal view. In the current study, we obtained regional coordinates of the six auditory cortical regions of the C57BL/6 mouse brain and illustrated these regions on template coronal brain slices. These results should reinforce the existing mouse brain atlases and support future studies in the auditory cortex. PMID:26924462

  4. Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development.

    PubMed

    Ohtaka-Maruyama, Chiaki; Okado, Haruo

    2015-01-01

    Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis. PMID:26733777

  5. Computational model of cerebral blood flow redistribution during cortical spreading depression

    NASA Astrophysics Data System (ADS)

    Verisokin, Andrey Y.; Verveyko, Darya V.; Postnov, Dmitry E.

    2016-04-01

    In recent decades modelling studies on cortical spreading depression (CSD) and migraine waves successfully contributed to formation of modern view on these fundamental phenomena of brain physiology. However, due to the extreme complexity of object under study (brain cortex) and the diversity of involved physiological pathways, the development of new mathematical models of CSD is still a very relevant and challenging research problem. In our study we follow the functional modelling approach aimed to map the action of known physiological pathways to the specific nonlinear mechanisms that govern formation and evolution of CSD wave patterns. Specifically, we address the role of cerebral blood flow (CBF) redistribution that is caused by excessive neuronal activity by means of neurovascular coupling and mediates a spatial pattern of oxygen and glucose delivery. This in turn changes the local metabolic status of neural tissue. To build the model we simplify the web of known cell-to-cell interactions within a neurovascular unit by selecting the most relevant ones, such as local neuron-induced elevation of extracellular potassium concentration and biphasic response of arteriole radius. We propose the lumped description of distance-dependent hemodynamic coupling that fits the most recent experimental findings.

  6. Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development

    PubMed Central

    Ohtaka-Maruyama, Chiaki; Okado, Haruo

    2015-01-01

    Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis. PMID:26733777

  7. Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development.

    PubMed

    Ohtaka-Maruyama, Chiaki; Okado, Haruo

    2015-01-01

    Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis.

  8. Statistical Analysis of Tract-Tracing Experiments Demonstrates a Dense, Complex Cortical Network in the Mouse

    PubMed Central

    Ypma, Rolf J. F.; Bullmore, Edward T.

    2016-01-01

    Anatomical tract tracing methods are the gold standard for estimating the weight of axonal connectivity between a pair of pre-defined brain regions. Large studies, comprising hundreds of experiments, have become feasible by automated methods. However, this comes at the cost of positive-mean noise making it difficult to detect weak connections, which are of particular interest as recent high resolution tract-tracing studies of the macaque have identified many more weak connections, adding up to greater connection density of cortical networks, than previously recognized. We propose a statistical framework that estimates connectivity weights and credibility intervals from multiple tract-tracing experiments. We model the observed signal as a log-normal distribution generated by a combination of tracer fluorescence and positive-mean noise, also accounting for injections into multiple regions. Using anterograde viral tract-tracing data provided by the Allen Institute for Brain Sciences, we estimate the connection density of the mouse intra-hemispheric cortical network to be 73% (95% credibility interval (CI): 71%, 75%); higher than previous estimates (40%). Inter-hemispheric density was estimated to be 59% (95% CI: 54%, 62%). The weakest estimable connections (about 6 orders of magnitude weaker than the strongest connections) are likely to represent only one or a few axons. These extremely weak connections are topologically more random and longer distance than the strongest connections, which are topologically more clustered and shorter distance (spatially clustered). Weak links do not substantially contribute to the global topology of a weighted brain graph, but incrementally increased topological integration of a binary graph. The topology of weak anatomical connections in the mouse brain, rigorously estimable down to the biological limit of a single axon between cortical areas in these data, suggests that they might confer functional advantages for integrative

  9. Statistical Analysis of Tract-Tracing Experiments Demonstrates a Dense, Complex Cortical Network in the Mouse.

    PubMed

    Ypma, Rolf J F; Bullmore, Edward T

    2016-09-01

    Anatomical tract tracing methods are the gold standard for estimating the weight of axonal connectivity between a pair of pre-defined brain regions. Large studies, comprising hundreds of experiments, have become feasible by automated methods. However, this comes at the cost of positive-mean noise making it difficult to detect weak connections, which are of particular interest as recent high resolution tract-tracing studies of the macaque have identified many more weak connections, adding up to greater connection density of cortical networks, than previously recognized. We propose a statistical framework that estimates connectivity weights and credibility intervals from multiple tract-tracing experiments. We model the observed signal as a log-normal distribution generated by a combination of tracer fluorescence and positive-mean noise, also accounting for injections into multiple regions. Using anterograde viral tract-tracing data provided by the Allen Institute for Brain Sciences, we estimate the connection density of the mouse intra-hemispheric cortical network to be 73% (95% credibility interval (CI): 71%, 75%); higher than previous estimates (40%). Inter-hemispheric density was estimated to be 59% (95% CI: 54%, 62%). The weakest estimable connections (about 6 orders of magnitude weaker than the strongest connections) are likely to represent only one or a few axons. These extremely weak connections are topologically more random and longer distance than the strongest connections, which are topologically more clustered and shorter distance (spatially clustered). Weak links do not substantially contribute to the global topology of a weighted brain graph, but incrementally increased topological integration of a binary graph. The topology of weak anatomical connections in the mouse brain, rigorously estimable down to the biological limit of a single axon between cortical areas in these data, suggests that they might confer functional advantages for integrative

  10. Diphenyl diselenide administration enhances cortical mitochondrial number and activity by increasing hemeoxygenase type 1 content in a methylmercury-induced neurotoxicity mouse model.

    PubMed

    Glaser, Viviane; Martins, Roberta de Paula; Vieira, Ana Julia Hoffmann; Oliveira, Eliana de Medeiros; Straliotto, Marcos Raniel; Mukdsi, Jorge Humberto; Torres, Alicia Inés; de Bem, Andreza Fabro; Farina, Marcelo; da Rocha, João Batista Teixeira; De Paul, Ana Lucia; Latini, Alexandra

    2014-05-01

    Interest in biochemistry of organoselenium compound has increased in the last decades, mainly due to their chemical and biological activities. Here, we investigated the protective effect of diphenyl diselenide (PhSe)2 (5 μmol/kg), in a mouse model of methylmercury (MeHg)-induced brain toxicity. Swiss male mice were divided into four experimental groups: control, (PhSe)2 (5 μmol/kg, subcutaneous administration), MeHg (40 mg/L, in tap water), and MeHg + (PhSe)2. After the treatment (21 days), the animals were killed and the cerebral cortex was analyzed. Electron microscopy indicated an enlarged and fused mitochondria leading to a reduced number of organelles, in the MeHg-exposed mice. Furthermore, cortical creatine kinase activity, a sensitive mitochondrial oxidative stress sensor, was almost abolished by MeHg. Subcutaneous (PhSe)2 co-treatment rescued from MeHg-induced mitochondrial alterations. (PhSe)2 also behaved as an enhancer of mitochondrial biogenesis, by increasing cortical mitochondria content in mouse-receiving (PhSe)2 alone. Mechanistically, (PhSe)2 (1 μM; 24 h) would trigger the cytoprotective Nrf-2 pathway for activating target genes, since astroglial cells exposed to the chalcogen showed increased content of hemeoxygenase type 1, a sensitive marker of the activation of this via. Thus, it is proposed that the (PhSe)2-neuroprotective effect might be linked to its mitoprotective activity. PMID:24623265

  11. Milk and dairy consumption correlates with cerebral cortical as well as cerebral white matter volume in healthy young adults.

    PubMed

    Darnai, Gergely; Plózer, Enikő; Perlaki, Gábor; Orsi, Gergely; Nagy, Szilvia Anett; Horváth, Réka; Schwarcz, Attila; Kovács, Norbert; Altbäcker, Anna; Janszky, József; Clemens, Zsófia

    2015-01-01

    The objective of this study was to investigate the relation between habitual milk and dairy consumption and brain morphology as assessed by magnetic resonance imaging (MRI) investigations in 119 young healthy university students. MRI measurements were performed on a Siemens Magnetom Trio Tim (3T) system while FreeSurfer software suite was used for volumetric segmentation. Dietary habits related to milk and dairy consumption were assessed by a structured questionnaire. Total cerebral cortex, total cerebral white matter, and total cerebral parenchyma were significantly related with cottage cheese and total protein intake from milk and dairy also when controlled for age and gender in the multivariate model. Our results indicate that dietary habits related with milk and dairy are proportionally associated with volumes of both cerebral cortex and cerebral white matter. PMID:26436708

  12. Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex.

    PubMed

    García-Díaz, Beatriz; Riquelme, Raquel; Varela-Nieto, Isabel; Jiménez, Antonio Jesús; de Diego, Isabel; Gómez-Conde, Ana Isabel; Matas-Rico, Elisa; Aguirre, José Ángel; Chun, Jerold; Pedraza, Carmen; Santín, Luis Javier; Fernández, Oscar; Rodríguez de Fonseca, Fernando; Estivill-Torrús, Guillermo

    2015-11-01

    Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases.

  13. Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease.

    PubMed

    Spampanato, J; Gu, X; Yang, X W; Mody, I

    2008-12-01

    Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in huntingtin. A newly developed bacterial artificial chromosome transgenic mouse model (BACHD) reproduces phenotypic features of HD including predominantly neuropil-associated protein aggregation and progressive motor dysfunction with selective neurodegenerative pathology. Motor dysfunction has been shown to precede neuropathology in BACHD mice. We therefore investigated the progression of synaptic pathology in pyramidal cells and interneurons of the superficial motor cortex of BACHD mice. Whole-cell patch clamp recordings were performed on layer 2/3 primary motor cortical pyramidal cells and parvalbumin interneurons from BACHD mice at 3 months, when the mice begin to demonstrate mild motor dysfunction, and at 6 months, when the motor dysfunction is more severe. Changes in synaptic variances were detectable at 3 months, and at 6 months BACHD mice display progressive synaptic pathology in the form of reduced cortical excitation and loss of inhibition onto pyramidal cells. These results suggest that progressive alterations of the superficial cortical circuitry may contribute to the decline of motor function in BACHD mice. The synaptic pathology occurs prior to neuronal degeneration and may therefore prove useful as a target for future therapeutic design. PMID:18854207

  14. Aneuploid cells are differentially susceptible to caspase-mediated death during embryonic cerebral cortical development.

    PubMed

    Peterson, Suzanne E; Yang, Amy H; Bushman, Diane M; Westra, Jurjen W; Yung, Yun C; Barral, Serena; Mutoh, Tetsuji; Rehen, Stevens K; Chun, Jerold

    2012-11-14

    Neural progenitor cells, neurons, and glia of the normal vertebrate brain are diversely aneuploid, forming mosaics of intermixed aneuploid and euploid cells. The functional significance of neural mosaic aneuploidy is not known; however, the generation of aneuploidy during embryonic neurogenesis, coincident with caspase-dependent programmed cell death (PCD), suggests that a cell's karyotype could influence its survival within the CNS. To address this hypothesis, PCD in the mouse embryonic cerebral cortex was attenuated by global pharmacological inhibition of caspases or genetic removal of caspase-3 or caspase-9. The chromosomal repertoire of individual brain cells was then assessed by chromosome counting, spectral karyotyping, fluorescence in situ hybridization, and DNA content flow cytometry. Reducing PCD resulted in markedly enhanced mosaicism that was comprised of increased numbers of cells with the following: (1) numerical aneuploidy (chromosome losses or gains); (2) extreme forms of numerical aneuploidy (>5 chromosomes lost or gained); and (3) rare karyotypes, including those with coincident chromosome loss and gain, or absence of both members of a chromosome pair (nullisomy). Interestingly, mildly aneuploid (<5 chromosomes lost or gained) populations remained comparatively unchanged. These data demonstrate functional non-equivalence of distinguishable aneuploidies on neural cell survival, providing evidence that somatically generated, cell-autonomous genomic alterations have consequences for neural development and possibly other brain functions. PMID:23152605

  15. Regional vulnerability of longitudinal cortical association connectivity: Associated with structural network topology alterations in preterm children with cerebral palsy.

    PubMed

    Ceschin, Rafael; Lee, Vince K; Schmithorst, Vince; Panigrahy, Ashok

    2015-01-01

    Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior-anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior-anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal-thalamic-striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with

  16. Regional vulnerability of longitudinal cortical association connectivity: Associated with structural network topology alterations in preterm children with cerebral palsy.

    PubMed

    Ceschin, Rafael; Lee, Vince K; Schmithorst, Vince; Panigrahy, Ashok

    2015-01-01

    Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior-anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior-anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal-thalamic-striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with

  17. Cortical Somatosensory Reorganization in Children with Spastic Cerebral Palsy: A Multimodal Neuroimaging Study

    PubMed Central

    Papadelis, Christos; Ahtam, Banu; Nazarova, Maria; Nimec, Donna; Snyder, Brian; Grant, Patricia Ellen; Okada, Yoshio

    2014-01-01

    Although cerebral palsy (CP) is among the most common causes of physical disability in early childhood, we know little about the functional and structural changes of this disorder in the developing brain. Here, we investigated with three different neuroimaging modalities [magnetoencephalography (MEG), diffusion tensor imaging (DTI), and resting-state fMRI] whether spastic CP is associated with functional and anatomical abnormalities in the sensorimotor network. Ten children participated in the study: four with diplegic CP (DCP), three with hemiplegic CP (HCP), and three typically developing (TD) children. Somatosensory (SS)-evoked fields (SEFs) were recorded in response to pneumatic stimuli applied to digits D1, D3, and D5 of both hands. Several parameters of water diffusion were calculated from DTI between the thalamus and the pre-central and post-central gyri in both hemispheres. The sensorimotor resting-state networks (RSNs) were examined by using an independent component analysis method. Tactile stimulation of the fingers elicited the first prominent cortical response at ~50 ms, in all except one child, localized over the primary SS cortex (S1). In five CP children, abnormal somatotopic organization was observed in the affected (or more affected) hemisphere. Euclidean distances were markedly different between the two hemispheres in the HCP children, and between DCP and TD children for both hemispheres. DTI analysis revealed decreased fractional anisotropy and increased apparent diffusion coefficient for the thalamocortical pathways in the more affected compared to less affected hemisphere in CP children. Resting-state functional MRI results indicated absent and/or abnormal sensorimotor RSNs for children with HCP and DCP consistent with the severity and location of their lesions. Our findings suggest an abnormal SS processing mechanism in the sensorimotor network of children with CP possibly as a result of diminished thalamocortical projections. PMID:25309398

  18. Rapid Changes in Cortical and Subcortical Brain Regions after Early Bilateral Enucleation in the Mouse

    PubMed Central

    Huffman, Kelly J.

    2015-01-01

    Functional sensory and motor areas in the developing mammalian neocortex are formed through a complex interaction of cortically intrinsic mechanisms, such as gene expression, and cortically extrinsic mechanisms such as those mediated by thalamic input from the senses. Both intrinsic and extrinsic mechanisms are believed to be involved in cortical patterning and the establishment of areal boundaries in early development; however, the nature of the interaction between intrinsic and extrinsic processes is not well understood. In a previous study, we used a perinatal bilateral enucleation mouse model to test some aspects of this interaction by reweighting sensory input to the developing cortex. Visual deprivation at birth resulted in a shift of intraneocortical connections (INCs) that aligned with ectopic ephrin A5 expression in the same location ten days later at postnatal day (P) 10. A prevailing question remained: Does visual deprivation first induce a change in gene expression, followed by a shift in INCs, or vice versa? In the present study, we address this question by investigating the neuroanatomy and patterns of gene expression in post-natal day (P) 1 and 4 mice following bilateral enucleation at birth. Our results demonstrate a rapid reduction in dorsal lateral geniculate nucleus (dLGN) size and ephrin A5 gene expression 24-hours post-enucleation, with more profound effects apparent at P4. The reduced nuclear size and diminished gene expression mirrors subtle changes in ephrin A5 expression evident in P1 and P4 enucleated neocortex, 11 and 8 days prior to natural eye opening, respectively. Somatosensory and visual INCs were indistinguishable between P1 and P4 mice bilaterally enucleated at birth, indicating that perinatal bilateral enucleation initiates a rapid change in gene expression (within one day) followed by an alteration of sensory INCs later on (second postnatal week). With these results, we gain a deeper understanding of how gene expression and

  19. Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons.

    PubMed

    Chen, Xiangdong; Shu, Shaofang; Bayliss, Douglas A

    2005-12-01

    The contributions of the hyperpolarization-activated current, I(h), to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native I(h) in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal I(h) currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating I(h) in cortical neurons at a clinically relevant concentration (5 microM); inhibition of I(h) involved a hyperpolarizing shift in half-activation voltage (DeltaV1/2 approximately -9 mV) and a decrease in maximal available current (approximately 36% inhibition, measured at -120 mV). With the slower form of I(h) expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 muM propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1-HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABA(A) and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the I(h) blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate I(h) in cortical pyramidal neurons-and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells. PMID:16093340

  20. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices

    PubMed Central

    Tremblay, Marie-Ève; Zettel, Martha L.; Ison, James R.; Allen, Paul D.; Majewska, Ania K.

    2011-01-01

    Normal aging is often accompanied by a progressive loss of receptor sensitivity in hearing and vision, whose consequences on cellular function in cortical sensory areas have remained largely unknown. By examining the primary auditory (A1) and visual (V1) cortices in two inbred strains of mice undergoing either age-related loss of audition (C57BL/6J) or vision (CBA/CaJ), we were able to describe cellular and subcellular changes that were associated with normal aging (occurring in A1 and V1 of both strains) or specifically with age-related sensory loss (only in A1 of C57BL/6J or V1 of CBA/CaJ), using immunocytochemical electron microscopy and light microscopy. While the changes were subtle in neurons, glial cells and especially microglia were transformed in aged animals. Microglia became more numerous and irregularly distributed, displayed more variable cell body and process morphologies, occupied smaller territories, and accumulated phagocytic inclusions that often displayed ultrastructural features of synaptic elements. Additionally, evidence of myelination defects were observed, and aged oligodendrocytes became more numerous and were more often encountered in contiguous pairs. Most of these effects were profoundly exacerbated by age-related sensory loss. Together, our results suggest that the age-related alteration of glial cells in sensory cortical areas can be accelerated by activity-driven central mechanisms that result from an age-related loss of peripheral sensitivity. In light of our observations, these age-related changes in sensory function should be considered when investigating cellular, cortical and behavioral functions throughout the lifespan in these commonly used C57BL/6J and CBA/CaJ mouse models. PMID:22223464

  1. Geniculo-Cortical Projection Diversity Revealed within the Mouse Visual Thalamus

    PubMed Central

    Leiwe, Marcus N.; Hendry, Aenea C.; Bard, Andrew D.; Eglen, Stephen J.; Lowe, Andrew S.; Thompson, Ian D.

    2016-01-01

    The mouse dorsal lateral geniculate nucleus (dLGN) is an intermediary between retina and primary visual cortex (V1). Recent investigations are beginning to reveal regional complexity in mouse dLGN. Using local injections of retrograde tracers into V1 of adult and neonatal mice, we examined the developing organisation of geniculate projection columns: the population of dLGN-V1 projection neurons that converge in cortex. Serial sectioning of the dLGN enabled the distribution of labelled projection neurons to be reconstructed and collated within a common standardised space. This enabled us to determine: the organisation of cells within the dLGN-V1 projection columns; their internal organisation (topology); and their order relative to V1 (topography). Here, we report parameters of projection columns that are highly variable in young animals and refined in the adult, exhibiting profiles consistent with shell and core zones of the dLGN. Additionally, such profiles are disrupted in adult animals with reduced correlated spontaneous activity during development. Assessing the variability between groups with partial least squares regression suggests that 4–6 cryptic lamina may exist along the length of the projection column. Our findings further spotlight the diversity of the mouse dLGN–an increasingly important model system for understanding the pre-cortical organisation and processing of visual information. Furthermore, our approach of using standardised spaces and pooling information across many animals will enhance future functional studies of the dLGN. PMID:26727264

  2. Observations on regional cerebral blood flow in cortical and subcortical structures during language production in normal man

    SciTech Connect

    Wallesch, C.W.; Henriksen, L.; Kornhuber, H.H.; Paulson, O.B.

    1985-07-01

    Regional cerebral blood flow (rCBF) was studied by single photon emission computerized tomography (SPECT) of inhaled xenon-133 in six normal volunteers during various language, articulatory, and control conditions. Language production increased rCBF in predominantly left-sided cortical and subcortical areas. The involved regions were anatomically related to a left frontal area (Broca's), to both caudate nuclei, to a left thalamic/pallidal area, and bilaterally in retrorolandic areas. The failure to demonstrate lateralized retrorolandic activity is thought to reflect the complexity of the tasks.

  3. Measurement of local cerebral blood flow with (/sup 14/C)iodoantipyrine in the mouse

    SciTech Connect

    Jay, T.M.; Lucignani, G.; Crane, A.M.; Jehle, J.; Sokoloff, L.

    1988-02-01

    Local cerebral blood flow was measured in the mouse by means of the (/sup 14/C)iodoantipyrine method. This method has been previously used in the monkey, dog, cat, and rat, but its application to small mammals such as the mouse requires special attention to potential sources of error. The small size of the mouse brain requires special attention to the rapid removal and freezing of the brain to minimize effects of postmortem diffusion of tracer in the tissue. Because of the relatively low diameter/length ratios of the catheters needed for arterial sampling in small animals, substantial errors can occur in the determination of the time course of the (/sup 14/C)iodoantipyrine concentration in the arterial blood unless corrections for lag time and dead space washout in the catheter are properly applied. Local cerebral blood flow was measured in seven awake mice with appropriate care to minimize these sources of error. The values were found to vary from 48 ml/100 g/min in the corpus callosum to 198 ml/100 g/min in the inferior colliculus. The results demonstrate that the (/sup 14/C)iodoantipyrine method can be used to measure local cerebral blood flow in the mouse and that the values in that species are, in general, somewhat higher than those in the rat.

  4. The forkhead transcription factors, Foxp1 and Foxp2, identify different subpopulations of projection neurons in the mouse cerebral cortex.

    PubMed

    Hisaoka, T; Nakamura, Y; Senba, E; Morikawa, Y

    2010-03-17

    Foxp1 and Foxp2, which belong to the forkhead transcription factor family, are expressed in the developing and adult mouse brain, including the striatum, thalamus, and cerebral cortex. Recent reports suggest that FOXP1 and FOXP2 are involved in the development of speech and language in humans. Although both Foxp1 and Foxp2 are expressed in the neural circuits that mediate speech and language, including the corticostriatal circuit, the functions of Foxp1 and Foxp2 in the cerebral cortex remain unclear. To gain insight into the functions of Foxp1 and Foxp2 in the cerebral cortex, we characterized Foxp1- and Foxp2-expressing cells in postnatal and adult mice using immunohistochemistry. In adult mice, Foxp1 was expressed in neurons of layers III-VIa in the neocortex, whereas the expression of Foxp2 was restricted to dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa (DARPP-32)(+) neurons of layer VI. In addition, Foxp2 was weakly expressed in the neurons of layer V of the motor cortex and hindlimb and forelimb regions of the primary somatosensory cortex. Both Foxp1 and Foxp2 were expressed in the ionotropic glutamate receptor (GluR) 2/3(+) neurons, and colocalized with none of GluR1, gamma-aminobutyric acid, calbindin, and parvalbumin, indicating that expression of Foxp1 and Foxp2 is restricted to projection neurons. During the postnatal stages, Foxp1 was predominantly expressed in Satb2(+)/Ctip2(-) corticocortical projection neurons of layers III-V and in Tbr1(+) corticothalamic projection neurons of layer VIa. Although Foxp2 was also expressed in Tbr1(+) corticothalamic projection neurons of layer VI, no colocalization of Foxp1 with Foxp2 was observed from postnatal day (P) 0 to P7. These findings suggest that Foxp1 and Foxp2 may be involved in the development of different cortical projection neurons during the early postnatal stages in addition to the establishment and maintenance of different cortical circuits from the late postnatal

  5. Retinal lesions induce fast intrinsic cortical plasticity in adult mouse visual system.

    PubMed

    Smolders, Katrien; Vreysen, Samme; Laramée, Marie-Eve; Cuyvers, Annemie; Hu, Tjing-Tjing; Van Brussel, Leen; Eysel, Ulf T; Nys, Julie; Arckens, Lutgarde

    2016-09-01

    Neuronal activity plays an important role in the development and structural-functional maintenance of the brain as well as in its life-long plastic response to changes in sensory stimulation. We characterized the impact of unilateral 15° laser lesions in the temporal lower visual field of the retina, on visually driven neuronal activity in the afferent visual pathway of adult mice using in situ hybridization for the activity reporter gene zif268. In the first days post-lesion, we detected a discrete zone of reduced zif268 expression in the contralateral hemisphere, spanning the border between the monocular segment of the primary visual cortex (V1) with extrastriate visual area V2M. We could not detect a clear lesion projection zone (LPZ) in areas lateral to V1 whereas medial to V2M, agranular and granular retrosplenial cortex showed decreased zif268 levels over their full extent. All affected areas displayed a return to normal zif268 levels, and this was faster in higher order visual areas than in V1. The lesion did, however, induce a permanent LPZ in the retinorecipient layers of the superior colliculus. We identified a retinotopy-based intrinsic capacity of adult mouse visual cortex to recover from restricted vision loss, with recovery speed reflecting the areal cortical magnification factor. Our observations predict incomplete visual field representations for areas lateral to V1 vs. lack of retinotopic organization for areas medial to V2M. The validation of this mouse model paves the way for future interrogations of cortical region- and cell-type-specific contributions to functional recovery, up to microcircuit level. PMID:26663520

  6. Inferring cortical function in the mouse visual system through large-scale systems neuroscience.

    PubMed

    Hawrylycz, Michael; Anastassiou, Costas; Arkhipov, Anton; Berg, Jim; Buice, Michael; Cain, Nicholas; Gouwens, Nathan W; Gratiy, Sergey; Iyer, Ramakrishnan; Lee, Jung Hoon; Mihalas, Stefan; Mitelut, Catalin; Olsen, Shawn; Reid, R Clay; Teeter, Corinne; de Vries, Saskia; Waters, Jack; Zeng, Hongkui; Koch, Christof

    2016-07-01

    The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort. PMID:27382147

  7. Neuroprotective effect of the endogenous neural peptide apelin in cultured mouse cortical neurons

    SciTech Connect

    Zeng, Xiang Jun; Yu, Shan Ping; Zhang, Like; Wei, Ling

    2010-07-01

    The adipocytokine apelin and its G protein-coupled APJ receptor were initially isolated from a bovine stomach and have been detected in the brain and cardiovascular system. Recent studies suggest that apelin can protect cardiomyocytes from ischemic injury. Here, we investigated the effect of apelin on apoptosis in mouse primary cultures of cortical neurons. Exposure of the cortical cultures to a serum-free medium for 24 h induced nuclear fragmentation and apoptotic death; apelin-13 (1.0-5.0 nM) markedly prevented the neuronal apoptosis. Apelin neuroprotective effects were mediated by multiple mechanisms. Apelin-13 reduced serum deprivation (SD)-induced ROS generation, mitochondria depolarization, cytochrome c release and activation of caspase-3. Apelin-13 prevented SD-induced changes in phosphorylation status of Akt and ERK1/2. In addition, apelin-13 attenuated NMDA-induced intracellular Ca{sup 2+} accumulation. These results indicate that apelin is an endogenous neuroprotective adipocytokine that may block apoptosis and excitotoxic death via cellular and molecular mechanisms. It is suggested that apelins may be further explored as a potential neuroprotective reagent for ischemia-induced brain damage.

  8. The Pattern of Cortical Dysfunction in a Mouse Model of a Schizophrenia-Related Microdeletion

    PubMed Central

    Fénelon, Karine; Xu, Bin; Lai, Cora S.; Mukai, Jun; Markx, Sander; Stark, Kimberly L.; Hsu, Pei-Ken; Gan, Wen-Biao; Fischbach, Gerald D.; MacDermott, Amy B.

    2013-01-01

    We used a mouse model of the schizophrenia-predisposing 22q11.2 microdeletion to evaluate how this genetic lesion affects cortical neural circuits at the synaptic, cellular, and molecular levels. Guided by cognitive deficits, we demonstrated that mutant mice display robust deficits in high-frequency synaptic transmission and short-term plasticity (synaptic depression and potentiation), as well as alterations in long-term plasticity and dendritic spine stability. Apart from previously reported reduction in dendritic complexity of layer 5 pyramidal neurons, altered synaptic plasticity occurs in the context of relatively circumscribed and often subtle cytoarchitectural changes in neuronal density and inhibitory neuron numbers. We confirmed the pronounced DiGeorge critical region 8 (Dgcr8)-dependent deficits in primary micro-RNA processing and identified additional changes in gene expression and RNA splicing that may underlie the effects of this mutation. Reduction in Dgcr8 levels appears to be a major driver of altered short-term synaptic plasticity in prefrontal cortex and working memory but not of long-term plasticity and cytoarchitecture. Our findings inform the cortical synaptic and neuronal mechanisms of working memory impairment in the context of psychiatric disorders. They also provide insight into the link between micro-RNA dysregulation and genetic liability to schizophrenia and cognitive dysfunction. PMID:24027283

  9. Inferring cortical function in the mouse visual system through large-scale systems neuroscience.

    PubMed

    Hawrylycz, Michael; Anastassiou, Costas; Arkhipov, Anton; Berg, Jim; Buice, Michael; Cain, Nicholas; Gouwens, Nathan W; Gratiy, Sergey; Iyer, Ramakrishnan; Lee, Jung Hoon; Mihalas, Stefan; Mitelut, Catalin; Olsen, Shawn; Reid, R Clay; Teeter, Corinne; de Vries, Saskia; Waters, Jack; Zeng, Hongkui; Koch, Christof

    2016-07-01

    The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

  10. Inferring cortical function in the mouse visual system through large-scale systems neuroscience

    PubMed Central

    Hawrylycz, Michael; Anastassiou, Costas; Arkhipov, Anton; Berg, Jim; Buice, Michael; Cain, Nicholas; Gouwens, Nathan W.; Gratiy, Sergey; Iyer, Ramakrishnan; Lee, Jung Hoon; Mihalas, Stefan; Mitelut, Catalin; Olsen, Shawn; Reid, R. Clay; Teeter, Corinne; de Vries, Saskia; Waters, Jack; Zeng, Hongkui; Koch, Christof

    2016-01-01

    The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort. PMID:27382147

  11. A fast, model-independent method for cerebral cortical thickness estimation using MRI.

    PubMed

    Scott, M L J; Bromiley, P A; Thacker, N A; Hutchinson, C E; Jackson, A

    2009-04-01

    Several algorithms for measuring the cortical thickness in the human brain from MR image volumes have been described in the literature, the majority of which rely on fitting deformable models to the inner and outer cortical surfaces. However, the constraints applied during the model fitting process in order to enforce spherical topology and to fit the outer cortical surface in narrow sulci, where the cerebrospinal fluid (CSF) channel may be obscured by partial voluming, may introduce bias in some circumstances, and greatly increase the processor time required. In this paper we describe an alternative, voxel based technique that measures the cortical thickness using inversion recovery anatomical MR images. Grey matter, white matter and CSF are identified through segmentation, and edge detection is used to identify the boundaries between these tissues. The cortical thickness is then measured along the local 3D surface normal at every voxel on the inner cortical surface. The method was applied to 119 normal volunteers, and validated through extensive comparisons with published measurements of both cortical thickness and rate of thickness change with age. We conclude that the proposed technique is generally faster than deformable model-based alternatives, and free from the possibility of model bias, but suffers no reduction in accuracy. In particular, it will be applicable in data sets showing severe cortical atrophy, where thinning of the gyri leads to points of high curvature, and so the fitting of deformable models is problematic. PMID:19068276

  12. PUMA is invovled in ischemia/reperfusion-induced apoptosis of mouse cerebral astrocytes.

    PubMed

    Chen, H; Tian, M; Jin, L; Jia, H; Jin, Y

    2015-01-22

    PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1 h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury.

  13. TFP5 prevents 1-methyl-4-phenyl pyridine ion-induced neurotoxicity in mouse cortical neurons

    PubMed Central

    Zhang, Qi-Shan; Liao, Yuan-Gao; Ji, Zhong; Gu, Yong; Jiang, Hai-Shan; Xie, Zuo-Shan; Pan, Su-Yue; Hu, Ya-Fang

    2016-01-01

    The present study aimed to investigate the protective effect of a modified p5 peptide, TFP5, on 1-methyl-4-phenyl pyridine ion (MPP+)-induced neurotoxicity in cortical neurons and explore the therapeutic effect of TFP5 on Parkinson's disease (PD). MPP+ was applied to a primary culture of mouse cortical neurons to establish the cell model of PD. Neurons were divided into four groups: Control, model (MPP+), scrambled peptide (Scb) (Scb + MPP+) and TFP5 (TFP5 + MPP+) groups. Pretreatment with Scb or TFP5 was applied to the latter two groups, respectively, for 3 h, while phosphate-buffered saline was applied to the control and model groups. MPP+ was then applied to all groups, with the exception of the control group, and neurons were cultured for an additional 24 h. Neuron viability was evaluated using a Cell Counting kit-8 (CCK8) assay. To explore the mechanism underlying the protective effects of TFP5, the expression levels of p35, p25 and phosphorylated myocyte enhancer factor 2 (p-MEF2D) were determined by western blotting. Fluorescence microscopy showed that TFP5 was able to pass through cell membranes and distribute around the nucleus. CCK8 assay showed that neuronal apoptosis was dependent on MPP+ concentration and exposure time. Cell viability decreased significantly in the model group compared with the control group (55±7 vs. 100±0%; P<0.01), and increased significantly in the TFP5 group compared with the model group (98±2 vs. 55±5%; P<0.01) and Scb group (98±2 vs. 54±4%; P<0.01). Scb exhibited no protective effect. Western blotting results showed that MPP+ induced p25 and p-MEF2D expression, TFP5 and Scb did not affect MPP+-induced p25 expression, but TFP5 reduced MPP+-induced p-MEF2D expression. In summary, TFP5 protects against MPP+-induced neurotoxicity in mouse cortical neurons, possibly through inhibiting the MPP+-induced formation and elevated kinase activity of a cyclin-dependent kinase 5/p25 complex.

  14. TFP5 prevents 1-methyl-4-phenyl pyridine ion-induced neurotoxicity in mouse cortical neurons

    PubMed Central

    Zhang, Qi-Shan; Liao, Yuan-Gao; Ji, Zhong; Gu, Yong; Jiang, Hai-Shan; Xie, Zuo-Shan; Pan, Su-Yue; Hu, Ya-Fang

    2016-01-01

    The present study aimed to investigate the protective effect of a modified p5 peptide, TFP5, on 1-methyl-4-phenyl pyridine ion (MPP+)-induced neurotoxicity in cortical neurons and explore the therapeutic effect of TFP5 on Parkinson's disease (PD). MPP+ was applied to a primary culture of mouse cortical neurons to establish the cell model of PD. Neurons were divided into four groups: Control, model (MPP+), scrambled peptide (Scb) (Scb + MPP+) and TFP5 (TFP5 + MPP+) groups. Pretreatment with Scb or TFP5 was applied to the latter two groups, respectively, for 3 h, while phosphate-buffered saline was applied to the control and model groups. MPP+ was then applied to all groups, with the exception of the control group, and neurons were cultured for an additional 24 h. Neuron viability was evaluated using a Cell Counting kit-8 (CCK8) assay. To explore the mechanism underlying the protective effects of TFP5, the expression levels of p35, p25 and phosphorylated myocyte enhancer factor 2 (p-MEF2D) were determined by western blotting. Fluorescence microscopy showed that TFP5 was able to pass through cell membranes and distribute around the nucleus. CCK8 assay showed that neuronal apoptosis was dependent on MPP+ concentration and exposure time. Cell viability decreased significantly in the model group compared with the control group (55±7 vs. 100±0%; P<0.01), and increased significantly in the TFP5 group compared with the model group (98±2 vs. 55±5%; P<0.01) and Scb group (98±2 vs. 54±4%; P<0.01). Scb exhibited no protective effect. Western blotting results showed that MPP+ induced p25 and p-MEF2D expression, TFP5 and Scb did not affect MPP+-induced p25 expression, but TFP5 reduced MPP+-induced p-MEF2D expression. In summary, TFP5 protects against MPP+-induced neurotoxicity in mouse cortical neurons, possibly through inhibiting the MPP+-induced formation and elevated kinase activity of a cyclin-dependent kinase 5/p25 complex. PMID:27698762

  15. Dysfunction of mouse cerebral arteries during early aging

    PubMed Central

    Balbi, Matilde; Ghosh, Mitrajit; Longden, Thomas A; Jativa Vega, Max; Gesierich, Benno; Hellal, Farida; Lourbopoulos, Athanasios; Nelson, Mark T; Plesnila, Nikolaus

    2015-01-01

    Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO2 or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca2+ were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO2 reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO2 reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable. PMID:26058694

  16. Focal cerebral ischemia activates neurovascular restorative dynamics in mouse brain.

    PubMed

    Chu, Min; Hu, Xiaoming; Lu, Shiduo; Gan, Yu; Li, Peiying; Guo, Yanling; Zhang, Jia; Chen, Jun; Gao, Yanqin

    2012-01-01

    Cerebral ischemia triggers regeneration of neural stem/progenitor cells (NSCs/NPCs), which are associated with neovascularization and white matter repair in the brain. This study analyzed the dynamics of neurogenesis, neovascularization, and white matter injury/repair after middle cerebral artery occlusion (MCAO) and elucidated their temporal association. Mice were subjected to MCAO for 60 minutes and sacrificed up to 28 days after reperfusion. Neurogenesis and angiogenesis, as measured by double staining of 5-bromo-2-deoxyuridine (BrdU) with DCX or tomato lectin, respectively, were substantially activated soon after ischemia and persisted for 4 weeks. Despite the moderate recovery of functional vessels in infarct margin from 7 days post-ischemia, a significant decrease in vascular density remained over time. Clusters of immature neurons localized proximal to angiogenic blood vessels beginning 14 days after ischemia, suggesting interplay between neurogenesis and revascularization. Progenitors of oligodendrocytes (NG2+) constitutively presented in the normal brain and proliferated soon after ischemia. However, axon damage and the loss of white matter integrity after ischemic stroke were almost irreversible, as revealed by sustained decreases of myelin basic protein (MBP) and neurofilament-200 expression. PMID:22202008

  17. Application of thinned-skull cranial window to mouse cerebral blood flow imaging using optical microangiography.

    PubMed

    Li, Yuandong; Baran, Utku; Wang, Ruikang K

    2014-01-01

    In vivo imaging of mouse brain vasculature typically requires applying skull window opening techniques: open-skull cranial window or thinned-skull cranial window. We report non-invasive 3D in vivo cerebral blood flow imaging of C57/BL mouse by the use of ultra-high sensitive optical microangiography (UHS-OMAG) and Doppler optical microangiography (DOMAG) techniques to evaluate two cranial window types based on their procedures and ability to visualize surface pial vessel dynamics. Application of the thinned-skull technique is found to be effective in achieving high quality images for pial vessels for short-term imaging, and has advantages over the open-skull technique in available imaging area, surgical efficiency, and cerebral environment preservation. In summary, thinned-skull cranial window serves as a promising tool in studying hemodynamics in pial microvasculature using OMAG or other OCT blood flow imaging modalities.

  18. Application of Thinned-Skull Cranial Window to Mouse Cerebral Blood Flow Imaging Using Optical Microangiography

    PubMed Central

    Wang, Ruikang K.

    2014-01-01

    In vivo imaging of mouse brain vasculature typically requires applying skull window opening techniques: open-skull cranial window or thinned-skull cranial window. We report non-invasive 3D in vivo cerebral blood flow imaging of C57/BL mouse by the use of ultra-high sensitive optical microangiography (UHS-OMAG) and Doppler optical microangiography (DOMAG) techniques to evaluate two cranial window types based on their procedures and ability to visualize surface pial vessel dynamics. Application of the thinned-skull technique is found to be effective in achieving high quality images for pial vessels for short-term imaging, and has advantages over the open-skull technique in available imaging area, surgical efficiency, and cerebral environment preservation. In summary, thinned-skull cranial window serves as a promising tool in studying hemodynamics in pial microvasculature using OMAG or other OCT blood flow imaging modalities. PMID:25426632

  19. Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model.

    PubMed

    Zhai, Yun; Yamashita, Toru; Nakano, Yumiko; Sun, Zhuoran; Shang, Jingwei; Feng, Tian; Morihara, Ryuta; Fukui, Yusuke; Ohta, Yasuyuki; Hishikawa, Nozomi; Abe, Koji

    2016-06-13

    Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action. PMID:27314529

  20. Vascular Function, Cerebral Cortical Thickness, and Cognitive Performance in Middle-Aged Hispanic and Non-Hispanic Caucasian Adults

    PubMed Central

    Pasha, Evan; Kaur, Sonya S.; Gonzales, Mitzi M.; Machin, Daniel R.; Kasischke, Kennon; Tanaka, Hirofumi; Haley, Andreana P.

    2015-01-01

    Hispanics are at increased risk of acquiring cardiovascular risk factors that contribute to cognitive dysfunction. To compare indices of vascular health to measures of cerebral gray matter integrity, 60 middle-aged Hispanic and non-Hispanic Caucasian participants were matched across age, gender, years of education, and mental status. Arterial stiffness was characterized via β-stiffness index and carotid-femoral pulse-wave velocity, and magnetic resonance imaging estimated cortical thickness in a priori regions of interest known to be susceptible to vascular risk factors. Measures of arterial stiffness were significantly higher in Hispanics than in non-Hispanic Caucasians. Hispanics exhibited thinner left inferior frontal gyrus (LIFG) cortical thickness (p=0.04) with concurrently lower language (p=0.02), memory (p=0.03), and attention-executive functioning (p=0.02). These results suggest that compromised vascular health may occur simultaneously with cortical thinning of the LIFG as an early neuropathological alteration in Hispanics. PMID:25720950

  1. Trends and properties of human cerebral cortex: correlations with cortical myelin content.

    PubMed

    Glasser, Matthew F; Goyal, Manu S; Preuss, Todd M; Raichle, Marcus E; Van Essen, David C

    2014-06-01

    "In vivo Brodmann mapping" or non-invasive cortical parcellation using MRI, especially by measuring cortical myelination, has recently become a popular research topic, though myeloarchitectonic cortical parcellation in humans previously languished in favor of cytoarchitecture. We review recent in vivo myelin mapping studies and discuss some of the different methods for estimating myelin content. We discuss some ways in which myelin maps may improve surface registration and be useful for cross-modal and cross-species comparisons, including some preliminary cross-species results. Next, we consider neurobiological aspects of why some parts of cortex are more myelinated than others. Myelin content is inversely correlated with intracortical circuit complexity - in general, more myelin content means simpler and perhaps less dynamic intracortical circuits. Using existing PET data and functional network parcellations, we examine metabolic differences in the differently myelinated cortical functional networks. Lightly myelinated cognitive association networks tend to have higher aerobic glycolysis than heavily myelinated early sensory-motor ones, perhaps reflecting greater ongoing dynamic anabolic cortical processes. This finding is consistent with the hypothesis that intracortical myelination may stabilize intracortical circuits and inhibit synaptic plasticity. Finally, we discuss the future of the in vivo myeloarchitectural field and cortical parcellation--"in vivo Brodmann mapping"--in general.

  2. Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex.

    PubMed

    García-Díaz, Beatriz; Riquelme, Raquel; Varela-Nieto, Isabel; Jiménez, Antonio Jesús; de Diego, Isabel; Gómez-Conde, Ana Isabel; Matas-Rico, Elisa; Aguirre, José Ángel; Chun, Jerold; Pedraza, Carmen; Santín, Luis Javier; Fernández, Oscar; Rodríguez de Fonseca, Fernando; Estivill-Torrús, Guillermo

    2015-11-01

    Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases. PMID:25226845

  3. Astrocytic adaptation during cerebral angiogenesis follows the new vessel formation induced through chronic hypoxia in adult mouse cortex

    NASA Astrophysics Data System (ADS)

    Masamoto, Kazuto; Kanno, Iwao

    2014-03-01

    We examined longitudinal changes of the neuro-glia-vascular unit during cerebral angiogenesis induced through chronic hypoxia in the adult mouse cortex. Tie2-GFP mice in which the vascular endothelial cells expressed green fluorescent proteins (GFP) were exposed to chronic hypoxia, while the spatiotemporal developments of the cortical capillary sprouts and the neighboring astrocytic remodeling were characterized with repeated two-photon microscopy. The capillary sprouts appeared at early phases of the hypoxia adaptation (1-2 weeks), while the morphological changes of the astrocytic soma and processes were not detected in this phase. In the later phases of the hypoxia adaptation (> 2 weeks), the capillary sprouts created a new connection with existing capillaries, and its neighboring astrocytes extended their processes to the newly-formed vessels. The findings show that morphological adaptation of the astrocytes follow the capillary development during the hypoxia adaptation, which indicate that the newly-formed vessels provoke cellular interactions with the neighboring astrocytes to strengthen the functional blood-brain barrier.

  4. The effects of aging and Alzheimer's disease on cerebral cortical anatomy: Specificity and differential relationships with cognition

    PubMed Central

    Bakkour, Akram; Morris, John C.; Wolk, David A.; Dickerson, Bradford C.

    2014-01-01

    Although both normal aging and Alzheimer's disease (AD) are associated with regional cortical atrophy, few studies have directly compared the spatial patterns and magnitude of effects of these two processes. The extant literature has not addressed two important questions: 1) Is the pattern of age-related cortical atrophy different if cognitively intact elderly individuals with silent AD pathology are excluded? and 2) Does the age- or AD-related atrophy relate to cognitive function? Here we studied 142 young controls, 87 older controls, and 28 mild AD patients. In addition, we studied 35 older controls with neuroimaging data indicating the absence of brain amyloid. Whole-cortex analyses identified regions of interest (ROIs) of cortical atrophy in aging and in AD. Results showed that some regions are predominantly affected by age with relatively little additional atrophy in patients with AD, e.g., calcarine cortex; other regions are predominantly affected by AD with much less of an effect of age, e.g., medial temporal cortex. Finally, other regions are affected by both aging and AD, e.g., dorsolateral prefrontal cortex and inferior parietal lobule. Thus, the processes of aging and AD have both differential and partially overlapping effects on specific regions of the cerebral cortex. In particular, some frontoparietal regions are affected by both processes, most temporal lobe regions are affected much more prominently by AD than aging, while sensorimotor and some prefrontal regions are affected specifically by aging and minimally more by AD. Within normal older adults, atrophy in aging-specific cortical regions relates to cognitive performance, while in AD patients atrophy in AD-specific regions relates to cognitive performance. Further work is warranted to investigate the behavioral and clinical relevance of these findings in additional detail, as well as their histological basis; ROIs generated from the present study could be used strategically in such

  5. The effects of aging and Alzheimer's disease on cerebral cortical anatomy: specificity and differential relationships with cognition.

    PubMed

    Bakkour, Akram; Morris, John C; Wolk, David A; Dickerson, Bradford C

    2013-08-01

    Although both normal aging and Alzheimer's disease (AD) are associated with regional cortical atrophy, few studies have directly compared the spatial patterns and magnitude of effects of these two processes. The extant literature has not addressed two important questions: 1) Is the pattern of age-related cortical atrophy different if cognitively intact elderly individuals with silent AD pathology are excluded? and 2) Does the age- or AD-related atrophy relate to cognitive function? Here we studied 142 young controls, 87 older controls, and 28 mild AD patients. In addition, we studied 35 older controls with neuroimaging data indicating the absence of brain amyloid. Whole-cortex analyses identified regions of interest (ROIs) of cortical atrophy in aging and in AD. Results showed that some regions are predominantly affected by age with relatively little additional atrophy in patients with AD, e.g., calcarine cortex; other regions are predominantly affected by AD with much less of an effect of age, e.g., medial temporal cortex. Finally, other regions are affected by both aging and AD, e.g., dorsolateral prefrontal cortex and inferior parietal lobule. Thus, the processes of aging and AD have both differential and partially overlapping effects on specific regions of the cerebral cortex. In particular, some frontoparietal regions are affected by both processes, most temporal lobe regions are affected much more prominently by AD than aging, while sensorimotor and some prefrontal regions are affected specifically by aging and minimally more by AD. Within normal older adults, atrophy in aging-specific cortical regions relates to cognitive performance, while in AD patients atrophy in AD-specific regions relates to cognitive performance. Further work is warranted to investigate the behavioral and clinical relevance of these findings in additional detail, as well as their histological basis; ROIs generated from the present study could be used strategically in such

  6. Successful serial imaging of the mouse cerebral arteries using conventional 3-T magnetic resonance imaging

    PubMed Central

    Makino, Hiroshi; Hokamura, Kazuya; Natsume, Takahiro; Kimura, Tetsuro; Kamio, Yoshinobu; Magata, Yasuhiro; Namba, Hiroki; Katoh, Takasumi; Sato, Shigehito; Hashimoto, Tomoki; Umemura, Kazuo

    2015-01-01

    Serial imaging studies can be useful in characterizing the pathologic and physiologic remodeling of cerebral arteries in various mouse models. We tested the feasibility of using a readily available, conventional 3-T magnetic resonance imaging (MRI) to serially image cerebrovascular remodeling in mice. We utilized a mouse model of intracranial aneurysm as a mouse model of the dynamic, pathologic remodeling of cerebral arteries. Aneurysms were induced by hypertension and a single elastase injection into the cerebrospinal fluid. For the mouse cerebrovascular imaging, we used a conventional 3-T MRI system and a 40-mm saddle coil. We used non-enhanced magnetic resonance angiography (MRA) to detect intracranial aneurysm formation and T2-weighted imaging to detect aneurysmal subarachnoid hemorrhage. A serial MRI was conducted every 2 to 3 days. MRI detection of aneurysm formation and subarachnoid hemorrhage was compared against the postmortem inspection of the brain that was perfused with dye. The imaging times for the MRA and T2-weighted imaging were 3.7±0.5 minutes and 4.8±0.0 minutes, respectively. All aneurysms and subarachnoid hemorrhages were correctly identified by two masked observers on MRI. This MRI-based serial imaging technique was useful in detecting intracranial aneurysm formation and subarachnoid hemorrhage in mice. PMID:25920958

  7. Auditory perception vs. recognition: representation of complex communication sounds in the mouse auditory cortical fields.

    PubMed

    Geissler, Diana B; Ehret, Günter

    2004-02-01

    Details of brain areas for acoustical Gestalt perception and the recognition of species-specific vocalizations are not known. Here we show how spectral properties and the recognition of the acoustical Gestalt of wriggling calls of mouse pups based on a temporal property are represented in auditory cortical fields and an association area (dorsal field) of the pups' mothers. We stimulated either with a call model releasing maternal behaviour at a high rate (call recognition) or with two models of low behavioural significance (perception without recognition). Brain activation was quantified using c-Fos immunocytochemistry, counting Fos-positive cells in electrophysiologically mapped auditory cortical fields and the dorsal field. A frequency-specific labelling in two primary auditory fields is related to call perception but not to the discrimination of the biological significance of the call models used. Labelling related to call recognition is present in the second auditory field (AII). A left hemisphere advantage of labelling in the dorsoposterior field seems to reflect an integration of call recognition with maternal responsiveness. The dorsal field is activated only in the left hemisphere. The spatial extent of Fos-positive cells within the auditory cortex and its fields is larger in the left than in the right hemisphere. Our data show that a left hemisphere advantage in processing of a species-specific vocalization up to recognition is present in mice. The differential representation of vocalizations of high vs. low biological significance, as seen only in higher-order and not in primary fields of the auditory cortex, is discussed in the context of perceptual strategies. PMID:15009150

  8. Cortical Efferents Lacking Mutant huntingtin Improve Striatal Neuronal Activity and Behavior in a Conditional Mouse Model of Huntington's Disease

    PubMed Central

    Estrada-Sánchez, Ana María; Burroughs, Courtney L.; Cavaliere, Stephen; Barton, Scott J.; Chen, Shirley; Yang, X. William

    2015-01-01

    Abnormal electrophysiological activity in the striatum, which receives dense innervation from the cerebral cortex, is believed to set the stage for the behavioral phenotype observed in Huntington's disease (HD), a neurodegenerative condition caused by mutation of the huntingtin (mhtt) protein. However, cortical involvement is far from clear. To determine whether abnormal striatal processing can be explained by mhtt alone (cell-autonomous model) or by mhtt in the corticostriatal projection cell–cell interaction model, we used BACHD/Emx1–Cre (BE) mice, a conditional HD model in which full-length mhtt is genetically reduced in cortical output neurons, including those that project to the striatum. Animals were assessed beginning at 20 weeks of age for at least the next 40 weeks, a range over which presymptomatic BACHD mice become symptomatic. Both open-field and nest-building behavior deteriorated progressively in BACHD mice relative to both BE and wild-type (WT) mice. Neuronal activity patterns in the dorsal striatum, which receives input from the primary motor cortex (M1), followed a similar age progression because BACHD activity changed more rapidly than either BE or WT mice. However, in the M1, BE neuronal activity differed significantly from both WT and BACHD. Although abnormal cortical activity in BE mice likely reflects input from mhtt-expressing afferents, including cortical interneurons, improvements in BE striatal activity and behavior suggest a critical role for mhtt in cortical output neurons in shaping the onset and progression of striatal dysfunction. PMID:25762686

  9. 20-Hydroxyeicosatetraenoic Acid Inhibition by HET0016 Offers Neuroprotection, Decreases Edema, and Increases Cortical Cerebral Blood Flow in a Pediatric Asphyxial Cardiac Arrest Model in Rats

    PubMed Central

    Shaik, Jafar Sadik B; Poloyac, Samuel M; Kochanek, Patrick M; Alexander, Henry; Tudorascu, Dana L; Clark, Robert SB; Manole, Mioara D

    2015-01-01

    Vasoconstrictive and vasodilatory eicosanoids generated after cardiac arrest (CA) may contribute to cerebral vasomotor disturbances and neurodegeneration. We evaluated the balance of vasodilator/vasoconstrictor eicosanoids produced by cytochrome P450 (CYP) metabolism, and determined their role on cortical perfusion, functional outcome, and neurodegeneration after pediatric asphyxial CA. Cardiac arrest of 9 and 12 minutes was induced in 16- to 18-day-old rats. At 5 and 120 minutes after CA, we quantified the concentration of CYP eicosanoids in the cortex and subcortical areas. In separate rats, we inhibited 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis after CA and assessed cortical cerebral blood flow (CBF), neurologic deficit score, neurodegeneration, and edema. After 9 minutes of CA, vasodilator eicosanoids markedly increased versus sham. Conversely, after 12 minutes of CA, vasoconstrictor eicosanoid 20-HETE increased versus sham, without compensatory increases in vasodilator eicosanoids. Inhibition of 20-HETE synthesis after 12 minutes of CA decreased cortical 20-HETE levels, increased CBF, reduced neurologic deficits at 3 hours, and reduced neurodegeneration and edema at 48 hours versus vehicle-treated rats. In conclusion, cerebral vasoconstrictor eicosanoids increased after a pediatric CA of 12 minutes. Inhibition of 20-HETE synthesis improved cortical perfusion and short-term neurologic outcome. These results suggest that alterations in CYP eicosanoids have a role in cerebral hypoperfusion and neurodegeneration after CA and may represent important therapeutic targets. PMID:26058691

  10. Cortical chemoarchitecture shapes macroscale effective functional connectivity patterns in macaque cerebral cortex.

    PubMed

    Turk, Elise; Scholtens, Lianne H; van den Heuvel, Martijn P

    2016-05-01

    The mammalian cortex is a complex system of-at the microscale level-interconnected neurons and-at the macroscale level-interconnected areas, forming the infrastructure for local and global neural processing and information integration. While the effects of regional chemoarchitecture on local cortical activity are well known, the effect of local neurotransmitter receptor organization on the emergence of large scale region-to-region functional interactions remains poorly understood. Here, we examined reports of effective functional connectivity-as measured by the action of strychnine administration acting on the chemical balance of cortical areas-in relation to underlying regional variation in microscale neurotransmitter receptor density levels in the macaque cortex. Linking cortical variation in microscale receptor density levels to collated information on macroscale functional connectivity of the macaque cortex, we show macroscale patterns of effective corticocortical functional interactions-and in particular, the strength of connectivity of efferent macroscale pathways-to be related to the ratio of excitatory and inhibitory neurotransmitter receptor densities of cortical areas. Our findings provide evidence for the microscale chemoarchitecture of cortical areas to have a direct stimulating influence on the emergence of macroscale functional connectivity patterns in the mammalian brain. Hum Brain Mapp 37:1856-1865, 2016. © 2016 Wiley Periodicals, Inc. PMID:26970255

  11. Slower postnatal growth is associated with delayed cerebral cortical maturation in preterm newborns.

    PubMed

    Vinall, Jillian; Grunau, Ruth E; Brant, Rollin; Chau, Vann; Poskitt, Kenneth J; Synnes, Anne R; Miller, Steven P

    2013-01-16

    Slower postnatal growth is an important predictor of adverse neurodevelopmental outcomes in infants born preterm. However, the relationship between postnatal growth and cortical development remains largely unknown. Therefore, we examined the association between neonatal growth and diffusion tensor imaging measures of microstructural cortical development in infants born very preterm. Participants were 95 neonates born between 24 and 32 weeks gestational age studied twice with diffusion tensor imaging: scan 1 at a median of 32.1 weeks (interquartile range, 30.4 to 33.6) and scan 2 at a median of 40.3 weeks (interquartile range, 38.7 to 42.7). Fractional anisotropy and eigenvalues were recorded from 15 anatomically defined cortical regions. Weight, head circumference, and length were recorded at birth and at the time of each scan. Growth between scans was examined in relation to diffusion tensor imaging measures at scans 1 and 2, accounting for gestational age, birth weight, sex, postmenstrual age, known brain injury (white matter injury, intraventricular hemorrhage, and cerebellar hemorrhage), and neonatal illness (patent ductus arteriosus, days intubated, infection, and necrotizing enterocolitis). Impaired weight, length, and head growth were associated with delayed microstructural development of the cortical gray matter (fractional anisotropy: P < 0.001), but not white matter (fractional anisotropy: P = 0.529), after accounting for prenatal growth, neonatal illness, and brain injury. Avoiding growth impairment during neonatal care may allow cortical development to proceed optimally and, ultimately, may provide an opportunity to reduce neurological disabilities related to preterm birth.

  12. Visualization of microhemorrhages with optical histology in mouse model of cerebral amyloid angiopathy (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-03-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microhemorrhages. Conventional methods, such as magnetic resonance imaging (MRI), can detect microhemorrhages while positron emission tomography (PET) with Pittsburgh Compound B can detect amyloid deposits. MRI and PET can separately demonstrate the presence of microhemorrhages and CAA in affected brains in vivo; however, there is still a lack of strong evidence for the direct involvement of CAA in the presence of microhemorrhage formation. In this study, we use optical histology, a method which combines histochemical staining, chemical optical clearing, and optical imaging, in a Tg2576 mouse model of Alzheimer's disease to enable simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microhemorrhages, and amyloid deposits. Our data strongly suggest that microhemorrhages are localized within the brain regions affected by amyloid deposits. All but two observed microhemorrhages (n=18) were closely localized with vessels affected by CAA whereas no microhemorrhages or amyloid deposits were observed in wild type mouse brain sections. Our data also suggest that the predominant type of CAA-related microhemorrhage is associated with leaky or ruptured hemorrhagic microvasculature within the hippocampus and cerebral cortex rather than occluded ischemic microvasculature. The proposed optical histology method will allow future studies about the relationship between CAA and microhemorrhages during disease development and in response to treatment strategies.

  13. Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis.

    PubMed

    Paris, Daniel; Patel, Nikunj; DelleDonne, Anthony; Quadros, Amita; Smeed, Robert; Mullan, Michael

    2004-08-01

    Abeta peptides are naturally occurring peptides, which are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). In AD cases, levels of soluble and insoluble Abeta peptides increase in the brain as well as in the cerebrovasculature, a phenomenon that does not occur in extra-cranial vessels. There are frequently anomalies in the cerebrovasculature in AD, and despite increases in several pro-angiogenic factors in AD brain, evidence for increased vascularity is lacking; in fact there is evidence to the contrary. It has also been recently shown that Abeta peptides may have profound anti-angiogenic effects in vitro and in vivo. We therefore investigated whether there is evidence for altered angiogenesis in the vasculature in a transgenic mouse model of Abeta amyloidosis (Tg APPsw line 2576). In vitro, the formation of capillary-like structures on a reconstituted extracellular matrix by endothelial cells isolated from Tg APPsw is impaired. Ex vivo, the sprouting of new capillaries from arterial explants (over expressing Abeta) isolated from 9-month-old Tg APPsw is reduced compared to arterial explants isolated from control littermates. In addition, Tg APPsw mice show a reduction in vascular density in the cortex and hippocampus compared to control littermates. Altogether, our data suggest that the over expression of APPsw in the vasculature may oppose angiogenesis.

  14. Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

    PubMed Central

    Drgonova, Jana; Walther, Donna; Hartstein, G Luke; Bukhari, Mohammad O; Baumann, Michael H; Katz, Jonathan; Hall, F Scott; Arnold, Elizabeth R; Flax, Shaun; Riley, Anthony; Rivero, Olga; Lesch, Klaus-Peter; Troncoso, Juan; Ranscht, Barbara; Uhl, George R

    2016-01-01

    The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

  15. Cortical Granule Exocytosis Is Mediated by Alpha-SNAP and N-Ethilmaleimide Sensitive Factor in Mouse Oocytes

    PubMed Central

    de Paola, Matilde; Bello, Oscar Daniel; Michaut, Marcela Alejandra

    2015-01-01

    Cortical granule exocytosis (CGE), also known as cortical reaction, is a calcium- regulated secretion that represents a membrane fusion process during meiotic cell division of oocytes. The molecular mechanism of membrane fusion during CGE is still poorly understood and is thought to be mediated by the SNARE pathway; nevertheless, it is unkown if SNAP (acronym for soluble NSF attachment protein) and NSF (acronym for N-ethilmaleimide sensitive factor), two key proteins in the SNARE pathway, mediate CGE in any oocyte model. In this paper, we documented the gene expression of α-SNAP, γ-SNAP and NSF in mouse oocytes. Western blot analysis showed that the expression of these proteins maintains a similar level during oocyte maturation and early activation. Their localization was mainly observed at the cortical region of metaphase II oocytes, which is enriched in cortical granules. To evaluate the function of these proteins in CGE we set up a functional assay based on the quantification of cortical granules metaphase II oocytes activated parthenogenetically with strontium. Endogenous α-SNAP and NSF proteins were perturbed by microinjection of recombinant proteins or antibodies prior to CGE activation. The microinjection of wild type α-SNAP and the negative mutant of α-SNAP L294A in metaphase II oocytes inhibited CGE stimulated by strontium. NEM, an irreversibly inhibitor of NSF, and the microinjection of the negative mutant NSF D1EQ inhibited cortical reaction. The microinjection of anti-α-SNAP and anti-NSF antibodies was able to abolish CGE in activated metaphase II oocytes. The microinjection of anti-γ SNAP antibody had no effect on CGE. Our findings indicate, for the first time in any oocyte model, that α-SNAP, γ-SNAP, and NSF are expressed in mouse oocytes. We demonstrate that α-SNAP and NSF have an active role in CGE and propose a working model. PMID:26267363

  16. Cortical Granule Exocytosis Is Mediated by Alpha-SNAP and N-Ethilmaleimide Sensitive Factor in Mouse Oocytes.

    PubMed

    de Paola, Matilde; Bello, Oscar Daniel; Michaut, Marcela Alejandra

    2015-01-01

    Cortical granule exocytosis (CGE), also known as cortical reaction, is a calcium- regulated secretion that represents a membrane fusion process during meiotic cell division of oocytes. The molecular mechanism of membrane fusion during CGE is still poorly understood and is thought to be mediated by the SNARE pathway; nevertheless, it is unkown if SNAP (acronym for soluble NSF attachment protein) and NSF (acronym for N-ethilmaleimide sensitive factor), two key proteins in the SNARE pathway, mediate CGE in any oocyte model. In this paper, we documented the gene expression of α-SNAP, γ-SNAP and NSF in mouse oocytes. Western blot analysis showed that the expression of these proteins maintains a similar level during oocyte maturation and early activation. Their localization was mainly observed at the cortical region of metaphase II oocytes, which is enriched in cortical granules. To evaluate the function of these proteins in CGE we set up a functional assay based on the quantification of cortical granules metaphase II oocytes activated parthenogenetically with strontium. Endogenous α-SNAP and NSF proteins were perturbed by microinjection of recombinant proteins or antibodies prior to CGE activation. The microinjection of wild type α-SNAP and the negative mutant of α-SNAP L294A in metaphase II oocytes inhibited CGE stimulated by strontium. NEM, an irreversibly inhibitor of NSF, and the microinjection of the negative mutant NSF D1EQ inhibited cortical reaction. The microinjection of anti-α-SNAP and anti-NSF antibodies was able to abolish CGE in activated metaphase II oocytes. The microinjection of anti-γ SNAP antibody had no effect on CGE. Our findings indicate, for the first time in any oocyte model, that α-SNAP, γ-SNAP, and NSF are expressed in mouse oocytes. We demonstrate that α-SNAP and NSF have an active role in CGE and propose a working model.

  17. Dynamics of the mouse brain cortical synaptic proteome during postnatal brain development

    PubMed Central

    Gonzalez-Lozano, Miguel A.; Klemmer, Patricia; Gebuis, Titia; Hassan, Chopie; van Nierop, Pim; van Kesteren, Ronald E.; Smit, August B.; Li, Ka Wan

    2016-01-01

    Development of the brain involves the formation and maturation of numerous synapses. This process requires prominent changes of the synaptic proteome and potentially involves thousands of different proteins at every synapse. To date the proteome analysis of synapse development has been studied sparsely. Here, we analyzed the cortical synaptic membrane proteome of juvenile postnatal days 9 (P9), P15, P21, P27, adolescent (P35) and different adult ages P70, P140 and P280 of C57Bl6/J mice. Using a quantitative proteomics workflow we quantified 1560 proteins of which 696 showed statistically significant differences over time. Synaptic proteins generally showed increased levels during maturation, whereas proteins involved in protein synthesis generally decreased in abundance. In several cases, proteins from a single functional molecular entity, e.g., subunits of the NMDA receptor, showed differences in their temporal regulation, which may reflect specific synaptic development features of connectivity, strength and plasticity. SNARE proteins, Snap 29/47 and Stx 7/8/12, showed higher expression in immature animals. Finally, we evaluated the function of Cxadr that showed high expression levels at P9 and a fast decline in expression during neuronal development. Knock down of the expression of Cxadr in cultured primary mouse neurons revealed a significant decrease in synapse density. PMID:27748445

  18. Resveratrol attenuates 4-hydroxy-2-hexenal-induced oxidative stress in mouse cortical collecting duct cells.

    PubMed

    Bae, Eun Hui; Joo, Soo Yeon; Ma, Seong Kwon; Lee, JongUn; Kim, Soo Wan

    2016-05-01

    Resveratrol (RSV) may provide numerous protective eff ects against chronic inflammatory diseases. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress, and aldehyde products formed during lipid peroxidation, such as 4-hydroxy-2-hexenal (HHE), might be responsible for tubular injury. This study aimed at investigating the eff ects of RSV on renal and its signaling mechanisms. While HHE treatment resulted in decreased expression of Sirt1, AQP2, and nuclear factor erythroid 2-related factor 2 (Nrf2), mouse cortical collecting duct cells (M1) cells treated with HHE exhibited increased activation of p38 MAPK, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and increased expression of NOX4, p47(phox), Kelch ECH associating protein 1 (Keap1) and COX2. HHE treatment also induced NF-κB activation by promoting IκB-α degradation. Meanwhile, the observed increases in nuclear NF-κB, NOX4, p47(phox), and COX2 expression were attenuated by treatment with Bay 117082, N-acetyl-l-cysteine (NAC), or RSV. Our findings indicate that RSV inhibits the expression of inflammatory proteins and the production of reactive oxygen species in M1 cells by inhibiting NF-κB activation. PMID:27162476

  19. Resveratrol attenuates 4-hydroxy-2-hexenal-induced oxidative stress in mouse cortical collecting duct cells

    PubMed Central

    Bae, Eun Hui; Joo, Soo Yeon; Ma, Seong Kwon; Lee, JongUn

    2016-01-01

    Resveratrol (RSV) may provide numerous protective eff ects against chronic inflammatory diseases. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress, and aldehyde products formed during lipid peroxidation, such as 4-hydroxy-2-hexenal (HHE), might be responsible for tubular injury. This study aimed at investigating the eff ects of RSV on renal and its signaling mechanisms. While HHE treatment resulted in decreased expression of Sirt1, AQP2, and nuclear factor erythroid 2-related factor 2 (Nrf2), mouse cortical collecting duct cells (M1) cells treated with HHE exhibited increased activation of p38 MAPK, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and increased expression of NOX4, p47phox, Kelch ECH associating protein 1 (Keap1) and COX2. HHE treatment also induced NF-κB activation by promoting IκB-α degradation. Meanwhile, the observed increases in nuclear NF-κB, NOX4, p47phox, and COX2 expression were attenuated by treatment with Bay 117082, N-acetyl-l-cysteine (NAC), or RSV. Our findings indicate that RSV inhibits the expression of inflammatory proteins and the production of reactive oxygen species in M1 cells by inhibiting NF-κB activation. PMID:27162476

  20. Regulation of Cerebral Cortical Size and Neuron Number by Fibroblast Growth Factors: Implications for Autism

    ERIC Educational Resources Information Center

    Vaccarino, Flora M.; Grigorenko, Elena L.; Smith, Karen Muller; Stevens, Hanna E.

    2009-01-01

    Increased brain size is common in children with autism spectrum disorders. Here we propose that an increased number of cortical excitatory neurons may underlie the increased brain volume, minicolumn pathology and excessive network excitability, leading to sensory hyper-reactivity and seizures, which are often found in autism. We suggest that…

  1. Point application with Angong Niuhuang sticker protects hippocampal and cortical neurons in rats with cerebral ischemia

    PubMed Central

    Zhang, Dong-shu; Liu, Yuan-liang; Zhu, Dao-qi; Huang, Xiao-jing; Luo, Chao-hua

    2015-01-01

    Angong Niuhuang pill, a Chinese materia medica preparation, can improve neurological functions after acute ischemic stroke. Because of its inconvenient application and toxic components (Cinnabaris and Realgar), we used transdermal enhancers to deliver Angong Niuhuang pill by modern technology, which expanded the safe dose range and clinical indications. In this study, Angong Niuhuang stickers administered at different point application doses (1.35, 2.7, and 5.4 g/kg) were administered to the Dazhui (DU14), Qihai (RN6) and Mingmen (DU4) of rats with chronic cerebral ischemia, for 4 weeks. The Morris water maze was used to determine the learning and memory ability of rats. Hematoxylin-eosin staining and Nissl staining were used to observe neuronal damage of the cortex and hippocampal CA1 region in rats with chronic cerebral ischemia. The middle- and high-dose point application of Angong Niuhuang stickers attenuated neuronal damage in the cortex and hippocampal CA1 region, and improved the memory of rats with chronic cerebral ischemia with an efficacy similar to interventions by electroacupuncture at Dazhui (DU14), Qihai (RN6) and Mingmen (DU4). Our experimental findings indicate that point application with Angong Niuhuang stickers can improve cognitive function after chronic cerebral ischemia in rats and is neuroprotective with an equivalent efficacy to acupuncture. PMID:25883629

  2. Performing Permanent Distal Middle Cerebral with Common Carotid Artery Occlusion in Aged Rats to Study Cortical Ischemia with Sustained Disability

    PubMed Central

    Roy, Lisa A.; Haenzi, Barbara; Tsai, Shi-Yen; Kartje, Gwendolyn; Beech, John S.; Cash, Diana; Moon, Lawrence

    2016-01-01

    Stroke typically occurs in elderly people with a range of comorbidities including carotid (or other arterial) atherosclerosis, high blood pressure, obesity and diabetes. Accordingly, when evaluating therapies for stroke in animals, it is important to select a model with excellent face validity. Ischemic stroke accounts for 80% of all strokes, and the majority of these occur in the territory of the middle cerebral artery (MCA), often inducing infarcts that affect the sensorimotor cortex, causing persistent plegia or paresis on the contralateral side of the body. We demonstrate in this video a method for producing ischemic stroke in elderly rats, which causes sustained sensorimotor disability and substantial cortical infarcts. Specifically, we induce permanent distal middle cerebral artery occlusion (MCAO) in elderly female rats by using diathermy forceps to occlude a short segment of this artery. The carotid artery on the ipsilateral side to the lesion was then permanently occluded and the contralateral carotid artery was transiently occluded for 60 min. We measure the infarct size using structural T2-weighted magnetic resonance imaging (MRI) at 24 hr and 8 weeks after stroke. In this study, the mean infarct volume was 4.5% ± 2.0% (standard deviation) of the ipsilateral hemisphere at 24 hr (corrected for brain swelling using Gerriet’s equation, n = 5). This model is feasible and clinically relevant as it permits the induction of sustained sensorimotor deficits, which is important for the elucidation of pathophysiological mechanisms and novel treatments. PMID:26967269

  3. Performing Permanent Distal Middle Cerebral with Common Carotid Artery Occlusion in Aged Rats to Study Cortical Ischemia with Sustained Disability.

    PubMed

    Wayman, Christina; Duricki, Denise A; Roy, Lisa A; Haenzi, Barbara; Tsai, Shi-Yen; Kartje, Gwendolyn; Beech, John S; Cash, Diana; Moon, Lawrence

    2016-02-23

    Stroke typically occurs in elderly people with a range of comorbidities including carotid (or other arterial) atherosclerosis, high blood pressure, obesity and diabetes. Accordingly, when evaluating therapies for stroke in animals, it is important to select a model with excellent face validity. Ischemic stroke accounts for 80% of all strokes, and the majority of these occur in the territory of the middle cerebral artery (MCA), often inducing infarcts that affect the sensorimotor cortex, causing persistent plegia or paresis on the contralateral side of the body. We demonstrate in this video a method for producing ischemic stroke in elderly rats, which causes sustained sensorimotor disability and substantial cortical infarcts. Specifically, we induce permanent distal middle cerebral artery occlusion (MCAO) in elderly female rats by using diathermy forceps to occlude a short segment of this artery. The carotid artery on the ipsilateral side to the lesion was then permanently occluded and the contralateral carotid artery was transiently occluded for 60 min. We measure the infarct size using structural T2-weighted magnetic resonance imaging (MRI) at 24 hr and 8 weeks after stroke. In this study, the mean infarct volume was 4.5% ± 2.0% (standard deviation) of the ipsilateral hemisphere at 24 hr (corrected for brain swelling using Gerriet's equation, n = 5). This model is feasible and clinically relevant as it permits the induction of sustained sensorimotor deficits, which is important for the elucidation of pathophysiological mechanisms and novel treatments.

  4. Cortical Blindness and Retrograde Amnesia Following Cerebral Angiography Studied by Early Diffusion Weighted MR imaging. A Case Report.

    PubMed

    Roccatagliata, L; Taveira-Lopes, L; Rossignol, M-D; Biondi, A

    2009-12-14

    Cortical blindness is a well described neuro-ophthalmologic complication of angiography due to neurotoxicity following contrast media exposure. A rarer association with retrograde amnesia has also been reported. Since ischemic stroke due to embolism remains the most common aetiology of neurological complications of diagnostic and therapeutic arterial catheterisation, prompt identification of the mechanism responsible for the clinical symptoms is essential for patient management. Although CT and conventional MRI findings have been reported in this condition, experience with diffusion weighted (DW) sequences is lacking especially in cases associated with memory impairment. A 65-year-old man with tinnitus underwent cerebral angiography for suspicion of a dural arteriovenous fistula. During the procedure the patient developed complete loss of vision and rapidly became confused. Brain CT showed bilateral cortical enhancement in the occipital lobes. MR with DWI was performed 3.5 hours after angiography. Early DWI showed no signal abnormalities thereby excluding an ischaemic complication. Gradual improvement of visual function occurred over the next 24 hours. After 48 hours the patient was alert and orientated but profound retrograde amnesia persisted with no memory for the events of the day of angiography. CT follow-up at one year was normal. DWI is invaluable in the evaluation of patients with cortical blindness with or without memory deficits precipitated by angiography and may advance understanding of the pathophysiology. Diffusion-weighted MRI is crucial in differentiating neuro-ophthalmologic complications precipitated by intracortical contrast leakage after angiography from an ischaemic stroke needing a prompt and often invasive treatment. PMID:24209406

  5. Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct.

    PubMed

    Cheng, Chih-Jen; Baum, Michel; Huang, Chou-Long

    2013-02-15

    Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is a kinase-deficient variant of WNK1 that is expressed exclusively in the kidney. It is abundantly expressed in the distal convoluted tubule (DCT) and to a lesser extent in the cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct (CCD). KS-WNK1 inhibits Na(+)-K(+)-2Cl(-)- and sodium chloride cotransporter-mediated Na(+) reabsorption in cTAL and DCT, respectively. Here, we investigated the role of KS-WNK1 in regulating Na(+) and K(+) transport in CCD using in vitro microperfusion of tubules isolated from KS-WNK1 knockout mice and control wild-type littermates. Because baseline K(+) secretion and Na(+) reabsorption were negligible in mouse CCD, we studied tubules isolated from mice fed a high-K(+) diet for 2 wk. Compared with that in wild-type tubules, K(+) secretion was reduced in KS-WNK1 knockout CCD perfused at a low luminal fluid rate of ~1.5 nl/min. Na(+) reabsorption and the lumen-negative transepithelial potential difference were also lower in the KS-WNK1 knockout CCD compared with control CCD. Increasing the perfusion rate to ~5.5 nl/min stimulated K(+) secretion in the wild-type as well as knockout CCD. The magnitudes of flow-stimulated increase in K(+) secretion were similar in wild-type and knockout CCD. Maxi-K(+) channel inhibitor iberiotoxin had no effect on K(+) secretion when tubules were perfused at ~1.5 nl/min, but completely abrogated the flow-dependent increase in K(+) secretion at ~5.5 nl/min. These findings support the notion that KS-WNK1 stimulates ROMK-mediated K(+) secretion, but not flow-dependent K(+) secretion mediated by maxi-K(+) channels in CCD. In addition, KS-WNK1 plays a role in regulating Na(+) transport in the CCD. PMID:23195681

  6. Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct.

    PubMed

    Cheng, Chih-Jen; Baum, Michel; Huang, Chou-Long

    2013-02-15

    Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is a kinase-deficient variant of WNK1 that is expressed exclusively in the kidney. It is abundantly expressed in the distal convoluted tubule (DCT) and to a lesser extent in the cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct (CCD). KS-WNK1 inhibits Na(+)-K(+)-2Cl(-)- and sodium chloride cotransporter-mediated Na(+) reabsorption in cTAL and DCT, respectively. Here, we investigated the role of KS-WNK1 in regulating Na(+) and K(+) transport in CCD using in vitro microperfusion of tubules isolated from KS-WNK1 knockout mice and control wild-type littermates. Because baseline K(+) secretion and Na(+) reabsorption were negligible in mouse CCD, we studied tubules isolated from mice fed a high-K(+) diet for 2 wk. Compared with that in wild-type tubules, K(+) secretion was reduced in KS-WNK1 knockout CCD perfused at a low luminal fluid rate of ~1.5 nl/min. Na(+) reabsorption and the lumen-negative transepithelial potential difference were also lower in the KS-WNK1 knockout CCD compared with control CCD. Increasing the perfusion rate to ~5.5 nl/min stimulated K(+) secretion in the wild-type as well as knockout CCD. The magnitudes of flow-stimulated increase in K(+) secretion were similar in wild-type and knockout CCD. Maxi-K(+) channel inhibitor iberiotoxin had no effect on K(+) secretion when tubules were perfused at ~1.5 nl/min, but completely abrogated the flow-dependent increase in K(+) secretion at ~5.5 nl/min. These findings support the notion that KS-WNK1 stimulates ROMK-mediated K(+) secretion, but not flow-dependent K(+) secretion mediated by maxi-K(+) channels in CCD. In addition, KS-WNK1 plays a role in regulating Na(+) transport in the CCD.

  7. Mild cognitive impairment, poor episodic memory, and late-life depression are associated with cerebral cortical thinning and increased white matter hyperintensities

    PubMed Central

    Fujishima, Motonobu; Maikusa, Norihide; Nakamura, Kei; Nakatsuka, Masahiro; Matsuda, Hiroshi; Meguro, Kenichi

    2014-01-01

    In various independent studies to date, cerebral cortical thickness and white matter hyperintensity (WMH) volume have been associated with episodic memory, depression, and mild cognitive impairment (MCI). The aim of this study was to uncover variations in cortical thickness and WMH volume in association with episodic memory, depressive state, and the presence of MCI simultaneously in a single study population. The participants were 186 individuals with MCI (clinical dementia rating [CDR] of 0.5) and 136 healthy elderly controls (HCs; CDR of 0) drawn from two community-based cohort studies in northern Japan. We computed cerebral cortical thickness and WMH volume by using MR scans and statistically analyzed differences in these indices between HCs and MCI participants. We also assessed the associations of these indices with memory performance and depressive state in participants with MCI. Compared with HCs, MCI participants exhibited thinner cortices in the temporal and inferior parietal lobes and greater WMH volumes in the corona radiata and semioval center. In MCI participants, poor episodic memory was associated with thinner cortices in the left entorhinal region and increased WMH volume in the posterior periventricular regions. Compared with non-depressed MCI participants, depressed MCI participants showed reduced cortical thickness in the anterior medial temporal lobe and gyrus adjacent to the amygdala bilaterally, as well as greater WMH volume as a percentage of the total intracranial volume (WMHr). A higher WMHr was associated with cortical thinning in the frontal, temporal, and parietal regions in MCI participants. These results demonstrate that episodic memory and depression are associated with both cortical thickness and WMH volume in MCI participants. Additional longitudinal studies are needed to clarify the dynamic associations and interactions among these indices. PMID:25426066

  8. An investigation of the mineral in ductile and brittle cortical mouse bone.

    PubMed

    Rodriguez-Florez, Naiara; Garcia-Tunon, Esther; Mukadam, Quresh; Saiz, Eduardo; Oldknow, Karla J; Farquharson, Colin; Millán, José Luis; Boyde, Alan; Shefelbine, Sandra J

    2015-05-01

    Bone is a strong and tough material composed of apatite mineral, organic matter, and water. Changes in composition and organization of these building blocks affect bone's mechanical integrity. Skeletal disorders often affect bone's mineral phase, either by variations in the collagen or directly altering mineralization. The aim of the current study was to explore the differences in the mineral of brittle and ductile cortical bone at the mineral (nm) and tissue (µm) levels using two mouse phenotypes. Osteogenesis imperfecta model, oim(-/-) , mice have a defect in the collagen, which leads to brittle bone; PHOSPHO1 mutants, Phospho1(-/-) , have ductile bone resulting from altered mineralization. Oim(-/-) and Phospho1(-/-) were compared with their respective wild-type controls. Femora were defatted and ground to powder to measure average mineral crystal size using X-ray diffraction (XRD) and to monitor the bulk mineral to matrix ratio via thermogravimetric analysis (TGA). XRD scans were run after TGA for phase identification to assess the fractions of hydroxyapatite and β-tricalcium phosphate. Tibiae were embedded to measure elastic properties with nanoindentation and the extent of mineralization with backscattered electron microscopy (BSE SEM). Results revealed that although both pathology models had extremely different whole-bone mechanics, they both had smaller apatite crystals, lower bulk mineral to matrix ratio, and showed more thermal conversion to β-tricalcium phosphate than their wild types, indicating deviations from stoichiometric hydroxyapatite in the original mineral. In contrast, the degree of mineralization of bone matrix was different for each strain: brittle oim(-/-) were hypermineralized, whereas ductile Phospho1(-/-) were hypomineralized. Despite differences in the mineralization, nanoscale alterations in the mineral were associated with reduced tissue elastic moduli in both pathologies. Results indicated that alterations from normal crystal size

  9. Lineage-specific laminar organization of cortical GABAergic interneurons.

    PubMed

    Ciceri, Gabriele; Dehorter, Nathalie; Sols, Ignasi; Huang, Z Josh; Maravall, Miguel; Marín, Oscar

    2013-09-01

    In the cerebral cortex, pyramidal cells and interneurons are generated in distant germinal zones, and so the mechanisms that control their precise assembly into specific microcircuits remain an enigma. Here we report that cortical interneurons labeled at the clonal level do not distribute randomly but rather have a strong tendency to cluster in the mouse neocortex. This behavior is common to different classes of interneurons, independently of their origin. Interneuron clusters are typically contained within one or two adjacent cortical layers, are largely formed by isochronically generated neurons and populate specific layers, as revealed by unbiased hierarchical clustering methods. Our results suggest that different progenitor cells give rise to interneurons populating infra- and supragranular cortical layers, which challenges current views of cortical neurogenesis. Thus, specific lineages of cortical interneurons seem to be produced to primarily mirror the laminar structure of the cerebral cortex, rather than its columnar organization.

  10. [The effect of millimeter-range electromagnetic radiation on the evoked potentials from the vestibular cortical area of the cerebral hemispheres (an experimental study)].

    PubMed

    Mal'tsev, A E; Abakarov, A T

    1994-01-01

    Acute experiments on 20 cats showed that EHF waves of nonthermal intensity can influence evoked potentials (EP) of the exposed vestibular zone of the cerebral hemispheres. Cerebral cortical exposure to low-frequency EHF waves stimulates negative EP component. Higher frequencies (78.33-118 GHz) reduce the above component amplitude. Changes in the positive EP component were minimal. It is suggested that different effects of millimetric waves diverse frequencies are related to the depth of the radiation penetration into the live tissue. The findings can be used in new techniques of physiotherapy.

  11. Nicotine induces leukocyte rolling and adhesion in the cerebral microcirculation of the mouse.

    PubMed

    Yong, T; Zheng, M Q; Linthicum, D S

    1997-12-01

    Nicotine and several related metabolites were examined for their ability to induce leukocyte rolling and adhesion in the cerebral microcirculation of the mouse. A cranial window was surgically prepared for the visualization of the pial microcirculation using an intra-vital microscopy imaging system. Using this technique rhodamine-labeled leukocytes could be visualized and video-recorded as they traveled within the microvessels, and the quantitation of their rolling and adhesion along the pial venule walls was assessed during an off-line video playback analysis. Nicotine was found to produce significant dose-related increases in leukocyte rolling and adhesion. Cotinine, a major nicotine metabolite, did not induce the same degree of leukocyte rolling and adhesion. Mecamylamine, a nicotine antagonist, was found to inhibit the nicotine-induced leukocyte rolling and adhesion. Anti-P-selectin antibody blocked nicotine-induced leukocyte rolling, while anti-CD18 antibody effectively inhibited leukocyte adhesion, but not rolling in similar experiments. Nicotine-induced leukocyte rolling and adhesion were also inhibited by superoxide dismutase and catalase. These data suggest that nicotine, the principle pharmacological agent in cigarette smoke and related tobacco products, acts via a ganglionic-type nicotinic receptor to enhance leukocyte rolling via P-selectin and reactive oxygen radical-dependent mechanisms in cerebral microcirculation of the mouse. PMID:9413272

  12. Brain immune cell composition and functional outcome after cerebral ischemia: comparison of two mouse strains

    PubMed Central

    Kim, Hyun Ah; Whittle, Stephanie C.; Lee, Seyoung; Chu, Hannah X.; Zhang, Shenpeng R.; Wei, Zihui; Arumugam, Thiruma V.; Vinh, Anthony; Drummond, Grant R.; Sobey, Christopher G.

    2014-01-01

    Inflammatory cells may contribute to secondary brain injury following cerebral ischemia. The C57Bl/6 mouse strain is known to exhibit a T helper 1-prone, pro-inflammatory type response to injury, whereas the FVB strain is relatively T helper 2-prone, or anti-inflammatory, in its immune response. We tested whether stroke outcome is more severe in C57Bl/6 than FVB mice. Male mice of each strain underwent sham surgery or 1 h occlusion of the middle cerebral artery followed by 23 h of reperfusion. Despite no difference in infarct size, C57Bl/6 mice displayed markedly greater functional deficits than FVB mice after stroke, as assessed by neurological scoring and hanging wire test. Total numbers of CD45+ leukocytes tended to be larger in the brains of C57Bl/6 than FVB mice after stroke, but there were marked differences in leukocyte composition between the two mouse strains. The inflammatory response in C57Bl/6 mice primarily involved T and B lymphocytes, whereas neutrophils, monocytes and macrophages were more prominent in FVB mice. Our data are consistent with the concept that functional outcome after stroke is dependent on the immune cell composition which develops following ischemic brain injury. PMID:25477780

  13. Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in Alzheimer's Disease Mouse Model.

    PubMed

    Zhai, Yun; Yamashita, Toru; Nakano, Yumiko; Sun, Zhuoran; Morihara, Ryuta; Fukui, Yusuke; Ohta, Yasuyuki; Hishikawa, Nozomi; Abe, Koji

    2016-04-12

    A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Nav1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier's nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action. PMID:27079724

  14. A Predictive Network Model of Cerebral Cortical Connectivity Based on a Distance Rule

    PubMed Central

    Ercsey-Ravasz, Mária; Markov, Nikola T.; Lamy, Camille; Van Essen, David C.; Knoblauch, Kenneth; Toroczkai, Zoltán; Kennedy, Henry

    2014-01-01

    SUMMARY Recent advances in neuroscience have engendered interest in large-scale brain networks. Using a consistent database of corticocortical connectivity, generated from hemisphere-wide, retrograde tracing experiments in the macaque, we analyzed interareal weights and distances to reveal an important organizational principle of brain connectivity. Using appropriate graph theoretical measures, we show that although very dense (66%), the interareal network has strong structural specificity. Connection weights exhibit a heavy-tailed lognormal distribution spanning five orders of magnitude and conform to a distance rule reflecting exponential decay with interareal separation. A single-parameter random graph model based on this rule predicts numerous features of the cortical network: (1) the existence of a network core and the distribution of cliques, (2) global and local binary properties, (3) global and local weight-based communication efficiencies modeled as network conductance, and (4) overall wire-length minimization. These findings underscore the importance of distance and weight-based heterogeneity in cortical architecture and processing. PMID:24094111

  15. Cerebral cortical respiratory-related evoked potentials elicited by inspiratory occlusion in lambs.

    PubMed

    Davenport, Paul W; Hutchison, Alastair A

    2002-07-01

    Respiratory-related evoked potentials (RREP) elicited by inspiratory mechanical loads have been recorded in humans. Early RREP peaks were hypothesized to be generated by activation of neurons in the somatosensory cortex. An animal model was developed to test this hypothesis in chronically instrumented, awake, spontaneously breathing lambs. Electrocorticogram (ECoG) was recorded bilaterally with ball electrodes on the dural surface over the somatosensory region. Inspiratory occlusions were presented through a face mask or endotracheal tube as interruptions of inspiration. Occlusion-elicited evoked potentials were obtained by computer-signal averaging the ECoG activity. A short-latency positive peak was observed bilaterally in the averaged occlusion-elicited evoked potentials in all animals breathing with the facemask and 5 of 8 lambs with the endotracheal tube. Postmortem identification of the electrode location demonstrated that the ECoG was recorded in the caudal-lateral portion of the somatosensory cortex. These results demonstrate that inspiratory occlusion elicits an evoked potential in the somatosensory cortical region of awake, spontaneously breathing lambs. The lamb cortical RREP is similar to human RREP.

  16. Adolescent mouse takes on an active transcriptomic expression during postnatal cerebral development.

    PubMed

    Xu, Wei; Xin, Chengqi; Lin, Qiang; Ding, Feng; Gong, Wei; Zhou, Yuanyuan; Yu, Jun; Cui, Peng; Hu, Songnian

    2014-06-01

    Postnatal cerebral development is a complicated biological process precisely controlled by multiple genes. To understand the molecular mechanism of cerebral development, we compared dynamics of mouse cerebrum transcriptome through three developmental stages using high-throughput RNA-seq technique. Three libraries were generated from the mouse cerebrum at infancy, adolescence and adulthood, respectively. Consequently, 44,557,729 (infancy), 59,257,530 (adolescence) and 72,729,636 (adulthood) reads were produced, which were assembled into 15,344, 16,048 and 15,775 genes, respectively. We found that the overall gene expression level increased from infancy to adolescence and decreased later on upon reaching adulthood. The adolescence cerebrum has the most active gene expression, with expression of a large number of regulatory genes up-regulated and some crucial pathways activated. Transcription factor (TF) analysis suggested the similar dynamics as expression profiling, especially those TFs functioning in neurogenesis differentiation, oligodendrocyte lineage determination and circadian rhythm regulation. Moreover, our data revealed a drastic increase in myelin basic protein (MBP)-coding gene expression in adolescence and adulthood, suggesting that the brain myelin may be generated since mouse adolescence. In addition, differential gene expression analysis indicated the activation of rhythmic pathway, suggesting the function of rhythmic movement since adolescence; Furthermore, during infancy and adolescence periods, gene expression related to axonrepulsion and attraction showed the opposite trends, indicating that axon repulsion was activated after birth, while axon attraction might be activated at the embryonic stage and declined during the postnatal development. Our results from the present study may shed light on the molecular mechanism underlying the postnatal development of the mammalian cerebrum.

  17. [Dynamics of driven rhythm in neuron in sensorimotor cerebral cortices in rabbit on electrodermal paw stimulation].

    PubMed

    Galashina, A G; Bogdanov, A V

    2014-01-01

    The dominant centre is a zone of proof higher excitation of neurons in the cortex of the brain, resulting from long stimulation or effector (in our case of a forepaw of an animal) or direct cortical representations of this effector. Besides of higher excitation and the firmness of excitation neurones, the dominant centre has two more very important properties--ability to summation (addition) coming to a cortex and extending on cortical neural networks excitations and inertia. Last property is shown what even in some days after the termination of the stimulations which have formed a dominant, in reply to testing stimulus (earlier indifferent for an animal) the centre is activated and puts in action effector. By means of irritation of a paw of rabbits rhythmic impulses of a current of threshold force us had been formed a rhythmic defensive dominant. Interconnected (coincidence) neuronal activity of the sensorimotor cortex of rabbits, in which the rhythmic defensive dominanta has been created, was investigated. Temporal of sequences intervals between the coincidence impulses in peaks of crosscorrelation histograms (CCH) was analyzed. Frequency of occurrence of the coincidence impulses (intervals between impulses), forming CCH was defined by means of "secondary" autocorrelation histograms (ACH) in during a minute. Peaks on "secondary" ACH showed prevalent intervals between of the coincidence impulses. For the further analysis only those peaks of "secondary" ACH, which prevailed over an average level of the histogram with significance p < 0.05 was used. It has been found that in the formed locus of the defensive dominant the coincidence impulses appear not only in the rhythm of stimulation applied in experiment-- s, but also in multiple beat to it (4, 6 and 8 s). Registration and analysis of neuronal activity were done after creation of a rhythmic dominant. At the beginning of each experiment (i.e. before a presentation of testing stimulus) single 2 --econd peaks were

  18. Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration

    PubMed Central

    Kawauchi, Takeshi

    2015-01-01

    The mammalian brain consists of numerous compartments that are closely connected with each other via neural networks, comprising the basis of higher order brain functions. The highly specialized structure originates from simple pseudostratified neuroepithelium-derived neural progenitors located near the ventricle. A long journey by neurons from the ventricular side is essential for the formation of a sophisticated brain structure, including a mammalian-specific six-layered cerebral cortex. Neuronal migration consists of several contiguous steps, but the locomotion mode comprises a large part of the migration. The locomoting neurons exhibit unique features; a radial glial fiber-dependent migration requiring the endocytic recycling of N-cadherin and a neuron-specific migration mode with dilation/swelling formation that requires the actin and microtubule organization possibly regulated by cyclin-dependent kinase 5 (Cdk5), Dcx, p27kip1, Rac1, and POSH. Here I will introduce the roles of various cellular events, such as cytoskeletal organization, cell adhesion, and membrane trafficking, in the regulation of the neuronal migration, with particular focus on the locomotion mode. PMID:26500496

  19. Genes expressed in mouse cortical progenitors are enriched in Pax, Lhx, and Sox transcription factor putative binding sites.

    PubMed

    Bery, Amandine; Mérot, Yohann; Rétaux, Sylvie

    2016-02-15

    Considerable progress has been made in the understanding of molecular and cellular mechanisms controlling the development of the mammalian cortex. The proliferative and neurogenic properties of cortical progenitors located in the ventricular germinal zone start being understood. Little is known however on the cis-regulatory control that finely tunes gene expression in these progenitors. Here, we undertook an in silico-based approach to address this question, followed by some functional validation. Using the Eurexpress database, we established a list of 30 genes specifically expressed in the cortical germinal zone, we selected mouse/human conserved non-coding elements (CNEs) around these genes and we performed motif-enrichment search in these CNEs. We found an over-representation of motifs corresponding to binding sites for Pax, Sox, and Lhx transcription factors, often found as pairs and located within 100bp windows. A small subset of CNEs (n=7) was tested for enhancer activity, by ex-vivo and in utero electroporation assays. Two showed strong enhancer activity in the germinal zone progenitors. Mutagenesis experiments on a selected CNE showed the functional importance of the Pax, Sox, and Lhx TFBS for conferring enhancer activity to the CNE. Overall, from a cis-regulatory viewpoint, our data suggest an input from Pax, Sox and Lhx transcription factors to orchestrate corticogenesis. These results are discussed with regards to the known functional roles of Pax6, Sox2 and Lhx2 in cortical development. PMID:26721689

  20. Effect of surface charge of immortalized mouse cerebral endothelial cell monolayer on transport of charged solutes.

    PubMed

    Yuan, Wei; Li, Guanglei; Gil, Eun Seok; Lowe, Tao Lu; Fu, Bingmei M

    2010-04-01

    Charge carried by the surface glycocalyx layer (SGL) of the cerebral endothelium has been shown to significantly modulate the permeability of the blood-brain barrier (BBB) to charged solutes in vivo. The cultured monolayer of bEnd3, an immortalized mouse cerebral endothelial cell line, is becoming a popular in vitro BBB model due to its easy growth and maintenance of many BBB characteristics over repeated passages. To test whether the SGL of bEnd3 monolayer carries similar charge as that in the intact BBB and quantify this charge, which can be characterized by the SGL thickness (L(f)) and charge density (C(mf)), we measured the solute permeability of bEnd3 monolayer to neutral solutes and to solutes with similar size but opposite charges: negatively charged alpha-lactalbumin (-11) and positively charged ribonuclease (+3). Combining the measured permeability data with a transport model across the cell monolayer, we predicted the L(f) and the C(mf) of bEnd3 monolayer, which is approximately 160 nm and approximately 25 mEq/L, respectively. We also investigated whether orosomucoid, a plasma glycoprotein modulating the charge of the intact BBB, alters the charge of bEnd3 monolayer. We found that 1 mg/mL orosomucoid would increase SGL charge density of bEnd3 monolayer to approximately 2-fold of its control value.

  1. Effect of surface charge of immortalized mouse cerebral endothelial cell monolayer on transport of charged solutes.

    PubMed

    Yuan, Wei; Li, Guanglei; Gil, Eun Seok; Lowe, Tao Lu; Fu, Bingmei M

    2010-04-01

    Charge carried by the surface glycocalyx layer (SGL) of the cerebral endothelium has been shown to significantly modulate the permeability of the blood-brain barrier (BBB) to charged solutes in vivo. The cultured monolayer of bEnd3, an immortalized mouse cerebral endothelial cell line, is becoming a popular in vitro BBB model due to its easy growth and maintenance of many BBB characteristics over repeated passages. To test whether the SGL of bEnd3 monolayer carries similar charge as that in the intact BBB and quantify this charge, which can be characterized by the SGL thickness (L(f)) and charge density (C(mf)), we measured the solute permeability of bEnd3 monolayer to neutral solutes and to solutes with similar size but opposite charges: negatively charged alpha-lactalbumin (-11) and positively charged ribonuclease (+3). Combining the measured permeability data with a transport model across the cell monolayer, we predicted the L(f) and the C(mf) of bEnd3 monolayer, which is approximately 160 nm and approximately 25 mEq/L, respectively. We also investigated whether orosomucoid, a plasma glycoprotein modulating the charge of the intact BBB, alters the charge of bEnd3 monolayer. We found that 1 mg/mL orosomucoid would increase SGL charge density of bEnd3 monolayer to approximately 2-fold of its control value. PMID:20087768

  2. Comparative three-dimensional connectome map of motor cortical projections in the mouse brain

    PubMed Central

    Jeong, Minju; Kim, Yongsoo; Kim, Jeongjin; Ferrante, Daniel D.; Mitra, Partha P.; Osten, Pavel; Kim, Daesoo

    2016-01-01

    The motor cortex orchestrates simple to complex motor behaviors through its output projections to target areas. The primary (MOp) and secondary (MOs) motor cortices are known to produce specific output projections that are targeted to both similar and different target areas. These projections are further divided into layer 5 and 6 neuronal outputs, thereby producing four cortical outputs that may target other areas in a combinatorial manner. However, the precise network structure that integrates these four projections remains poorly understood. Here, we constructed a whole-brain, three-dimensional (3D) map showing the tract pathways and targeting locations of these four motor cortical outputs in mice. Remarkably, these motor cortical projections showed unique and separate tract pathways despite targeting similar areas. Within target areas, various combinations of these four projections were defined based on specific 3D spatial patterns, reflecting anterior-posterior, dorsal-ventral, and core-capsular relationships. This 3D topographic map ultimately provides evidence for the relevance of comparative connectomics: motor cortical projections known to be convergent are actually segregated in many target areas with unique targeting patterns, a finding that has anatomical value for revealing functional subdomains that have not been classified by conventional methods. PMID:26830143

  3. Effects of prenatal irradiation on the development of cerebral cortex and corpus callosum of the mouse

    SciTech Connect

    Schmidt, S.L.; Lent, R.

    1987-10-08

    Defects of the cerebral cortex and corpus callosum of mice subjected prenatally to gamma irradiation were evaluated as a function of dose and of embryonic age at irradiation. Pregnant mice were exposed to a gamma source at 16, 17, and 19 days of gestation (E16, E17, and E19, respectively), with total doses of 2 Gy and 3 Gy, in order to produce brain defects on their progeny. At 60 postnatal days, the brains of the offspring were analyzed qualitatively and quantitatively and compared with those of nonirradiated animals. Mice irradiated at E16 were all acallosal. Those that were exposed to 2 Gy displayed an aberrant longitudinal bundle typical of other acallosals, but this was not the case in those irradiated with 3 Gy. The corpus callosum of animals irradiated at E17 with 3 Gy was pronouncedly hypotrophic, but milder effects were observed in the other groups. Quantitative analysis confirmed a dependence of callosal midsagittal area upon dose and age at irradiation, and, in addition, indicated an interaction between these variables. The neocortex of irradiated animals was hypotrophic: layers II-III were much more affected than layer V, and this was more affected than layer VI. Quantitative analysis indicated that this effect also depended on dose and age at irradiation and that it was due to a loss of cortical neurons. Furthermore, a positive correlation was found between the number of neurons within layers II-III, and V and the midsagittal area of the corpus callosum. Ectopic neurons were found in the white matter and in layer I of animals irradiated at E16 and E17, indicating that fetal exposure to ionizing radiation interfered with the migration of cortical neuroblasts.

  4. Characterization of cerebral malaria in the outbred Swiss Webster mouse infected by Plasmodium berghei ANKA.

    PubMed

    Martins, Yuri Chaves; Smith, Mary Jane; Pelajo-Machado, Marcelo; Werneck, Guilherme Loureiro; Lenzi, Henrique Leonel; Daniel-Ribeiro, Claudio Tadeu; Carvalho, Leonardo José de Moura

    2009-04-01

    Plasmodium berghei ANKA (PbA) infection in susceptible inbred mouse strains is the most commonly used experimental model to study pathogenesis of cerebral malaria (CM). Indeed, many concepts on mechanisms related to this complication have arisen from works using this model. Although inbred strains present several advantages and are indicated for most studies, the use of outbred models can show unique usefulness in a number of approaches such as fine post-quantitative trait loci mapping and discovery of genes relevant to CM susceptibility or resistance, as well as pharmacological and vaccine studies. Here we describe the features of PbA infection and CM incidence, and characterize the associated multiorgan pathology in the outbred Swiss Webster mouse. This model showed a sizeable (62.7%) and reproducible incidence of CM demonstrated by clinical signs and histopathological changes in brain (microhaemorrhages, oedema and vessel plugging by mononuclear cells). Major pathological changes were also observed in lungs, liver, thymus and spleen, analogous to those observed in inbred strains. Parasitaemia levels were associated with the risk of CM development, the risk being significantly higher in mice showing higher values of parasitaemia on days 6-7 of infection. This outbred CM model is then suitable for genetic, vaccine and drug studies targeting this malaria complication.

  5. Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse.

    PubMed

    Unal, Gunes; Joshi, Abhilasha; Viney, Tim J; Kis, Viktor; Somogyi, Peter

    2015-12-01

    Temporal coordination of neuronal assemblies among cortical areas is essential for behavioral performance. GABAergic projections from the medial septum and diagonal band complex exclusively innervate GABAergic interneurons in the rat hippocampus, contributing to the coordination of neuronal activity, including the generation of theta oscillations. Much less is known about the synaptic target neurons outside the hippocampus. To reveal the contribution of synaptic circuits involving the medial septum of mice, we have identified postsynaptic cortical neurons in wild-type and parvalbumin-Cre knock-in mice. Anterograde axonal tracing from the septum revealed extensive innervation of the hippocampus as well as the subiculum, presubiculum, parasubiculum, the medial and lateral entorhinal cortices, and the retrosplenial cortex. In all examined cortical regions, many septal GABAergic boutons were in close apposition to somata or dendrites immunopositive for interneuron cell-type molecular markers, such as parvalbumin, calbindin, calretinin, N-terminal EF-hand calcium-binding protein 1, cholecystokinin, reelin, or a combination of these molecules. Electron microscopic observations revealed septal boutons forming axosomatic or axodendritic type II synapses. In the CA1 region of hippocampus, septal GABAergic projections exclusively targeted interneurons. In the retrosplenial cortex, 93% of identified postsynaptic targets belonged to interneurons and the rest to pyramidal cells. These results suggest that the GABAergic innervation from the medial septum and diagonal band complex contributes to temporal coordination of neuronal activity via several types of cortical GABAergic interneurons in both hippocampal and extrahippocampal cortices. Oscillatory septal neuronal firing at delta, theta, and gamma frequencies may phase interneuron activity. PMID:26631464

  6. High-Resolution Magnetic Resonance Angiography of the Mouse Brain: Application to Murine Focal Cerebral Ischemia Models

    NASA Astrophysics Data System (ADS)

    Beckmann, Nicolau; Stirnimann, Roger; Bochelen, Damien

    1999-10-01

    Three-dimensional time-of-flight high-resolution magnetic resonance angiography was applied to visualize the cerebral vasculature of the mouse brain. In normal mice, angiograms of good quality, showing the essential details of the arterial cerebrovascular anatomy, could be obtained in only 2.5 min without the use of contrast agents. Signals from slowly flowing blood, e.g., in veins, could also be detected after administration of a blood pool contrast agent. The technique was applied to mouse models of permanent and transient brain ischemia, involving the occlusion of the middle cerebral artery. High-resolution magnetic resonance angiography proved to be a very useful tool for verifying the success of the occlusion in these models.

  7. Activation of antioxidant response element in mouse primary cortical cultures with sesquiterpene lactones isolated from Tanacetum parthenium

    PubMed Central

    Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A.; De Vos, Ric C.H.; Todorović, Slađana; Banjanac, Tijana; Verpoorte, Rob; Johnson, Jeffrey A.

    2012-01-01

    Tanacetum parthenium (Asteraceae) produces biologically active sesquiterpene lactones (SL). Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to activate a series of genes termed the antioxidant response element (ARE). Activation of the Nrf2/ARE may be useful for the treatment of neurodegenerative disease. In this study we isolated 11 sesquiterpene lactones from T. parthenium with centrifugal partition chromatography and semi-preparative HPLC. Compounds were screened in-vitro for their ability to activate the ARE on primary mouse cortical cultures as well as for their toxicity towards the cultures. All sesquiterpene lactones containing the α-methylene-γ-lactone moiety were able to activate the ARE although a number of compounds displayed significant cellular toxicity towards the cultures. The structure activity relationship of the sesquiterpene lactones indicate that the guaianolides isolated were more active and less toxic then the germacranolides. PMID:22923197

  8. During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons

    PubMed Central

    Brown, Adam R.; Mitchell, Scott J.; Peden, Dianne R.; Herd, Murray B.; Seifi, Mohsen; Swinny, Jerome D.; Belelli, Delia; Lambert, Jeremy J.

    2016-01-01

    As neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5α-pregnan-3α-ol-20-one (5α3α), the GABAAR-inactive 5α-dihydroprogesterone, (5α-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABAARs incorporating the α1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from α1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABAARs of L2/3 interneurons were modulated by native neurosteroids in a development-dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity. PMID:26626485

  9. Distinct microRNA Expression Profiles in Mouse Renal Cortical Tissue after 177Lu-octreotate Administration

    PubMed Central

    Schüler, Emil; Parris, Toshima Z.; Helou, Khalil; Forssell-Aronsson, Eva

    2014-01-01

    Aim The aim of this study was to investigate the variation of the miRNA expression levels in normal renal cortical tissue after 177Lu-octreotate administration, a radiopharmaceutical used for treatment of neuroendocrine cancers. Methods Female BALB/c nude mice were i.v. injected with 1.3, 3.6, 14, 45, or 140 MBq 177Lu-octreotate, while control animals received saline. The animals were killed at 24 h after injection and total RNA, including miRNA, was extracted from the renal cortical tissue and hybridized to the Mouse miRNA Oligo chip 4plex to identify differentially regulated miRNAs between exposed and control samples. Results In total, 57 specific miRNAs were differentially regulated in the exposed renal cortical tissues with 1, 29, 21, 27, and 31 miRNAs identified per dose-level (0.13, 0.34, 1.3, 4.3, and 13 Gy, respectively). No miRNAs were commonly regulated at all dose levels. miR-194, miR-107, miR-3090, and miR-3077 were commonly regulated at 0.34, 1.3, 4.3, and 13 Gy. Strong effects on cellular mechanisms ranging from immune response to p53 signaling and cancer-related pathways were observed at the highest absorbed dose. Thirty-nine of the 57 differentially regulated miRNAs identified in the present study have previously been associated with response to ionizing radiation, indicating common radiation responsive pathways. Conclusion In conclusion, the 177Lu-octreotate associated miRNA signatures were generally dose-specific, thereby illustrating transcriptional regulation of radiation responsive miRNAs. Taken together, these results imply the importance of miRNAs in early immunological responses in the kidneys following 177Lu-octreotate administration. PMID:25386939

  10. Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy

    PubMed Central

    Liao, Fan; Xiao, Qingli; Kraft, Andrew; Gonzales, Ernie; Perez, Ron; Greenberg, Steven M.; Holtzman, David; Lee, Jin-Moo

    2015-01-01

    Background and Purpose Cerebral Amyloid Angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage (ICH) in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and -9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine if spontaneous ICH could be reduced. Methods Tg2576 (n=16) and 5×FAD/ApoE4 knock-in mice (n=16), aged to 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, i.p.) or saline every other day for two months. Brains were extracted and stained with X-34 (to quantify amyloid), Perl’s blue (to quantify hemorrhage), and immunostained to examined Aβ load, gliosis (GFAP, Iba-1), and vascular markers of blood-brain-barrier integrity (ZO-1 and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. Results Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5×FAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (MMP-9, Nox4, CD45, S-100b, Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. Conclusions Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in two different mouse models of CAA, supporting the importance of MMP-related and inflammatory pathways in ICH pathogenesis. As an FDA-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related ICH. PMID:25944329

  11. Quantification of Alterations in Cortical Bone Geometry Using Site Specificity Software in Mouse models of Aging and the Responses to Ovariectomy and Altered Loading.

    PubMed

    Galea, Gabriel L; Hannuna, Sion; Meakin, Lee B; Delisser, Peter J; Lanyon, Lance E; Price, Joanna S

    2015-01-01

    Investigations into the effect of (re)modeling stimuli on cortical bone in rodents normally rely on analysis of changes in bone mass and architecture at a narrow cross-sectional site. However, it is well established that the effects of axial loading produce site-specific changes throughout bones' structure. Non-mechanical influences (e.g., hormones) can be additional to or oppose locally controlled adaptive responses and may have more generalized effects. Tools currently available to study site-specific cortical bone adaptation are limited. Here, we applied novel site specificity software to measure bone mass and architecture at each 1% site along the length of the mouse tibia from standard micro-computed tomography (μCT) images. Resulting measures are directly comparable to those obtained through μCT analysis (R (2) > 0.96). Site Specificity analysis was used to compare a number of parameters in tibiae from young adult (19-week-old) versus aged (19-month-old) mice; ovariectomized and entire mice; limbs subjected to short periods of axial loading or disuse induced by sciatic neurectomy. Age was associated with uniformly reduced cortical thickness and site-specific decreases in cortical area most apparent in the proximal tibia. Mechanical loading site-specifically increased cortical area and thickness in the proximal tibia. Disuse uniformly decreased cortical thickness and decreased cortical area in the proximal tibia. Ovariectomy uniformly reduced cortical area without altering cortical thickness. Differences in polar moment of inertia between experimental groups were only observed in the proximal tibia. Aging and ovariectomy also altered eccentricity in the distal tibia. In summary, site specificity analysis provides a valuable tool for measuring changes in cortical bone mass and architecture along the entire length of a bone. Changes in the (re)modeling response determined at a single site may not reflect the response at different locations within the same

  12. Nanoscopy of filamentous actin in cortical dendrites of a living mouse.

    PubMed

    Willig, Katrin I; Steffens, Heinz; Gregor, Carola; Herholt, Alexander; Rossner, Moritz J; Hell, Stefan W

    2014-01-01

    We demonstrate superresolution fluorescence microscopy (nanoscopy) of protein distributions in a mammalian brain in vivo. Stimulated emission depletion microscopy reveals the morphology of the filamentous actin in dendritic spines down to 40 μm in the molecular layer of the visual cortex of an anesthetized mouse. Consecutive recordings at 43-70 nm resolution reveal dynamical changes in spine morphology.

  13. A Neural Circuit That Controls Cortical State, Plasticity, and the Gain of Sensory Responses in Mouse

    PubMed Central

    Stryker, Michael P.

    2015-01-01

    Neurons in the visual cortex were first found to be exquisitely selective for particular properties of visual stimuli in anesthetized animals, including mice. Studies of alert mice in an apparatus that allowed them to stand or run revealed that locomotion causes a change in cortical state that dramatically increases the magnitude of responses in neurons of the visual cortex without altering selectivity, effectively changing the gain of sensory responses. Locomotion also dramatically enhances adult plasticity in the recovery from long-term visual deprivation. We have studied the elements and operation of the neural circuit responsible for the enhancement of activity and shown that it enhances plasticity even in mice not free to run. The circuit consists of projections ascending from the midbrain locomotor region (MLR) to the basal forebrain, activating cholinergic and perhaps other projections to excite inhibitory interneurons expressing vasoactive intestinal peptide (VIP) in the visual cortex. VIP cells activated by locomotion inhibit interneurons that express somatostatin (SST), thereby disinhibiting the excitatory principal neurons and allowing them to respond more strongly to effective visual stimuli. These findings reveal in alert animals how the ascending reticular activating system described in anesthetized animals 50 years ago operates to control cortical state. PMID:25948638

  14. Effect of chronic ethanol treatment in vivo on excitability in mouse cortical neurones in vitro

    PubMed Central

    Ibbotson, T; Field, M J; Boden, P R

    1997-01-01

    The effects of cessation of chronic ethanol ingestion on seizure activity in vivo and on the characteristics of the evoked synaptic potentials in cortical neurones in vitro have been investigated in mice. Withdrawal from chronic ethanol treatment increased handling seizure ratings in mice between 4 and 16 h post-withdrawal. This ethanol-induced increase in seizure rating was unaffected by carbamazepine (30 mg kg−1) but significantly reduced at a higher concentration (130 mg kg−1). Intracellular recordings were made from cortical layer II neurones in vitro from control mice and from mice following chronic ethanol ingestion. Evoked synaptic potentials were generated in these neurones through intralaminar stimulation. Neurones from control mice displayed an evoked potential consisting of a fast excitatory postsynaptic potential (e.p.s.p.) mediated by AMPA-type glutamate receptors and an inhibitory postsynaptic potential (i.p.s.p.) mediated via GABAA receptors. Application of pentylenetetrazole (PTZ) or bicuculline onto these neurones inhibited the i.p.s.p., caused a large increase in both the amplitude and duration of the e.p.s.p. and initiated spontaneous excitatory activity. The resulting large evoked e.p.s.p. was mediated via both NMDA- and AMPA-type glutamate receptors. Most neurones (77%) from ethanol treated mice displayed an evoked potential which comprised a large e.p.s.p. and no i.p.s.p. The e.p.s.p. consisted of several distinct components and in addition these neurones displayed spontaneous paroxysmal depolarizing shifts. This multi-component e.p.s.p. was mediated through both NMDA- and AMPA-type glutamate receptors. A population (23%) of neurones from ethanol treated mice exhibited evoked potentials which possessed both inhibitory and excitatory components and these neurones were effectively identical to those obtained from control mice. Carbamazepine reduced the duration of the e.p.s.p. in neurones from ethanol treated mice and in PTZ

  15. Spatiotemporal SERT expression in cortical map development.

    PubMed

    Chen, Xiaoning; Petit, Emilie I; Dobrenis, Kostantin; Sze, Ji Ying

    2016-09-01

    The cerebral cortex is organized into morphologically distinct areas that provide biological frameworks underlying perception, cognition, and behavior. Profiling mouse and human cortical transcriptomes have revealed temporal-specific differential gene expression modules in distinct neocortical areas during cortical map establishment. However, the biological roles of spatiotemporal gene expression in cortical patterning and how cortical topographic gene expression is regulated are largely unknown. Here, we characterize temporal- and spatial-defined expression of serotonin (5-HT) transporter (SERT) in glutamatergic neurons during sensory map development in mice. SERT is transiently expressed in glutamatergic thalamic neurons projecting to sensory cortices and in pyramidal neurons in the prefrontal cortex (PFC) and hippocampus (HPC) during the period that lays down the basic functional neural circuits. We previously identified that knockout of SERT in the thalamic neurons blocks 5-HT uptake by their thalamocortical axons, resulting in excessive 5-HT signaling that impairs sensory map architecture. In contrast, here we show that selective SERT knockout in the PFC and HPC neurons does not perturb sensory map patterning. These data suggest that transient SERT expression in specific glutamatergic neurons provides area-specific instructions for cortical map patterning. Hence, genetic and pharmacological manipulations of this SERT function could illuminate the fundamental genetic programming of cortex-specific maps and biological roles of temporal-specific cortical topographic gene expression in normal development and mental disorders. PMID:27282696

  16. Selective 14-3-3γ induction quenches p-β-catenin Ser37/Bax-enhanced cell death in cerebral cortical neurons during ischemia.

    PubMed

    Lai, X J; Ye, S Q; Zheng, L; Li, L; Liu, Q R; Yu, S B; Pang, Y; Jin, S; Li, Q; Yu, A C H; Chen, X Q

    2014-01-01

    Ischemia-induced cell death is a major cause of disability or death after stroke. Identifying the key intrinsic protective mechanisms induced by ischemia is critical for the development of effective stroke treatment. Here, we reported that 14-3-3γ was a selective ischemia-inducible survival factor in cerebral cortical neurons reducing cell death by downregulating Bax depend direct 14-3-3γ/p-β-catenin Ser37 interactions in the nucleus. 14-3-3γ, but not other 14-3-3 isoforms, was upregulated in primary cerebral cortical neurons upon oxygen-glucose deprivation (OGD) as measured by quantitative PCR, western blot and fluorescent immunostaining. The selective induction of 14-3-3γ in cortical neurons by OGD was verified by the in vivo ischemic stroke model. Knocking down 14-3-3γ alone or inhibiting 14-3-3/client interactions was sufficient to induce cell death in normal cultured neurons and exacerbate OGD-induced neuronal death. Ectopic overexpression of 14-3-3γ significantly reduced OGD-induced cell death in cultured neurons. Co-immunoprecipitation and fluorescence resonance energy transfer demonstrated that endogenous 14-3-3γ bound directly to more p-β-catenin Ser37 but not p-Bad, p-Ask-1, p-p53 and Bax. During OGD, p-β-catenin Ser37 but not p-β-catenin Ser45 was increased prominently, which correlated with Bax elevation in cortical neurons. OGD promoted the entry of 14-3-3γ into the nuclei, in correlation with the increase of nuclear p-β-catenin Ser37 in neurons. Overexpression of 14-3-3γ significantly reduced Bax expression, whereas knockdown of 14-3-3γ increased Bax in cortical neurons. Abolishing β-catenin phosphorylation at Ser37 (S37A) significantly reduced Bax and cell death in neurons upon OGD. Finally, 14-3-3γ overexpression completely suppressed β-catenin-enhanced Bax and cell death in neurons upon OGD. Based on these data, we propose that the 14-3-3γ/p-β-catenin Ser37/Bax axis determines cell survival or death of neurons during ischemia

  17. The magnitude of the somatosensory cortical activity is related to the mobility and strength impairments seen in children with cerebral palsy

    PubMed Central

    Heinrichs-Graham, Elizabeth; Becker, Katherine M.; Wilson, Tony W.

    2015-01-01

    The noted disruption of thalamocortical connections and abnormalities in tactile sensory function has resulted in a new definition of cerebral palsy (CP) that recognizes the sensorimotor integration process as central to the motor impairments seen in these children. Despite this updated definition, the connection between a child's motor impairments and somatosensory processing remains almost entirely unknown. In this investigation, we explored the relationship between the magnitude of neural activity within the somatosensory cortices, the strength of the ankle plantarflexors, and the gait spatiotemporal kinematics of a group of children with CP and a typically developing matched cohort. Our results revealed that the magnitude of somatosensory cortical activity in children with CP had a strong positive relationship with the ankle strength, step length, and walking speed. These results suggest that stronger activity within the somatosensory cortices in response to foot somatosensations was related to enhanced ankle plantarflexor strength and improved mobility in the children with CP. These results provide further support for the notion that children with CP exhibit, not only musculoskeletal deficits, but also somatosensory deficits that potentially contribute to their overall functional mobility and strength limitations. PMID:25717160

  18. The magnitude of the somatosensory cortical activity is related to the mobility and strength impairments seen in children with cerebral palsy.

    PubMed

    Kurz, Max J; Heinrichs-Graham, Elizabeth; Becker, Katherine M; Wilson, Tony W

    2015-05-01

    The noted disruption of thalamocortical connections and abnormalities in tactile sensory function has resulted in a new definition of cerebral palsy (CP) that recognizes the sensorimotor integration process as central to the motor impairments seen in these children. Despite this updated definition, the connection between a child's motor impairments and somatosensory processing remains almost entirely unknown. In this investigation, we explored the relationship between the magnitude of neural activity within the somatosensory cortices, the strength of the ankle plantarflexors, and the gait spatiotemporal kinematics of a group of children with CP and a typically developing matched cohort. Our results revealed that the magnitude of somatosensory cortical activity in children with CP had a strong positive relationship with the ankle strength, step length, and walking speed. These results suggest that stronger activity within the somatosensory cortices in response to foot somatosensations was related to enhanced ankle plantarflexor strength and improved mobility in the children with CP. These results provide further support for the notion that children with CP exhibit, not only musculoskeletal deficits, but also somatosensory deficits that potentially contribute to their overall functional mobility and strength limitations.

  19. Reversed electrogenic sodium bicarbonate cotransporter 1 is the major acid loader during recovery from cytosolic alkalosis in mouse cortical astrocytes

    PubMed Central

    Theparambil, Shefeeq M; Naoshin, Zinnia; Thyssen, Anne; Deitmer, Joachim W

    2015-01-01

    Recovery of intracellular pH from cytosolic alkalosis has been attributed primarily to Cl– coupled acid loaders/base extruders such as Cl–/HCO3– or Cl–/OH– exchangers. We have studied this process in cortical astrocytes from wild-type and transgenic mouse models with gene deletion for the electrogenic sodium bicarbonate cotransporter 1 (NBCe1) and for carbonic anhydrase (CA) isoform II. An acute cytosolic alkalosis was induced by the removal of either CO2/HCO3– or butyric acid, and the subsequent acid loading was analysed by monitoring changes in cytosolic H+ or Na+ using ion-sensitive fluorescent dyes. We have identified that NBCe1 reverses during alkalosis and contributes more than 70% to the rate of recovery from alkalosis by extruding Na+ and HCO3–. After CA inhibition or in CAII-knockout (KO) cells, the rate of recovery was reduced by 40%, and even by 70% in the nominal absence of CO2/HCO3–. Increasing the extracellular K+ concentration modulated the rate of acid loading in wild-type cells, but not in NBCe1-KO cells. Removing chloride had only a minor effect on the recovery from alkalosis. Reversal of NBCe1 by reducing pH/[HCO3–] was demonstrated in astrocytes and in Xenopus oocytes, in which human NBCe1 was heterologously expressed. The results obtained suggest that reversed NBCe1, supported by CAII activity, plays a major role in acid-loading cortical astrocytes to support recovery from cytosolic alkalosis. PMID:25990710

  20. Comparative analysis of H&E and Prussian blue staining in a mouse model of cerebral microbleeds.

    PubMed

    Liu, Shuo; Grigoryan, Mher Mahoney; Vasilevko, Vitaly; Sumbria, Rachita K; Paganini-Hill, Annlia; Cribbs, David H; Fisher, Mark J

    2014-11-01

    Cerebral microbleeds are microscopic hemorrhages with deposits of blood products in the brain, which can be visualized with MRI and are implicated in cerebrovascular diseases. Hematoxylin and eosin (H&E) and Perl's Prussian blue are popular staining methods used to localize cerebral microbleeds in pathology. This paper compared these two staining techniques in a mouse model of cerebral microbleeds. We used lipopolysaccharide (LPS) to induce cerebral microhemorrhages. C57B6 mice were treated with LPS (5 mg/kg, i.p.) or vehicle at baseline and at 24 hr. The brains were extracted 48 hr after the first injection and adjacent coronal sections were stained with H&E and Prussian blue to compare the effectiveness of the two staining techniques. H&E-positive stains were increased with LPS treatment and were correlated with grossly visible microhemorrhages on the brain surface; Prussian blue-positive stains, by comparison, showed no significant increase with LPS treatment and did not correlate with either H&E-positive stains or surface microhemorrhages. H&E staining is thus a more reliable indicator of acute bleeding events induced by LPS in this model within a short time span.

  1. Uptake of (/sup 3/H)serotonin into plasma membrane vesicles from mouse cerebral cortex

    SciTech Connect

    O'Reilly, C.A.; Reith, M.E.A.

    1988-05-05

    Preparations of plasma membrane vesicles were used as a tool to study the properties of the serotonin transporter in the central nervous system. The vesicles were obtained after hypotonic shock of synaptosomes purified from mouse cerebral cortex. Uptake of (/sup 3/H)serotonin had a Na/sup +/-dependent and Na/sup +/-independent component. The Na/sup +/-dependent uptake was inhibited by classical blockers of serotonin uptake and had a K/sub m/ of 63-180 nM, and a V/sub max/ of 0.1-0.3 pmol mg/sup -1/ s/sup -1/ at 77 mM Na/sup +/. The uptake required the presence of external Na/sup +/ and internal K/sup +/. Replacement of Cl/sup -/ by other anions (NO/sub 2//sup -/, S/sub 2/O/sub 3//sup 2 -/) reduced uptake appreciably. Gramicidin prevented uptake. Although valinomycin increased uptake somewhat, the membrane potential per se could not drive uptake because no uptake was observed when a membrane potential was generated by the SCN/sup -/ ion in the absence of internal K/sup +/ and with equal (Na/sup +/) inside and outside. The increase of uptake as a function of (Na/sup +/) indicated a K/sub m/ for Na/sup +/ of 118 mM and a Hill number of 2.0, suggesting a requirement of two sodium ions for serotonin transport. The present results are accommodated very well by the model developed for porcine platelet serotonin transport except for the number of sodium ions that are required for transport.

  2. Differential effects of methylmercury on gamma-aminobutyric acid type A receptor currents in rat cerebellar granule and cerebral cortical neurons in culture.

    PubMed

    Herden, Christina J; Pardo, Nicole E; Hajela, Ravindra K; Yuan, Yukun; Atchison, William D

    2008-02-01

    Cerebellar granule cells are particularly sensitive to inhibition by methylmercury (MeHg) on GABA(A) receptor function. This is manifested as a more rapid block of inhibitory postsynaptic currents/inhibitory postsynaptic potentials than for Purkinje cells. The underlying mechanism(s) for differential sensitivity of GABAergic transmission to MeHg in cerebellar neurons is unknown. Differential expression of alpha(6) subunit-containing GABA(A) receptors in cerebellar granule and Purkinje neurons could partially explain this. GABA-evoked currents (I(GABA)) were recorded in response to MeHg in alpha(6) subunit-containing cerebellar granule cells and alpha(6) subunit-deficient cerebral cortical cells in culture. Cortical cells were substituted for Purkinje cells, which do not express alpha(6) subunits. They express the same alpha(1)-containing GABA(A) receptor as Purkinje cells but lack characteristics that enhance Purkinje cell resistance to MeHg. I(GABA) were obtained using whole-cell recording and symmetrical [Cl(-)]. MeHg reduced I(GABA) to complete block in both cell types in a time- and concentration-dependent manner. This effect was faster in granule cells than cortical cells. Effects of MeHg on I(GABA) were recorded in granule cells at various developmental stages (days in vitro 4, 6, and 8) to alter the expression level of alpha(6) subunit-containing GABA(A) receptors. Effects of MeHg on I(GABA) were similar in cells at all days. In human embryonic kidney 293 cells expressing either alpha(6) or alpha(1) subunit-containing GABA(A) receptors, time to block of I(GABA) by MeHg was comparable. Thus, the presence of the alpha(6) subunit alone may not underlie the differential effects of MeHg on I(GABA) observed in cerebellar granule and cortical neurons; other factors are likely to be involved as well. PMID:17977981

  3. Immunophilin Deficiency Augments Ca2+-Dependent Glutamate Release from Mouse Cortical Astrocytes

    PubMed Central

    Reyes, Reno C.; Perry, Giselle; Lesort, Mathieu; Parpura, Vladimir

    2010-01-01

    SUMMARY Immunophilins are receptors for immunosuppressive drugs such as the macrolides cyclosporin A (CsA) and FK506; correspondingly these immunophilins are referred as cyclophilins and FK506-binding proteins (FKBPs). In particular, CsA targets cyclophilin D (CypD), which can modulate mitochondrial Ca2+ dynamics. Since mitochondria have been implicated in the regulation of astrocytic cytosolic Ca2+ (Ca2+cyt) dynamics and consequential Ca2+-dependent exocytotic release of glutamate, we investigated the role of CypD in this process. Cortical astrocytes isolated from CypD deficient mice Ppif −/− displayed reduced mechanically-induced Ca2+cyt increases, even though these cells showed augmented exocytotic release of glutamate, when compared to responses obtained from astrocytes isolated from wild-type mice. Furthermore, acute treatment with CsA to inhibit CypD modulation of mitochondrial Ca2+ buffering, or with FK506 to inhibit FKBP12 interaction with inositol-trisphosphate receptor of the endoplasmic reticulum, led to similar reductive effects on astrocytic Ca2+cyt dynamics, but also to an enhanced Ca2+-dependent exocytotic release of glutamate in wild-type astrocytes. These findings point to a possible role of immunophilin signal transduction pathways in astrocytic modulation of neuronal activity at the tripartite synapse. PMID:21163525

  4. Substance P receptors in primary cultures of cortical astrocytes from the mouse.

    PubMed Central

    Torrens, Y; Beaujouan, J C; Saffroy, M; Daguet de Montety, M C; Bergström, L; Glowinski, J

    1986-01-01

    Binding sites for substance P were labeled on intact cortical glial cells from newborn mice in primary culture using 125I-labeled Bolton-Hunter-labeled substance P. Maximal specific binding (95% of total binding) was reached after 2-3 weeks in culture. The binding was saturable, reversible, and temperature dependent. Scatchard and Hill analysis revealed a single population of noninteracting high-affinity binding sites (Kd, 0.33 nM; Bmax, 14.4 fmol per dish). Competition studies made with tachykinins and substance P analogues indicated that the characteristics of the 125I-labeled Bolton-Hunter labeled substance P binding sites on glial cells were identical to those on rat brain synaptosomes. 125I-labeled Bolton-Hunter labeled substance P binding sites were visualized by autoradiography, and differences in the intensity of labeling were seen among astrocytes. Substance P was found to stimulate phosphatidylinositol turnover; the EC50 value (0.36 nM) was identical to the IC50 value (0.38 nM) determined in binding studies. 125I-labeled Bolton-Hunter labeled substance P binding sites were also found on astrocytes derived from other brain structures and from the spinal cord of mice. Images PMID:2431412

  5. Acute systemic LPS-mediated inflammation induces lasting changes in mouse cortical neuromodulation and behavior.

    PubMed

    Ming, Z; Sawicki, G; Bekar, L K

    2015-03-17

    Systemic lipopolysaccharide (LPS) is widely used to induce a neuroinflammatory response that is associated with short-term 'sickness'-behavior that can include fever, loss of activity, loss of appetite, impaired cognition, anxiety and depression. If large enough or left unchecked, this neuroinflammatory response can become self-perpetuating and lead to long-term neurodegenerative processes. In this study, we assess the longer-term effects of a single systemic LPS injection on electrophysiological neuromodulator effects and basic behavioral analysis in mice. Five months after LPS injection, we find a mild reduction in cortical inhibition and altered temporal dynamics of acetylcholine but not norepinephrine or serotonin neuromodulator effects. Consistent with electrophysiological findings, LPS treated mice showed a deficit in memory performance in the novel object recognition test with no effect on measures of anxiety or despair as measured in the open field test and tail suspension test, respectively. Furthermore, LPS-treated mice showed an increase in acetylcholinesterase activity. As increased acetylcholinesterase activity is associated with reduced acetylcholine signaling and impaired cognitive ability, these studies demonstrate the potential for a single inflammatory event to initiate processes that may lead to long-term neurodegeneration. PMID:25650524

  6. Large-scale mass spectrometry imaging investigation of consequences of cortical spreading depression in a transgenic mouse model of migraine.

    PubMed

    Carreira, Ricardo J; Shyti, Reinald; Balluff, Benjamin; Abdelmoula, Walid M; van Heiningen, Sandra H; van Zeijl, Rene J; Dijkstra, Jouke; Ferrari, Michel D; Tolner, Else A; McDonnell, Liam A; van den Maagdenberg, Arn M J M

    2015-06-01

    Cortical spreading depression (CSD) is the electrophysiological correlate of migraine aura. Transgenic mice carrying the R192Q missense mutation in the Cacna1a gene, which in patients causes familial hemiplegic migraine type 1 (FHM1), exhibit increased propensity to CSD. Herein, mass spectrometry imaging (MSI) was applied for the first time to an animal cohort of transgenic and wild type mice to study the biomolecular changes following CSD in the brain. Ninety-six coronal brain sections from 32 mice were analyzed by MALDI-MSI. All MSI datasets were registered to the Allen Brain Atlas reference atlas of the mouse brain so that the molecular signatures of distinct brain regions could be compared. A number of metabolites and peptides showed substantial changes in the brain associated with CSD. Among those, different mass spectral features showed significant (t-test, P < 0.05) changes in the cortex, 146 and 377 Da, and in the thalamus, 1820 and 1834 Da, of the CSD-affected hemisphere of FHM1 R192Q mice. Our findings reveal CSD- and genotype-specific molecular changes in the brain of FHM1 transgenic mice that may further our understanding about the role of CSD in migraine pathophysiology. The results also demonstrate the utility of aligning MSI datasets to a common reference atlas for large-scale MSI investigations.

  7. Large-Scale Mass Spectrometry Imaging Investigation of Consequences of Cortical Spreading Depression in a Transgenic Mouse Model of Migraine

    NASA Astrophysics Data System (ADS)

    Carreira, Ricardo J.; Shyti, Reinald; Balluff, Benjamin; Abdelmoula, Walid M.; van Heiningen, Sandra H.; van Zeijl, Rene J.; Dijkstra, Jouke; Ferrari, Michel D.; Tolner, Else A.; McDonnell, Liam A.; van den Maagdenberg, Arn M. J. M.

    2015-06-01

    Cortical spreading depression (CSD) is the electrophysiological correlate of migraine aura. Transgenic mice carrying the R192Q missense mutation in the Cacna1a gene, which in patients causes familial hemiplegic migraine type 1 (FHM1), exhibit increased propensity to CSD. Herein, mass spectrometry imaging (MSI) was applied for the first time to an animal cohort of transgenic and wild type mice to study the biomolecular changes following CSD in the brain. Ninety-six coronal brain sections from 32 mice were analyzed by MALDI-MSI. All MSI datasets were registered to the Allen Brain Atlas reference atlas of the mouse brain so that the molecular signatures of distinct brain regions could be compared. A number of metabolites and peptides showed substantial changes in the brain associated with CSD. Among those, different mass spectral features showed significant ( t-test, P < 0.05) changes in the cortex, 146 and 377 Da, and in the thalamus, 1820 and 1834 Da, of the CSD-affected hemisphere of FHM1 R192Q mice. Our findings reveal CSD- and genotype-specific molecular changes in the brain of FHM1 transgenic mice that may further our understanding about the role of CSD in migraine pathophysiology. The results also demonstrate the utility of aligning MSI datasets to a common reference atlas for large-scale MSI investigations.

  8. Assessment of MRI-Based Automated Fetal Cerebral Cortical Folding Measures in Prediction of Gestational Age in the Third Trimester

    PubMed Central

    Wu, J.; Awate, S.P.; Licht, D.J.; Clouchoux, C.; du Plessis, A.J.; Avants, B.B.; Vossough, A.; Gee, J.C.; Limperopoulos, C.

    2016-01-01

    BACKGROUND AND PURPOSE Traditional methods of dating a pregnancy based on history or sonographic assessment have a large variation in the third trimester. We aimed to assess the ability of various quantitative measures of brain cortical folding on MR imaging in determining fetal gestational age in the third trimester. MATERIALS AND METHODS We evaluated 8 different quantitative cortical folding measures to predict gestational age in 33 healthy fetuses by using T2-weighted fetal MR imaging. We compared the accuracy of the prediction of gestational age by these cortical folding measureswiththeaccuracyofpredictionbybrainvolumemeasurementandbyapreviouslyreportedsemiquantitativevisualscaleofbrain maturity. Regression models were constructed, and measurement biases and variances were determined via a cross-validation procedure. RESULTS The cortical folding measures are accurate in the estimation and prediction of gestational age (mean of the absolute error, 0.43 ± 0.45 weeks) and perform better than (P = .024) brain volume (mean of the absolute error, 0.72 ± 0.61 weeks) or sonography measures (SDs approximately 1.5 weeks, as reported in literature). Prediction accuracy is comparable with that of the semiquantitative visual assessment score (mean, 0.57 ± 0.41 weeks). CONCLUSIONS Quantitative cortical folding measures such as global average curvedness can be an accurate and reliable estimator of gestational age and brain maturity for healthy fetuses in the third trimester and have the potential to be an indicator of brain-growth delays for at-risk fetuses and preterm neonates. PMID:26045578

  9. High effective cytosolic H+ buffering in mouse cortical astrocytes attributable to fast bicarbonate transport.

    PubMed

    Theparambil, Shefeeq M; Deitmer, Joachim W

    2015-09-01

    Cytosolic H(+) buffering plays a major role for shaping intracellular H(+) shifts and hence for the availability of H(+) for biochemical reactions and acid/base-coupled transport processes. H(+) buffering is one of the prime means to protect the cell from large acid/base shifts. We have used the H(+) indicator dye BCECF and confocal microscopy to monitor the cytosolic H(+) concentration, [H(+)]i, in cultured cortical astrocytes of wild-type mice and of mice deficient in sodium/bicarbonate cotransporter NBCe1 (NBCe1-KO) or in carbonic anhydrase isoform II (CAII-KO). The steady-state buffer strength was calculated from the amplitude of [H(+)]i transients as evoked by CO2/HCO3(-) and by butyric acid in the presence and absence of CO2/HCO3(-). We tested the hypotheses if, in addition to instantaneous physicochemical H(+) buffering, rapid acid/base transport across the cell membrane contributes to the total, "effective" cytosolic H(+) buffering. In the presence of 5% CO2/26 mM HCO3(-), H(+) buffer strength in astrocytes was increased 4-6 fold, as compared with that in non-bicarbonate, HEPES-buffered solution, which was largely attributable to fast HCO3 (-) transport into the cells via NBCe1, supported by CAII activity. Our results show that within the time frame of determining physiological H(+) buffering in cells, fast transport and equilibration of CO2/H(+)/HCO3(-) can make a major contribution to the total "effective" H(+) buffer strength. Thus, "effective" cellular H(+) buffering is, to a large extent, attributable to membrane transport of base equivalents rather than a purely passive physicochemical process, and can be much larger than reported so far. Not only physicochemical H(+) buffering, but also rapid import of HCO3(-) via the electrogenic sodium-bicarbonate cotransporter NBCe1, supported by carbonic anhydrase II (CA II), was identified to enhance cytosolic H(+) buffer strength substantially.

  10. Feasibility of event-related potential methodology to evaluate changes in cortical processing after rehabilitation in children with cerebral palsy: A pilot study

    PubMed Central

    Maitre, Nathalie L.; Henderson, Gena; Gogliotti, Shirley; Pearson, Jennifer; Simmons, Ashley; Wang, Lu; Slaughter, James C.; Key, Alexandra P.

    2016-01-01

    This study examined the feasibility of using event-related potentials (ERPs) to measure changes in cortical processing following an established rehabilitative intervention (constraint-induced movement therapy, CIMT) for children with cerebral palsy (CP). Sixteen participants with a diagnosis of hemiparetic CP, with a median age of 6 years, were assessed pre and immediately post CIMT and at 6-month follow-up, using a picture–word match/mismatch discrimination task and standard neurobehavioral measures. Intervention effects were evident in improved performance on behavioral tests of sensory and motor function and the increased mean ERP amplitude of the N400 match/mismatch response on the side ipsilateral to the lesion. These effects were maintained 6 months after the intervention. No such changes were observed on the side contralateral to the lesion. This research suggests that ERPs can measure rehabilitation-induced changes in neural function in children with CP. PMID:24953907

  11. A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor

    PubMed Central

    Bertini, Eva; Ribot, Jérôme; Di Nardo, Ariel A.; Volovitch, Michel; Prochiantz, Alain

    2016-01-01

    During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these “transfer” sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system. PMID:27171438

  12. Arsenic Exposure Induces Unscheduled Mitotic S Phase Entry Coupled with Cell Death in Mouse Cortical Astrocytes

    PubMed Central

    Htike, Nang T. T.; Maekawa, Fumihiko; Soutome, Haruka; Sano, Kazuhiro; Maejima, Sho; Aung, Kyaw H.; Tokuda, Masaaki; Tsukahara, Shinji

    2016-01-01

    There is serious concern about arsenic in the natural environment, which exhibits neurotoxicity and increases the risk of neurodevelopmental disorders. Adverse effects of arsenic have been demonstrated in neurons, but it is not fully understood how arsenic affects other cell types in the brain. In the current study, we examined whether sodium arsenite (NaAsO2) affects the cell cycle, viability, and apoptosis of in vitro-cultured astrocytes isolated from the cerebral cortex of mice. Cultured astrocytes from transgenic mice expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) were subjected to live imaging analysis to assess the effects of NaAsO2 (0, 1, 2, and 4 μM) on the cell cycle and number of cells. Fucci was designed to express monomeric Kusabira Orange2 (mKO2) fused with the ubiquitylation domain of hCdt1, a marker of G1 phase, and monomeric Azami Green (mAG) fused with the ubiquitylation domain of hGem, a marker of S, G2, and M phases. NaAsO2 concentration-dependently decreased the peak levels of the mAG/mKO2 emission ratio when the ratio had reached a peak in astrocytes without NaAsO2 exposure, which was due to attenuating the increase in the mAG-expressing cell number. In contrast, the mAG/mKO2 emission ratio and number of mAG-expressing cells were concentration-dependently increased by NaAsO2 before their peak levels, indicating unscheduled S phase entry. We further examined the fate of cells forced to enter S phase by NaAsO2. We found that most of these cells died up to the end of live imaging. In addition, quantification of the copy number of the glial fibrillary acidic protein gene expressed specifically in astrocytes revealed a concentration-dependent decrease caused by NaAsO2. However, NaAsO2 did not increase the amount of nucleosomes generated from DNA fragmentation and failed to alter the gene expression of molecules relevant to unscheduled S phase entry-coupled apoptosis (p21, p53, E2F1, E2F4, and Gm36566). These findings

  13. Combination of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 technique with the piggybac transposon system for mouse in utero electroporation to study cortical development.

    PubMed

    Cheng, Man; Jin, Xubin; Mu, Lili; Wang, Fangyu; Li, Wei; Zhong, Xiaoling; Liu, Xuan; Shen, Wenchen; Liu, Ying; Zhou, Yan

    2016-09-01

    In utero electroporation (IUE) is commonly used to study cortical development of cerebrum by downregulating or overexpressing genes of interest in neural progenitor cells (NPCs) of small mammals. However, exogenous plasmids are lost or diluted over time. Furthermore, gene knockdown based on short-hairpin RNAs may exert nonspecific effects that lead to aberrant neuronal migration. Genomic engineering by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system has great research and therapeutic potentials. Here we integrate the CRISPR/Cas9 components into the piggyBac (PB) transposon system (the CRISPR/Cas9-PB toolkit) for cortical IUEs. The mouse Sry-related HMG box-2 (Sox2) gene was selected as the target for its application. Most transduced cortical NPCs were depleted of SOX2 protein as early as 3 days post-IUE, whereas expressions of SOX1 and PAX6 remained intact. Furthermore, both the WT Cas9 and the D10A nickase mutant Cas9n showed comparable knockout efficiency. Transduced cortical cells were purified with fluorescence-activated cell sorting, and effective gene editing at the Sox2 loci was confirmed. Thus, application of the CRISPR/Cas9-PB toolkit in IUE is a promising strategy to study gene functions in cortical NPCs and their progeny. © 2016 Wiley Periodicals, Inc. PMID:27317429

  14. Combination of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 technique with the piggybac transposon system for mouse in utero electroporation to study cortical development.

    PubMed

    Cheng, Man; Jin, Xubin; Mu, Lili; Wang, Fangyu; Li, Wei; Zhong, Xiaoling; Liu, Xuan; Shen, Wenchen; Liu, Ying; Zhou, Yan

    2016-09-01

    In utero electroporation (IUE) is commonly used to study cortical development of cerebrum by downregulating or overexpressing genes of interest in neural progenitor cells (NPCs) of small mammals. However, exogenous plasmids are lost or diluted over time. Furthermore, gene knockdown based on short-hairpin RNAs may exert nonspecific effects that lead to aberrant neuronal migration. Genomic engineering by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system has great research and therapeutic potentials. Here we integrate the CRISPR/Cas9 components into the piggyBac (PB) transposon system (the CRISPR/Cas9-PB toolkit) for cortical IUEs. The mouse Sry-related HMG box-2 (Sox2) gene was selected as the target for its application. Most transduced cortical NPCs were depleted of SOX2 protein as early as 3 days post-IUE, whereas expressions of SOX1 and PAX6 remained intact. Furthermore, both the WT Cas9 and the D10A nickase mutant Cas9n showed comparable knockout efficiency. Transduced cortical cells were purified with fluorescence-activated cell sorting, and effective gene editing at the Sox2 loci was confirmed. Thus, application of the CRISPR/Cas9-PB toolkit in IUE is a promising strategy to study gene functions in cortical NPCs and their progeny. © 2016 Wiley Periodicals, Inc.

  15. Maturation of neuronal form and function in a mouse thalamo-cortical circuit.

    PubMed

    Warren, R A; Jones, E G

    1997-01-01

    Postnatal development of physiological properties underlying slow intrathalamic oscillations was studied by whole-cell recording from synaptically coupled neurons of the reticular nucleus (RTN) and ventral posterior nucleus (VPN) of mouse brain slices in vitro and compared with the morphological development of dye-injected cells. Between postnatal days 3 and 11 (P3-P11), progressive changes in RTN and VPN neurons included shortening of the membrane time constant, decreasing input resistance, and lowering of the resting membrane potential (RMP). Low-threshold Ca2+ spikes (LTS) were present from P3, but their capacity to sustain multispike bursts was limited before P11. Synaptic responses were evoked in RTN and VPN neurons by electrical stimulation of the internal capsule from P3. Younger RTN neurons responded with a single spike, but their capacity to fire bursts gradually improved as the RMP reached levels below the LTS activation potential. Concomitantly, as the reversal potential of the inhibitory postsynaptic potential in VPN neurons became more negative, its capacity to deinactivate the LTS increased, and rebound bursts that could maintain oscillations were produced; sustained oscillations became the typical response to internal capsule stimulation at P12. The functional maturation of the intrathalamic circuitry, particularly between P10 and P14, occurs in parallel with the morphological maturation (size, dendritic growth, and dendritic field structure) of individual RTN and VPN neurons, as studied by confocal microscopy. Maturation of RTN cells led that of VPN cells by 2-3 d. The appearance of intrathalamic oscillations is probably correlated with the appearance of slow-wave sleep in postnatal animals.

  16. Topography of Cortical Microbleeds in Alzheimer's Disease with and without Cerebral Amyloid Angiopathy: A Post-Mortem 7.0-Tesla MRI Study.

    PubMed

    De Reuck, J; Auger, F; Durieux, N; Deramecourt, V; Cordonnier, C; Pasquier, F; Maurage, C A; Leys, D; Bordet, R

    2015-11-01

    Cortical microbleeds (CMBs) detected on T2*-weighted gradient-echo (GRE) magnetic resonance imaging (MRI) are considered as a possible hallmark of cerebral amyloid angiopathy (CAA). The present post-mortem 7.0-tesla MRI study investigates whether topographic differences exist in Alzheimer's brains without (AD) and with CAA (AD-CAA). The distribution of CMBs in thirty-two post-mortem brains, consisting of 12 AD, 8 AD-CAA and 12 controls, was mutually compared on T2*-GRE MRI of six coronal sections of a cerebral hemisphere. The mean numbers of CMBs were determined in twenty-two different gyri. As a whole there was a trend of more CMBs on GRE MRI in the prefrontal section of the AD, the AD-CAA as well as of the control brains. Compared to controls AD brains had significantly more CMBs in the superior frontal, the inferior temporal, the rectus and the cinguli gyrus, and in the insular cortex. In AD-CAA brains CMBs were increased in all gyri with exception of the medial parietal gyrus and the hippocampus. AD-CAA brains showed a highly significant increase of CMBs in the inferior parietal gyrus (p value: 0.001) and a significant increase in the precuneus and the cuneus (p value: 0.01) compared to the AD brains. The differences in topographic distribution of CMBs between AD and AD-CAA brains should be further investigated on MRI in clinically suspected patients.

  17. PDGFR-β as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia

    PubMed Central

    Shen, Jie; Ishii, Yoko; Xu, Guihua; Dang, Thanh Chung; Hamashima, Takeru; Matsushima, Takako; Yamamoto, Seiji; Hattori, Yuichi; Takatsuru, Yusuke; Nabekura, Junichi; Sasahara, Masakiyo

    2012-01-01

    Although platelet-derived growth factors (PDGFs) and receptors (PDGFRs) are abundantly expressed in the central nervous system, their functions largely remain elusive. We investigated the role of PDGFR-β in tissue responses and functional recovery after photothrombolic middle cerebral artery occlusion (MCAO). In the normal adult mouse brain, PDGFR-β was mainly localized in neurons and in pericyte/vascular smooth muscle cells (PC/vSMCs). From 3 to 28 days after MCAO, postnatally induced systemic PDGFR-β knockout mice (Esr-KO) exhibited the delayed recovery of body weight and behavior, and larger infarction volume than controls. In Esr-KO, PC/vSMC coverage was decreased and vascular leakage of infused fluorescent-labeled albumin was extensive within the ischemic lesion, but not in the uninjured cerebral cortex. Angiogenesis levels were comparable between Esr-KO and controls. In another PDGFR-β conditional KO mouse (Nestin-KO), PDGFR-β was deleted in neurons and astrocytes from embryonic day 10.5, but was preserved in PC/vSMCs. After MCAO, vascular leakage and infarction volume in Nestin-KO were worse than controls, but partly improved compared with Esr-KO. Astroglial scar formation in both Esr-KO and Nestin-KO was similarly reduced compared with controls after MCAO. These data suggested that PDGFR-β signaling is crucial for neuroprotection, endogenous tissue repair, and functional recovery after stroke by targeting neurons, PC/vSMCs, and astrocytes. PMID:21952111

  18. Strong Impact of Chronic Cerebral Hypoperfusion on Neurovascular Unit, Cerebrovascular Remodeling, and Neurovascular Trophic Coupling in Alzheimer's Disease Model Mouse.

    PubMed

    Shang, Jingwei; Yamashita, Toru; Zhai, Yun; Nakano, Yumiko; Morihara, Ryuta; Fukui, Yusuke; Hishikawa, Nozomi; Ohta, Yasuyuki; Abe, Koji

    2016-03-01

    Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer's disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on an AD mouse model in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of α7 subunit of nicotinic acetylcholine receptors (α7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities. PMID:27060955

  19. [Effect of rabies virus infection on the expression of parvalbumin, calbindin and calretinin in mouse cerebral cortex].

    PubMed

    Torres-Fernández, Orlando; Yepes, Gloria E; Gómez, Javier E; Pimienta, Hernán J

    2004-03-01

    Some clinical features of rabies and experimental evidence from cell culture and laboratory animals suggest impairment of gabaergic neurotransmission. Several types of gabaergic neurons occur in the cerebral cortex. They can be identified by three neuronal markers: the calcium binding proteins (CaBPs) parvalbumin (PV), calbindin (CB) and calretinin (CR). Rabies virus spreads throughout the cerebral cortex; however, rabies cytopathic effects on gabaergic neurons are unknown. The expression of calcium-binding proteins (CaBPs) parvalbumin (PV), calbindin (CB) and calretinin (CR) was studied in the frontal cortex of mice. The effect of gabaergic neurons was evaluated immunohistochemically. The distribution patterns of CaBPs in normal mice and in mice infected with 'fixed' or 'street' rabies virus were compared. PV was found in multipolar neurons located in all cortical layers except layer I, and in pericellular clusters of terminal knobs surrounding the soma of pyramidal neurons. CB-immunoreactivity was distributed in two cortical bands. One was composed of round neurons enclosed by a heavily labeled neuropil; this band corresponds to supragranular layers II and III. The other was a weakly stained band of neuropil which contained scattered multipolar CB-ir neurons; this corresponds to infragranular layers V and VI. The CR-ir neurons were bipolar fusiform cells located in all layers of cortex, but concentrated in layers II and III. A feature common to samples infected with both types of viruses was a more intense immunoreactivity to PV in contrast to normal samples. The infection with 'street' virus did not cause additional changes in the expression of CaBPs. However, the infection with 'fixed' virus produced a remarkable reduction of CB-immunoreactivity demonstrated by the loss of CB-ir neurons and low neuropil stain in the frontal cortex. In addition, the size of CR-ir neurons in the cingulate cortex was decreased.

  20. Neuroprotective properties of lifarizine compared with those of other agents in a mouse model of focal cerebral ischaemia.

    PubMed Central

    Brown, C. M.; Calder, C.; Linton, C.; Small, C.; Kenny, B. A.; Spedding, M.; Patmore, L.

    1995-01-01

    1. Changes in the peripheral type benzodiazepine binding site density following middle cerebral artery occlusion in the mouse, have been used as a marker of neuronal damage. These sites can be identified using the selective ligand [3H]-PK 11195 located on non neuronal cells, macrophages and astroglia, within the CNS. Glial cell proliferation and macrophage invasion is an unvoidable sequelae to cerebral ischaemic injury, secondary to neuronal loss. Following occlusion of the left middle cerebral artery (left MCA) a reproducible lesion was found in the parietal cortex within 7 days which gave rise to a significant increase in [3H]-PK 11195 binding. 2. Treatment of animals with the sodium channel blocker, lifarizine, significantly reduced the ischaemia-induced increase in [3H]-PK 11195 binding when given either 30 min pre-ischaemia and three times daily for 7 days at 0.5 mg kg-1, i.p. (P < 0.01) or delayed until 15 min post-ischaemia and three times daily for 7 days at 0.5 mg kg-1, i.p. (P < 0.001). Lifarizine was an effective neuroprotective agent in this model of focal ischaemia in the mouse. 3. Lifarizine also showed a dose-related protection against the ischaemia-induced increase in [3H]-PK 11195 binding with significant protection at doses of 0.1 mg kg-1, i.p. (P < 0.05), 0.25 mg kg-1, i.p. (P < 0.01) or 0.5 mg kg-1, i.p. (P < 0.01) 15 min post-ischaemia and b.i.d. for 7 days.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8564201

  1. Cerebral Apolipoprotein-D Is Hypoglycosylated Compared to Peripheral Tissues and Is Variably Expressed in Mouse and Human Brain Regions

    PubMed Central

    Li, Hongyun; Ruberu, Kalani; Karl, Tim; Garner, Brett

    2016-01-01

    Recent studies have shown that cerebral apoD levels increase with age and in Alzheimer’s disease (AD). In addition, loss of cerebral apoD in the mouse increases sensitivity to lipid peroxidation and accelerates AD pathology. Very little data are available, however, regarding the expression of apoD protein levels in different brain regions. This is important as both brain lipid peroxidation and neurodegeneration occur in a region-specific manner. Here we addressed this using western blotting of seven different regions (olfactory bulb, hippocampus, frontal cortex, striatum, cerebellum, thalamus and brain stem) of the mouse brain. Our data indicate that compared to most brain regions, the hippocampus is deficient in apoD. In comparison to other major organs and tissues (liver, spleen, kidney, adrenal gland, heart and skeletal muscle), brain apoD was approximately 10-fold higher (corrected for total protein levels). Our analysis also revealed that brain apoD was present at a lower apparent molecular weight than tissue and plasma apoD. Utilising peptide N-glycosidase-F and neuraminidase to remove N-glycans and sialic acids, respectively, we found that N-glycan composition (but not sialylation alone) were responsible for this reduction in molecular weight. We extended the studies to an analysis of human brain regions (hippocampus, frontal cortex, temporal cortex and cerebellum) where we found that the hippocampus had the lowest levels of apoD. We also confirmed that human brain apoD was present at a lower molecular weight than in plasma. In conclusion, we demonstrate apoD protein levels are variable across different brain regions, that apoD levels are much higher in the brain compared to other tissues and organs, and that cerebral apoD has a lower molecular weight than peripheral apoD; a phenomenon that is due to the N-glycan content of the protein. PMID:26829325

  2. Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study

    PubMed Central

    Lerch, Jason; Furukawa, Yoshiaki; Tong, Junchao; McCluskey, Tina; Wilkins, Diana; Houle, Sylvain; Meyer, Jeffrey; Mundo, Emanuela; Wilson, Alan A.; Rusjan, Pablo M.; Saint-Cyr, Jean A.; Guttman, Mark; Collins, D. Louis; Shapiro, Colin; Warsh, Jerry J.; Boileau, Isabelle

    2010-01-01

    Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [11C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range –19 to –46%) and hippocampus (–21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self

  3. Mouse cystic fibrosis transmembrane conductance regulator forms cAMP-PKA-regulated apical chloride channels in cortical collecting duct.

    PubMed

    Lu, Ming; Dong, Ke; Egan, Marie E; Giebisch, Gerhard H; Boulpaep, Emile L; Hebert, Steven C

    2010-03-30

    The cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in many segments of the mammalian nephron, where it may interact with and modulate the activity of a variety of apical membrane proteins, including the renal outer medullary potassium (ROMK) K(+) channel. However, the expression of CFTR in apical cell membranes or its function as a Cl(-) channel in native renal epithelia has not been demonstrated. Here, we establish that CFTR forms protein kinase A (PKA)-activated Cl(-) channels in the apical membrane of principal cells from the cortical collecting duct obtained from mice. These Cl(-) channels were observed in cell-attached apical patches of principal cells after stimulation by forskolin/3-isobutyl-1-methylxanthine. Quiescent Cl(-) channels were present in patches excised from untreated tubules because they could be activated after exposure to Mg-ATP and the catalytic subunit of PKA. The single-channel conductance, kinetics, and anion selectivity of these Cl(-) channels were the same as those of recombinant mouse CFTR channels expressed in Xenopus laevis oocytes. The CFTR-specific closed-channel blocker CFTR(inh)-172 abolished apical Cl(-) channel activity in excised patches. Moreover, apical Cl(-) channel activity was completely absent in principal cells from transgenic mice expressing the DeltaF508 CFTR mutation but was present and unaltered in ROMK-null mice. We discuss the physiologic implications of open CFTR Cl(-) channels on salt handling by the collecting duct and on the functional CFTR-ROMK interactions in modulating the metabolic ATP-sensing of ROMK. PMID:20231442

  4. Aging Exacerbates Pressure-Induced Mitochondrial Oxidative Stress in Mouse Cerebral Arteries.

    PubMed

    Springo, Zsolt; Tarantini, Stefano; Toth, Peter; Tucsek, Zsuzsanna; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2015-11-01

    Epidemiological studies demonstrate that in addition to the increased prevalence of hypertension in old patients, the deleterious cerebrovascular effects of hypertension (including atherosclerosis, stroke, and vascular cognitive impairment) are also exacerbated in elderly individuals. The cellular mechanisms by which aging and hypertension interact to promote cerebrovascular pathologies are not well understood. To test the hypothesis that aging exacerbates high pressure-induced mitochondrial oxidative stress, we exposed isolated segments of the middle cerebral arteries of young (3 months) and aged (24 months) C57BL/6 mice to 60 or 140 mmHg intraluminal pressure and assessed changes in mitochondrial reactive oxygen species production using a mitochondria-targeted redox-sensitive fluorescent indicator dye (MitoSox) by confocal microscopy. Perinuclear MitoSox fluorescence was significantly stronger in high pressure-exposed middle cerebral arteries compared with middle cerebral arteries of the same animals exposed to 60 mmHg, indicating that high pressure increases mitochondrial reactive oxygen species production in the smooth muscle cells of cerebral arteries. Comparison of young and aged middle cerebral arteries showed that aging exacerbates high pressure-induced mitochondrial reactive oxygen species production in cerebral arteries. We propose that increased mechanosensitive mitochondrial oxidative stress may potentially exacerbate cerebrovascular injury and vascular inflammation in aging.

  5. Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

    PubMed Central

    Wang, Peng-qian; Li, Bing; Liu, Jun; Zhang, Ying-ying; Yu, Ya-nan; Zhang, Xiao-xu; Yuan, Ye; Guo, Zhi-li; Wu, Hong-li; Li, Hai-xia; Dang, Hai-xia; Guo, Shan-shan; Wang, Zhong

    2015-01-01

    Aim: Our previous studies have showed that ursodeoxycholic acid (UA) and jasminoidin (JA) effectively reduce cerebral infarct volume in mice. In this study we explored the pure synergistic mechanism of these compounds in treatment of mouse cerebral ischemia, which was defined as synergistic actions specific for phenotype variations after excluding interference from ineffective compounds. Methods: Mice with focal cerebral ischemia were treated with UA, JA or a combination JA and UA (JU). Concha margaritifera (CM) was taken as ineffective compound. Cerebral infarct volume of the mice was determined, and the hippocampi were taken for microarray analysis. Particular signaling pathways and biological functions were enriched based on differentially expressed genes, and corresponding networks were constructed through Ingenuity Pathway Analysis. Results: In phenotype analysis, UA, JA, and JU significantly reduced the ischemic infarct volume with JU being superior to UA or JA alone, while CM was ineffective. As a result, 4 pathways enriched in CM were excluded. Core pathways in the phenotype-positive groups (UA or JA) were involved in neuronal homeostasis and neuropathology. JU-contributing pathways included all UA-contributing and the majority (71.7%) of JA-contributing pathways, and 10 new core pathways whose effects included inflammatory immunity, apoptosis and nervous system development. The functions of JU group included all functions of JA group, the majority (93.1%) of UA-contributing functions, and 3 new core functions, which focused on physiological system development and function. Conclusion: The pure synergism between UA and JA underlies 10 new core pathways and 3 new core functions, which are involved in inflammation, immune responses, apoptosis and nervous system development. PMID:25960134

  6. Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism.

    PubMed

    Marowsky, A; Burgener, J; Falck, J R; Fritschy, J-M; Arand, M

    2009-10-01

    Epoxide hydrolases comprise a family of enzymes important in detoxification and conversion of lipid signaling molecules, namely epoxyeicosatrienoic acids (EETs), to their supposedly less active form, dihydroxyeicosatrienoic acids (DHETs). EETs control cerebral blood flow, exert analgesic, anti-inflammatory and angiogenic effects and protect against ischemia. Although the role of soluble epoxide hydrolase (sEH) in EET metabolism is well established, knowledge on its detailed distribution in rodent brain is rather limited. Here, we analyzed the expression pattern of sEH and of another important member of the EH family, microsomal epoxide hydrolase (mEH), in mouse brain by immunohistochemistry. To investigate the functional relevance of these enzymes in brain, we explored their individual contribution to EET metabolism in acutely isolated brain cells from respective EH -/- mice and wild type littermates by mass spectrometry. We find sEH immunoreactivity almost exclusively in astrocytes throughout the brain, except in the central amygdala, where neurons are also positive for sEH. mEH immunoreactivity is abundant in brain vascular cells (endothelial and smooth muscle cells) and in choroid plexus epithelial cells. In addition, mEH immunoreactivity is present in specific neuronal populations of the hippocampus, striatum, amygdala, and cerebellum, as well as in a fraction of astrocytes. In freshly isolated cells from hippocampus, where both enzymes are expressed, sEH mediates the bulk of EET metabolism. Yet we observe a significant contribution of mEH, pointing to a novel role of this enzyme in the regulation of physiological processes. Furthermore, our findings indicate the presence of additional, hitherto unknown cerebral epoxide hydrolases. Taken together, cerebral EET metabolism is driven by several epoxide hydrolases, a fact important in view of the present targeting of sEH as a potential therapeutic target. Our findings suggest that these different enzymes have

  7. Regional changes of AQP0-dependent square array junction and gap junction associated with cortical cataract formation in the Emory mutant mouse.

    PubMed

    Biswas, Sondip K; Brako, Lawrence; Gu, Sumin; Jiang, Jean X; Lo, Woo-Kuen

    2014-10-01

    The Emory mutant mouse has been widely used as an animal model for human senile cataract since it develops late-onset hereditary cataract. Here, we focus on the regional changes of aquaporin-0 (AQP0) and connexins that are associated with the cortical cataract formation in the Emory mutant mice. Emory mutant and CFW wild-type mice at age 1-16 months were used in this study. By using an established photography system with dissecting microscopy, the opacities were first detected at the anterior or posterior lens center surface in Emory mice at age 7 months, and gradually extended toward the equator during the 16 months examined. Scanning EM verified that disorganized and fragmented fiber cells were associated with the areas of opacities within approximately 200 μm from the lens surface, indicating that Emory mouse cataracts belong to the cortical cataracts. Freeze-fracture TEM further confirmed that cortical cataracts exhibited extensive wavy square array junctions, small gap junctions and globules. Immunofluorescence analysis showed that in contrast to the high labeling intensity of AQP0-loop antibody, the labeling of AQP0 C-terminus antibody was decreased considerably in superficial fibers in Emory cataracts. Similarly, a significant decrease in the labeling of the antibody against Cx50 C-terminus, but not Cx46 C-terminus, occurred in superficial and outer cortical fibers in Emory cataracts. Western blotting further revealed that the C-termini of both AQP0 and Cx50 in Emory cataracts were decreased to over 50% to that of the wild-type. Thus, this systematic study concludes that the Emory mouse cataract belongs to the cortical cataract which is due to regional breakdown of superficial fibers associated with formation of AQP0-dependent wavy square array junctions, small gap junctions and globules. The marked decreases of the C-termini of both AQP0 and Cx50 in the superficial fibers may disturb the needed interaction between these two proteins during fiber cell

  8. Ontogeny of four blood-brain barrier markers: an immunocytochemical comparison of pial and cerebral cortical microvessels.

    PubMed Central

    Cassella, J P; Lawrenson, J G; Allt, G; Firth, J A

    1996-01-01

    Pial and cortical microvessels possess many blood-brain barrier (BBB) properties in common, including impermeability to electron dense tracers, high transendothelial electrical resistance and specialised endothelial cell ultrastructural features. To compare pial and cortical microvessels further, a developmental, immunocytochemical study was undertaken of 4 BBB markers in the rat: OX-47, EBA, GLUT-1 and s-laminin. The appearance of the markers was monitored from embryonic d 16, to postnatal and adult stages. Each of the 4 markers appeared simultaneously in both pial and cortical vessels. GLUT-1 and OX-47 were present in endothelial cells of the BBB from E 16 to the adult. EBA and s-laminin appeared from postnatal d 7 through to the adult. Pial microvessels lack the ensheathment of astrocytes which may be involved in the induction and/or maintenance of BBB markers in the cortex. It is possible that astrocyte-derived factors diffusing from the brain surface are responsible for induction of BBB properties in the pial microvessels. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:8886962

  9. Effects of Shaoyao-Gancao Decoction on Infarcted Cerebral Cortical Neurons: Suppression of the Inflammatory Response following Cerebral Ischemia-Reperfusion in a Rat Model

    PubMed Central

    Jia, Xinling; Yang, Jian; Li, Qing; Yan, Guofeng; Xu, Zhongju; Wang, Jingye

    2016-01-01

    The mechanisms by which Shaoyao-Gancao decoction (SGD) inhibits the production of inflammatory cytokines in serum and brain tissue after cerebral ischemia-reperfusion (CI-RP) in rats were investigated. A right middle cerebral artery occlusion was used to induce CI-RP after which the rats were divided into model (n = 39), SGD (n = 28), clopidogrel (n = 25) and sham operated (n = 34) groups. The Bederson scale was used to evaluate changes in behavioral indices. The levels of IL-1β, TNF-α, MCP-1, IL-10, RANTES, VEGF, and TGF-β1 in the serum and infarcted brain tissues were measured. Nissl body and immunohistochemical staining methods were used to detect biochemical changes in neurons, microglial cells, and astrocytes. Serum levels of VEGF, TNF-α, MCP-1, IL-1β, and IL-10 increased significantly 24 h after CI-RP. In brain tissue, levels of TNF-α and IL-1β significantly increased 24 h after CI-RP, whereas levels of TGF-β1 and MCP-1 were significantly higher 96 h after CI-RP (P < 0.05). SGD or clopidogrel after CI-RP reduced TNF-α and IL-1β levels in brain tissue and serum levels of MCP-1, IL-1β, and IL-10. SGD increased the number of NeuN-positive cells in infarcted brain tissue and reduced the number of IBA1-positive and GFAP-positive cells. The efficacy of SGD was significantly higher than that of clopidogrel. PMID:27413737

  10. Optical measurement of mouse strain differences in cerebral blood flow using indocyanine green.

    PubMed

    Kang, Hye-Min; Sohn, Inkyung; Kim, Seunggyu; Kim, Daehwan; Jung, Junyang; Jeong, Joo-Won; Park, Chan

    2015-06-01

    C57BL/6 mice have more cerebral arterial branches and collaterals than BALB/c mice. We measured and compared blood flow dynamics of the middle cerebral artery (MCA) in these two strains, using noninvasive optical imaging with indocyanine green (ICG). Relative maximum fluorescence intensity (Imax) and the time needed for ICG to reach Imax in the MCA of C57BL/c were lower than that in BALB/c mice. Moreover, the mean transit time was significantly lower in C57BL/6 than in BALB/c mice. These data suggest that the higher number of arterial branches and collaterals in C57BL/6 mice yields a lower blood flow per cerebral artery.

  11. Optical measurement of mouse strain differences in cerebral blood flow using indocyanine green

    PubMed Central

    Kang, Hye-Min; Sohn, Inkyung; Kim, Seunggyu; Kim, Daehwan; Jung, Junyang; Jeong, Joo-Won; Park, Chan

    2015-01-01

    C57BL/6 mice have more cerebral arterial branches and collaterals than BALB/c mice. We measured and compared blood flow dynamics of the middle cerebral artery (MCA) in these two strains, using noninvasive optical imaging with indocyanine green (ICG). Relative maximum fluorescence intensity (Imax) and the time needed for ICG to reach Imax in the MCA of C57BL/c were lower than that in BALB/c mice. Moreover, the mean transit time was significantly lower in C57BL/6 than in BALB/c mice. These data suggest that the higher number of arterial branches and collaterals in C57BL/6 mice yields a lower blood flow per cerebral artery. PMID:25833343

  12. Age-dependent alterations in the cortical entrainment of subthalamic nucleus neurons in the YAC128 mouse model of Huntington's disease.

    PubMed

    Callahan, Joshua W; Abercrombie, Elizabeth D

    2015-06-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that results in motor, cognitive and psychiatric abnormalities. Dysfunction in neuronal processing between the cortex and the basal ganglia is fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a crucial role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in hyperkinetic movement abnormalities, similar to the motor symptoms associated with HD. The aim of the present study was to examine whether changes in the fidelity of information transmission between the cortex and the STN emerge as a function of phenotypic severity in the YAC128 mouse model of HD. We obtained in vivo extracellular recordings in the STN and concomitant electrocorticogram (ECoG) recordings during discrete brain states that reflected global cortical network synchronization or desynchronization. At early ages in YAC128 mice, both the cortex and the STN exhibited patterns of hyperexcitability. As symptom severity progressed, cortical entrainment of STN activity was disrupted and there was an increase in the proportion of non-oscillating, tonically firing STN neurons that were less phase-locked to cortical activity. Concomitant to the dissipation of STN entrainment, there was a reduction in the evoked response of STN neurons to focal cortical stimulation. The spontaneous discharge of STN neurons in YAC128 mice also decreased with age and symptom severity. These results indicate dysfunction in the flow of information within the corticosubthalamic circuit and demonstrate progressive age-related disconnection of the hyperdirect pathway in a transgenic mouse model of HD.

  13. Cerebral cortical amyloid protein precursor mRNA expression is similar in Alzheimer's disease and other neurodegenerative diseases.

    PubMed

    Ohyagi, Y; Takahashi, K; Satoh, Y; Makifuchi, T; Tabira, T

    1992-08-01

    The expression of 3 beta-amyloid protein precursor (APP) mRNAs (695, 751, and 770) in the cerebral cortex in Alzheimer's disease and other neurodegenerative diseases was analyzed by the S1 nuclease protection assay. We found no significant Alzheimer's disease-specific alteration of APP mRNA expression when compared to the other neurological diseases as controls. Since the expression of this mRNA was not correlated with amyloid deposition, it is possible that gliosis/neuronal loss may secondarily alter APP mRNA expression. However, the current study revealed no significant correlation between them.

  14. Ethanol exposure during neurogenesis induces persistent effects on neural maturation: evidence from an ex vivo model of fetal cerebral cortical neuroepithelial progenitor maturation.

    PubMed

    Camarillo, Cynthia; Miranda, Rajesh C

    2008-01-01

    Ethanol is a significant neuroteratogen. We previously used fetal cortical-derived neurosphere cultures as an ex vivo model of the second trimester ventricular neuroepithelium, and showed that ethanol directly induced fetal stem and progenitor cell proliferation and maturation without inducing death. However, ethanol is defined as a teratogen because of its capacity to persistently disrupt neural maturation beyond a specific exposure period. We therefore utilized a simplified neuronal maturation paradigm to examine the immediate and persistent changes in neuronal migration following ethanol exposure during the phase of neuroepithelial proliferation. Our data indicate that mRNA transcripts for migration-associated genes RhoA, Paxillin (Pxn), and CDC42 were immediately induced following ethanol exposure, whereas dynein light chain, LC8-type 1 (DYNLL1), and growth-associated protein (Gap)-43 were suppressed. With the exception of Gap43, ethanol did not induce persistent changes in the other mRNAs, suggesting that ethanol had an activational, rather than organizational, impact on migration-associated mRNAs. However, despite this lack of persistent effects on these mRNAs, ethanol exposure during the proliferation period significantly increased subsequent neuronal migration. Moreover, differentiating neurons, pretreated with ethanol during the proliferation phase, exhibited reduced neurite branching and an increased length of primary neurites, indicating a persistent destabilization of neuronal maturation. Collectively, our data indicate that ethanol-exposed proliferating neuroepithelial precursors exhibit subsequent differentiation-associated increases in migratory behavior, independent of mRNA transcript levels. These data help explain the increased incidence of cerebral cortical neuronal heterotopias associated with the fetal alcohol syndrome.

  15. Regulation of Extrasynaptic GABAA α4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons.

    PubMed

    Carlson, Stephen L; Bohnsack, J Peyton; Patel, Vraj; Morrow, A Leslie

    2016-01-01

    Ethanol produces changes in GABAA receptor trafficking and function that contribute to ethanol dependence symptomatology. Extrasynaptic γ-aminobutyric acid A receptors (GABAA-R) mediate inhibitory tonic current and are of particular interest because they are potentiated by physiologically relevant doses of ethanol. Here, we isolate GABAA α4δ receptors by western blotting in subsynaptic fractions to investigate protein kinase A (PKA) and protein kinase C (PKC) modulation of ethanol-induced receptor trafficking, while extrasynaptic receptor function is determined by measurement of tonic inhibition and responses evoked by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Rat cerebral cortical neurons were grown for 18 days in vitro and exposed to ethanol and/or PKA/PKC modulators. Ethanol exposure (1 hour) did not alter GABAA α4 receptor abundance, but it increased tonic current amplitude, an effect that was prevented by inhibiting PKA, but not PKC. Direct activation of PKA, but not PKC, increased the abundance and tonic current of extrasynaptic α4δ receptors. In contrast, prolonged ethanol exposure (4 hours) reduced α4δ receptor abundance as well as tonic current, and this effect was also PKA dependent. Finally, PKC activation by ethanol or phorbol-12,13-dibutyrate (PdBu) had no effect on extrasynaptic α4δ subunit abundance or activity. We conclude that ethanol alters extrasynaptic α4δ receptor function and expression in cortical neurons in a PKA-dependent manner, but ethanol activation of PKC does not influence these receptors. These results could have clinical relevance for therapeutic strategies to restore normal GABAergic functioning for the treatment of alcohol use disorders.

  16. Bidirectional radial Ca2+ activity regulates neurogenesis and migration during early cortical column formation

    PubMed Central

    Rash, Brian G.; Ackman, James B.; Rakic, Pasko

    2016-01-01

    Cortical columns are basic cellular and functional units of the cerebral cortex that are malformed in many brain disorders, but how they initially develop is not well understood. Using an optogenetic sensor in the mouse embryonic forebrain, we demonstrate that Ca2+ fluxes propagate bidirectionally within the elongated fibers of radial glial cells (RGCs), providing a novel communication mechanism linking the proliferative and postmitotic zones before the onset of synaptogenesis. Our results indicate that Ca2+ activity along RGC fibers provides feedback information along the radial migratory pathway, influencing neurogenesis and migration during early column development. Furthermore, we find that this columnar Ca2+ propagation is induced by Notch and fibroblast growth factor activities classically implicated in cortical expansion and patterning. Thus, cortical morphogens and growth factors may influence cortical column assembly in part by regulating long-distance Ca2+ communication along the radial axis of cortical development. PMID:26933693

  17. Thiazine Red(+) platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer's Disease mouse model.

    PubMed

    Kniewallner, Kathrin M; Wenzel, Daniela; Humpel, Christian

    2016-01-01

    Strong evidence shows an association between cerebral vascular diseases and Alzheimer´s disease (AD). In order to study the interaction of beta-amyloid (Aβ) plaques with brain vessels, we crossbred an AD mouse model (overexpressing amyloid precursor protein with the Swedish-Dutch-Iowa mutations, APP_SweDI) with mice expressing green fluorescent protein (GFP) under the flt-1/VEGFR1 promoter in vessels (GFP_FLT1). Our data show, that only very few Aβ plaques were seen in 4-months old mice, focused in the mammillary body and in the lateral septal nucleus. The number of plaques markedly increased with age being most prominent in 12-months old mice. Thiazine Red was used to verify the plaques. Several Thiazine Red(+) inclusions were found in GFP(+) vessels, but only in non-perfused 4-months old mice. These inclusions were verified by Resorufin stainings possibly representing cerebral amyloid angiopathy. The inclusions were also seen in non-crossbred APP_SweDI but not in wildtype and GFP_FLT1 mice. In order to characterize these inclusions Flow Cytometry (FACS) analysis demonstrated that platelets were specifically stained by Thiazine Red(+), more pronounced when aggregated. In conclusion, our data show that Thiazine Red(+) inclusions representing aggregated platelets are a first pathological sign in AD before plaque development and may become important therapeutic targets in early AD. PMID:27345467

  18. Asiatic Acid, a Pentacyclic Triterpene From Centella asiatica, Is Neuroprotective in a Mouse Model of Focal Cerebral Ischemia

    PubMed Central

    Krishnamurthy, Rajanikant G.; Senut, Marie-Claude; Zemke, Daniel; Min, Jiangyong; Frenkel, Mark B.; Greenberg, Eric J.; Yu, Seong-Woon; Ahn, Nick; Goudreau, John; Kassab, Mounzer; Panickar, Kiran S.; Majid, Arshad

    2010-01-01

    Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or β-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood–brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood–brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia. PMID:19382233

  19. Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer’s Disease mouse model

    PubMed Central

    Kniewallner, Kathrin M.; Wenzel, Daniela; Humpel, Christian

    2016-01-01

    Strong evidence shows an association between cerebral vascular diseases and Alzheimer´s disease (AD). In order to study the interaction of beta-amyloid (Aβ) plaques with brain vessels, we crossbred an AD mouse model (overexpressing amyloid precursor protein with the Swedish-Dutch-Iowa mutations, APP_SweDI) with mice expressing green fluorescent protein (GFP) under the flt-1/VEGFR1 promoter in vessels (GFP_FLT1). Our data show, that only very few Aβ plaques were seen in 4-months old mice, focused in the mammillary body and in the lateral septal nucleus. The number of plaques markedly increased with age being most prominent in 12-months old mice. Thiazine Red was used to verify the plaques. Several Thiazine Red+ inclusions were found in GFP+ vessels, but only in non-perfused 4-months old mice. These inclusions were verified by Resorufin stainings possibly representing cerebral amyloid angiopathy. The inclusions were also seen in non-crossbred APP_SweDI but not in wildtype and GFP_FLT1 mice. In order to characterize these inclusions Flow Cytometry (FACS) analysis demonstrated that platelets were specifically stained by Thiazine Red+, more pronounced when aggregated. In conclusion, our data show that Thiazine Red+ inclusions representing aggregated platelets are a first pathological sign in AD before plaque development and may become important therapeutic targets in early AD. PMID:27345467

  20. FNIRS-based evaluation of cortical plasticity in children with cerebral palsy undergoing constraint-induced movement therapy

    NASA Astrophysics Data System (ADS)

    Cao, Jianwei; Khan, Bilal; Hervey, Nathan; Tian, Fenghua; Delgado, Mauricio R.; Clegg, Nancy J.; Smith, Linsley; Roberts, Heather; Tulchin-Francis, Kirsten; Shierk, Angela; Shagman, Laura; MacFarlane, Duncan; Liu, Hanli; Alexandrakis, George

    2015-03-01

    Sensorimotor cortex plasticity induced by constraint-induced movement therapy (CIMT) in six children (10.2 ± 2.1 years old) with hemiplegic cerebral palsy (CP) was assessed by functional near-infrared spectroscopy (fNIRS). The activation laterality index and time-to-peak/duration during a finger tapping task were quantified before, immediately after, and six months after CIMT. Five age-matched healthy children (9.8 ± 1.3 years old) were also imaged at the same time points to provide comparative activation metrics for normal controls. In children with CP the activation time-to-peak/duration for all sensorimotor centers displayed significant normalization immediately after CIMT that persisted six months later. In contrast to this longer term improvement in localized activation response, the laterality index that depended on communication between sensorimotor centers improved immediately after CIMT, but relapsed six months later.

  1. Impaired vascular remodeling after endothelial progenitor cell transplantation in MMP9-deficient mice suffering cortical cerebral ischemia

    PubMed Central

    Morancho, Anna; Ma, Feifei; Barceló, Verónica; Giralt, Dolors; Montaner, Joan; Rosell, Anna

    2015-01-01

    Endothelial progenitor cells (EPCs) are being investigated for advanced therapies, and matrix metalloproteinase 9 (MMP9) has an important role in stroke recovery. Our aim was to determine whether tissue MMP9 influences the EPC-induced angiogenesis after ischemia. Wild-type (WT) and MMP9-deficient mice (MMP9/KO) were subjected to cerebral ischemia and treated with vehicle or outgrowth EPCs. After 3 weeks, we observed an increase in the peri-infarct vessel density in WT animals but not in MMP9/KO mice; no differences were found in the vehicle-treated groups. Our data suggest that tissue MMP9 has a crucial role in EPC-induced vascular remodeling after stroke. PMID:26219597

  2. In vivo simultaneous cortical and intracortical monitoring of cerebral blood flow and mitochondrial redox state in experimental animals

    NASA Astrophysics Data System (ADS)

    Barbiro-Michaely, E.; Zuckerman, T.; Zarchin, N.; Rinkevich, S.; Knoller, N.; Hadani, M.; Mayevsky, A.

    2003-07-01

    Monitoring of intra-mitochondrial NADH redox state is a common in-vivo technique in experimental animals and is rare in clinical studies. The combination of NADH monitoring with the Laser Doppler flowmetry for cerebral blood flow monitoring was described in various publications. Until now, very small effort was made to monitor NADH and CBF inside the cortex of experimental animals. The significance of this monitoring is in its application to experimental models of Parkinson"s disease or to clinical monitoring situations in the intensive care unit, when ICP is monitored. Here we compared the responses of the gerbil or rat brain to oxygen deficiency, monitored on the brain surface and in different depths. After the animals were anesthetized, the two common carotid arteries (gerbil) were isolated and prepared for following occlusion. The brain was exposed and two optical probes were located on its surface. Ischemia was induced by occluding the two carotid arteries, and anoxia was preformed by inhalation of pure N2. After recovery, one of the probes was inserted into the cortex (0.5-3mm) and a second ischemia or anoxia was preformed. The results showed that: 1. It is possible to monitor both CBF and NADH on the brain surface simultaneously with intracortical location. 2. The responses of the brain to ischemia or anoxia was smaller inside the cortex comparing to brain surface. 3. Negative correlation was found between CBF and NADH in both locations and models. In conclusion, this new model of simultaneously monitoring of CBF and NADH in different cerebral locations can shed light on various pathophysiological situations.

  3. Cerebral cortical abnormalities seen in a non-human primate model of prenatal cocaine exposure are not related to vasoconstriction.

    PubMed

    He, Na; Lidow, Michael S

    2004-03-01

    In our previous studies [J. Comp. Neurol. 435 (2001) 263] we demonstrated that rhesus monkeys born to mothers receiving cocaine orally during the period of pregnancy when neurons destined for the cerebral neocortex were generated displayed inappropriate positioning of neocortical neurons, loss of normal neocortical lamination, and reduction in neocortical volume, density and total number of neocortical neurons. In the present paper, we examined whether these cytoarchitectural abnormalities were related to the relatively high blood levels of the cocaine metabolite, benzoylecgonine, associated with oral cocaine administration. We also evaluated the role of vasoconstriction of the uteroumbilical and fetal brain vessels in the generation of these abnormalities. For these purposes, we compared cerebral neocortical cytoarchitecture in 2-month-old monkeys from five groups of mothers: (1). a drug-naïve group, (2). a cocaine-treated group, (3). a group treated with benzoylecgonine at doses producing higher blood levels of this metabolite and stronger vasoconstriction that those in the cocaine-treated group, (4). a group treated with cocaine plus the vasodilator, isosorbide dinitrate, which counteracted the vasoconstrictive actions of cocaine, and (5). a group exposed to isosorbide dinitrate alone. All treatments were carried out from the 45 th through 102 nd day of pregnancy. We found that the general appearance of the neocortex and the position and number of neocortical neurons in the offspring of benzoylecgonine- and isosorbide dinitrate-treated mothers were indistinguishable from those in the offspring of drug-naïve mothers. In contrast, significant alterations in these parameters (similar to those seen in our previous studies) were observed in the offspring of cocaine and cocaine + isosorbide dinitrate-treated mothers. These findings suggest that it is unlikely that either benzoylecgonine or vasoconstriction are responsible for the abnormalities seen in the

  4. Quantitative Analyses of Postmortem Heat Shock Protein mRNA Profiles in the Occipital Lobes of Human Cerebral Cortices: Implications in Cause of Death

    PubMed Central

    Chung, Ukhee; Seo, Joong-Seok; Kim, Yu-Hoon; Son, Gi Hoon; Hwang, Juck-Joon

    2012-01-01

    Quantitative RNA analyses of autopsy materials to diagnose the cause and mechanism of death are challenging tasks in the field of forensic molecular pathology. Alterations in mRNA profiles can be induced by cellular stress responses during supravital reactions as well as by lethal insults at the time of death. Here, we demonstrate that several gene transcripts encoding heat shock proteins (HSPs), a gene family primarily responsible for cellular stress responses, can be differentially expressed in the occipital region of postmortem human cerebral cortices with regard to the cause of death. HSPA2 mRNA levels were higher in subjects who died due to mechanical asphyxiation (ASP), compared with those who died by traumatic injury (TI). By contrast, HSPA7 and A13 gene transcripts were much higher in the TI group than in the ASP and sudden cardiac death (SCD) groups. More importantly, relative abundances between such HSP mRNA species exhibit a stronger correlation to, and thus provide more discriminative information on, the death process than does routine normalization to a housekeeping gene. Therefore, the present study proposes alterations in HSP mRNA composition in the occipital lobe as potential forensic biological markers, which may implicate the cause and process of death. PMID:23135635

  5. The role of cerebral spinal fluid in light propagation through the mouse head: improving fluorescence tomography with Monte Carlo modeling

    NASA Astrophysics Data System (ADS)

    Ancora, Daniele; Zacharopoulos, Athanasios; Ripoll, Jorge; Zacharakis, Giannis

    2016-03-01

    Optical Neuroimaging is a highly dynamical field of research owing to the combination of many advanced imaging techniques and computational tools that uncovered unexplored paths through the functioning of the brain. Light propagation modelling through such complicated structures has always played a crucial role as the basis for a high resolution and quantitative imaging where even the slightest improvement could lead to significant results. Fluorescence Diffuse Optical Tomography (fDOT), a widely used technique for three dimensional imaging of small animals and tissues, has been proved to be inaccurate for neuroimaging the mouse head without the knowledge of a-priori anatomical information of the subject. Commonly a normalized Born approximation model is used in fDOT reconstruction based on forward photon propagation using Diffusive Equation (DE) which has strong limitations in the optically clear regime. The presence of the Cerebral Spinal Fluid (CSF) instead, a thin optically clear layer surrounding the brain, can be more accurately taken into account using Monte Carlo approaches which nowadays is becoming more usable thanks to parallelized GPU algorithms. In this work we discuss the results of a synthetic experimental comparison, resulting to the increase of the accuracy for the Born approximation by introducing the CSF layer in a realistic mouse head structure with respect to the current model. We point out the importance of such clear layer for complex geometrical models, while for simple slab phantoms neglecting it does not introduce a significant error.

  6. Cerebral hemodynamic responses to seizure in the mouse brain: simultaneous near-infrared spectroscopy-electroencephalography study

    NASA Astrophysics Data System (ADS)

    Lee, Seungduk; Lee, Mina; Koh, Dalkwon; Kim, Beop-Min; Choi, Jee Hyun

    2010-05-01

    We applied near-infrared spectroscopy (NIRS) and electroencephalography (EEG) simultaneously on the mouse brain and investigated the hemodynamic response to epileptic episodes under pharmacologically driven seizure. γ-butyrolactone (GBL) and 4-aminopyridine (4-AP) were applied to induce absence and tonic-clonic seizures, respectively. The epileptic episodes were identified from the single-channel EEG, and the corresponding hemodynamic changes in different regions of the brain were characterized by multichannel frequency-domain NIRS. Our results are the following: (i) the oxyhemoglobin level increases in the case of GBL-treated mice but not 4-AP-treated mice compared to the predrug state; (ii) the dominant response to each absence seizure is a decrease in deoxyhemolobin; (iii) the phase shift between oxy- and deoxyhemoglobin reduces in GBL-treated mice but no 4-AP-treated mice; and (iv) the spatial correlation of hemodynamics increased significantly in 4-AP-treated mice but not in GBL-treated mice. Our results shows that spatiotemporal tracking of cerebral hemodynamics using NIRS can be successfully applied to the mouse brain in conjunction with electrophysiological recording, which will support the study of molecular, cellular, and network origin of neurovascular coupling in vivo.

  7. Mouse embryos and chimera cloned from neural cells in the postnatal cerebral cortex.

    PubMed

    Makino, Hatsune; Yamazaki, Yukiko; Hirabayashi, Takahiro; Kaneko, Ryosuke; Hamada, Shun; Kawamura, Yoshimi; Osada, Tomoharu; Yanagimachi, Ryuzo; Yagi, Takeshi

    2005-01-01

    Cloning of mice has been achieved by transferring nuclei of various types of somatic cell nuclei into enucleated oocytes. However, all attempts to produce live cloned offspring using the nuclei of neurons from adult cerebral cortex have failed. Previously we obtained cloned mice using the nuclei of neural cells collected from fetal cerebral cortex. Here, we attempted to generate cloned mice using differentiated neurons from the cerebral cortex of postnatal (day 0-4) mice. Although we were unable to obtain live cloned pups, many fetuses reached day 10.5 days of development. These fetuses showed various abnormalities such as spherical omission of the neuroepithelium, collapsed lumen of neural tube, and aberrant expressions of marker proteins of neurons. We produced chimeric mice in which some hair cells and kidney cells were originated from differentiated neurons. In chimeric fetuses, LacZ-positive donor cells were in all three germ cell layers. However, chimeras with large contribution of donor-derived cells were not obtained. These results indicate that nuclei of differentiated neurons have lost their developmental totipotency. In other words, the conventional nuclear transfer technique does not allow nuclei of differentiated neurons to undergo complete genomic reprogramming required for normal embryonic development.

  8. Proteomic analysis of cortical brain tissue from the BTBR mouse model of autism: Evidence for changes in STOP and myelin-related proteins.

    PubMed

    Wei, H; Ma, Y; Liu, J; Ding, C; Hu, F; Yu, L

    2016-01-15

    Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. However, the widely accepted biomarkers for autism are still lacking. In this study, we carried out a quantitative proteomic profiling study of cortical brain tissue from BTBR T(+)Itpr3(tf) (BTBR) mice, a mouse model that displays an autism-like phenotype. Using isobaric tag for relative and absolute quantification (iTRAQ) coupled with LC-MS/MS, a total of 3611 proteins were quantitated in mouse cortices. As compared to C57BL/6J (B6) mice, 126 differentially expressed proteins were found in the brain from BTBR mice. The functional annotation and categories of differentially expressed proteins were analyzed. Especially, the stable tubule only polypeptide (STOP) protein and myelin-related proteins down-regulated significantly in BTBR mice were confirmed by Western blotting. Furthermore, the BTBR mice displayed reduced levels of staining with ferric alum in comparison to B6 controls, indicative of myelin disruption. Finally, we propose that reduced STOP expression in the brain could be involved in the mediation of autism-like behaviors through impairments of myelination in oligodendrocytes and synaptic function in neurons. Manipulation of STOP protein could be a promising avenue for therapeutic interventions to autism.

  9. Mouse model of intraluminal MCAO: cerebral infarct evaluation by cresyl violet staining.

    PubMed

    Rousselet, Estelle; Kriz, Jasna; Seidah, Nabil G

    2012-01-01

    Stroke is the third cause of mortality and the leading cause of disability in the World. Ischemic stroke accounts for approximately 80% of all strokes. However, the thrombolytic tissue plasminogen activator (tPA) is the only treatment of acute ischemic stroke that exists. This led researchers to develop several ischemic stroke models in a variety of species. Two major types of rodent models have been developed: models of global cerebral ischemia or focal cerebral ischemia. To mimic ischemic stroke in patients, in whom approximately 80% thrombotic or embolic strokes occur in the territory of the middle cerebral artery (MCA), the intraluminal middle cerebral artery occlusion (MCAO) model is quite relevant for stroke studies. This model was first developed in rats by Koizumi et al. in 1986 (1). Because of the ease of genetic manipulation in mice, these models have also been developed in this species (2-3). Herein, we present the transient MCA occlusion procedure in C57/Bl6 mice. Previous studies have reported that physical properties of the occluder such as tip diameter, length, shape, and flexibility are critical for the reproducibility of the infarct volume (4). Herein, a commercial silicon coated monofilaments (Doccol Corporation) have been used. Another great advantage is that this monofilament reduces the risk to induce subarachnoid hemorrhages. Using the Zeiss stereo-microscope Stemi 2000, the silicon coated monofilament was introduced into the internal carotid artery (ICA) via a cut in the external carotid artery (ECA) until the monofilament occludes the base of the MCA. Blood flow was restored 1 hour later by removal of the monofilament to mimic the restoration of blood flow after lysis of a thromboembolic clot in humans. The extent of cerebral infarct may be evaluated first by a neurologic score and by the measurement of the infarct volume. Ischemic mice were thus analyzed for their neurologic score at different post-reperfusion times. To evaluate the infarct

  10. Rate of neurodegeneration in the mouse controlled cortical impact model is influenced by impactor tip shape: implications for mechanistic and therapeutic studies.

    PubMed

    Pleasant, Jennifer M; Carlson, Shaun W; Mao, Haojie; Scheff, Stephen W; Yang, King H; Saatman, Kathryn E

    2011-11-01

    Controlled cortical impact (CCI), one of the most common models of traumatic brain injury, is being increasingly used with mice for exploration of cell injury mechanisms and pre-clinical evaluation of therapeutic strategies. Although CCI brain injury was originally effected using an impactor with a rounded tip, the majority of studies with mouse CCI use a flat or beveled tip. Recent finite element modeling analyses demonstrate that tip geometry is a significant determinant of predicted cortical tissue strains in rat CCI, and that cell death is proportional to predicted tissue strains. In the current study, a three-dimensional finite element model of a C57BL/6J mouse brain predicted higher maximum principal strains during a simulated 1.0-mm, 3.5-m/s CCI injury with a flat tip when compared to a rounded tip. Consistent with this prediction, experimental CCI with a flat-tip impactor resulted in greater acute cortical hemorrhage and neuron loss in adult male C57BL/6J mice. The amount of neocortical tissue damage was equivalent for the two tip geometries at 9 days following injury, but the rate of neocortical neurodegeneration was markedly slower following CCI with a rounded-tip impactor, with damage reaching a plateau after 24?h as opposed to after 4?h for the flat tip. The flat-tip impactor was associated in general with more regional hippocampal neurodegeneration, especially at early time points such as 4?h. Impactor tip geometry did not have a notable effect on blood?brain barrier breakdown, traumatic axonal injury, or motor and cognitive dysfunction. Execution of CCI injury with a rounded-tip impactor is posited to provide a substantially enhanced temporal window for the study of cellular injury mechanisms and therapeutic intervention while maintaining critical aspects of the pathophysiological response to contusion brain injury.

  11. Comparison of stimulus-evoked cerebral hemodynamics in the awake mouse and under a novel anesthetic regime

    PubMed Central

    Sharp, Paul S.; Shaw, Kira; Boorman, Luke; Harris, Samuel; Kennerley, Aneurin J.; Azzouz, Mimoun; Berwick, Jason

    2015-01-01

    Neural activity is closely followed by a localised change in cerebral blood flow, a process termed neurovascular coupling. These hemodynamic changes form the basis of contrast in functional magnetic resonance imaging (fMRI) and are used as a correlate for neural activity. Anesthesia is widely employed in animal fMRI and neurovascular studies, however anesthetics are known to profoundly affect neural and vascular physiology, particularly in mice. Therefore, we investigated the efficacy of a novel ‘modular’ anesthesia that combined injectable (fentanyl-fluanisone/midazolam) and volatile (isoflurane) anesthetics in mice. To characterize sensory-evoked cortical hemodynamic responses, we used optical imaging spectroscopy to produce functional maps of changes in tissue oxygenation and blood volume in response to mechanical whisker stimulation. Following fine-tuning of the anesthetic regime, stimulation elicited large and robust hemodynamic responses in the somatosensory cortex, characterized by fast arterial activation, increases in total and oxygenated hemoglobin, and decreases in deoxygenated hemoglobin. Overall, the magnitude and speed of evoked hemodynamic responses under anesthesia resembled those in the awake state, indicating that the novel anesthetic combination significantly minimizes the impact of anesthesia. Our findings have broad implications for both neurovascular research and longitudinal fMRI studies that increasingly require the use of genetically engineered mice. PMID:26218081

  12. Competing Interactions between Micro-RNAs Determine Neural Progenitor Survival and Proliferation after Ethanol Exposure: Evidence from an Ex Vivo Model of the Fetal Cerebral Cortical Neuroepithelium

    PubMed Central

    Sathyan, Pratheesh; Golden, Honey B.; Miranda, Rajesh C.

    2010-01-01

    The fetal brain is sensitive to a variety of teratogens, including ethanol. We showed previously that ethanol induced mitosis and stem cell maturation, but not death, in fetal cerebral cortex-derived progenitors. We tested the hypothesis that micro-RNAs (miRNAs) could mediate the teratogenic effects of ethanol in a fetal mouse cerebral cortex-derived neurosphere culture model. Ethanol, at a level attained by alcoholics, significantly suppressed the expression of four miRNAs, miR-21, -335, -9, and -153, whereas a lower ethanol concentration, attainable during social drinking, induced miR-335 expression. A GABAA receptor-dependent mechanism mediated miR-21, but not miR-335 suppression, suggesting that divergent mechanisms regulate ethanol-sensitive miRNAs. Antisense-mediated suppression of miR-21 expression resulted in apoptosis, suggesting that miR-21 is an antiapoptotic factor. miR-335 knockdown promoted cell proliferation and prevented death induced by concurrently suppressing miR-21, indicating that miR-335 is a proapoptotic, antimitogenic factor whose actions are antagonistic to miR-21. Computational analyses identified two genes, Jagged-1, a Notch-receptor ligand, and embryonic-lethal abnormal vision, Drosophila-like 2 (ELAVL2), a brain-specific regulator of RNA stability, as presumptive targets of three of four ethanol-sensitive micro-RNAs. Combined knockdown of miR-335, -21, and -153 significantly increased Jagged-1 mRNA. Furthermore, ethanol induced both Jagged-1 and ELAVL2 mRNA. The collective suppression of micro-RNAs is consistent with ethanol induction of cell cycle and neuroepithelial maturation in the absence of apoptosis. These data identify a role for micro-RNAs as epigenetic intermediaries, which permit teratogens to shape complex, divergent developmental processes, and additionally demonstrate that coordinately regulated miRNAs exhibit both functional synergy and antagonism toward each other. PMID:17687032

  13. In Vivo Voltage-Sensitive Dye Study of Lateral Spreading of Cortical Activity in Mouse Primary Visual Cortex Induced by a Current Impulse

    PubMed Central

    Fehérvári, Tamás Dávid; Sawai, Hajime; Yagi, Tetsuya

    2015-01-01

    In the mammalian primary visual cortex (V1), lateral spreading of excitatory potentials is believed to be involved in spatial integrative functions, but the underlying cortical mechanism is not well understood. Visually-evoked population-level responses have been shown to propagate beyond the V1 initial activation site in mouse, similar to higher mammals. Visually-evoked responses are, however, affected by neuronal circuits prior to V1 (retina, LGN), making the separate analysis of V1 difficult. Intracortical stimulation eliminates these initial processing steps. We used in vivo RH1691 voltage-sensitive dye (VSD) imaging and intracortical microstimulation in adult C57BL/6 mice to elucidate the spatiotemporal properties of population-level signal spreading in V1 cortical circuits. The evoked response was qualitatively similar to that measured in single-cell electrophysiological experiments in rodents: a fast transient fluorescence peak followed by a fast and a slow decrease or hyperpolarization, similar to EPSP and fast and slow IPSPs in single cells. The early cortical response expanded at speeds commensurate with long horizontal projections (at 5% of the peak maximum, 0.08–0.15 m/s) however, the bulk of the VSD signal propagated slowly (at half-peak maximum, 0.05–0.08 m/s) suggesting an important role of regenerative multisynaptic transmission through short horizontal connections in V1 spatial integrative functions. We also found a tendency for a widespread and fast cortical response suppression in V1, which was eliminated by GABAA-antagonists gabazine and bicuculline methiodide. Our results help understand the neuronal circuitry involved in lateral spreading in V1. PMID:26230520

  14. Axonal elongation and dendritic branching is enhanced by adenosine A2A receptors activation in cerebral cortical neurons.

    PubMed

    Ribeiro, Filipa F; Neves-Tomé, Raquel; Assaife-Lopes, Natália; Santos, Telma E; Silva, Rui F M; Brites, Dora; Ribeiro, Joaquim A; Sousa, Mónica M; Sebastião, Ana M

    2016-06-01

    Axon growth and dendrite development are key processes for the establishment of a functional neuronal network. Adenosine, which is released by neurons and glia, is a known modulator of synaptic transmission but its influence over neuronal growth has been much less investigated. We now explored the action of adenosine A2A receptors (A2AR) upon neurite outgrowth, discriminating actions over the axon or dendrites, and the mechanisms involved. Morphometric analysis of primary cultures of cortical neurons from E18 Sprague-Dawley rats demonstrated that an A2AR agonist, CGS 21680, enhances axonal elongation and dendritic branching, being the former prevented by inhibitors of phosphoinositide 3-kinase, mitogen-activated protein kinase and phospholipase C, but not of protein kinase A. By testing the influence of a scavenger of BDNF (brain-derived neurotrophic factor) over the action of the A2AR agonist and the action of a selective A2AR antagonist over the action of BDNF, we could conclude that while the action of A2ARs upon dendritic branching is dependent on the presence of endogenous BDNF, the influence of A2ARs upon axonal elongation is independent of endogenous BDNF. In consonance with the action over axonal elongation, A2AR activation promoted a decrease in microtubule stability and an increase in microtubule growth speed in axonal growth cones. In conclusion, we disclose a facilitatory action of A2ARs upon axonal elongation and microtubule dynamics, providing new insights for A2ARs regulation of neuronal differentiation and axonal regeneration.

  15. In vivo photoacoustic tomography of mouse cerebral edema induced by cold injury

    NASA Astrophysics Data System (ADS)

    Xu, Zhun; Zhu, Quing; Wang, Lihong V.

    2011-06-01

    For the first time, we have implemented photoacoustic tomography (PAT) to image the water content of an edema in vivo. We produced and imaged a cold-induced cerebral edema transcranially, then obtained blood vessel and water accumulation images at 610 and 975 nm, respectively. We tracked the changes at 12, 24, and 36 h after the cold injury. The blood volume decreased after the cold injury, and the maximum area of edema was observed 24 h after the cold injury. We validated PAT of the water content of the edema through magnetic Resonance Imaging and the water spectrum from the spectrophotometric measurement.

  16. A mouse model for testing remyelinating therapies.

    PubMed

    Bai, C Brian; Sun, Sunny; Roholt, Andrew; Benson, Emily; Edberg, Dale; Medicetty, Satish; Dutta, Ranjan; Kidd, Grahame; Macklin, Wendy B; Trapp, Bruce

    2016-09-01

    Used in combination with immunomodulatory therapies, remyelinating therapies are a viable therapeutic approach for treating individuals with multiple sclerosis. Studies of postmortem MS brains identified greater remyelination in demyelinated cerebral cortex than in demyelinated brain white matter and implicated reactive astrocytes as an inhibitor of white matter remyelination. An animal model that recapitulates these phenotypes would benefit the development of remyelination therapeutics. We have used a modified cuprizone protocol that causes a consistent and robust demyelination of mouse white matter and cerebral cortex. Spontaneous remyelination occurred significantly faster in the cerebral cortex than in white matter and reactive astrocytes were more abundant in white matter lesions. Remyelination of white matter and cerebral cortex was therapeutically enhanced by daily injections of thyroid hormone triiodothyronine (T3). In summary, we describe an in vivo demyelination/remyelination paradigm that can be powered to determine efficacy of therapies that enhance white matter and cortical remyelination. PMID:27384502

  17. Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall.

    PubMed

    Novikova, Svetlana I; He, Fang; Bai, Jie; Badan, Irina; Lidow, Irina A; Lidow, Michael S

    2005-01-01

    It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms.

  18. Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall.

    PubMed

    Novikova, Svetlana I; He, Fang; Bai, Jie; Badan, Irina; Lidow, Irina A; Lidow, Michael S

    2005-01-01

    It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms. PMID:15681117

  19. Effects of Hypocretin/Orexin and Major Transmitters of Arousal on Fast Spiking Neurons in Mouse Cortical Layer 6B

    PubMed Central

    Wenger Combremont, Anne-Laure; Bayer, Laurence; Dupré, Anouk; Mühlethaler, Michel; Serafin, Mauro

    2016-01-01

    Fast spiking (FS) GABAergic neurons are thought to be involved in the generation of high-frequency cortical rhythms during the waking state. We previously showed that cortical layer 6b (L6b) was a specific target for the wake-promoting transmitter, hypocretin/orexin (hcrt/orx). Here, we have investigated whether L6b FS cells were sensitive to hcrt/orx and other transmitters associated with cortical activation. Recordings were thus made from L6b FS cells in either wild-type mice or in transgenic mice in which GFP-positive GABAergic cells are parvalbumin positive. Whereas in a control condition hcrt/orx induced a strong increase in the frequency, but not amplitude, of spontaneous synaptic currents, in the presence of TTX, it had no effect at all on miniature synaptic currents. Hcrt/orx effect was thus presynaptic although not by an action on glutamatergic terminals but rather on neighboring cells. In contrast, noradrenaline and acetylcholine depolarized and excited these cells through a direct postsynaptic action. Neurotensin, which is colocalized in hcrt/orx neurons, also depolarized and excited these cells but the effect was indirect. Morphologically, these cells exhibited basket-like features. These results suggest that hcrt/orx, noradrenaline, acetylcholine, and neurotensin could contribute to high-frequency cortical activity through an action on L6b GABAergic FS cells. PMID:27235100

  20. Differential effect of sodium ions and guanine nucleotides on the binding of thioperamide and clobenpropit to histamine H3-receptors in rat cerebral cortical membranes.

    PubMed

    Clark, E A; Hill, S J

    1995-01-01

    1. Conflicting reports in the literature over heterogeneity (West et al., 1990) or homogeneity (Arrange et al., 1990) of histamine H3-receptor binding sites may be attributed to the use of different incubation conditions. In the present study we have investigated the extent to which the binding of H3-receptor ligands to rat cerebral cortical membranes can be modified by both sodium ions and guanine nucleotides. 2. The H3-selective antagonist, thioperamide, discriminated between two specific binding sites for [3H]-N alpha-methylhistamine (IC50 1 = 2.75 +/- 0.87 nM, IC50 2 101.6 +/- 12.0 nM, % site 1 = 24 +/- 2%) in 50 mM Tris HCl buffer, but showed homogeneity of binding in 50 mM Na/K phosphate buffer. 3. Sodium ions markedly altered the binding characteristics of thioperamide (i.e. heterogeneity was lost and IC50 value shifted towards the high affinity site). The competition curves for a second H3-antagonist, clobenpropit and the H3-agonist N alpha-methylhistamine however, were unaltered in the presence of sodium ions. 4. Guanylnucleotides displaced only 60% of specific [3H]-N alpha- methylhistamine binding and modulated thioperamide binding in the same way as sodium ions. 5. These data suggest that the H3-receptor can exist in different conformations for which thioperamide, but not N alpha-methylhistamine and clobenpropit, show differential affinity. 6. The potential nature of these sites, and the implications of this apparent receptor heterogeneity for H3-receptor antagonism by thioperamide, are discussed.

  1. Long-term sensory stimulation therapy improves hand function and restores cortical responsiveness in patients with chronic cerebral lesions. Three single case studies

    PubMed Central

    Kattenstroth, Jan-Christoph; Kalisch, Tobias; Peters, Sören; Tegenthoff, Martin; Dinse, Hubert R.

    2012-01-01

    Rehabilitation of sensorimotor impairment resulting from cerebral lesion (CL) utilizes task specific training and massed practice to drive reorganization and sensorimotor improvement due to induction of neuroplasticity mechanisms. Loss of sensory abilities often complicates recovery, and thus the individual's ability to use the affected body part for functional tasks. Therefore, the development of additional and alternative approaches that supplement, enhance, or even replace conventional training procedures would be advantageous. Repetitive sensory stimulation protocols (rSS) have been shown to evoke sensorimotor improvements of the affected limb in patients with chronic stroke. However, the possible impact of long-term rSS on sensorimotor performance of patients with CL, where the incident dated back many years remains unclear. The particular advantage of rSS is its passive nature, which does not require active participation of the subjects. Therefore, rSS can be applied in parallel to other occupations, making the intervention easier to implement and more acceptable to the individual. Here we report the effects of applying rSS for 8, 36, and 76 weeks to the paretic hand of three long-term patients with different types of CL. Different behavioral tests were used to assess sensory and/or sensorimotor performance of the upper extremities prior, after, and during the intervention. In one patient, the impact of long-term rSS on restoration of cortical activation was investigated by recording somatosensory evoked potentials (SEP). After long-term rSS all three patients showed considerable improvements of their sensory and motor abilities. In addition, almost normal evoked potentials could be recorded after rSS in one patient. Our data show that long-term rSS applied to patients with chronic CL can improve tactile and sensorimotor functions, which, however, developed in some cases only after many weeks of stimulation, and continued to further improve on a time scale of

  2. Long-term sensory stimulation therapy improves hand function and restores cortical responsiveness in patients with chronic cerebral lesions. Three single case studies.

    PubMed

    Kattenstroth, Jan-Christoph; Kalisch, Tobias; Peters, Sören; Tegenthoff, Martin; Dinse, Hubert R

    2012-01-01

    Rehabilitation of sensorimotor impairment resulting from cerebral lesion (CL) utilizes task specific training and massed practice to drive reorganization and sensorimotor improvement due to induction of neuroplasticity mechanisms. Loss of sensory abilities often complicates recovery, and thus the individual's ability to use the affected body part for functional tasks. Therefore, the development of additional and alternative approaches that supplement, enhance, or even replace conventional training procedures would be advantageous. Repetitive sensory stimulation protocols (rSS) have been shown to evoke sensorimotor improvements of the affected limb in patients with chronic stroke. However, the possible impact of long-term rSS on sensorimotor performance of patients with CL, where the incident dated back many years remains unclear. The particular advantage of rSS is its passive nature, which does not require active participation of the subjects. Therefore, rSS can be applied in parallel to other occupations, making the intervention easier to implement and more acceptable to the individual. Here we report the effects of applying rSS for 8, 36, and 76 weeks to the paretic hand of three long-term patients with different types of CL. Different behavioral tests were used to assess sensory and/or sensorimotor performance of the upper extremities prior, after, and during the intervention. In one patient, the impact of long-term rSS on restoration of cortical activation was investigated by recording somatosensory evoked potentials (SEP). After long-term rSS all three patients showed considerable improvements of their sensory and motor abilities. In addition, almost normal evoked potentials could be recorded after rSS in one patient. Our data show that long-term rSS applied to patients with chronic CL can improve tactile and sensorimotor functions, which, however, developed in some cases only after many weeks of stimulation, and continued to further improve on a time scale of

  3. Circadian rhythm in adenosine A1 receptor of mouse cerebral cortex

    SciTech Connect

    Florio, C.; Rosati, A.M.; Traversa, U.; Vertua, R. )

    1991-01-01

    In order to investigate diurnal variation in adenosine A1 receptors binding parameters, Bmax and Kd values of specifically bound N6-cyclohexyl-({sup 3}H)adenosine were determined in the cerebral cortex of mice that had been housed under controlled light-dark cycles for 4 weeks. Significant differences were found for Bmax values measured at 3-hr intervals across a 24-h period, with low Bmax values during the light period and high Bmax values during the dark period. The amplitude between 03.00 and 18.00 hr was 33%. No substantial rhythm was found in the Kd values. It is suggested that the changes in the density of A1 receptors could reflect a physiologically-relevant mechanism by which adenosine exerts its modulatory role in the central nervous system.

  4. Characterization of oligodendrocyte lineage precursor cells in the mouse cerebral cortex: a confocal microscopy approach to demyelinating diseases.

    PubMed

    Girolamo, Francesco; Strippoli, Maurizio; Errede, Mariella; Benagiano, Vincenzo; Roncali, Luisa; Ambrosi, Glauco; Virgintino, Daniela

    2010-01-01

    The identification of stem cells resident in the adult central nervous system has redirected the focus of research into demyelinating diseases, such as multiple sclerosis, mainly affecting the brain white matter. This immunocytochemical and morphometrical study was carried out by confocal microscopy in the adult mouse cerebral cortex, with the aim of analysing, in the brain grey matter, the characteristics of the oligodendrocyte lineage cells, whose capability to remyelinate is still controversial. The observations demonstrated the presence in all the cortex layers of glial restricted progenitors, reactive to A2B5 marker, oligodendrocyte precursor cells, expressing the NG2 proteoglycan, and pre-oligodendrocytes and pre-myelinating oligodendrocytes, reactive to the specific marker O4. NG2 expressing cells constitute the major immature population of the cortex, since not only oligodendrocyte precursor cells and pre-oligodendrocytes but also a part of the glial restrict progenitors express the NG2 proteoglycan. Together with the population of these immature cells, a larger population of mature oligodendrocytes was revealed by the classical oligodendrocyte and myelin markers, 2',3'-cyclic nucleotide 3'-phosphodiesterase, myelin basic protein and myelin oligodendrocyte glycoprotein. The results indicate that oligodendrocyte precursors committed to differentiate into myelin forming oligodendrocytes are present through all layers of the adult cortex and that their phenotypic features exactly recall those of the oligodendroglial lineage cells during development.

  5. Vision Loss Shifts the Balance of Feedforward and Intracortical Circuits in Opposite Directions in Mouse Primary Auditory and Visual Cortices

    PubMed Central

    Petrus, Emily; Rodriguez, Gabriela; Patterson, Ryan; Connor, Blaine; Kanold, Patrick O.

    2015-01-01

    Loss of a sensory modality leads to widespread changes in synaptic function across sensory cortices, which are thought to be the basis for cross-modal adaptation. Previous studies suggest that experience-dependent cross-modal regulation of the spared sensory cortices may be mediated by changes in cortical circuits. Here, we report that loss of vision, in the form of dark exposure (DE) for 1 week, produces laminar-specific changes in excitatory and inhibitory circuits in the primary auditory cortex (A1) of adult mice to promote feedforward (FF) processing and also strengthens intracortical inputs to primary visual cortex (V1). Specifically, DE potentiated FF excitatory synapses from layer 4 (L4) to L2/3 in A1 and recurrent excitatory inputs in A1–L4 in parallel with a reduction in the strength of lateral intracortical excitatory inputs to A1–L2/3. This suggests a shift in processing in favor of FF information at the expense of intracortical processing. Vision loss also strengthened inhibitory synaptic function in L4 and L2/3 of A1, but via laminar specific mechanisms. In A1–L4, DE specifically potentiated the evoked synaptic transmission from parvalbumin-positive inhibitory interneurons to principal neurons without changes in spontaneous miniature IPSCs (mIPSCs). In contrast, DE specifically increased the frequency of mIPSCs in A1–L2/3. In V1, FF excitatory inputs were unaltered by DE, whereas lateral intracortical connections in L2/3 were strengthened, suggesting a shift toward intracortical processing. Our results suggest that loss of vision produces distinct circuit changes in the spared and deprived sensory cortices to shift between FF and intracortical processing to allow adaptation. PMID:26063913

  6. An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons

    PubMed Central

    Hayashi, Yoshinori; Morinaga, Saori; Liu, Xia; Zhang, Jing; Wu, Zhou; Yokoyama, Takeshi; Nakanishi, Hiroshi

    2016-01-01

    Prostaglandin E2 (PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2 enables modulating N-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca2+-activated K+ (BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (INMDA-OUT), which are associated with the BK channel activation. Patch-clamp recordings from the acutely dissociated mouse cortical neurons revealed that an EP2 receptor agonist activated INMDA-OUT, whereas an EP3 receptor agonist reduced it. Agonists of EP1 or EP4 receptors showed no significant effects on INMDA-OUT. A direct perfusion of 3,5′-cyclic adenosine monophosphate (cAMP) through the patch pipette facilitated INMDA-OUT, which was abolished by the presence of protein kinase A (PKA) inhibitor. Furthermore, facilitation of INMDA-OUT caused by an EP2 receptor agonist was significantly suppressed by PKA inhibitor. Finally, the activation of BK channels through EP2 receptors facilitated the recovery phase of NMDA-induced dendritic beading in the primary cultured cortical neurons. These results suggest that a direct activation of BK channels by EP2 receptor-mediated signaling pathways plays neuroprotective roles in cortical neurons. PMID:27298516

  7. An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons.

    PubMed

    Hayashi, Yoshinori; Morinaga, Saori; Liu, Xia; Zhang, Jing; Wu, Zhou; Yokoyama, Takeshi; Nakanishi, Hiroshi

    2016-01-01

    Prostaglandin E2 (PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2 enables modulating N-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca(2+)-activated K(+) (BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (I NMDA-OUT), which are associated with the BK channel activation. Patch-clamp recordings from the acutely dissociated mouse cortical neurons revealed that an EP2 receptor agonist activated I NMDA-OUT, whereas an EP3 receptor agonist reduced it. Agonists of EP1 or EP4 receptors showed no significant effects on I NMDA-OUT. A direct perfusion of 3,5'-cyclic adenosine monophosphate (cAMP) through the patch pipette facilitated I NMDA-OUT, which was abolished by the presence of protein kinase A (PKA) inhibitor. Furthermore, facilitation of I NMDA-OUT caused by an EP2 receptor agonist was significantly suppressed by PKA inhibitor. Finally, the activation of BK channels through EP2 receptors facilitated the recovery phase of NMDA-induced dendritic beading in the primary cultured cortical neurons. These results suggest that a direct activation of BK channels by EP2 receptor-mediated signaling pathways plays neuroprotective roles in cortical neurons. PMID:27298516

  8. Structure of cortical cytoskeleton in fibers of mouse muscle cells after being exposed to a 30-day space flight on board the BION-M1 biosatellite.

    PubMed

    Ogneva, I V; Maximova, M V; Larina, I M

    2014-05-15

    The aim of the work was to analyze changes in the organization of the cortical cytoskeleton in fibers of the mouse soleus muscle, tibialis anterior muscle and left ventricular cardiomyocytes after completion of a 30-day space flight on board the BION-M1 biosatellite (Russia, 2013). The transversal stiffness of the cortical cytoskeleton of the cardiomyocytes and fibers of the skeletal muscles did not differ significantly within the study groups compared with the vivarium control group. The content of beta- and gamma-actin in the membranous fraction of proteins in the left ventricular cardiomyocytes did not differ significantly within all study groups and correlated with the transversal stiffness. A similar situation was revealed in fibers of the soleus muscle and tibialis anterior muscle. At the same time, the content of beta-actin in the cytoplasmic fraction of proteins was found to be decreased in all types of studied tissues compared with the control levels in the postflight group, with lowered beta-actin gene expression rates in the postflight group. After completion of the space flight, the content of alpha-actinin-4 was found to be reduced in the membranous fraction of proteins from the mouse cardiomyocytes, while its content in the cytoplasmic fraction of proteins did not change significantly. Furthermore, gene expression rates of this protein were decreased at the time of dissection (it was started after 13 h after landing). At the same time, the content of alpha-actinin-1 decreased in the membranous fraction and increased in the cytoplasmic fraction of proteins from the soleus muscle fibers.

  9. Validation of optical voltage reporting by the genetically encoded voltage indicator VSFP-Butterfly from cortical layer 2/3 pyramidal neurons in mouse brain slices

    PubMed Central

    Empson, Ruth M; Goulton, Chelsea; Scholtz, David; Gallero-Salas, Yasir; Zeng, Hongkui; Knöpfel, Thomas

    2015-01-01

    Understanding how behavior emerges from brain electrical activity is one of the ultimate goals of neuroscience. To achieve this goal we require methods for large-scale recording of the electrical activity of specific neuronal circuits. A very promising approach is to use optical reporting of membrane voltage transients, particularly if the voltage reporter is genetically targeted to specific neuronal populations. Targeting in this way allows population signals to be recorded and interpreted without blindness to neuronal diversity. Here, we evaluated the voltage-sensitive fluorescent protein, VSFP Butterfly 2.1, a genetically encoded voltage indicator (GEVI), for monitoring electrical activity of layer 2/3 cortical pyramidal neurons in mouse brain slices. Standard widefield fluorescence and two-photon imaging revealed robust, high signal-to-noise ratio read-outs of membrane voltage transients that are predominantly synaptic in nature and can be resolved as discrete areas of synaptically connected layer 2/3 neurons. We find that targeted expression of this GEVI in the cortex provides a flexible and promising tool for the analysis of L2/3 cortical network function. PMID:26229003

  10. Electroacupuncture ameliorates memory impairments by enhancing oligodendrocyte regeneration in a mouse model of prolonged cerebral hypoperfusion

    PubMed Central

    Ahn, Sung Min; Kim, Yu Ri; Kim, Ha Neui; Shin, Yong-Il; Shin, Hwa Kyoung; Choi, Byung Tae

    2016-01-01

    We modeled prolonged cerebral hypoperfusion in mice using bilateral common carotid artery stenosis (BCAS) and electroacupuncture (EA) stimulation was applied at two acupoints, Baihui (GV20) and Dazhui (GV14). In behavioral tests of memory, BCAS produced impairments in spatial and short-term memory in mice that were attenuated by therapeutic EA stimulation. Therapeutic use of EA in BCAS also enhanced oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs), in association with white matter improvements in the corpus callosum (CC). In PCR analyses of growth factor gene expression, significant positive changes in 3 genes were observed following EA stimulation in BCAS, and here we highlight alterations in neurotrophin-4/5 (NT4/5). We confirmed EA-mediated positive changes in the expression of NT4/5 and its receptor, tyrosine receptor kinase B (TrkB). Treatment of naïve and BCAS + EA animals with a selective TrkB antagonist, ANA-12, produced losses of myelin and cognitive function that were ameliorated by EA therapy. Moreover, following BCAS we observed an EA-dependent increase in phospho-activated CREB (a downstream mediator of NT4/5-TrkB signaling) in OPCs and OLs of the CC. Our results suggest that EA stimulation promotes the recovery of memory function following white matter injury via a mechanism that promotes oligodendrocyte regeneration and involves NT4/5-TrkB signaling. PMID:27350403

  11. Assessing mouse alternatives to access to computer: a case study of a user with cerebral palsy.

    PubMed

    Pousada, Thais; Pareira, Javier; Groba, Betania; Nieto, Laura; Pazos, Alejandro

    2014-01-01

    The purpose of this study is to describe the process of assessment of three assistive devices to meet the needs of a woman with cerebral palsy (CP) in order to provide her with computer access and use. The user has quadriplegic CP, with anarthria, using a syllabic keyboard. Devices were evaluated through a three-step approach: (a) use of a questionnaire to preselect potential assistive technologies, (b) use of an eTAO tool to determine the effectiveness of each devised, and (c) a conducting semi-structured interview to obtain qualitative data. Touch screen, joystick, and trackball were the preselected devices. The best device that met the user's needs and priorities was joystick. The finding was corroborated by both the eTAO tool and the semi-structured interview. Computers are a basic form of social participation. It is important to consider the special needs and priorities of users and to try different devices when undertaking a device-selection process. Environmental and personal factors have to be considered, as well. This leads to a need to evaluate new tools in order to provide the appropriate support. The eTAO could be a suitable instrument for this purpose. Additional research is also needed to understand how to better match devices with different user populations and how to comprehensively evaluate emerging technologies relative to users with disabilities.

  12. Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex.

    PubMed

    He, Miao; Tucciarone, Jason; Lee, SooHyun; Nigro, Maximiliano José; Kim, Yongsoo; Levine, Jesse Maurica; Kelly, Sean Michael; Krugikov, Illya; Wu, Priscilla; Chen, Yang; Gong, Lin; Hou, Yongjie; Osten, Pavel; Rudy, Bernardo; Huang, Z Josh

    2016-09-21

    Systematic genetic access to GABAergic cell types will facilitate studying the function and development of inhibitory circuitry. However, single gene-driven recombinase lines mark relatively broad and heterogeneous cell populations. Although intersectional approaches improve precision, it remains unclear whether they can capture cell types defined by multiple features. Here we demonstrate that combinatorial genetic and viral approaches target restricted GABAergic subpopulations and cell types characterized by distinct laminar location, morphology, axonal projection, and electrophysiological properties. Intersectional embryonic transcription factor drivers allow finer fate mapping of progenitor pools that give rise to distinct GABAergic populations, including laminar cohorts. Conversion of progenitor fate restriction signals to constitutive recombinase expression enables viral targeting of cell types based on their lineage and birth time. Properly designed intersection, subtraction, conversion, and multi-color reporters enhance the precision and versatility of drivers and viral vectors. These strategies and tools will facilitate studying GABAergic neurons throughout the mouse brain. PMID:27618674

  13. Neonatal seizures induced by pentylenetetrazol or kainic acid disrupt primary cilia growth on developing mouse cortical neurons.

    PubMed

    Parker, Alexander K; Le, Megan M; Smith, Tyler S; Hoang-Minh, Lan B; Atkinson, Eric W; Ugartemendia, George; Semple-Rowland, Susan; Coleman, Jason E; Sarkisian, Matthew R

    2016-08-01

    Neonatal or early-life seizures (ELS) are often associated with life-long neurophysiological, cognitive and behavioral deficits, but the underlying mechanisms contributing to these deficits remain poorly understood. Newborn, post-migratory cortical neurons sprout ciliary buds (procilia) that mature into primary cilia. Disruption of the growth or signaling capabilities of these cilia has been linked to atypical neurite outgrowth from neurons and abnormalities in neuronal circuitry. Here, we tested the hypothesis that generalized seizures induced by pentylenetetrazol (PTZ) or kainic acid (KA) during early postnatal development impair neuronal and/or glial ciliogenesis. Mice received PTZ (50 or 100mg/kg), KA (2mg/kg), or saline either once at birth (P0), or once daily from P0 to P4. Using immunohistochemistry and electron microscopy, the cilia of neurons and glia were examined at P7, P14, and P42. A total of 83 regions were analyzed, representing 13 unique neocortical and hippocampal regions. Neuronal cilia were identified by co-expression of NeuN and type 3 adenylyl cyclase (ACIII) or somatostatin receptor 3 (SSTR3), while glial cilia were identified by co-expression of GFAP, Arl13b, and gamma-tubulin. We found that PTZ exposure at either P0 or from P0 to P4 induced convulsive behavior, followed by acute and lasting effects on neuronal cilia lengths that varied depending on the cortical region, PTZ dose, injection frequency, and time post-PTZ. Both increases and decreases in neuronal cilia length were observed. No changes in the length of glial cilia were observed under any of the test conditions. Lastly, we found that a single KA seizure at P0 led to similar abnormalities in neuronal cilia lengths. Our results suggest that seizure(s) occurring during early stages of cortical development induce persistent and widespread changes in neuronal cilia length. Given the impact neuronal cilia have on neuronal differentiation, ELS-induced changes in ciliogenesis may

  14. The Effects of Different Repetitive Transcranial Magnetic Stimulation (rTMS) Protocols on Cortical Gene Expression in a Rat Model of Cerebral Ischemic-Reperfusion Injury

    PubMed Central

    Ljubisavljevic, Milos R.; Javid, Asma; Oommen, Joji; Parekh, Khatija; Nagelkerke, Nico; Shehab, Safa; Adrian, Thomas E.

    2015-01-01

    Although repetitive Transcranial Magnetic Stimulation (rTMS) in treatment of stroke in humans has been explored over the past decade the data remain controversial in terms of optimal stimulation parameters and the mechanisms of rTMS long-term effects. This study aimed to explore the potential of different rTMS protocols to induce changes in gene expression in rat cortices after acute ischemic-reperfusion brain injury. The stroke was induced by middle cerebral artery occlusion (MCAO) with subsequent reperfusion. Changes in the expression of 96 genes were examined using low-density expression arrays after MCAO alone and after MCAO combined with 1Hz, 5Hz, continuous (cTBS) and intermittent (iTBS) theta-burst rTMS. rTMS over the lesioned hemisphere was given for two weeks (with a 2-day pause) in a single daily session and a total of 2400 pulses. MCAO alone induced significant upregulation in the expression of 44 genes and downregulation in 10. Two weeks of iTBS induced significant increase in the expression of 52 genes. There were no downregulated genes. 1Hz and 5Hz had no significant effects on gene expression, while cTBS effects were negligible. Upregulated genes included those involved in angiogenesis, inflammation, injury response and cellular repair, structural remodeling, neuroprotection, neurotransmission and neuronal plasticity. The results show that long-term rTMS in acute ischemic-reperfusion brain injury induces complex changes in gene expression that span multiple pathways, which generally promote the recovery. They also demonstrate that induced changes primarily depend on the rTMS frequency (1Hz and 5Hz vs. iTBS) and pattern (cTBS vs. iTBS). The results further underlines the premise that one of the benefits of rTMS application in stroke may be to prime the brain, enhancing its potential to cope with the injury and to rewire. This could further augment its potential to favorably respond to rehabilitation, and to restore some of the loss functions. PMID

  15. Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder

    PubMed Central

    Schmidt, Ulrike; Herrmann, Leonie; Hagl, Kathrin; Novak, Bozidar; Huber, Christine; Holsboer, Florian; Wotjak, Carsten T.; Buell, Dominik R.

    2013-01-01

    MicroRNAs (miRNA) are a class of small non-coding RNAs that have recently emerged as epigenetic modulators of gene expression in psychiatric diseases like schizophrenia and major depression. So far, miRNAs have neither been studied in patients suffering from posttraumatic stress disorder (PTSD) nor in PTSD animal models. Here, we present the first study exploring the connection between miRNAs and PTSD. Employing our previously established PTSD mouse model, we assessed miRNA profiles in prefrontal cortices (PFCs) dissected from either fluoxetine or control-treated wildtype C57BL/6N mice 74 days after their subjection to either a single traumatic electric footshock or mock-treatment. Fluoxetine is an antidepressant known to be effective both in PTSD patients and in mice suffering from a PTSD-like syndrome. Screening for differences in the relative expression levels of all potential miRNA target sequences of miRBase 18.0 by pairwise comparison of the PFC miRNA profiles of the four mouse groups mentioned resulted in identification of five miRNA candidate molecules. Validation of these miRNA candidates by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) revealed that the therapeutic action of fluoxetine in shocked mice is associated with a significant reduction in mmu-miR-1971 expression. Furthermore, our findings suggest that traumatic stress and fluoxetine interact to cause distinct alterations in the mouse PFC miRNA signature in the long-term. PMID:23847554

  16. Coevolution of radial glial cells and the cerebral cortex

    PubMed Central

    De Juan Romero, Camino

    2015-01-01

    Abstract Radial glia cells play fundamental roles in the development of the cerebral cortex, acting both as the primary stem and progenitor cells, as well as the guides for neuronal migration and lamination. These critical functions of radial glia cells in cortical development have been discovered mostly during the last 15 years and, more recently, seminal studies have demonstrated the existence of a remarkable diversity of additional cortical progenitor cell types, including a variety of basal radial glia cells with key roles in cortical expansion and folding, both in ontogeny and phylogeny. In this review, we summarize the main cellular and molecular mechanisms known to be involved in cerebral cortex development in mouse, as the currently preferred animal model, and then compare these with known mechanisms in other vertebrates, both mammal and nonmammal, including human. This allows us to present a global picture of how radial glia cells and the cerebral cortex seem to have coevolved, from reptiles to primates, leading to the remarkable diversity of vertebrate cortical phenotypes. GLIA 2015;63:1303–1319 PMID:25808466

  17. Alterations of caveolin-1 expression in a mouse model of delayed cerebral vasospasm following subarachnoid hemorrhage

    PubMed Central

    Xiong, Ye; Wang, Xue-Min; Zhong, Ming; Li, Ze-Qun; Wang, Zhi; Tian, Zuo-Fu; Zheng, Kuang; Tan, Xian-Xi

    2016-01-01

    The aim of the present study was to evaluate the expression levels of caveolin-1 in the basilar artery following delayed cerebral vasospasm (DCVS) in a rat model of subarachnoid hemorrhage (SAH), in order to investigate the association between caveolin-1 and DCVS, and its potential as a treatment for DCVS of SAH. A total of 150 Sprague Dawley rats were randomly allocated into blank, saline and SAH groups. The SAH and saline groups were subdivided into days 3, 5, 7 and 14 following the establishment of the model. The murine model of SAH was established by double injection of autologous arterial blood into the cisterna magana and DCVS was detected using Bederson neurological severity scores. Hematoxylin and eosin (HE) staining was used to observe the inner perimeter of the basilar artery pipe and variations in the thickness of the basilar artery wall. Alterations in the levels of caveolin-1 protein in the basilar artery were measured using immunofluorescence and western blot analysis; whereas alterations in the mRNA expression levels of caveolin-1 were detected by reverse transcription-quantitative polymerase chain reaction. In the present study, 15 mice succumbed to SAH-induced DCVS in the day 3 (n=3), 5 (n=5) and 7 (n=2) groups. No mortality was observed in the blank control and saline groups during the process of observation in the SAH group, All mice in the SAH groups exhibited Bederson neurological severity scores ≥1; whereas no neurological impairment was detected in the blank and normal saline groups, demonstrating the success of the model. HE staining was used to assess vasospasm and the results demonstrated that the inner perimeter of the basal artery pipe decreased at day 3 in the SAH group; whereas values peaked in the day 7 group. The thickness of the basal artery wall significantly increased (P<0.05), as compared with the blank and saline groups, in which no significant alterations in the wall thickness and the inner perimeter of the basal artery pipe

  18. Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model.

    PubMed

    Kolodziejczyk, Karolina; Raymond, Lynn A

    2016-02-01

    Huntington disease (HD), a neurodegenerative disorder caused by CAG repeat expansion in the gene encoding huntingtin, predominantly affects the striatum, especially the spiny projection neurons (SPN). The striatum receives excitatory input from cortex and thalamus, and the role of the former has been well-studied in HD. Here, we report that mutated huntingtin alters function of thalamostriatal connections. We used a novel thalamostriatal (T-S) coculture and an established corticostriatal (C-S) coculture, generated from YAC128 HD and WT (FVB/NJ background strain) mice, to investigate excitatory neurotransmission onto striatal SPN. SPN in T-S coculture from WT mice showed similar mini-excitatory postsynaptic current (mEPSC) frequency and amplitude as in C-S coculture; however, both the frequency and amplitude were significantly reduced in YAC128 T-S coculture. Further investigation in T-S coculture showed similar excitatory synapse density in WT and YAC128 SPN dendrites by immunostaining, suggesting changes in total dendritic length or probability of release as possible explanations for mEPSC frequency changes. Synaptic N-methyl-D-aspartate receptor (NMDAR) current was similar, but extrasynaptic current, associated with cell death signaling, was enhanced in YAC128 SPN in T-S coculture. Employing optical stimulation of cortical versus thalamic afferents and recording from striatal SPN in brain slice, we found increased glutamate release probability and reduced AMPAR/NMDAR current ratios in thalamostriatal synapses, most prominently in YAC128. Enhanced extrasynaptic NMDAR current in YAC128 SPN was apparent with both cortical and thalamic stimulation. We conclude that thalamic afferents to the striatum are affected early, prior to an overt HD phenotype; however, changes in NMDAR localization in SPN are independent of the source of glutamatergic input.

  19. [Characteristics of the functional coupling of cerebral cortical neurons in cats and the signal meaning of the stimulus (the hypothesis of the information switching of conditioned reflex activity)].

    PubMed

    Komissarov, V I

    1988-01-01

    In chronic experiments on cats interrelations were studied between impulse activity of neurones of various auditory cortical zones and associative area under the action of defensive, alimentary or differential acoustic signals. It was found that shifts of the impulse activity of neurones in the studied cortical zones and correlation dependence between them appearing in the given conditions, were of a selective character and were connected with signal meaning of acoustic signals. Neurophysiological mechanisms are discussed of the revealed reorganization of the composition of functional relations of neurones of the cortical representation of the conditioned stimulus analyzer.

  20. A radical scavenger edaravone inhibits matrix metalloproteinase-9 upregulation and blood-brain barrier breakdown in a mouse model of prolonged cerebral hypoperfusion

    PubMed Central

    Maki, Takakuni; Liang, Anna C.; Arai, Ken

    2014-01-01

    Matrix metalloproteinase-9 (MMP-9) plays key roles in the brain pathophysiology, especially in blood-brain barrier (BBB) breakdown. Therefore, inhibiting MMP-9 activity may be a promising therapy for protecting brains in cerebrovascular diseases. Here we show that in a mouse prolonged cerebral hypoperfusion model, a clinically proven radical scavenger edaravone suppressed MMP-9 and reduced BBB damage in cerebral white matter. Prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in male adult C57BL/6J mice (10 weeks old). After 7 days of cerebral hypoperfusion, white matter region (e.g. corpus callosum) exhibited significant BBB leakage, assessed by IgG staining. Correspondingly, immunostaining and western blotting showed that MMP-9 was upregulated in the white matter. Edaravone treatment (3 mg/kg, i.p. at day 0 and 3) inhibited both BBB leakage and MMP-9 increase. Under the early phase of cerebral hypoperfusion conditions, oligodendrocyte precursor cells (OPCs) mainly contribute to the MMP-9 increase, but our immunostaining data showed that very little OPCs expressed MMP-9 in the edaravone-treated animals at day 7. Therefore, in vitro studies with primary rat OPCs were conducted to examine whether edaravone would directly suppressed MMP-9 expressions in OPCs. OPC cultures were exposed to sub-lethal CoCl2 for 7 days to induce prolonged chemical hypoxic stress. Prolonged chemical hypoxic stress increased MMP-9 expression in OPCs, and radical scavenging with edaravone (10 μM for 7 days) ameliorated the increase. Taken together, our proof-of-concept study demonstrates that radical scavengers may provide a potential therapeutic approach for white matter injury by suppressing BBB damage. PMID:24820542

  1. Cortical dynamics revisited.

    PubMed

    Singer, Wolf

    2013-12-01

    Recent discoveries on the organisation of the cortical connectome together with novel data on the dynamics of neuronal interactions require an extension of classical concepts on information processing in the cerebral cortex. These new insights justify considering the brain as a complex, self-organised system with nonlinear dynamics in which principles of distributed, parallel processing coexist with serial operations within highly interconnected networks. The observed dynamics suggest that cortical networks are capable of providing an extremely high-dimensional state space in which a large amount of evolutionary and ontogenetically acquired information can coexist and be accessible to rapid parallel search.

  2. Cyproheptadine enhances the I(K) of mouse cortical neurons through sigma-1 receptor-mediated intracellular signal pathway.

    PubMed

    He, Yan-Lin; Zhang, Chun-Lei; Gao, Xiao-Fei; Yao, Jin-Jing; Hu, Chang-Long; Mei, Yan-Ai

    2012-01-01

    Cyproheptadine (CPH) is a histamine- and serotonin-receptor antagonist, and its effects are observed recently in the modulation of multiple intracellular signals. In this study, we used cortical neurons and HEK-293 cells transfected with Kv2.1 α-subunit to address whether CPH modify neural voltage-gated K(+) channels by a mechanism independent of its serotonergic and histaminergic properties. Our results demonstrate that intracellularly delivered CPH increased the I(K) by reducing the activity of protein kinas A (PKA). Inhibition of G(i) eliminated the CPH-induced effect on both the I(K) and PKA. Blocking of 5-HT-, M-, D(2)-, H(1)- or H(2)-type GPCR receptors with relevant antagonists did not eliminate the CPH-induced effect on the I(K). Antagonists of the sigma-1 receptor, however, blocked the effect of CPH. Moreover, the inhibition of sigma-1 by siRNA knockdown significantly reduced the CPH-induced effect on the I(K). On the contrary, sigma-1 receptor agonist mimicked the effects of CPH on the induction of I(K). A ligand-receptor binding assay indicated that CPH bound to the sigma-1 receptor. Similar effect of CPH were obtained from HEK-293 cells transfected with the α-subunit of Kv2.1. In overall, we reveal for the first time that CPH enhances the I(K) by modulating activity of PKA, and that the associated activation of the sigma-1 receptor/G(i)-protein pathway might be involved. Our findings illustrate an uncharacterized effect of CPH on neuron excitability through the I(K), which is independent of histamine H(1) and serotonin receptors.

  3. Slow Bursting Neurons of Mouse Cortical Layer 6b Are Depolarized by Hypocretin/Orexin and Major Transmitters of Arousal

    PubMed Central

    Wenger Combremont, Anne-Laure; Bayer, Laurence; Dupré, Anouk; Mühlethaler, Michel; Serafin, Mauro

    2016-01-01

    Neurons firing spontaneously in bursts in the absence of synaptic transmission have been previously recorded in different layers of cortical brain slices. It has been suggested that such neurons could contribute to the generation of alternating UP and DOWN states, a pattern of activity seen during slow-wave sleep. Here, we show that in layer 6b (L6b), known from our previous studies to contain neurons highly responsive to the wake-promoting transmitter hypocretin/orexin (hcrt/orx), there is a set of neurons, endowed with distinct intrinsic properties, which displayed a strong propensity to fire spontaneously in rhythmic bursts. In response to small depolarizing steps, they responded with a delayed firing of action potentials which, upon higher depolarizing steps, invariably inactivated and were followed by a depolarized plateau potential and a depolarizing afterpotential. These cells also displayed a strong hyperpolarization-activated rectification compatible with the presence of an Ih current. Most L6b neurons with such properties were able to fire spontaneously in bursts. Their bursting activity was of intrinsic origin as it persisted not only in presence of blockers of ionotropic glutamatergic and GABAergic receptors but also in a condition of complete synaptic blockade. However, a small number of these neurons displayed a mix of intrinsic bursting and synaptically driven recurrent UP and DOWN states. Most of the bursting L6b neurons were depolarized and excited by hcrt/orx through a direct postsynaptic mechanism that led to tonic firing and eventually inactivation. Similarly, they were directly excited by noradrenaline, histamine, dopamine, and neurotensin. Finally, the intracellular injection of these cells with dye and their subsequent Neurolucida reconstruction indicated that they were spiny non-pyramidal neurons. These results lead us to suggest that the propensity for slow rhythmic bursting of this set of L6b neurons could be directly impeded by hcrt

  4. A New Mouse Model of Mild Ornithine Transcarbamylase Deficiency (spf-j) Displays Cerebral Amino Acid Perturbations at Baseline and upon Systemic Immune Activation

    PubMed Central

    Tarasenko, Tatyana N.; Rosas, Odrick R.; Singh, Larry N.; Kristaponis, Kara; Vernon, Hilary; McGuire, Peter J.

    2015-01-01

    Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans. PMID:25647322

  5. Near-infrared fluorescent imaging of cerebral thrombi and blood-brain barrier disruption in a mouse model of cerebral venous sinus thrombosis.

    PubMed

    Kim, Dong-Eog; Schellingerhout, Dawid; Jaffer, Farouc A; Weissleder, Ralph; Tung, Ching-Hsuan

    2005-02-01

    An intravital microscopy imaging method was developed to visualize active cerebral thrombus and blood-brain barrier (BBB) disruption using Near Infrared Fluorescent (NIRF) probes. A circular craniotomy was made in CD-1 mice. Thrombi were formed by applying 10%-FeCl3 to the entire exposed superior sagittal sinus (SSS, 5 mm), or to the posterior 2.5 mm of the SSS for 5 mins. Control animals were pretreated with heparin (50 U/kg) before thrombus induction. Three hours after thrombus formation, a FXIIIa-targeted NIRF imaging probe (A15) was intravenously injected, and the SSS was imaged by intravital microscopy. This was followed by injection of indocyanine green (ICG) to assess BBB permeability. The A15 optical probe bound to thrombus, and the fluorescent signal emitted by the bound agent corresponded well with histologically confirmed thrombus. A15 initially remained intravascular, followed by excretion and subsequent decrease in all tissues except for thrombus, where it was retained. The subsequent ICG was also intravascular immediately after injection, but then began to leak into the cerebral parenchyma at 3 to 5 mins. The sites of leakage were adjacent to thrombosed areas. Heparin pretreatment prevented thrombus formation and reduced ICG leakage significantly. This demonstrates the feasibility of simultaneous in vivo monitoring of thrombus and BBB permeability in an animal model of cerebral venous thrombosis.

  6. Micro-heterogeneity of flow in a mouse model of chronic cerebral hypoperfusion revealed by longitudinal Doppler optical coherence tomography and angiography

    PubMed Central

    Srinivasan, Vivek J; Yu, Esther; Radhakrishnan, Harsha; Can, Anil; Climov, Mihail; Leahy, Conor; Ayata, Cenk; Eikermann-Haerter, Katharina

    2015-01-01

    Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimer's disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC)-perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity. PMID:26243708

  7. Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia

    PubMed Central

    Inan, Melis; Petros, Timothy J.

    2013-01-01

    GABAergic interneurons of the cerebral cortex (cINs) play crucial roles in many aspects of cortical function. The diverse types of cINs are classified into subgroups according to their morphology, intrinsic physiology, neurochemical markers and synaptic targeting. Recent advances in mouse genetics, imaging and electrophysiology techniques have greatly advanced our efforts to understand the role of normal cIN function and its dysfunction in neuropsychiatric disorders. In schizophrenia (SCZ), a wealth of data suggests that cIN function is perturbed, and that interneuron dysfunction may underlie key symptoms of the disease. In this review, we discuss the link between cINs and SCZ, focusing on the evidence for GABAergic signaling deficits from both SCZ patients and mouse models. PMID:23201207

  8. Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: implications for studying obesity-brain interactions in mice.

    PubMed

    Zhang, Le; Dasuri, Kalavathi; Fernandez-Kim, Sun-Ok; Bruce-Keller, Annadora J; Freeman, Linnea R; Pepping, Jennifer K; Beckett, Tina L; Murphy, M Paul; Keller, Jeffrey N

    2013-09-01

    Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.

  9. High Glucose-Induced Mitochondrial Respiration and Reactive Oxygen Species in Mouse Cerebral Pericytes is Reversed by Pharmacological Inhibition of Mitochondrial Carbonic Anhydrases: Implications for Cerebral Microvascular Disease in Diabetes

    PubMed Central

    Shah, Gul N.; Morofuji, Yoichi; Banks, William A.; Price, Tulin O.

    2013-01-01

    Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration. PMID:24076121

  10. High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes.

    PubMed

    Shah, Gul N; Morofuji, Yoichi; Banks, William A; Price, Tulin O

    2013-10-18

    Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration.

  11. Functional Doppler optical coherence tomography for cortical blood flow imaging

    NASA Astrophysics Data System (ADS)

    Yu, Lingfeng; Liu, Gangjun; Nguyen, Elaine; Choi, Bernard; Chen, Zhongping

    2010-02-01

    Optical methods have been widely used in basic neuroscience research to study the cerebral blood flow dynamics in order to overcome the low spatial resolution associated with magnetic resonance imaging and positron emission tomography. Although laser Doppler imaging and laser speckle imaging can map out en face cortical hemodynamics and columns, depth resolution is not available. Two-photon microscopy has been used for mapping cortical activity. However, flow measurement requires fluorescent dye injection, which can be problematic. The noninvasive and high resolution tomographic capabilities of optical coherence tomography make it a promising technique for mapping depth resolved cortical blood flow. Here, we present a functional Doppler optical coherence tomography (OCT) imaging modality for quantitative evaluation of cortical blood flow in a mouse model. Fast, repeated, Doppler OCT scans across a vessel of interest were performed to record flow dynamic information with a high temporal resolution of the cardiac cycles. Spectral Doppler analysis of continuous Doppler images demonstrates how the velocity components and longitudinally projected flow-volume-rate change over time, thereby providing complementary temporal flow information to the spatially distributed flow information of Doppler OCT. The proposed functional Doppler OCT imaging modality can be used to diagnose vessel stenosis/blockage or monitor blood flow changes due to pharmacological agents/neuronal activities. Non-invasive in-vivo mice experiments were performed to verify the capabilities of function Doppler OCT.

  12. Focal and Generalized Patterns of Cerebral Cortical Veins Due to Non-Convulsive Status Epilepticus or Prolonged Seizure Episode after Convulsive Status Epilepticus – A MRI Study Using Susceptibility Weighted Imaging

    PubMed Central

    Verma, Rajeev Kumar; Abela, Eugenio; Schindler, Kaspar; Krestel, Heinz; Springer, Elisabeth; Huber, Adrian; Weisstanner, Christian; Hauf, Martinus; Gralla, Jan; Wiest, Roland

    2016-01-01

    Objective The aim of this study was to investigate variant patterns of cortical venous oxygenation during status epilepticus (SE) using susceptibility-weighted imaging (SWI). Methods We analyzed magnetic resonance imaging (MRI) scans of 26 patients with clinically witnessed prolonged seizures and/or EEG-confirmed SE. All MRI exams encompassed SWI, dynamic susceptibility contrast perfusion MRI (MRI-DSC) and diffusion-weighted imaging (DWI). We aimed to identify distinct patterns of SWI signal alterations that revealed regional or global increases of cerebral blood flow (CBF) and DWI restrictions. We hypothesized that SWI-related oxygenation patterns reflect ictal or postictal patterns that resemble SE or sequelae of seizures. Results Sixteen patients were examined during nonconvulsive status epilepticus (NCSE) as confirmed by EEG, a further ten patients suffered from witnessed and prolonged seizure episode ahead of imaging without initial EEG. MRI patterns of 15 of the 26 patients revealed generalized hyperoxygenation by SWI in keeping with either global or multifocal cortical hyperperfusion. Eight patients revealed a focal hyperoxygenation pattern related to focal CBF increase and three patients showed a focal deoxygenation pattern related to focal CBF decrease. Conclusions SWI-related hyper- and deoxygenation patterns resemble ictal and postictal CBF changes within a range from globally increased to focally decreased perfusion. In all 26 patients the SWI patterns were in keeping with ictal hyperperfusion (hyperoxygenation patterns) or postictal hypoperfusion (deoxygenation patterns) respectively. A new finding of this study is that cortical venous patterns in SWI can be not only focally, but globally attenuated. SWI may thus be considered as an alternative contrast-free MR sequence to identify perfusion changes related to ictal or postictal conditions. PMID:27486662

  13. C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment.

    PubMed

    Voss, Anne K; Britto, Joanne M; Dixon, Mathew P; Sheikh, Bilal N; Collin, Caitlin; Tan, Seong-Seng; Thomas, Tim

    2008-06-01

    Neuronal migration is integral to the development of the cerebral cortex and higher brain function. Cortical neuron migration defects lead to mental disorders such as lissencephaly and epilepsy. Interaction of neurons with their extracellular environment regulates cortical neuron migration through cell surface receptors. However, it is unclear how the signals from extracellular matrix proteins are transduced intracellularly. We report here that mouse embryos lacking the Ras family guanine nucleotide exchange factor, C3G (Rapgef1, Grf2), exhibit a cortical neuron migration defect resulting in a failure to split the preplate into marginal zone and subplate and a failure to form a cortical plate. C3G-deficient cortical neurons fail to migrate. Instead, they arrest in a multipolar state and accumulate below the preplate. The basement membrane is disrupted and radial glial processes are disorganised and lack attachment in C3G-deficient brains. C3G is activated in response to reelin in cortical neurons, which, in turn, leads to activation of the small GTPase Rap1. In C3G-deficient cells, Rap1 GTP loading in response to reelin stimulation is reduced. In conclusion, the Ras family regulator C3G is essential for two aspects of cortex development, namely radial glial attachment and neuronal migration.

  14. A Rare Hydrocephalus Complication: Cortical Blindness.

    PubMed

    Ünal, Emre; Göçmen, Rahşan; Işıkay, Ayşe İlksen; Tekşam, Özlem

    2015-01-01

    Cortical blindness related to bilateral occipital lobe infarction is an extremely rare complication of hydrocephalus. Compression of the posterior cerebral artery, secondary to tentorial herniation, is the cause of occipital infarction. Particularly in children and mentally ill patients, cortical blindness may be missed. Therefore, early diagnosis and treatment of hydrocephalus is important. We present herein a child of ventricular shunt malfunction complicated by cortical blindness. PMID:27411424

  15. A Rare Hydrocephalus Complication: Cortical Blindness.

    PubMed

    Ünal, Emre; Göçmen, Rahşan; Işıkay, Ayşe İlksen; Tekşam, Özlem

    2015-01-01

    Cortical blindness related to bilateral occipital lobe infarction is an extremely rare complication of hydrocephalus. Compression of the posterior cerebral artery, secondary to tentorial herniation, is the cause of occipital infarction. Particularly in children and mentally ill patients, cortical blindness may be missed. Therefore, early diagnosis and treatment of hydrocephalus is important. We present herein a child of ventricular shunt malfunction complicated by cortical blindness.

  16. 17Beta-estradiol differentially protects cortical pericontusional zone from programmed cell death after traumatic cerebral contusion at distinct stages via non-genomic and genomic pathways.

    PubMed

    Bao, Yi-Jun; Li, Li-Zhuo; Li, Xin-Guo; Wang, Yun-Jie

    2011-11-01

    Pericontusional zone (PCZ) of traumatic cerebral contusion is a target of pharmacological intervention. Our previous study indicated that 17beta-estradiol has a protective role in PCZ after traumatic cerebral contusion via the upregulation of estrogen receptor (ER) alpha mRNA induction and protein expression as well as inhibition of caspase-3 activation, suggesting that genomic signaling pathway is implicated in the protective effect of 17beta-estrodiol. Recent findings demonstrated that 17beta-estradiol also acts on the extranuclear/membrane ER to activate non-genomic signaling pathway to regulate cellular functions and exert the protective effect in the brain. It is still unclear how and whether genomic and non-genomic pathways of 17beta-estradiol are involved in the neuroprotection in PCZ. Our current study demonstrates that 17beta-estradiol activates ERK1/2 and Akt at the early stage and induces ERalpha and survivin mRNA at the late stage to modulate its protection via the suppression of caspase-3 activation in PCZ. These findings suggest that 17beta-estrodiol differentially plays its protective roles via genomic and non-genomic signaling pathways in PCZ after traumatic cerebral contusion.

  17. The Niche Factor Syndecan-1 Regulates the Maintenance and Proliferation of Neural Progenitor Cells during Mammalian Cortical Development

    PubMed Central

    Wang, Qingjie; Yang, Landi; Alexander, Caroline; Temple, Sally

    2012-01-01

    Neural progenitor cells (NPCs) divide and differentiate in a precisely regulated manner over time to achieve the remarkable expansion and assembly of the layered mammalian cerebral cortex. Both intrinsic signaling pathways and environmental factors control the behavior of NPCs during cortical development. Heparan sulphate proteoglycans (HSPG) are critical environmental regulators that help modulate and integrate environmental cues and downstream intracellular signals. Syndecan-1 (Sdc1), a major transmembrane HSPG, is highly enriched in the early neural germinal zone, but its function in modulating NPC behavior and cortical development has not been explored. In this study we investigate the expression pattern and function of Sdc1 in the developing mouse cerebral cortex. We found that Sdc1 is highly expressed by cortical NPCs. Knockdown of Sdc1 in vivo by in utero electroporation reduces NPC proliferation and causes their premature differentiation, corroborated in isolated cells in vitro. We found that Sdc1 knockdown leads to reduced levels of β-catenin, indicating reduced canonical Wnt signaling. Consistent with this, GSK3β inhibition helps rescue the Sdc1 knockdown phenotype, partially restoring NPC number and proliferation. Moreover, exogenous Wnt protein promotes cortical NPC proliferation, but this is prevented by Sdc1 knockdown. Thus, Sdc1 in the germinal niche is a key HSPG regulating the maintenance and proliferation of NPCs during cortical neurogenesis, in part by modulating the ability of NPCs to respond to Wnt ligands. PMID:22936997

  18. Expression pattern of cadherins in the naked mole rat (Heterocephalus glaber) suggests innate cortical diversification of the cerebrum.

    PubMed

    Matsunaga, Eiji; Nambu, Sanae; Iriki, Atsushi; Okanoya, Kazuo

    2011-06-15

    The cerebral cortex is an indispensable region for higher cognitive function that is remarkably diverse among mammalian species. Although previous research has shown that the cortical area map in the mammalian cerebral cortex is formed by innate and activity-dependent mechanisms, it remains unknown how these mechanisms contribute to the evolution and diversification of the functional cortical areas in various species. The naked mole rat (Heterocephalus glaber) is a subterranean, eusocial rodent. Physiological and anatomical studies have revealed that the visual system is regressed and the somatosensory system is enlarged. To examine whether species differences in cortical area development are caused by intrinsic factors or environmental factors, we performed comparative gene expression analysis of neonatal naked mole rat and mouse brains. The expression domain of cadherin-6, a somatosensory marker, was expanded caudally and shifted dorsally in the cortex, whereas the expression domain of cadherin-8, a visual marker, was reduced caudally in the neonatal naked mole rat cortex. The expression domain of cadherin-8 was also reduced in other visual areas, such as the lateral geniculate nucleus and superior colliculus. Immunohistochemical analysis of thalamocortical fibers further suggested that somatosensory input did not affect cortical gene expression in the neonatal naked mole rat brain. These results suggest that the development of the somatosensory system and the regression of the visual system in the naked mole rat cortex are due to intrinsic genetic mechanisms as well as sensory input-dependent mechanisms. Intrinsic genetic mechanisms thus appear to contribute to species diversity in cortical area formation.

  19. Substantial Reduction of Parenchymal Cerebral Blood Flow in Mice with Bilateral Common Carotid Artery Stenosis

    PubMed Central

    Hattori, Yorito; Enmi, Jun-ichiro; Iguchi, Satoshi; Saito, Satoshi; Yamamoto, Yumi; Nagatsuka, Kazuyuki; Iida, Hidehiro; Ihara, Masafumi

    2016-01-01

    The bilateral common carotid artery stenosis (BCAS) mouse model, which replicates chronic cerebral hypoperfusion and white matter ischemic lesions, is considered to model some aspects of vascular cognitive impairment. Cerebral blood flow (CBF) changes in the brain surface post-BCAS have been demonstrated by laser speckle flowmetry, but CBF levels in the brain parenchyma remain unknown. Adult C57BL/6J male mice were subjected to BCAS using external microcoils. Brain magnetic resonance angiography (MRA) was conducted to visualize the intracranial main arteries while arterial spin labeling (ASL) was used to measure cortical and subcortical parenchymal CBF levels before and after BCAS. Brain MRA showed anterior circulation flow was substantially decreased until 14 days post-BCAS, which gradually but incompletely recovered over the following 14 days, with probable growth of collaterals from the posterior cerebral artery. ASL showed that cortical and subcortical parenchymal CBF remained decreased at approximately 50% of the baseline level during 1 and 14 days post-BCAS, recovering to approximately 70% at day 28. CBF levels in the parenchyma were lower than the cortical superficial region in the BCAS model and remained decreased without recovery during the first 2 weeks post-BCAS. These results suggest that the BCAS model reliably replicates chronic cerebral hypoperfusion. PMID:27535801

  20. Alterations in local cerebral glucose metabolism and endogenous thyrotropin-releasing hormone levels in rolling mouse Nagoya and effect of thyrotropin-releasing hormone tartrate.

    PubMed

    Nakayama, T; Nagai, Y

    1996-11-01

    To identify the brain region(s) responsible for the expression of ataxic gaits in an ataxic mutant mouse model, Rolling mouse Nagoya (RMN), changes in local cerebral glucose metabolism in various brain regions and the effect of thyrotropin-releasing hormone tartrate (TRH-T), together with alterations in endogenous thyrotropin-releasing hormone (TRH) levels in the brains of RMN, were investigated. Ataxic mice [RMN (rol/rol)] showed significant decreases in glucose metabolism in regions of the diencephalon: thalamic dorsomedial nucleus, lateral geniculate body and superior colliculus; brain stem: substantia nigra, raphe nucleus and vestibular nucleus; and cerebellar nucleus as compared with normal controls [RMN (+/+)]. When RMN (rol/rol) was treated with TRH-T (10 mg/kg, equivalent to 7 mg/kg free TRH), glucose metabolism was significantly increased in these regions. These results suggest that these regions may be responsible for ataxia. We also found that TRH levels in the cerebellum and brain stem of RMN (rol/rol) were significantly higher than those of RMN (+/+). These results suggest that ataxic symptoms in RMN (rol/rol) may relate to the abnormal metabolism of TRH and energy metabolism in the cerebellum and/or brain stem and that exogenously given TRH normalizes them.

  1. Anti-CD31 delays platelet adhesion/aggregation at sites of endothelial injury in mouse cerebral arterioles.

    PubMed

    Rosenblum, W I; Murata, S; Nelson, G H; Werner, P K; Ranken, R; Harmon, R C

    1994-07-01

    The arterioles on the surface of the mouse brain (pial arterioles) were observed by in vivo microscopy. A focus of minor endothelial damage was produced in a single pial arteriole in each mouse by briefly exposing the site to a helium neon laser after an intravenous injection of Evans blue. Mice were injected 10 minutes before injury with a monoclonal antibody (MAb) to mouse CD31, also known as platelet endothelial cell adhesion molecule. This treatment doubled (P < .01) the time required for the laser to produce a recognizable platelet aggregate. In additional experiments, an MAb to mouse CD61 and an MAb to mouse intercellular adhesion molecule 1 had no effect. The data support previous observations indicating that platelet adhesion/aggregation in this model is induced by endothelial injury without exposure of basal lamina. The data are consistent with the hypothesis that the endothelial injury exposes or activates a platelet endothelial cell adhesion molecule on the endothelium which is blocked by the MAb directed against CD31. This may be the first demonstration of an effect of an anti-platelet endothelial cell adhesion molecule on platelet endothelial cell adhesion molecule on platelet adhesion/aggregation in vivo. PMID:8030753

  2. Human Auditory and Adjacent Nonauditory Cerebral Cortices Are Hypermetabolic in Tinnitus as Measured by Functional Near-Infrared Spectroscopy (fNIRS)

    PubMed Central

    Issa, Mohamad; Bisconti, Silvia; Kovelman, Ioulia; Kileny, Paul

    2016-01-01

    Tinnitus is the phantom perception of sound in the absence of an acoustic stimulus. To date, the purported neural correlates of tinnitus from animal models have not been adequately characterized with translational technology in the human brain. The aim of the present study was to measure changes in oxy-hemoglobin concentration from regions of interest (ROI; auditory cortex) and non-ROI (adjacent nonauditory cortices) during auditory stimulation and silence in participants with subjective tinnitus appreciated equally in both ears and in nontinnitus controls using functional near-infrared spectroscopy (fNIRS). Control and tinnitus participants with normal/near-normal hearing were tested during a passive auditory task. Hemodynamic activity was monitored over ROI and non-ROI under episodic periods of auditory stimulation with 750 or 8000 Hz tones, broadband noise, and silence. During periods of silence, tinnitus participants maintained increased hemodynamic responses in ROI, while a significant deactivation was seen in controls. Interestingly, non-ROI activity was also increased in the tinnitus group as compared to controls during silence. The present results demonstrate that both auditory and select nonauditory cortices have elevated hemodynamic activity in participants with tinnitus in the absence of an external auditory stimulus, a finding that may reflect basic science neural correlates of tinnitus that ultimately contribute to phantom sound perception. PMID:27042360

  3. Human Auditory and Adjacent Nonauditory Cerebral Cortices Are Hypermetabolic in Tinnitus as Measured by Functional Near-Infrared Spectroscopy (fNIRS).

    PubMed

    Issa, Mohamad; Bisconti, Silvia; Kovelman, Ioulia; Kileny, Paul; Basura, Gregory J

    2016-01-01

    Tinnitus is the phantom perception of sound in the absence of an acoustic stimulus. To date, the purported neural correlates of tinnitus from animal models have not been adequately characterized with translational technology in the human brain. The aim of the present study was to measure changes in oxy-hemoglobin concentration from regions of interest (ROI; auditory cortex) and non-ROI (adjacent nonauditory cortices) during auditory stimulation and silence in participants with subjective tinnitus appreciated equally in both ears and in nontinnitus controls using functional near-infrared spectroscopy (fNIRS). Control and tinnitus participants with normal/near-normal hearing were tested during a passive auditory task. Hemodynamic activity was monitored over ROI and non-ROI under episodic periods of auditory stimulation with 750 or 8000 Hz tones, broadband noise, and silence. During periods of silence, tinnitus participants maintained increased hemodynamic responses in ROI, while a significant deactivation was seen in controls. Interestingly, non-ROI activity was also increased in the tinnitus group as compared to controls during silence. The present results demonstrate that both auditory and select nonauditory cortices have elevated hemodynamic activity in participants with tinnitus in the absence of an external auditory stimulus, a finding that may reflect basic science neural correlates of tinnitus that ultimately contribute to phantom sound perception.

  4. Effect of vitamin E on cerebral cortical oxidative stress and brain-derived neurotrophic factor gene expression induced by hypoxia and exercise in rats.

    PubMed

    Sakr, H F; Abbas, A M; El Samanoudy, A Z

    2015-04-01

    Brain-derived neurotrophic factor (BDNF) is involved in the proliferation of neurons, and its expression increases significantly with exercise. We aimed to investigate the effects of chronic exercise (swimming) and sustained hypoxia on cortical BDNF expression in both the presence and absence of vitamin E. Sixty four male Sprague-Dawley rats were divided into two equal groups; a normoxic group and a hypoxic group. Both groups were equally subdivided into four subgroups: sedentary, sedentary with vitamin E, chronic exercise either with or without vitamin E supplementation. Arterial PO(2), and the levels of cortical malondialdehyde (MDA), antioxidants (reduced glutathione GSH, superoxide dismutase (SOD), catalase (CAT) and vitamin E) and BDNF gene expression were investigated. Hypoxia significantly increased MDA production and BDNF gene expression and decreased the antioxidants compared to control rats. Chronic exercise in hypoxic and normoxic rats increased MDA level and BDNF gene expression and decreased the antioxidants. Providing vitamin E supplementation to the hypoxic and normoxic rats significantly reduced MDA and BDNF gene expression and increased antioxidants. We conclude that sustained hypoxia and chronic exercise increased BDNF gene expression and induced oxidative stress. Moreover, vitamin E attenuated the oxidative stress and decreased BDNF gene expression in sustained hypoxia and chronic exercise which confirms the oxidative stress-induced stimulation of BDNF gene expression.

  5. Partial loss of presenilin impairs age-dependent neuronal survival in the cerebral cortex.

    PubMed

    Watanabe, Hirotaka; Iqbal, Minah; Zheng, Jin; Wines-Samuelson, Mary; Shen, Jie

    2014-11-26

    Mutations in the presenilin (PSEN1 and PSEN2) genes are linked to familial Alzheimer's disease (AD) and cause loss of its essential function. Complete inactivation of presenilins in excitatory neurons of the adult mouse cerebral cortex results in progressive memory impairment and age-dependent neurodegeneration, recapitulating key features of AD. In this study, we examine the effects of varying presenilin dosage on cortical neuron survival by generating presenilin-1 conditional knock-out (PS1 cKO) mice carrying two, one, or zero copies of the PS2 gene. We found that PS1 cKO;PS2(+/-) mice at 16 months exhibit marked neurodegeneration in the cerebral cortex with ∼17% reduction of cortical volume and neuron number, as well as astrogliosis and microgliosis compared with ∼50% reduction of cortical volume and neuron number in PS1 cKO;PS2(-/-) mice. Moreover, there are more apoptotic neurons labeled by activated caspase-3 immunoreactivity and TUNEL assay in PS1 cKO;PS2(+/-) mice at 16 months, whereas apoptotic neurons are increased in the PS1 cKO;PS2(-/-) cerebral cortex at 4 months. The accumulation of the C-terminal fragments of the amyloid precursor protein is inversely correlated with PS dosage. Interestingly, levels of PS2 are higher in the cerebral cortex of PS1 cKO mice, suggesting a compensatory upregulation that may provide protection against neurodegeneration in these mice. Together, our findings show that partial to complete loss of presenilin activity causes progressively more severe neurodegeneration in the mouse cerebral cortex during aging, suggesting that impaired presenilin function by PSEN mutations may lead to neurodegeneration and dementia in AD. PMID:25429133

  6. Principal component and cluster analysis of layer V pyramidal cells in visual and non-visual cortical areas projecting to the primary visual cortex of the mouse.

    PubMed

    Laramée, M E; Rockland, K S; Prince, S; Bronchti, G; Boire, D

    2013-03-01

    The long-distance corticocortical connections between visual and nonvisual sensory areas that arise from pyramidal neurons located within layer V can be considered as a subpopulation of feedback connections. The purpose of the present study is to determine if layer V pyramidal neurons from visual and nonvisual sensory cortical areas that project onto the visual cortex (V1) constitute a homogeneous population of cells. Additionally, we ask whether dendritic arborization relates to the target, the sensory modality, the hierarchical level, or laterality of the source cortical area. Complete 3D reconstructions of dendritic arbors of retrogradely labeled layer V pyramidal neurons were performed for neurons of the primary auditory (A1) and somatosensory (S1) cortices and from the lateral (V2L) and medial (V2M) parts of the secondary visual cortices of both hemispheres. The morphological parameters extracted from these reconstructions were subjected to principal component analysis (PCA) and cluster analysis. The PCA showed that neurons are distributed within a continuous range of morphologies and do not form discrete groups. Nevertheless, the cluster analysis defines neuronal groups that share similar features. Each cortical area includes neurons belonging to several clusters. We suggest that layer V feedback connections within a single cortical area comprise several cell types. PMID:22426333

  7. Oxidized low-density lipoprotein induces apoptotic insults to mouse cerebral endothelial cells via a Bax-mitochondria-caspase protease pathway

    SciTech Connect

    Chen, T.-G.; Chen, T.-L.; Chang, H.-C.; Tai, Y.-T.; Cherng, Y.-G.; Chang, Y.-T.; Chen, R.-M. . E-mail: rmchen@tmu.edu.tw

    2007-02-15

    Cerebral endothelial cells (CECs) are crucial components of the blood-brain barrier. Oxidized low-density lipoprotein (oxLDL) can induce cell injuries. In this study, we attempted to evaluate the effects of oxLDL on mouse CECs and its possible mechanisms. Mouse CECs were isolated from brain tissues and identified by immunocytochemical staining of vimentin and Factor VIII. oxLDL was prepared from LDL oxidation by copper sulfate. Exposure of mouse CECs to oxLDL decreased cell viability in concentration- and time-dependent manners. oxLDL time-dependently caused shrinkage of cell morphologies. Administration of oxLDL to CECs induced DNA fragmentation in concentration- and time-dependent manners. Analysis of the cell cycle revealed that oxLDL concentration- and time-dependently increased the proportion of CECs which underwent apoptosis. Analysis of confocal microscopy and immunoblot revealed that oxLDL significantly increased cellular and mitochondrial Bax levels as well as the translocation of this proapoptotic protein from the cytoplasm to mitochondria. In parallel with the increase in the levels and translocation of Bax, oxLDL time-dependently decreased the mitochondrial membrane potential. Exposure of mouse CECs to oxLDL decreased the amounts of mitochondrial cytochrome c, but enhanced cytosolic cytochrome c levels. The amounts of intracellular reactive oxygen species were significantly augmented after oxLDL administration. Sequentially, oxLDL increased activities of caspase-9, -3, and -6 in time-dependent manners. Pretreatment with Z-VEID-FMK, an inhibitor of caspase-6, significantly decreased caspase-6 activity and the oxLDL-induced DNA fragmentation and cell apoptosis. This study showed that oxLDL induces apoptotic insults to CECs via signal-transducing events, including enhancing Bax translocation, mitochondrial dysfunction, cytochrome c release, increases in intracellular reactive oxygen species, and cascade activation of caspase-9, -3, and -6. Therefore, ox

  8. Oxidized low-density lipoprotein induces apoptotic insults to mouse cerebral endothelial cells via a Bax-mitochondria-caspase protease pathway.

    PubMed

    Chen, Tyng-Guey; Chen, Ta-Liang; Chang, Huai-Chia; Tai, Yu-Ting; Cherng, Yih-Giun; Chang, Ya-Ting; Chen, Ruei-Ming

    2007-02-15

    Cerebral endothelial cells (CECs) are crucial components of the blood-brain barrier. Oxidized low-density lipoprotein (oxLDL) can induce cell injuries. In this study, we attempted to evaluate the effects of oxLDL on mouse CECs and its possible mechanisms. Mouse CECs were isolated from brain tissues and identified by immunocytochemical staining of vimentin and Factor VIII. oxLDL was prepared from LDL oxidation by copper sulfate. Exposure of mouse CECs to oxLDL decreased cell viability in concentration- and time-dependent manners. oxLDL time-dependently caused shrinkage of cell morphologies. Administration of oxLDL to CECs induced DNA fragmentation in concentration- and time-dependent manners. Analysis of the cell cycle revealed that oxLDL concentration- and time-dependently increased the proportion of CECs which underwent apoptosis. Analysis of confocal microscopy and immunoblot revealed that oxLDL significantly increased cellular and mitochondrial Bax levels as well as the translocation of this proapoptotic protein from the cytoplasm to mitochondria. In parallel with the increase in the levels and translocation of Bax, oxLDL time-dependently decreased the mitochondrial membrane potential. Exposure of mouse CECs to oxLDL decreased the amounts of mitochondrial cytochrome c, but enhanced cytosolic cytochrome c levels. The amounts of intracellular reactive oxygen species were significantly augmented after oxLDL administration. Sequentially, oxLDL increased activities of caspase-9, -3, and -6 in time-dependent manners. Pretreatment with Z-VEID-FMK, an inhibitor of caspase-6, significantly decreased caspase-6 activity and the oxLDL-induced DNA fragmentation and cell apoptosis. This study showed that oxLDL induces apoptotic insults to CECs via signal-transducing events, including enhancing Bax translocation, mitochondrial dysfunction, cytochrome c release, increases in intracellular reactive oxygen species, and cascade activation of caspase-9, -3, and -6. Therefore, ox

  9. Morphological and functional aspects of progenitors perturbed in cortical malformations

    PubMed Central

    Bizzotto, Sara; Francis, Fiona

    2015-01-01

    In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area. PMID:25729350

  10. Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions.

    PubMed

    Kasischke, Karl A; Lambert, Elton M; Panepento, Ben; Sun, Anita; Gelbard, Harris A; Burgess, Robert W; Foster, Thomas H; Nedergaard, Maiken

    2011-01-01

    Oxygen transport imposes a possible constraint on the brain's ability to sustain variable metabolic demands, but oxygen diffusion in the cerebral cortex has not yet been observed directly. We show that concurrent two-photon fluorescence imaging of endogenous nicotinamide adenine dinucleotide (NADH) and the cortical microcirculation exposes well-defined boundaries of tissue oxygen diffusion in the mouse cortex. The NADH fluorescence increases rapidly over a narrow, very low pO(2) range with a p(50) of 3.4 ± 0.6 mm Hg, thereby establishing a nearly binary reporter of significant, metabolically limiting hypoxia. The transient cortical tissue boundaries of NADH fluorescence exhibit remarkably delineated geometrical patterns, which define the limits of tissue oxygen diffusion from the cortical microcirculation and bear a striking resemblance to the ideal Krogh tissue cylinder. The visualization of microvessels and their regional contribution to oxygen delivery establishes penetrating arterioles as major oxygen sources in addition to the capillary network and confirms the existence of cortical oxygen fields with steep microregional oxygen gradients. Thus, two-photon NADH imaging can be applied to expose vascular supply regions and to localize functionally relevant microregional cortical hypoxia with micrometer spatial resolution.

  11. SUMO2/3 is associated with ubiquitinated protein aggregates in the mouse neocortex after middle cerebral artery occlusion

    PubMed Central

    Hochrainer, Karin; Jackman, Katherine; Benakis, Corinne; Anrather, Josef; Iadecola, Costantino

    2015-01-01

    Protein modifications cooperatively act to protect the proteome from cellular stress. Focal cerebral ischemia increases protein ubiquitination, resulting in formation of ubiquitin-rich aggregates. A concurrent elevation in small ubiquitin-related modifier (SUMO)-conjugated proteins has also been reported, but a potential connection to ubiquitin remains unexplored. Here we show that SUMO2/3 conjugates are present in postischemic ubiquitin-rich aggregates, physically associated with ubiquitin. The coaggregation of SUMO2/3 and ubiquitin is induced rapidly after ischemia, depends on reperfusion, and is also observed in the absence of ischemic damage. The association between SUMO and ubiquitin suggests overlapping functional roles after ischemia/reperfusion. PMID:25352045

  12. Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model.

    PubMed

    Yoshiyama, Yasumasa; Uryu, Kunihiro; Higuchi, Makoto; Longhi, Luca; Hoover, Rachel; Fujimoto, Scott; McIntosh, Tracy; Lee, Virginia M-Y; Trojanowski, John Q

    2005-10-01

    Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in dementia pugilistica (DP), a syndrome characterized by progressive dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), formed by abnormal tau filaments and senile plaques (SPs) composed of Abeta fibrils. Previous study showed that mild rTBI (mrTBI) accelerated the deposition of Abeta in the brains of transgenic (Tg) mice (Tg2576) that over-express human Abeta precursor proteins with the familial AD Swedish mutations (APP695swe) and model of AD-like amyloidosis. Here, we report studies of the effects of mrTBI on AD-like tau pathologies in Tg mice expressing the shortest human tau isoform (T44) subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP. Twelve-month-old Tg T44 (n = 18) and wild-type (WT; n = 24) mice were subjected to mrTBI (four times a day, 1 day per week, for 4 weeks; n = 24) or sham treatment (n = 18). Histopathological analysis of mice at 9 months after mrTBI revealed that one of the Tg T44 mice showed extensive telencephalic NFT and cerebral atrophy. Although statistical analysis of neurobehavioral tests at 6 months after mrTBI did not show any significant difference in any of groups of mice, the Tg T44 mouse with extensive NFT had an exceptionally low neurobehavioral score. The reasons for the augmentation of tau pathologies in only one T44 tau Tg mouse subjected to mrTBI remain to be elucidated.

  13. Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome

    PubMed Central

    Harrison, Susan J.; Nishinakamura, Ryuichi; Jones, Kevin R.; Monaghan, A. Paula

    2012-01-01

    SUMMARY Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS) is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ∼10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5). These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS. PMID:22228756

  14. Evaluation of cortical plasticity in children with cerebral palsy undergoing constraint-induced movement therapy based on functional near-infrared spectroscopy.

    PubMed

    Cao, Jianwei; Khan, Bilal; Hervey, Nathan; Tian, Fenghua; Delgado, Mauricio R; Clegg, Nancy J; Smith, Linsley; Roberts, Heather; Tulchin-Francis, Kirsten; Shierk, Angela; Shagman, Laura; MacFarlane, Duncan; Liu, Hanli; Alexandrakis, George

    2015-04-01

    Sensorimotor cortex plasticity induced by constraint-induced movement therapy (CIMT) in six children (10.2±2.1 years old) with hemiplegic cerebral palsy was assessed by functional near-infrared spectroscopy (fNIRS). The activation laterality index and time-to-peak/duration during a finger-tapping task and the resting-state functional connectivity were quantified before, immediately after, and 6 months after CIMT. These fNIRS-based metrics were used to help explain changes in clinical scores of manual performance obtained concurrently with imaging time points. Five age-matched healthy children (9.8±1.3 years old) were also imaged to provide comparative activation metrics for normal controls. Interestingly, the activation time-to-peak/duration for all sensorimotor centers displayed significant normalization immediately after CIMT that persisted 6 months later. In contrast to this improved localized activation response, the laterality index and resting-state connectivity metrics that depended on communication between sensorimotor centers improved immediately after CIMT, but relapsed 6 months later. In addition, for the subjects measured in this work, there was either a trade-off between improving unimanual versus bimanual performance when sensorimotor activation patterns normalized after CIMT, or an improvement occurred in both unimanual and bimanual performance but at the cost of very abnormal plastic changes in sensorimotor activity.

  15. Evaluation of cortical plasticity in children with cerebral palsy undergoing constraint-induced movement therapy based on functional near-infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Cao, Jianwei; Khan, Bilal; Hervey, Nathan; Tian, Fenghua; Delgado, Mauricio R.; Clegg, Nancy J.; Smith, Linsley; Roberts, Heather; Tulchin-Francis, Kirsten; Shierk, Angela; Shagman, Laura; MacFarlane, Duncan; Liu, Hanli; Alexandrakis, George

    2015-04-01

    Sensorimotor cortex plasticity induced by constraint-induced movement therapy (CIMT) in six children (10.2±2.1 years old) with hemiplegic cerebral palsy was assessed by functional near-infrared spectroscopy (fNIRS). The activation laterality index and time-to-peak/duration during a finger-tapping task and the resting-state functional connectivity were quantified before, immediately after, and 6 months after CIMT. These fNIRS-based metrics were used to help explain changes in clinical scores of manual performance obtained concurrently with imaging time points. Five age-matched healthy children (9.8±1.3 years old) were also imaged to provide comparative activation metrics for normal controls. Interestingly, the activation time-to-peak/duration for all sensorimotor centers displayed significant normalization immediately after CIMT that persisted 6 months later. In contrast to this improved localized activation response, the laterality index and resting-state connectivity metrics that depended on communication between sensorimotor centers improved immediately after CIMT, but relapsed 6 months later. In addition, for the subjects measured in this work, there was either a trade-off between improving unimanual versus bimanual performance when sensorimotor activation patterns normalized after CIMT, or an improvement occurred in both unimanual and bimanual performance but at the cost of very abnormal plastic changes in sensorimotor activity.

  16. Evaluation of cortical plasticity in children with cerebral palsy undergoing constraint-induced movement therapy based on functional near-infrared spectroscopy

    PubMed Central

    Cao, Jianwei; Khan, Bilal; Hervey, Nathan; Tian, Fenghua; Delgado, Mauricio R.; Clegg, Nancy J.; Smith, Linsley; Roberts, Heather; Tulchin-Francis, Kirsten; Shierk, Angela; Shagman, Laura; MacFarlane, Duncan; Liu, Hanli; Alexandrakis, George

    2015-01-01

    Abstract. Sensorimotor cortex plasticity induced by constraint-induced movement therapy (CIMT) in six children (10.2±2.1 years old) with hemiplegic cerebral palsy was assessed by functional near-infrared spectroscopy (fNIRS). The activation laterality index and time-to-peak/duration during a finger-tapping task and the resting-state functional connectivity were quantified before, immediately after, and 6 months after CIMT. These fNIRS-based metrics were used to help explain changes in clinical scores of manual performance obtained concurrently with imaging time points. Five age-matched healthy children (9.8±1.3 years old) were also imaged to provide comparative activation metrics for normal controls. Interestingly, the activation time-to-peak/duration for all sensorimotor centers displayed significant normalization immediately after CIMT that persisted 6 months later. In contrast to this improved localized activation response, the laterality index and resting-state connectivity metrics that depended on communication between sensorimotor centers improved immediately after CIMT, but relapsed 6 months later. In addition, for the subjects measured in this work, there was either a trade-off between improving unimanual versus bimanual performance when sensorimotor activation patterns normalized after CIMT, or an improvement occurred in both unimanual and bimanual performance but at the cost of very abnormal plastic changes in sensorimotor activity. PMID:25900145

  17. Cerebral blood flow in posterior cortical nodes of the default mode network decreases with task engagement but remains higher than in most brain regions.

    PubMed

    Pfefferbaum, Adolf; Chanraud, Sandra; Pitel, Anne-Lise; Müller-Oehring, Eva; Shankaranarayanan, Ajit; Alsop, David C; Rohlfing, Torsten; Sullivan, Edith V

    2011-01-01

    Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic "default mode network" and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus' heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion.

  18. Neuronal damage and changes in the expression of muscarinic acetylcholine receptor subtypes in the neonatal rat cerebral cortical upon exposure to sparteine, a quinolizidine alkaloid.

    PubMed

    Flores-Soto, M E; Bañuelos-Pineda, J; Orozco-Suárez, S; Schliebs, R; Beas-Zárate, C

    2006-10-01

    Sparteine is a quinolizidine alkaloid (QA) produced by Lupine species that has generated much interest due to its anti-hypertensive, anti-pyretic, and anti-inflammatory properties. In the nervous system, sparteine has been shown to display anti-cholinergic and depressive activity, although how sparteine exerts its toxic effects in the brain remains unclear. We have addressed this issue by administering subcutaneous injections of sparteine (25 mg/kg of body weight) to rats on postnatal days 1 and 3, and then examining the expression of the muscarinic acetylcholine receptor (mAChR) subunits m1-m4 in the brains of the neonatal rats 14-60 days later. Administration of sparteine to neonatal rats caused neuronal damage in the cerebral motor cortex accompanied by transient changes in the expression of m1-m4 mAChR subunits as revealed by both RT-PCR and Western blotting. This effect could be prevented by pre-treatment with atropine (10 mg/kg) 1 h prior to the injection of sparteine, suggesting that the cytotoxic activity of sparteine is mediated through mAChRs. PMID:16843632

  19. Genetic deletion of neuronal pentraxin 1 expression prevents brain injury in a neonatal mouse model of cerebral hypoxia-ischemia.

    PubMed

    Thatipamula, Shabarish; Al Rahim, Md; Zhang, Jiangyang; Hossain, Mir Ahamed

    2015-03-01

    Neonatal hypoxic-ischemic (HI) brain injury is a leading cause of mortality and morbidity in infants and children for which there is no promising therapy at present. Previously, we reported induction of neuronal pentraxin 1 (NP1), a novel neuronal protein of the long-pentraxin family, following HI injury in neonatal brain. Here, we report that genetic deletion of NP1 expression prevents HI injury in neonatal brain. Elevated expression of NP1 was observed in neurons, not in astrocytes, of the ipsilateral cortical layers (I-IV) and in the hippocampal CA1 and CA3 areas of WT brains following hypoxia-ischemia; brain areas that developed infarcts (at 24-48 h), showed significantly increased numbers of TUNEL-(+) cells and tissue loss (at 7 days). In contrast, NP1-KO mice showed no evidence of brain infarction and tissue loss after HI. The immunofluorescence staining of brain sections with mitochondrial protein COX IV and subcellular fractionation analysis showed increased accumulation of NP1 in mitochondria, pro-death protein Bax activation and NP1 co-localization with activated caspase-3 in WT, but not in the NP1-KO brains; corroborating NP1 interactions with the mitochondria-derived pro-death pathways. Disruption of NP1 translocation to mitochondria by NP1-siRNA in primary cortical cultures significantly reduced ischemic neuronal death. NP1 was immunoprecipitated with activated Bax [6A7] proteins; HI caused increased interactions of NP1 with Bax, thereby, facilitating Bax translocation to mitochondrial and neuronal death. To further delineate the specificity of NPs, we found that NP1 but not the NP2 induction is specifically involved in brain injury mechanisms and that knockdown of NP1 only results in neuroprotection. Furthermore, live in vivo T2-weighted magnetic resonance imaging (MRI) including fractional anisotropy (FA) mapping showed no sign of delayed brain injury or tissue loss in the NP1-KO mice as compared to the WT at different post-HI periods (4-24 weeks

  20. Cerebral Palsy

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Cerebral Palsy KidsHealth > For Teens > Cerebral Palsy Print A A ... do just what everyone else does. What Is Cerebral Palsy? Cerebral palsy (CP) is a disorder of the ...

  1. DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome.

    PubMed

    Najas, Sònia; Arranz, Juan; Lochhead, Pamela A; Ashford, Anne L; Oxley, David; Delabar, Jean M; Cook, Simon J; Barallobre, María José; Arbonés, Maria L

    2015-01-01

    Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome. PMID:26137553

  2. Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia

    PubMed Central

    McKittrick, Craig M; Lawrence, Catherine E; Carswell, Hilary V O

    2015-01-01

    Blood brain barrier (BBB) breakdown and neuroinflammation are key events in ischemic stroke morbidity and mortality. The present study investigated the effects of mast cell deficiency and stabilization on BBB breakdown and neutrophil infiltration in mice after transient middle cerebral artery occlusion (tMCAo). Adult male C57BL6/J wild type (WT) and mast cell-deficient (C57BL6/J KitWsh/Wsh (Wsh)) mice underwent tMCAo and BBB breakdown, brain edema and neutrophil infiltration were examined after 4 hours of reperfusion. Blood brain barrier breakdown, brain edema, and neutrophil infiltration were significantly reduced in Wsh versus WT mice (P<0.05). These results were reproduced pharmacologically using mast cell stabilizer, cromoglycate. Wild-type mice administered cromoglycate intraventricularly exhibited reduced BBB breakdown, brain edema, and neutrophil infiltration versus vehicle (P<0.05). There was no effect of cromoglycate versus vehicle in Wsh mice, validating specificity of cromoglycate on brain mast cells. Proteomic analysis in Wsh versus WT indicated that effects may be via expression of endoglin, endothelin-1, and matrix metalloproteinase-9. Using an in vivo model of mast cell deficiency, this is the first study showing that mast cells promote BBB breakdown in focal ischemia in mice, and opens up future opportunities for using mice to identify specific mechanisms of mast cell-related BBB injury. PMID:25564235

  3. Protective Effects of Forskolin on Behavioral Deficits and Neuropathological Changes in a Mouse Model of Cerebral Amyloidosis.

    PubMed

    Owona, Brice Ayissi; Zug, Caroline; Schluesener, Hermann J; Zhang, Zhi-Yuan

    2016-07-01

    The production of amyloid-β peptides in the brains of patients with Alzheimer disease (AD) may contribute to memory loss and impairments in social behavior. Here, an efficient adenylate cyclase activator, forskolin, was orally administered by gavage (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, which serve as an animal model of cerebral amyloidosis. Analyses of nest construction, sociability, and immunohistochemical features were used to determine the effects of forskolin treatment. After a relatively short term of treatment (10 days), forskolin-treated transgenic mice showed restored nest construction ability (p < 0.05) and their sociability (p < 0.01). There was a reduction of Aβ plaque deposition in the cortex and in the hippocampus. Furthermore, expression of transforming growth factor β, glial fibrillary acidic protein, and Iba-1 in the cortex was reduced in the forskolin-treated group, suggesting regulation of the inflammatory response mediated by activated microglia and astrocytes in the brains of the APP/PS1 mice (p < 0.01). Taken together, these findings suggest that forskolin shows neuroprotective effects in APP/PS1 Tg mice and may be a promising drug in the treatment of patients with AD. PMID:27251043

  4. Communication and wiring in the cortical connectome

    PubMed Central

    Budd, Julian M. L.; Kisvárday, Zoltán F.

    2012-01-01

    In cerebral cortex, the huge mass of axonal wiring that carries information between near and distant neurons is thought to provide the neural substrate for cognitive and perceptual function. The goal of mapping the connectivity of cortical axons at different spatial scales, the cortical connectome, is to trace the paths of information flow in cerebral cortex. To appreciate the relationship between the connectome and cortical function, we need to discover the nature and purpose of the wiring principles underlying cortical connectivity. A popular explanation has been that axonal length is strictly minimized both within and between cortical regions. In contrast, we have hypothesized the existence of a multi-scale principle of cortical wiring where to optimize communication there is a trade-off between spatial (construction) and temporal (routing) costs. Here, using recent evidence concerning cortical spatial networks we critically evaluate this hypothesis at neuron, local circuit, and pathway scales. We report three main conclusions. First, the axonal and dendritic arbor morphology of single neocortical neurons may be governed by a similar wiring principle, one that balances the conservation of cellular material and conduction delay. Second, the same principle may be observed for fiber tracts connecting cortical regions. Third, the absence of sufficient local circuit data currently prohibits any meaningful assessment of the hypothesis at this scale of cortical organization. To avoid neglecting neuron and microcircuit levels of cortical organization, the connectome framework should incorporate more morphological description. In addition, structural analyses of temporal cost for cortical circuits should take account of both axonal conduction and neuronal integration delays, which appear mostly of the same order of magnitude. We conclude the hypothesized trade-off between spatial and temporal costs may potentially offer a powerful explanation for cortical wiring patterns

  5. Principles of Network Architecture Emerging from Comparisons of the Cerebral Cortex in Large and Small Brains.

    PubMed

    Finlay, Barbara L

    2016-09-01

    The cerebral cortex retains its fundamental organization, layering, and input-output relations as it scales in volume over many orders of magnitude in mammals. How is its network architecture affected by size scaling? By comparing network organization of the mouse and rhesus macaque cortical connectome derived from complete neuroanatomical tracing studies, a recent study in PLOS Biology shows that an exponential distance rule emerges that reveals the falloff in connection probability with distance in the two brains that in turn determines common organizational features. PMID:27631433

  6. Principles of Network Architecture Emerging from Comparisons of the Cerebral Cortex in Large and Small Brains

    PubMed Central

    Finlay, Barbara L.

    2016-01-01

    The cerebral cortex retains its fundamental organization, layering, and input–output relations as it scales in volume over many orders of magnitude in mammals. How is its network architecture affected by size scaling? By comparing network organization of the mouse and rhesus macaque cortical connectome derived from complete neuroanatomical tracing studies, a recent study in PLOS Biology shows that an exponential distance rule emerges that reveals the falloff in connection probability with distance in the two brains that in turn determines common organizational features. PMID:27631433

  7. Unraveling the Specific Ischemic Core and Penumbra Transcriptome in the Permanent Middle Cerebral Artery Occlusion Mouse Model Brain Treated with the Neuropeptide PACAP38

    PubMed Central

    Hori, Motohide; Nakamachi, Tomoya; Shibato, Junko; Rakwal, Randeep; Shioda, Seiji; Numazawa, Satoshi

    2015-01-01

    Our group has been systematically investigating the effects of the neuropeptide pituitary adenylate-cyclase activating polypeptide (PACAP) on the ischemic brain. To do so, we have established and utilized the permanent middle cerebral artery occlusion (PMCAO) mouse model, in which PACAP38 (1 pmol) injection is given intracerebroventrically and compared to a control saline (0.9% sodium chloride, NaCl) injection, to unravel genome-wide gene expression changes using a high-throughput DNA microarray analysis approach. In our previous studies, we have accumulated a large volume of data (gene inventory) from the whole brain (ipsilateral and contralateral hemispheres) after both PMCAO and post-PACAP38 injection. In our latest research, we have targeted specifically infarct or ischemic core (hereafter abbreviated IC) and penumbra (hereafter abbreviated P) post-PACAP38 injections in order to re-examine the transcriptome at 6 and 24 h post injection. The current study aims to delineate the specificity of expression and localization of differentially expressed molecular factors influenced by PACAP38 in the IC and P regions. Utilizing the mouse 4 × 44 K whole genome DNA chip we show numerous changes (≧/≦ 1.5/0.75-fold) at both 6 h (654 and 456, and 522 and 449 up- and down-regulated genes for IC and P, respectively) and 24 h (2568 and 2684, and 1947 and 1592 up- and down-regulated genes for IC and P, respectively) after PACAP38 treatment. Among the gene inventories obtained here, two genes, brain-derived neurotrophic factor (Bdnf) and transthyretin (Ttr) were found to be induced by PACAP38 treatment, which we had not been able to identify previously using the whole hemisphere transcriptome analysis. Using bioinformatics analysis by pathway- or specific-disease-state focused gene classifications and Ingenuity Pathway Analysis (IPA) the differentially expressed genes are functionally classified and discussed. Among these, we specifically discuss some novel and previously

  8. High-spatial-resolution mapping of the oxygen concentration in cortical tissue (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Jaswal, Rajeshwer S.; Yaseen, Mohammad A.; Fu, Buyin; Boas, David A.; Sakadžic, Sava

    2016-03-01

    Due to a lack of imaging tools for high-resolution imaging of cortical tissue oxygenation, the detailed maps of the oxygen partial pressure (PO2) around arterioles, venules, and capillaries remain largely unknown. Therefore, we have limited knowledge about the mechanisms that secure sufficient oxygen delivery in microvascular domains during brain activation, and provide some metabolic reserve capacity in diseases that affect either microvascular networks or the regulation of cerebral blood flow (CBF). To address this challenge, we applied a Two-Photon PO2 Microscopy to map PO2 at different depths in mice cortices. Measurements were performed through the cranial window in the anesthetized healthy mice as well as in the mouse models of microvascular dysfunctions. In addition, microvascular morphology was recorded by the two-photon microscopy at the end of each experiment and subsequently segmented. Co-registration of the PO2 measurements and exact microvascular morphology enabled quantification of the tissue PO2 dependence on distance from the arterioles, capillaries, and venules at various depths. Our measurements reveal significant spatial heterogeneity of the cortical tissue PO2 distribution that is dominated by the high oxygenation in periarteriolar spaces. In cases of impaired oxygen delivery due to microvascular dysfunction, significant reduction in tissue oxygenation away from the arterioles was observed. These tissue domains may be the initial sites of cortical injury that can further exacerbate the progression of the disease.

  9. Sleep loss reduces the DNA-binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex.

    PubMed

    Mongrain, Valérie; La Spada, Francesco; Curie, Thomas; Franken, Paul

    2011-01-01

    We have previously demonstrated that clock genes contribute to the homeostatic aspect of sleep regulation. Indeed, mutations in some clock genes modify the markers of sleep homeostasis and an increase in homeostatic sleep drive alters clock gene expression in the forebrain. Here, we investigate a possible mechanism by which sleep deprivation (SD) could alter clock gene expression by quantifying DNA-binding of the core-clock transcription factors CLOCK, NPAS2, and BMAL1 to the cis-regulatory sequences of target clock genes in mice. Using chromatin immunoprecipitation (ChIP), we first showed that, as reported for the liver, DNA-binding of CLOCK and BMAL1 to target clock genes changes in function of time-of-day in the cerebral cortex. Tissue extracts were collected at ZT0 (light onset), -6, -12, and -18, and DNA enrichment of E-box or E'-box containing sequences was measured by qPCR. CLOCK and BMAL1 binding to Cry1, Dbp, Per1, and Per2 depended on time-of-day, with maximum values reached at around ZT6. We then observed that SD, performed between ZT0 and -6, significantly decreased DNA-binding of CLOCK and BMAL1 to Dbp, consistent with the observed decrease in Dbp mRNA levels after SD. The DNA-binding of NPAS2 and BMAL1 to Per2 was also decreased by SD, although SD is known to increase Per2 expression in the cortex. DNA-binding to Per1 and Cry1 was not affected by SD. Our results show that the sleep-wake history can affect the clock molecular machinery directly at the level of chromatin binding thereby altering the cortical expression of Dbp and Per2 and likely other targets. Although the precise dynamics of the relationship between DNA-binding and mRNA expression, especially for Per2, remains elusive, the results also suggest that part of the reported circadian changes in DNA-binding of core clock components in tissues peripheral to the suprachiasmatic nuclei could, in fact, be sleep-wake driven.

  10. Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex

    PubMed Central

    Curie, Thomas; Franken, Paul

    2011-01-01

    We have previously demonstrated that clock genes contribute to the homeostatic aspect of sleep regulation. Indeed, mutations in some clock genes modify the markers of sleep homeostasis and an increase in homeostatic sleep drive alters clock gene expression in the forebrain. Here, we investigate a possible mechanism by which sleep deprivation (SD) could alter clock gene expression by quantifying DNA-binding of the core-clock transcription factors CLOCK, NPAS2, and BMAL1 to the cis-regulatory sequences of target clock genes in mice. Using chromatin immunoprecipitation (ChIP), we first showed that, as reported for the liver, DNA-binding of CLOCK and BMAL1 to target clock genes changes in function of time-of-day in the cerebral cortex. Tissue extracts were collected at ZT0 (light onset), −6, −12, and −18, and DNA enrichment of E-box or E'-box containing sequences was measured by qPCR. CLOCK and BMAL1 binding to Cry1, Dbp, Per1, and Per2 depended on time-of-day, with maximum values reached at around ZT6. We then observed that SD, performed between ZT0 and −6, significantly decreased DNA-binding of CLOCK and BMAL1 to Dbp, consistent with the observed decrease in Dbp mRNA levels after SD. The DNA-binding of NPAS2 and BMAL1 to Per2 was also decreased by SD, although SD is known to increase Per2 expression in the cortex. DNA-binding to Per1 and Cry1 was not affected by SD. Our results show that the sleep-wake history can affect the clock molecular machinery directly at the level of chromatin binding thereby altering the cortical expression of Dbp and Per2 and likely other targets. Although the precise dynamics of the relationship between DNA-binding and mRNA expression, especially for Per2, remains elusive, the results also suggest that part of the reported circadian changes in DNA-binding of core clock components in tissues peripheral to the suprachiasmatic nuclei could, in fact, be sleep-wake driven. PMID:22039518

  11. Postnatal day 7 ethanol treatment causes persistent reductions in adult mouse brain volume and cortical neurons with sex specific effects on neurogenesis.

    PubMed

    Coleman, Leon G; Oguz, Ipek; Lee, Joohwi; Styner, Martin; Crews, Fulton T

    2012-09-01

    Ethanol treatment on postnatal day seven (P7) causes robust brain cell death and is a model of late gestational alcohol exposure (Ikonomidou et al., 2000). To investigate the long-term effects of P7 ethanol treatment on adult brain, mice received either two doses of saline or ethanol on P7 (2.5 g/kg, s.c., 2 h apart) and were assessed as adults (P82) for brain volume (using postmortem MRI) and cellular architecture (using immunohistochemistry). Adult mice that received P7 ethanol had reduced MRI total brain volume (4%) with multiple brain regions being reduced in both males and females. Immunohistochemistry indicated reduced frontal cortical parvalbumin immunoreactive (PV + IR) interneurons (18-33%) and reduced Cux1+IR layer II pyramidal neurons (15%) in both sexes. Interestingly, markers of adult hippocampal neurogenesis differed between sexes, with only ethanol treated males showing increased doublecortin and Ki67 expression (52 and 57% respectively) in the dentate gyrus, consistent with increased neurogenesis compared to controls. These findings suggest that P7 ethanol treatment causes persistent reductions in adult brain volume and frontal cortical neurons in both males and females. Increased adult neurogenesis in males, but not females, is consistent with differential adaptive responses to P7 ethanol toxicity between the sexes. One day of ethanol exposure, e.g. P7, causes persistent adult brain dysmorphology.

  12. Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy

    PubMed Central

    De Stasi, Angela Michela; Farisello, Pasqualina; Marcon, Iacopo; Cavallari, Stefano; Forli, Angelo; Vecchia, Dania; Losi, Gabriele; Mantegazza, Massimo; Panzeri, Stefano; Carmignoto, Giorgio; Bacci, Alberto; Fellin, Tommaso

    2016-01-01

    Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a−/+ mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a−/+ mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a−/+ during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a−/+ mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a−/+ compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a−/+ mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI. PMID:26819275

  13. Cerebral White Matter

    PubMed Central

    Schmahmann, Jeremy D.; Smith, Eric E.; Eichler, Florian S.; Filley, Christopher M.

    2013-01-01

    Lesions of the cerebral white matter (WM) result in focal neurobehavioral syndromes, neuropsychiatric phenomena, and dementia. The cerebral WM contains fiber pathways that convey axons linking cerebral cortical areas with each other and with subcortical structures, facilitating the distributed neural circuits that subserve sensorimotor function, intellect, and emotion. Recent neuroanatomical investigations reveal that these neural circuits are topographically linked by five groupings of fiber tracts emanating from every neocortical area: (1) cortico-cortical association fibers; (2) corticostriatal fibers; (3) commissural fibers; and cortico-subcortical pathways to (4) thalamus and (5) pontocerebellar system, brain stem, and/or spinal cord. Lesions of association fibers prevent communication between cortical areas engaged in different domains of behavior. Lesions of subcortical structures or projection/striatal fibers disrupt the contribution of subcortical nodes to behavior. Disconnection syndromes thus result from lesions of the cerebral cortex, subcortical structures, and WM tracts that link the nodes that make up the distributed circuits. The nature and the severity of the clinical manifestations of WM lesions are determined, in large part, by the location of the pathology: discrete neurological and neuropsychiatric symptoms result from focal WM lesions, whereas cognitive impairment across multiple domains—WM dementia—occurs in the setting of diffuse WM disease. We present a detailed review of the conditions affecting WM that produce these neurobehavioral syndromes, and consider the pathophysiology, clinical effects, and broad significance of the effects of aging and vascular compromise on cerebral WM, in an attempt to help further the understanding, diagnosis, and treatment of these disorders. PMID:18990132

  14. Cerebral Hypoxia

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Hypoxia Information Page Synonym(s): Hypoxia, Anoxia Table of Contents ( ... Trials Organizations Publicaciones en Español What is Cerebral Hypoxia? Cerebral hypoxia refers to a condition in which ...

  15. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis.

    PubMed

    Zhou, Jun-Hao; Zhang, Tong-Tong; Song, Dan-Dan; Xia, Yun-Fei; Qin, Zheng-Hong; Sheng, Rui

    2016-01-01

    Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis. PMID:27256465

  16. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis

    PubMed Central

    Zhou, Jun-Hao; Zhang, Tong-Tong; Song, Dan-Dan; Xia, Yun-Fei; Qin, Zheng-Hong; Sheng, Rui

    2016-01-01

    Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis. PMID:27256465

  17. Corticofugal GABAergic projection neurons in the mouse frontal cortex

    PubMed Central

    Tomioka, Ryohei; Sakimura, Kenji; Yanagawa, Yuchio

    2015-01-01

    Cortical projection neurons are classified by hodology in corticocortical, commissural and corticofugal subtypes. Although cortical projection neurons had been regarded as only glutamatergic neurons, recently corticocortical GABAergic projection neurons has been also reported in several species. Here, we demonstrate corticofugal GABAergic projection neurons in the mouse frontal cortex. We employed viral-vector-mediated anterograde tracing, classical retrograde tracing, and immunohistochemistry to characterize neocortical GABAergic projection neurons. Injections of the Cre-dependent adeno-associated virus into glutamate decarboxylase 67 (GAD67)-Cre knock-in mice revealed neocortical GABAergic projections widely to the forebrain, including the cerebral cortices, caudate putamen (CPu), ventral pallidum (VP), lateral globus pallidus (LGP), nucleus accumbens, and olfactory tubercle (Tu). Minor GABAergic projections were also found in the mediodorsal thalamic nucleus, diagonal band of Broca, medial globus pallidus, substantial nigra, and dorsal raphe nucleus. Retrograde tracing studies also demonstrated corticofugal GABAergic projection neurons in the mouse frontal cortex. Further immunohistochemical screening with neurochemical markers revealed the majority of corticostriatal GABAergic projection neurons were positive for somatostatin (SS)-immunoreactivity. In contrast, corticothalamic GABAergic projection neurons were not identified by representative neurochemical markers for GABAergic neurons. These findings suggest that corticofugal GABAergic projection neurons are heterogeneous in terms of their neurochemical properties and target nuclei, and provide axonal innervations mainly to the nuclei in the basal ganglia. PMID:26578895

  18. Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections

    PubMed Central

    Nguyen, Hoang Nam; Huppé-Gourgues, Frédéric; Vaucher, Elvire

    2015-01-01

    The medial prefrontal cortex (mPFC) exerts top-down control of primary visual cortex (V1) activity. As there is no direct neuronal projection from mPFC to V1, this functional connection may use an indirect route, i.e., via basalo-cortical cholinergic projections. The cholinergic projections to V1 originate from neurons in the horizontal limb of the diagonal band of Broca (HDB), which receive neuronal projections from the ventral part of the mPFC, composed of prelimbic (PrL) and infralimbic cortices (IL). Therefore, the objective of this study was to determine whether electrical stimulation of mice mPFC subregions activate (1) V1 neurons; and (2) HDB cholinergic neurons, suggesting that the HDB serves as a relay point in the mPFC-V1 interaction. Neuronal activation was quantified using c-Fos immunocytochemistry or thallium autometallography for each V1 layer using automated particle analysis tools and optical density measurement. Stimulation of IL and PrL induced significantly higher c-Fos expression or thallium labeling in layers II/III and V of V1 in the stimulated hemisphere only. A HDB cholinergic neuron-specific lesion by saporin administration reduced IL-induced c-Fos expression in layers II/III of V1 but not in layer V. However, there was no c-Fos expression or thallium labeling in the HDB neurons, suggesting that this area was not activated by IL stimulation. Stimulation of another mPFC subarea, the anterior cingulate cortex (AC), which is involved in attention and receives input from V1, activated neither V1 nor HDB. The present results indicate that IL and PrL, but not AC, stimulation activates V1 with the minor involvement of the HDB cholinergic projections. These results suggest a functional link between the ventral mPFC and V1, but this function is only marginally supported by HDB cholinergic neurons and may involve other brain regions. PMID:25709570

  19. Correlation of CT cerebral vascular territories with function. 3. Middle cerebral artery

    SciTech Connect

    Berman, S.A.; Hayman, L.A.; Hinck, V.C.

    1984-05-01

    Schematic displays are presented of the cerebral territories supplied by branches of the middle cerebral artery as they would appear on axial and coronal computed tomographic (CT) scan sections. Companion diagrams of regional cortical function and a discussion of the fiber tracts are provided to simplify correlation of clinical deficits with coronal and axial CT abnormalities.

  20. Cortical F-actin, the exocytic mode, and neuropeptide release in mouse chromaffin cells is regulated by myristoylated alanine-rich C-kinase substrate and myosin II.

    PubMed

    Doreian, Bryan W; Fulop, Tiberiu G; Meklemburg, Robert L; Smith, Corey B

    2009-07-01

    Adrenal medullary chromaffin cells are innervated by the sympathetic splanchnic nerve and translate graded sympathetic firing into a differential hormonal exocytosis. Basal sympathetic firing elicits a transient kiss-and-run mode of exocytosis and modest catecholamine release, whereas elevated firing under the sympathetic stress response results in full granule collapse to release catecholamine and peptide transmitters into the circulation. Previous studies have shown that rearrangement of the cell actin cortex regulates the mode of exocytosis. An intact cortex favors kiss-and-run exocytosis, whereas disrupting the cortex favors the full granule collapse mode. Here, we investigate the specific roles of two actin-associated proteins, myosin II and myristoylated alanine-rich C-kinase substrate (MARCKS) in this process. Our data demonstrate that MARCKS phosphorylation under elevated cell firing is required for cortical actin disruption but is not sufficient to elicit peptide transmitter exocytosis. Our data also demonstrate that myosin II is phospho-activated under high stimulation conditions. Inhibiting myosin II activity prevented disruption of the actin cortex, full granule collapse, and peptide transmitter release. These results suggest that phosphorylation of both MARCKS and myosin II lead to disruption of the actin cortex. However, myosin II, but not MARCKS, is required for the activity-dependent exocytosis of the peptide transmitters.

  1. Down-regulation of ASICs current and the calcium transients by disrupting PICK1 protects primary cultured mouse cortical neurons from OGD-Rep insults.

    PubMed

    Cheng, Jin; Chen, Yu; Xing, Hui; Jiang, Hua; Ye, Xihong

    2015-01-01

    Acid sensing ion channels (ASICs), activated by lowering extracellular pH, play an important role in normal synaptic transmission in brain and in the pathology of brain ischemia. ASICs activation involving in glutamate receptor-independent ischemic brain injury has been generally accepted, and PICK1 is recently shown to be one of partner proteins interacting with ASICs through its PDZ domain. Here we showed that ASICs and PICK1 played key roles in OGD-Rep process. In wild-type cultured cortical neurons, not only the amplitude of ASICs current and the calcium transients induced by acidosis were both increased after OGD-Rep, but also the total protein levels of ASIC1 and ASIC2a were up-regulated progressively after ischemia insults, indicating that ASICs play a vital role in neuronal ischemia. However, these activities were reversed with PICK1-knockout after OGD-Rep, accompanied with the dramatically down-regulating the protein abundances of ASIC1 and ASIC2a, which suggested the neuroprotection activity in brain ischemia by PICK1-knockout. These results indicate that knocking-out PICK1 gene casts the neuroprotection effect by reducing ASICs current and the calcium transients in OGD-Rep neuronal cells, which will offer a promising strategy in the therapy of brain ischemia.

  2. Multiple quantitative trait loci for cortical and trabecular bone regulation map to mid-distal mouse chromosome 4 that shares linkage homology to human chromosome 1p36.

    PubMed

    Beamer, Wesley G; Shultz, Kathryn L; Coombs, Harold F; Horton, Lindsay G; Donahue, Leah Rae; Rosen, Clifford J

    2012-01-01

    The mid-distal region of mouse chromosome 4 (Chr 4) is homologous with human Chr 1p36. Previously, we reported that mouse Chr 4 carries a quantitative trait locus (QTL) with strong regulatory effect on volumetric bone mineral density (vBMD). The intent of this study is to utilize nested congenic strains to decompose the genetic complexity of this gene-rich region. Adult females and males from 18 nested congenic strains carrying discrete C3H sequences were phenotyped for femoral mineral and volume by pQCT and for trabecular bone volume (BV), tissue volume (TV), trabecular number (Trab.no), and trabecular thickness (Trab.thk) by MicroCT 40. Our data show that the mouse Chr 4 region consists of at least 10 regulatory QTL regions that affected either or both pQCT and MicroCT 40 phenotypes. The pQCT phenotypes were typically similar between sexes, whereas the MicroCT 40 phenotypes were divergent. Individual congenic strains contained one to seven QTL regions. These regions conferred large positive or negative effects in some congenic strains, depending on the particular bone phenotype. The QTL regions II to X are syntenic with human 1p36, containing from 1 to 102 known genes. We identified 13 candidate genes that can be linked to bone within these regions. Six of these genes were linked to osteoblasts, three linked to osteoclasts, and two linked to skeletal development. Three of these genes have been identified in Genome Wide Association Studies (GWAS) linked to 1p36. In region III, there is only one gene, Lck, which conferred negative pQCT and MicroCT 40 phenotypes in both sexes. This gene is important to development and functioning of T cells, has been associated with osteoclast activity, and represents a novel bone regulatory gene that merits further experimental evaluation. In summary, congenic strains are powerful tools for identifying regulatory regions that influence bone biology and offer models for testing hypotheses about gene-gene and gene

  3. Multiple quantitative trait loci for cortical and trabecular bone regulation map to mid-distal mouse chromosome 4 that shares linkage homology to human chromosome 1p36.

    PubMed

    Beamer, Wesley G; Shultz, Kathryn L; Coombs, Harold F; Horton, Lindsay G; Donahue, Leah Rae; Rosen, Clifford J

    2012-01-01

    The mid-distal region of mouse chromosome 4 (Chr 4) is homologous with human Chr 1p36. Previously, we reported that mouse Chr 4 carries a quantitative trait locus (QTL) with strong regulatory effect on volumetric bone mineral density (vBMD). The intent of this study is to utilize nested congenic strains to decompose the genetic complexity of this gene-rich region. Adult females and males from 18 nested congenic strains carrying discrete C3H sequences were phenotyped for femoral mineral and volume by pQCT and for trabecular bone volume (BV), tissue volume (TV), trabecular number (Trab.no), and trabecular thickness (Trab.thk) by MicroCT 40. Our data show that the mouse Chr 4 region consists of at least 10 regulatory QTL regions that affected either or both pQCT and MicroCT 40 phenotypes. The pQCT phenotypes were typically similar between sexes, whereas the MicroCT 40 phenotypes were divergent. Individual congenic strains contained one to seven QTL regions. These regions conferred large positive or negative effects in some congenic strains, depending on the particular bone phenotype. The QTL regions II to X are syntenic with human 1p36, containing from 1 to 102 known genes. We identified 13 candidate genes that can be linked to bone within these regions. Six of these genes were linked to osteoblasts, three linked to osteoclasts, and two linked to skeletal development. Three of these genes have been identified in Genome Wide Association Studies (GWAS) linked to 1p36. In region III, there is only one gene, Lck, which conferred negative pQCT and MicroCT 40 phenotypes in both sexes. This gene is important to development and functioning of T cells, has been associated with osteoclast activity, and represents a novel bone regulatory gene that merits further experimental evaluation. In summary, congenic strains are powerful tools for identifying regulatory regions that influence bone biology and offer models for testing hypotheses about gene-gene and gene

  4. Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring.

    PubMed

    Wang, Yanyan; Surzenko, Natalia; Friday, Walter B; Zeisel, Steven H

    2016-04-01

    Maternal diets low in choline, an essential nutrient, increase the risk of neural tube defects and lead to low performance on cognitive tests in children. However, the consequences of maternal dietary choline deficiency for the development and structural organization of the cerebral cortex remain unknown. In this study, we fed mouse dams either control (CT) or low-choline (LC) diets and investigated the effects of choline on cortical development in the offspring. As a result of a low choline supply between embryonic day (E)11 and E17 of gestation, the number of 2 types of cortical neural progenitor cells (NPCs)-radial glial cells and intermediate progenitor cells-was reduced in fetal brains (P< 0.01). Furthermore, the number of upper layer cortical neurons was decreased in the offspring of dams fed an LC diet at both E17 (P< 0.001) and 4 mo of age (P< 0.001). These effects of LC maternal diet were mediated by a decrease in epidermal growth factor receptor (EGFR) signaling in NPCs related to the disruption of EGFR posttranscriptional regulation. Our findings describe a novel mechanism whereby low maternal dietary intake of choline alters brain development.-Wang, Y., Surzenko, N., Friday, W. B., Zeisel, S. H. Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring. PMID:26700730

  5. K(v) 7 (KCNQ) channel openers normalize central 2-deoxyglucose uptake in a mouse model of mania and increase prefrontal cortical and hippocampal serine-9 phosphorylation levels of GSK3β.

    PubMed

    Kristensen, Line V; Sandager-Nielsen, Karin; Hansen, Henrik H

    2012-05-01

    Several metabolic neuroimaging studies have indicated that bipolar patients with mania exhibit alterations in metabolic activity, suggesting that perturbations in corticolimbic function contribute to the functional deficits associated with the disease. Because pharmacological stimulation of K(v)7 channel function has shown anti-manic like efficacy in the D-amphetamine and chlordiazepoxide (AMPH+CDP) induced hyperactivity mouse model of mania, we addressed whether this effect of K(v)7 channels could be associated with changes in cerebral [¹⁴C]2-deoxyglucose (2-DG) uptake, a surrogate marker of brain metabolic activity. Acute administration of the Kv7 channel modulators, retigabine (pan K(v)7.2-K(v)7.5 channel opener) and ICA-27243 (K(v)7.2/K(v)7.3 channel-preferring opener) reduced 2-DG uptake in several mouse forebrain structures with a brain regional signature similar to the mood stabilizers, lithium and valproate. Combined administration of AMPH+CDP enhanced 2-DG uptake in the striatum, cortex and thalamus, and both retigabine and ICA-27243 fully prevented this stimulatory effect of AMPH+CDP. In addition, both K(v)7 channel openers dose-dependently increased phospho-serine-9 levels of GSK3β in the prefrontal cortex and hippocampus, a common molecular mechanism shared by anti-manic drugs. In combination, these data emphasize the potential of K(v)7 channel openers in the treatment of bipolar disorder, and suggest that heteromeric K(v)7.2/K(v)7.3 channels may present a novel anti-manic therapeutic target. PMID:22356228

  6. Dynamic integration of subplate neurons into the cortical barrel field circuitry during postnatal development in the Golli-tau-eGFP (GTE) mouse

    PubMed Central

    Piñon, Maria Carmen; Jethwa, Ankeet; Jacobs, Erin; Campagnoni, Anthony; Molnár, Zoltán

    2009-01-01

    In the Golli-tau-eGFP (GTE) transgenic mouse the reporter gene expression is largely confined to the layer of subplate neurons (SPn), providing an opportunity to study their intracortical and extracortical projections. In this study, we examined the thalamic afferents and layer IV neuron patterning in relation to the SPn neurites in the developing barrel cortex in GTE mouse at ages embryonic day 17 (E17) to postnatal day 14 (P14). Serotonin transporter immunohistochemistry or cytochrome oxydase histochemistry was used to reveal thalamic afferent patterning. Bizbenzimide staining identified the developing cytoarchitecture in coronal and tangential sections of GTE brains. Enhanced green fluorescent protein (GFP)-labelled neurites and thalamic afferents were both initially diffusely present in layer IV but by P4–P6 both assumed the characteristic periphery-related pattern and became restricted to the barrel hollows. This pattern gradually changed and by P10 the GFP-labelled neurites largely accumulated at the layer IV–V boundary within the barrel septa whereas thalamic afferents remained in the hollows. To investigate whether this reorganisation is dependent on sensory input, the whiskers of row ‘a’ or ‘c’ were removed at P0 or P5 and the organisation of GFP-labelled neurites in the barrel cortex was examined at P6 or P10. In the contralateral region corresponding to row ‘a’ or ‘c’ the lack of hollow to septa rearrangement of the GFP-labelled neurites was observed after P0 row removal at P10 but not at P6. Our findings suggest a dynamic, sensory periphery-dependent integration of SPn neurites into the primary somatosensory cortex during the period of barrel formation. PMID:19289548

  7. Malformations of Cortical Development: From Postnatal to Fetal Imaging.

    PubMed

    Lerman-Sagie, Tally; Leibovitz, Zvi

    2016-09-01

    Abnormal fetal corticogenesis results in malformations of cortical development (MCD). Abnormal cell proliferation leads to microcephaly or megalencephaly, incomplete neuronal migration results in heterotopia and lissencephaly, neuronal overmigration manifests as cobblestone malformations, and anomalous postmigrational cortical organization is responsible for polymicrogyria and focal cortical dysplasias. MCD comprises various congenital brain disorders, caused by different genetic, infectious, or vascular etiologies and is associated with significant neurological morbidity. Although MCD are rarely diagnosed prenatally, both dedicated multiplanar neurosonography and magnetic resonance imaging enable good demonstration of fetal cortical development. The imaging signs of fetal MCD are: delayed or absent cerebral sulcation; premature abnormal sulci; thin and irregular hemispheric parenchyma; wide abnormal overdeveloped gyri; wide opening of isolated sulci; nodular bulging into the lateral ventricles; cortical clefts; intraparenchymal echogenic nodules; and cortical thickening. The postnatal and prenatal imaging features of four main malformations of cortical development-lissencephaly, cobblestone malformations, periventricular nodular heterotopia, and polymicrogyria-are described. PMID:27670206

  8. L-type calcium channel blockers and substance P induce angiogenesis of cortical vessels associated with beta-amyloid plaques in an Alzheimer mouse model.

    PubMed

    Daschil, Nina; Kniewallner, Kathrin M; Obermair, Gerald J; Hutter-Paier, Birgit; Windisch, Manfred; Marksteiner, Josef; Humpel, Christian

    2015-03-01

    It is well established that L-type calcium channels (LTCCs) are expressed in astroglia. However, their functional role is still speculative, especially under pathologic conditions. We recently showed that the α1 subunit-like immunoreactivity of the CaV1.2 channel is strongly expressed in reactive astrocytes around beta-amyloid plaques in 11-month-old Alzheimer transgenic (tg) mice with the amyloid precursor protein London and Swedish mutations. The aim of the present study was to examine the cellular expression of all LTCC subunits around beta-amyloid plaques by in situ hybridization using (35)S-labeled oligonucleotides. Our data show that messenger RNAs (mRNAs) of the LTCC CaV1.2 α1 subunit as well as all auxiliary β and α2δ subunits, except α2δ-4, were expressed in the hippocampus of age-matched wild-type mice. It was unexpected to see, that cells directly located in the plaque core in the cortex expressed mRNAs for CaV1.2 α1, β2, β4, and α2δ-1, whereas no expression was detected in the halo. Furthermore, cells in the plaque core also expressed preprotachykinin-A mRNA, the precursor for substance P. By means of confocal microscopy, we demonstrated that collagen-IV-stained brain vessels in the cortex were associated with the plaque core and were immunoreactive for substance P. In cortical organotypic brain slices of adult Alzheimer mice, we could demonstrate that LTCC blockers increased angiogenesis, which was further potentiated by substance P. In conclusion, our data show that brain vessels associated with beta-amyloid plaques express substance P and an LTCC and may play a role in angiogenesis. PMID:25619662

  9. Cerebral metabolic rate of oxygen (CMRO2) assessed by combined Doppler and spectroscopic OCT

    PubMed Central

    Chong, Shau Poh; Merkle, Conrad W.; Leahy, Conor; Srinivasan, Vivek J.

    2015-01-01

    A method of measuring cortical oxygen metabolism in the mouse brain that uses independent quantitative measurements of three key parameters: cerebral blood flow (CBF), arteriovenous oxygen extraction (OE), and hemoglobin concentration ([HbT]) is presented. Measurements were performed using a single visible light spectral/Fourier domain OCT microscope, with Doppler and spectroscopic capabilities, through a thinned-skull cranial window in the mouse brain. Baseline metabolic measurements in mice are shown to be consistent with literature values. Oxygen consumption, as measured by this method, did not change substantially during minor changes either in the fraction of inspired oxygen (FiO2) or in the fraction of inspired carbon dioxide (FiCO2), in spite of larger variations in oxygen saturations. This set of experiments supports, but does not prove, the validity of the proposed method of measuring brain oxygen metabolism. PMID:26504644

  10. Rbm8a Haploinsufficiency Disrupts Embryonic Cortical Development Resulting in Microcephaly

    PubMed Central

    Mao, Hanqian; Pilaz, Louis-Jan; McMahon, John J.; Golzio, Christelle; Wu, Danwei; Shi, Lei; Katsanis, Nicholas

    2015-01-01

    The cerebral cortex is built during embryonic neurogenesis, a period when excitatory neurons are generated from progenitors. Defects in neurogenesis can cause acute neurodevelopmental disorders, such as microcephaly (reduced brain size). Altered dosage of the 1q21.1 locus has been implicated in the etiology of neurodevelopmental phenotypes; however, the role of 1q21.1 genes in neurogenesis has remained elusive. Here, we show that haploinsufficiency for Rbm8a, an exon junction complex (EJC) component within 1q21.1, causes severe microcephaly and defective neurogenesis in the mouse. At the onset of neurogenesis, Rbm8a regulates radial glia proliferation and prevents premature neuronal differentiation. Reduced Rbm8a levels result in subsequent apoptosis of neurons, and to a lesser extent, radial glia. Hence, compared to control, Rbm8a-haploinsufficient brains have fewer progenitors and neurons, resulting in defective cortical lamination. To determine whether reciprocal dosage change of Rbm8a alters embryonic neurogenesis, we overexpressed human RBM8A in two animal models. Using in utero electroporation of mouse neocortices as well as zebrafish models, we find RBM8A overexpression does not significantly perturb progenitor number or head size. Our findings demonstrate that Rbm8a is an essential neurogenesis regulator, and add to a growing literature highlighting roles for EJC components in cortical development and neurodevelopmental pathology. Our results indicate that disruption of RBM8A may contribute to neurodevelopmental phenotypes associated with proximal 1q21.1 microdeletions. PMID:25948253

  11. Slit Modulates Cerebrovascular Inflammation and Mediates Neuroprotection Against Global Cerebral Ischemia

    PubMed Central

    Altay, Tamer; McLaughlin, BethAnn; Wu, Jane Y.; Park, T.S.; Gidday, Jeffrey M.

    2008-01-01

    Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFα application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygen-glucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFα and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFα. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy. PMID:17714707

  12. A circuit for motor cortical modulation of auditory cortical activity.

    PubMed

    Nelson, Anders; Schneider, David M; Takatoh, Jun; Sakurai, Katsuyasu; Wang, Fan; Mooney, Richard

    2013-09-01

    Normal hearing depends on the ability to distinguish self-generated sounds from other sounds, and this ability is thought to involve neural circuits that convey copies of motor command signals to various levels of the auditory system. Although such interactions at the cortical level are believed to facilitate auditory comprehension during movements and drive auditory hallucinations in pathological states, the synaptic organization and function of circuitry linking the motor and auditory cortices remain unclear. Here we describe experiments in the mouse that characterize circuitry well suited to transmit motor-related signals to the auditory cortex. Using retrograde viral tracing, we established that neurons in superficial and deep layers of the medial agranular motor cortex (M2) project directly to the auditory cortex and that the axons of some of these deep-layer cells also target brainstem motor regions. Using in vitro whole-cell physiology, optogenetics, and pharmacology, we determined that M2 axons make excitatory synapses in the auditory cortex but exert a primarily suppressive effect on auditory cortical neuron activity mediated in part by feedforward inhibition involving parvalbumin-positive interneurons. Using in vivo intracellular physiology, optogenetics, and sound playback, we also found that directly activating M2 axon terminals in the auditory cortex suppresses spontaneous and stimulus-evoked synaptic activity in auditory cortical neurons and that this effect depends on the relative timing of motor cortical activity and auditory stimulation. These experiments delineate the structural and functional properties of a corticocortical circuit that could enable movement-related suppression of auditory cortical activity. PMID:24005287

  13. Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons.

    PubMed

    Rakić, Sonja; Kanatani, Shigeaki; Hunt, David; Faux, Clare; Cariboni, Anna; Chiara, Francesca; Khan, Shabana; Wansbury, Olivia; Howard, Beatrice; Nakajima, Kazunori; Nikolić, Margareta; Parnavelas, John G

    2015-04-01

    Interneuron dysfunction in humans is often associated with neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism. Some of these disorders are believed to emerge during brain formation, at the time of interneuron specification, migration, and synapse formation. Here, using a mouse model and a host of histological and molecular biological techniques, we report that the signaling molecule cyclin-dependent kinase 5 (Cdk5), and its activator p35, control the tangential migration of interneurons toward and within the cerebral cortex by modulating the critical neurodevelopmental signaling pathway, ErbB4/phosphatidylinositol 3-kinase, that has been repeatedly linked to schizophrenia. This finding identifies Cdk5 as a crucial signaling factor in cortical interneuron development in mammals. PMID:24142862

  14. FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry.

    PubMed

    La Fata, Giorgio; Gärtner, Annette; Domínguez-Iturza, Nuria; Dresselaers, Tom; Dawitz, Julia; Poorthuis, Rogier B; Averna, Michele; Himmelreich, Uwe; Meredith, Rhiannon M; Achsel, Tilmann; Dotti, Carlos G; Bagni, Claudia

    2014-12-01

    Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity.

  15. Evidence of cortical reorganization in hemiparetic patients

    SciTech Connect

    Brion, J.P.; Demeurisse, G.; Capon, A. )

    1989-08-01

    We studied the mechanisms underlying the recovery of motor function of the hand using a bidimensional xenon-133 inhalation technique to measure regional cerebral blood flow at rest and during the performance of a motor task (test condition). The regional cerebral blood flow patterns under rest and test conditions were compared in normal control and in stroke patients with either a cortico-subcortical or a deep-seated lesion. Functional recovery appears to depend upon cortical reorganization involving both hemispheres, particularly in both parietal regions in the subgroup of patients with cortico-subcortical lesions.

  16. Cerebral Palsy

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Cerebral Palsy KidsHealth > For Kids > Cerebral Palsy Print A A ... the things that kids do every day. What's CP? Some kids with CP use wheelchairs and others ...

  17. Cerebral Palsy

    MedlinePlus

    ... Loss > Birth defects & other health conditions > Cerebral palsy Cerebral palsy E-mail to a friend Please fill in ... movement problems a child has. What is spastic CP? Spastic means tight or stiff muscles, or muscles ...

  18. Cerebral Palsy

    MedlinePlus

    Cerebral palsy is a group of disorders that affect a person's ability to move and to maintain balance ... do not get worse over time. People with cerebral palsy may have difficulty walking. They may also have ...

  19. The Chinese traditional medicine 'Bushen Yinao Pian' increased the level of ageing-related gene LRPAP-1 expression in the cerebral tissue of accelerated senescence-prone mouse 8/Ta.

    PubMed

    Zhang, Chong; Yang, Ting; Wang, Jingang; Liu, Guisheng; Chen, Qingxuan

    2005-04-01

    The molecular mechanism of the Chinese traditional medicine 'Bushen Yinao Pian' (a complex prescription used for clinical anti-ageing in China for over 20 years) is elusive. In this study, the cDNA of low-density lipoprotein related-receptor associated protein-1 (LRPAP-1), an ageing-related gene, which functions as a chaperon or escort protein in the intracellular transport of low-density lipoprotein related-receptor, a transporter of amyloid beta protein (AbetaP), had been cloned by screening cDNA library based on analyzing the gene expression in cerebral tissue between the test and the control accelerated senescence-prone mouse 8/Ta (SAMP8/Ta). The result shows that this complex prescription increased the expression level of LRPAP-1. It indicated that the Chinese traditional medicine 'Bushen Yinao Pian' plays an important role in anti-ageing by increasing LRPAP-1 expression level. PMID:15763364

  20. Cerebral Palsy

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Cerebral Palsy Information Page Clinical Trials Trial of Erythropoietin Neuroprotection ... en Español Additional resources from MedlinePlus What is Cerebral Palsy? The term cerebral palsy refers to a group ...

  1. Cerebral Aneurysms

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Aneurysms Information Page Synonym(s): Aneurysm, Brain Aneurysm Condensed from ... Español Additional resources from MedlinePlus What is Cerebral Aneurysms? A cerebral aneurysm is a weak or thin ...

  2. Lithium stimulates glutamate "release" and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-D-aspartate receptor in monkey and mouse cerebral cortex slices.

    PubMed Central

    Dixon, J F; Los, G V; Hokin, L E

    1994-01-01

    Beginning at therapeutic concentrations (1-1.5 mM), the anti-manic-depressive drug lithium stimulated the release of glutamate, a major excitatory neurotransmitter in the brain, in monkey cerebral cortex slices in a time- and concentration-dependent manner, and this was associated with increased inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] accumulation. (+/-)-3-(2-Carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP), dizocilpine (MK-801), ketamine, and Mg(2+)-antagonists to the N-methyl-D-aspartate (NMDA) receptor/channel complex selectively inhibited lithium-stimulated Ins(1,4,5)P3 accumulation. Antagonists to cholinergic-muscarinic, alpha 1-adrenergic, 5-hydroxytryptamine2 (serotoninergic), and H1 histaminergic receptors had no effect. Antagonists to non-NMDA glutamate receptors had no effect on lithium-stimulated Ins(1,4,5)P3 accumulation. Possible reasons for this are discussed. Similar results were obtained in mouse cerebral cortex slices. Carbetapentane, which inhibits glutamate release, inhibited lithium-induced Ins(1,4,5)P3 accumulation in this model. It is concluded that the primary effect of lithium in the cerebral cortex slice model is stimulation of glutamate release, which, presumably via activation of the NMDA receptor, leads to Ca2+ entry. Ins(1,4,5)P3 accumulation increases due to the presumed increased influx of intracellular Ca2+, which activates phospholipase C. These effects may have relevance to the therapeutic action of lithium in the treatment of manic depression as well as its toxic effects, especially at lithium blood levels above 1.5 mM. Images PMID:8078888

  3. Strain differences of the effect of enucleation and anophthalmia on the size and growth of sensory cortices in mice.

    PubMed

    Massé, Ian O; Guillemette, Sonia; Laramée, Marie-Eve; Bronchti, Gilles; Boire, Denis

    2014-11-01

    Anophthalmia is a condition in which the eye does not develop from the early embryonic period. Early blindness induces cross-modal plastic modifications in the brain such as auditory and haptic activations of the visual cortex and also leads to a greater solicitation of the somatosensory and auditory cortices. The visual cortex is activated by auditory stimuli in anophthalmic mice and activity is known to alter the growth pattern of the cerebral cortex. The size of the primary visual, auditory and somatosensory cortices and of the corresponding specific sensory thalamic nuclei were measured in intact and enucleated C57Bl/6J mice and in ZRDCT anophthalmic mice (ZRDCT/An) to evaluate the contribution of cross-modal activity on the growth of the cerebral cortex. In addition, the size of these structures were compared in intact, enucleated and anophthalmic fourth generation backcrossed hybrid C57Bl/6J×ZRDCT/An mice to parse out the effects of mouse strains and of the different visual deprivations. The visual cortex was smaller in the anophthalmic ZRDCT/An than in the intact and enucleated C57Bl/6J mice. Also the auditory cortex was larger and the somatosensory cortex smaller in the ZRDCT/An than in the intact and enucleated C57Bl/6J mice. The size differences of sensory cortices between the enucleated and anophthalmic mice were no longer present in the hybrid mice, showing specific genetic differences between C57Bl/6J and ZRDCT mice. The post natal size increase of the visual cortex was less in the enucleated than in the anophthalmic and intact hybrid mice. This suggests differences in the activity of the visual cortex between enucleated and anophthalmic mice and that early in-utero spontaneous neural activity in the visual system contributes to the shaping of functional properties of cortical networks.

  4. Human Pluripotent Stem Cell-Derived Radial Glia Recapitulate Developmental Events and Provide Real-Time Access to Cortical Neurons and Astrocytes

    PubMed Central

    Peng, Chian-Yu; Pan, Liuliu; Kessler, John A.

    2015-01-01

    Studies of human cerebral cortex development are limited by difficulties in accessing and manipulating human neural tissue at specific development stages. We have derived human radial glia (hRG), which are responsible for most cerebral cortex neurogenesis, from human pluripotent stem cells. These hRG display the hallmark morphological, cellular, and molecular features of radial glia in vitro. They can be passaged and generate layer-specific subtypes of cortical neurons in a temporal and passage-dependent fashion. In later passages, they adopt a distinct progenitor phenotype that gives rise to cortical astrocytes and GABAergic interneurons. These hRG are also capable of following developmental cues to engraft, differentiate, migrate, and integrate into the embryonic mouse cortex when injected into E14 lateral ventricles. Moreover, hRG-derived cells can be cryopreserved at specific stages and retain their stage-specific phenotypes and competence when revived. Our study demonstrates that cultured hRG maintain a cell-intrinsic clock that regulates the progressive generation of stage-specific neuronal and glial subtypes. It also describes an easily accessible cell source for studying hRG lineage specification and progression and an on-demand supply of specific cortical neuron subtypes and astrocytes. PMID:25834120

  5. Simulating Cortical Feedback Modulation as Changes in Excitation and Inhibition in a Cortical Circuit Model.

    PubMed

    Zagha, Edward; Murray, John D; McCormick, David A

    2016-01-01

    Cortical feedback pathways are hypothesized to distribute context-dependent signals during flexible behavior. Recent experimental work has attempted to understand the mechanisms by which cortical feedback inputs modulate their target regions. Within the mouse whisker sensorimotor system, cortical feedback stimulation modulates spontaneous activity and sensory responsiveness, leading to enhanced sensory representations. However, the cellular mechanisms underlying these effects are currently unknown. In this study we use a simplified neural circuit model, which includes two recurrent excitatory populations and global inhibition, to simulate cortical modulation. First, we demonstrate how changes in the strengths of excitation and inhibition alter the input-output processing responses of our model. Second, we compare these responses with experimental findings from cortical feedback stimulation. Our analyses predict that enhanced inhibition underlies the changes in spontaneous and sensory evoked activity observed experimentally. More generally, these analyses provide a framework for relating cellular and synaptic properties to emergent circuit function and dynamic modulation. PMID:27595137

  6. Simulating Cortical Feedback Modulation as Changes in Excitation and Inhibition in a Cortical Circuit Model

    PubMed Central

    Murray, John D.; McCormick, David A.

    2016-01-01

    Abstract Cortical feedback pathways are hypothesized to distribute context-dependent signals during flexible behavior. Recent experimental work has attempted to understand the mechanisms by which cortical feedback inputs modulate their target regions. Within the mouse whisker sensorimotor system, cortical feedback stimulation modulates spontaneous activity and sensory responsiveness, leading to enhanced sensory representations. However, the cellular mechanisms underlying these effects are currently unknown. In this study we use a simplified neural circuit model, which includes two recurrent excitatory populations and global inhibition, to simulate cortical modulation. First, we demonstrate how changes in the strengths of excitation and inhibition alter the input–output processing responses of our model. Second, we compare these responses with experimental findings from cortical feedback stimulation. Our analyses predict that enhanced inhibition underlies the changes in spontaneous and sensory evoked activity observed experimentally. More generally, these analyses provide a framework for relating cellular and synaptic properties to emergent circuit function and dynamic modulation.

  7. Simulating Cortical Feedback Modulation as Changes in Excitation and Inhibition in a Cortical Circuit Model.

    PubMed

    Zagha, Edward; Murray, John D; McCormick, David A

    2016-01-01

    Cortical feedback pathways are hypothesized to distribute context-dependent signals during flexible behavior. Recent experimental work has attempted to understand the mechanisms by which cortical feedback inputs modulate their target regions. Within the mouse whisker sensorimotor system, cortical feedback stimulation modulates spontaneous activity and sensory responsiveness, leading to enhanced sensory representations. However, the cellular mechanisms underlying these effects are currently unknown. In this study we use a simplified neural circuit model, which includes two recurrent excitatory populations and global inhibition, to simulate cortical modulation. First, we demonstrate how changes in the strengths of excitation and inhibition alter the input-output processing responses of our model. Second, we compare these responses with experimental findings from cortical feedback stimulation. Our analyses predict that enhanced inhibition underlies the changes in spontaneous and sensory evoked activity observed experimentally. More generally, these analyses provide a framework for relating cellular and synaptic properties to emergent circuit function and dynamic modulation.

  8. Simulating Cortical Feedback Modulation as Changes in Excitation and Inhibition in a Cortical Circuit Model

    PubMed Central

    Murray, John D.; McCormick, David A.

    2016-01-01

    Abstract Cortical feedback pathways are hypothesized to distribute context-dependent signals during flexible behavior. Recent experimental work has attempted to understand the mechanisms by which cortical feedback inputs modulate their target regions. Within the mouse whisker sensorimotor system, cortical feedback stimulation modulates spontaneous activity and sensory responsiveness, leading to enhanced sensory representations. However, the cellular mechanisms underlying these effects are currently unknown. In this study we use a simplified neural circuit model, which includes two recurrent excitatory populations and global inhibition, to simulate cortical modulation. First, we demonstrate how changes in the strengths of excitation and inhibition alter the input–output processing responses of our model. Second, we compare these responses with experimental findings from cortical feedback stimulation. Our analyses predict that enhanced inhibition underlies the changes in spontaneous and sensory evoked activity observed experimentally. More generally, these analyses provide a framework for relating cellular and synaptic properties to emergent circuit function and dynamic modulation. PMID:27595137

  9. Crucial Role of Rapgef2 and Rapgef6, a Family of Guanine Nucleotide Exchange Factors for Rap1 Small GTPase, in Formation of Apical Surface Adherens Junctions and Neural Progenitor Development in the Mouse Cerebral Cortex123

    PubMed Central

    Maeta, Kazuhiro; Edamatsu, Hironori; Nishihara, Kaori; Ikutomo, Junji; Bilasy, Shymaa E.

    2016-01-01

    Abstract Cerebral neocortex development in mammals requires highly orchestrated events involving proliferation, differentiation, and migration of neural progenitors and neurons. Rapgef2 and Rapgef6 constitute a unique family of guanine nucleotide exchange factors for Rap1 small GTPase, which is known to play crucial roles in migration of postmitotic neurons. We previously reported that conditional knockout of Rapgef2 in dorsal telencephalon (Rapgef2-cKO) resulted in the formation of an ectopic cortical mass (ECM) resembling that of subcortical band heterotopia. Here we show that double knockout of Rapgef6 in Rapgef2-cKO mice (Rapgef2/6-dKO) results in marked enlargement of the ECM. While Rapgef2-cKO affects late-born neurons only, Rapgef2/6-dKO affects both early-born and late-born neurons. The Rapgef2-cKO cortex at embryonic day (E) 15.5, and the Rapgef2/6-dKO cortex at E13.5 and E15.5 show disruption of the adherens junctions (AJs) on the apical surface, detachment of radial glial cells (RGCs) from the apical surface and disorganization of the radial glial fiber system, which are accompanied by aberrant distribution of RGCs and intermediate progenitors, normally located in the ventricular zone and the subventricular zone, respectively, over the entire cerebral cortex. Moreover, intrauterine transduction of Cre recombinase into the Rapgef2flox/flox brains also results in the apical surface AJ disruption and the RGC detachment from the apical surface, both of which are effectively suppressed by cotransduction of the constitutively active Rap1 mutant Rap1G12V. These results demonstrate a cell-autonomous role of the Rapgef2/6-Rap1 pathway in maintaining the apical surface AJ structures, which is necessary for the proper development of neural progenitor cells. PMID:27390776

  10. The basic nonuniformity of the cerebral cortex

    PubMed Central

    Herculano-Houzel, Suzana; Collins, Christine E.; Wong, Peiyan; Kaas, Jon H.; Lent, Roberto

    2008-01-01

    Evolutionary changes in the size of the cerebral cortex, a columnar structure, often occur through the addition or subtraction of columnar modules with the same number of neurons underneath a unit area of cortical surface. This view is based on the work of Rockel et al. [Rockel AJ, Hiorns RW, Powell TP (1980) The basic uniformity in structure of the neocortex. Brain 103:221–244], who found a steady number of approximately 110 neurons underneath a surface area of 750 μm2 (147,000 underneath 1 mm2) of the cerebral cortex of five species from different mammalian orders. These results have since been either corroborated or disputed by different groups. Here, we show that the number of neurons underneath 1 mm2 of the cerebral cortical surface of nine primate species and the closely related Tupaia sp. is not constant and varies by three times across species. We found that cortical thickness is not inversely proportional to neuronal density across species and that total cortical surface area increases more slowly than, rather than linearly with, the number of neurons underneath it. The number of neurons beneath a unit area of cortical surface varies linearly with neuronal density, a parameter that is neither related to cortical size nor total number of neurons. Our finding of a variable number of neurons underneath a unit area of the cerebral cortex across primate species indicates that models of cortical organization cannot assume that cortical columns in different primates consist of invariant numbers of neurons. PMID:18689685

  11. Dynamic cortical lateralization during olfactory discrimination learning

    PubMed Central

    Cohen, Yaniv; Putrino, David; Wilson, Donald A

    2015-01-01

    Key points Odour discrimination and memory involve changes in the primary olfactory (piriform) cortex. The results obtained in the present study suggest that there is an asymmetry in piriform cortical change, with learning-related changes in cortical oscillations emerging with different time courses over the course of multiday training in the left and right piriform cortices in rats. There is an initial decrease in coherence between the left and right piriform cortices during the early stages of the odour discrimination task, which recovers as the animals approach criterion performance. This decreased coherence is expressed when the animals are performing the task relative to when they are in their home cage. The results suggest a transient cortical asymmetry during learning and raise new questions about the functions and mechanisms of cerebral lateralization. Abstract Bilateral cortical circuits are not necessarily symmetrical. Asymmetry, or cerebral lateralization, allows functional specialization of bilateral brain regions and has been described in humans for such diverse functions as perception, memory and emotion. There is also evidence for asymmetry in the human olfactory system, although evidence in non-human animal models is lacking. In the present study, we took advantage of the known changes in olfactory cortical local field potentials that occur over the course of odour discrimination training to test for functional asymmetry in piriform cortical activity during learning. Both right and left piriform cortex local field potential activities were recorded. The results obtained demonstrate a robust interhemispheric asymmetry in anterior piriform cortex activity that emerges during specific stages of odour discrimination learning, with a transient bias toward the left hemisphere. This asymmetry is not apparent during error trials. Furthermore, functional connectivity (coherence) between the bilateral anterior piriform cortices is learning- and context

  12. Decision by division: making cortical maps.

    PubMed

    Rakic, Pasko; Ayoub, Albert E; Breunig, Joshua J; Dominguez, Martin H

    2009-05-01

    In the past three decades, mounting evidence has revealed that specification of the basic cortical neuronal classes starts at the time of their final mitotic divisions in the embryonic proliferative zones. This early cell determination continues during the migration of the newborn neurons across the widening cerebral wall, and it is in the cortical plate that they attain their final positions and establish species-specific cytoarchitectonic areas. Here, the development and evolutionary expansion of the neocortex is viewed in the context of the radial unit and protomap hypotheses. A broad spectrum of findings gave insight into the pathogenesis of cortical malformations and the biological bases for the evolution of the modern human neocortex. We examine the history and evidence behind the concept of early specification of neurons and provide the latest compendium of genes and signaling molecules involved in neuronal fate determination and specification.

  13. Unveiling astrocytic control of cerebral blood flow with optogenetics.

    PubMed

    Masamoto, Kazuto; Unekawa, Miyuki; Watanabe, Tatsushi; Toriumi, Haruki; Takuwa, Hiroyuki; Kawaguchi, Hiroshi; Kanno, Iwao; Matsui, Ko; Tanaka, Kenji F; Tomita, Yutaka; Suzuki, Norihiro

    2015-06-16

    Cortical neural activities lead to changes in the cerebral blood flow (CBF), which involves astrocytic control of cerebrovascular tone. However, the manner in which astrocytic activity specifically leads to vasodilation or vasoconstriction is difficult to determine. Here, cortical astrocytes genetically expressing a light-sensitive cation channel, channelrhodopsin-2 (ChR2), were transcranially activated with a blue laser while the spatiotemporal changes in CBF were noninvasively monitored with laser speckle flowgraphy in the anesthetised mouse cortex. A brief photostimulation induced a fast transient increase in CBF. The average response onset time was 0.7 ± 0.7 sec at the activation foci, and this CBF increase spread widely from the irradiation spot with an apparent propagation speed of 0.8-1.1 mm/sec. The broad increase in the CBF could be due to a propagation of diffusible vasoactive signals derived from the stimulated astrocytes. Pharmacological manipulation showed that topical administration of a K(+) channel inhibitor (BaCl2; 0.1-0.5 mM) significantly reduced the photostimulation-induced CBF responses, which indicates that the ChR2-evoked astrocytic activity involves K(+) signalling to the vascular smooth muscle cells. These findings demonstrate a unique model for exploring the role of the astrocytes in gliovascular coupling using non-invasive, time-controlled, cell-type specific perturbations.

  14. Cortical Neural Computation by Discrete Results Hypothesis

    PubMed Central

    Castejon, Carlos; Nuñez, Angel

    2016-01-01

    One of the most challenging problems we face in neuroscience is to understand how the cortex performs computations. There is increasing evidence that the power of the cortical processing is produced by populations of neurons forming dynamic neuronal ensembles. Theoretical proposals and multineuronal experimental studies have revealed that ensembles of neurons can form emergent functional units. However, how these ensembles are implicated in cortical computations is still a mystery. Although cell ensembles have been associated with brain rhythms, the functional interaction remains largely unclear. It is still unknown how spatially distributed neuronal activity can be temporally integrated to contribute to cortical computations. A theoretical explanation integrating spatial and temporal aspects of cortical processing is still lacking. In this Hypothesis and Theory article, we propose a new functional theoretical framework to explain the computational roles of these ensembles in cortical processing. We suggest that complex neural computations underlying cortical processing could be temporally discrete and that sensory information would need to be quantized to be computed by the cerebral cortex. Accordingly, we propose that cortical processing is produced by the computation of discrete spatio-temporal functional units that we have called “Discrete Results” (Discrete Results Hypothesis). This hypothesis represents a novel functional mechanism by which information processing is computed in the cortex. Furthermore, we propose that precise dynamic sequences of “Discrete Results” is the mechanism used by the cortex to extract, code, memorize and transmit neural information. The novel “Discrete Results” concept has the ability to match the spatial and temporal aspects of cortical processing. We discuss the possible neural underpinnings of these functional computational units and describe the empirical evidence supporting our hypothesis. We propose that fast

  15. Thyroid hormone-regulated mouse cerebral cortex genes are differentially dependent on the source of the hormone: a study in monocarboxylate transporter-8- and deiodinase-2-deficient mice.

    PubMed

    Morte, Beatriz; Ceballos, Ainhoa; Diez, Diego; Grijota-Martínez, Carmen; Dumitrescu, Alexandra M; Di Cosmo, Caterina; Galton, Valerie Anne; Refetoff, Samuel; Bernal, Juan

    2010-05-01

    Thyroid hormones influence brain development through the control of gene expression. The concentration of the active hormone T(3) in the brain depends on T(3) transport through the blood-brain barrier, mediated in part by the monocarboxylate transporter 8 (Mct8/MCT8) and the activity of type 2 deiodinase (D2) generating T(3) from T(4). The relative roles of each of these pathways in the regulation of brain gene expression is not known. To shed light on this question, we analyzed thyroid hormone-dependent gene expression in the cerebral cortex of mice with inactivated Mct8 (Slc16a2) and Dio2 genes, alone or in combination. We used 34 target genes identified to be controlled by thyroid hormone in microarray comparisons of cerebral cortex from wild-type control and hypothyroid mice on postnatal d 21. Inactivation of the Mct8 gene (Mct8KO) was without effect on the expression of 31 of these genes. Normal gene expression in the absence of the transporter was mostly due to D2 activity because the combined disruption of Mct8 and Dio2 led to similar effects as hypothyroidism on the expression of 24 genes. Dio2 disruption alone did not affect the expression of positively regulated genes, but, as in hypothyroidism, it increased that of negatively regulated genes. We conclude that gene expression in the Mct8KO cerebral cortex is compensated in part by D2-dependent mechanisms. Intriguingly, positive or negative regulation of genes by thyroid hormone is sensitive to the source of T(3) because Dio2 inactivation selectively affects the expression of negatively regulated genes. PMID:20211971

  16. Change in the cortical complexity of spinocerebellar ataxia type 3 appears earlier than clinical symptoms.

    PubMed

    Wang, Tzu-Yun; Jao, Chii-Wen; Soong, Bing-Wen; Wu, Hsiu-Mei; Shyu, Kuo-Kai; Wang, Po-Shan; Wu, Yu-Te

    2015-01-01

    Patients with spinocerebellar ataxia type 3 (SCA3) have exhibited cerebral cortical involvement and various mental deficits in previous studies. Clinically, conventional measurements, such as the Mini-Mental State Examination (MMSE) and electroencephalography (EEG), are insensitive to cerebral cortical involvement and mental deficits associated with SCA3, particularly at the early stage of the disease. We applied a three-dimensional fractal dimension (3D-FD) method, which can be used to quantify the shape complexity of cortical folding, in assessing cortical degeneration. We evaluated 48 genetically confirmed SCA3 patients by employing clinical scales and magnetic resonance imaging and using 50 healthy participants as a control group. According to the Scale for the Assessment and Rating of Ataxia (SARA), the SCA3 patients were diagnosed with cortical dysfunction in the cerebellar cortex; however, no significant difference in the cerebral cortex was observed according to the patients' MMSE ratings. Using the 3D-FD method, we determined that cortical involvement was more extensive than involvement of traditional olivopontocerebellar regions and the corticocerebellar system. Moreover, the significant correlation between decreased 3D-FD values and disease duration may indicate atrophy of the cerebellar cortex and cerebral cortex in SCA3 patients. The change of the cerebral complexity in the SCA3 patients can be detected throughout the disease duration, especially it becomes substantial at the late stage of the disease. Furthermore, we determined that atrophy of the cerebral cortex may occur earlier than changes in MMSE scores and EEG signals.

  17. Cerebral cortex: an MRI-based study of volume and variance with age and sex.

    PubMed

    Carne, Ross P; Vogrin, Simon; Litewka, Lucas; Cook, Mark J

    2006-01-01

    The aim of the present study was to examine quantitative differences in lobar cerebral cortical volumes in a healthy adult population. Quantitative volumetric MRI of whole brain, cerebral and cerebellar volumes was performed in a cross-sectional analysis of 97 normal volunteers, with segmented frontal, temporal, parietal and occipital cortical volumes measured in a subgroup of 60 subjects, 30 male and 30 female, matched for age and sex. The right cerebral hemisphere was larger than the left across the study group with a small (<1%) but significant difference in symmetry (P<0.001). No difference was found between volumes of right and left cerebellar hemispheres. Rightward cerebral cortical asymmetry (right larger than left) was found to be significant across all lobes except parietal. Males had greater cerebral, cerebellar and cerebral cortical lobar volumes than females. Larger male cerebral cortical volumes were seen in all lobes except for left parietal. Females had greater left parietal to left cerebral hemisphere and smaller left temporal to left cerebral hemisphere ratios. There was a mild reduction in cerebral volumes with age, more marked in males. This study confirms and augments past work indicating underlying structural asymmetries in the human brain, and provides further evidence that brain structures in humans are differentially sensitive to the effects of both age and sex.

  18. Angiopoietin-1 blocks neurotoxic zinc entry into cortical cells via PIP2 hydrolysis-mediated ion channel inhibition.

    PubMed

    Lim, Joon Seo; Koh, Gou Young; Koh, Jae-Young

    2015-09-01

    Excessive entry of zinc ions into the soma of neurons and glial cells results in extensive oxidative stress and necrosis of cortical cells, which underlies acute neuronal injury in cerebral ischemia and epileptic seizures. Here, we show that angiopoietin-1 (Ang1), a potent angiogenic ligand for the receptor tyrosine kinase Tie2 and integrins, inhibits the entry of zinc into primary mouse cortical cells and exerts a substantial protective effect against zinc-induced neurotoxicity. The neuroprotective effect of Ang1 was mediated by the integrin/focal adhesion kinase (FAK) signaling axis, as evidenced by the blocking effects of a pan-integrin inhibitory RGD peptide and PF-573228, a specific chemical inhibitor of FAK. Notably, blockade of zinc-permeable ion channels by Ang1 was attributable to phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. Collectively, these data reveal a novel role of Ang1 in regulating the activity of zinc-permeable ion channels, and thereby protecting cortical cells against zinc-induced neurotoxicity.

  19. Migration Speed of Cajal-Retzius Cells Modulated by Vesicular Trafficking Controls the Size of Higher-Order Cortical Areas.

    PubMed

    Barber, Melissa; Arai, Yoko; Morishita, Yoshihiro; Vigier, Lisa; Causeret, Frédéric; Borello, Ugo; Ledonne, Fanny; Coppola, Eva; Contremoulins, Vincent; Pfrieger, Frank W; Tissir, Fadel; Govindan, Subashika; Jabaudon, Denis; Proux-Gillardeaux, Véronique; Galli, Thierry; Pierani, Alessandra

    2015-10-01

    In the neocortex, higher-order areas are essential to integrate sensory-motor information and have expanded in size during evolution. How higher-order areas are specified, however, remains largely unknown. Here, we show that the migration and distribution of early-born neurons, the Cajal-Retzius cells (CRs), controls the size of higher-order areas in the mouse somatosensory, auditory, and visual cortex. Using live imaging, genetics, and in silico modeling, we show that subtype-specific differences in the onset, speed, and directionality of CR migration determine their differential invasion of the developing cortical surface. CR migration speed is cell autonomously modulated by vesicle-associated membrane protein 3 (VAMP3), a classically non-neuronal mediator of endosomal recycling. Increasing CR migration speed alters their distribution in the developing cerebral cortex and leads to an expansion of postnatal higher-order areas and congruent rewiring of thalamo-cortical input. Our findings thus identify novel roles for neuronal migration and VAMP3-dependent vesicular trafficking in cortical wiring.

  20. Quantitative imaging of microvascular blood flow networks in deep cortical layers by 1310 nm µODT

    PubMed Central

    You, Jiang; Zhang, Qiujia; Park, Kicheon; Du, Congwu

    2016-01-01

    There is growing interest in new neuroimage techniques that permit not only high-resolution quantification of cerebral blood flow velocity (CBFv) in capillaries, but also a large field of view to map the CBFv network dynamics. Such image capabilities are of great importance for decoding the functional difference across multiple cortical layers under stimuli. To tackle the limitation of optical penetration depth, we present a new ultrahigh-resolution optical coherence Doppler tomography (µODT) system at 1310 nm and compare it with a prior 800 nm µODT system for mouse brain 3D CBFv imaging. We show that the new 1310 nm µODT allows for dramatically increased depth (~4 times) of quantitative CBFv imaging to 1.4 mm, thus covering the full thickness of the mouse cortex (i.e., layers I–VI). Interestingly, we show that such a unique 3D CBFv imaging capability allows identification of microcirculatory redistribution across different cortical layers resulting from repeated cocaine exposures. PMID:26371919

  1. Distribution of the orexin-1 receptor (OX1R) in the mouse forebrain and rostral brainstem: A characterisation of OX1R-eGFP mice.

    PubMed

    Ch'ng, Sarah Sulaiman; Lawrence, Andrew J

    2015-01-01

    We have utilised a transgenic reporter mouse in which green fluorescent protein (GFP) expression is driven by the orexin-1 receptor (OX1R) promoter to systematically map the distribution of OX1R-expressing neurons throughout the mouse forebrain and rostral brainstem. GFP labelling was observed in perikarya and fibres in an extensive range of brain loci encompassing the olfactory and cerebral cortices, dorsal and ventral pallidum, hippocampus, amygdaloid regions, septal areas, thalamic nuclei, hypothalamic nuclei and several brainstem regions, consistent with previous studies of OX1R mRNA expression. This is the first study to systematically characterise the neuroanatomical distribution of OX1R in the OX1R-eGFP mouse, confirming its veracity as a faithful reporter of OX1R expression and utility for future studies assessing the role of OX1R in more complex behaviours.

  2. Malformations of cortical development and epilepsy.

    PubMed

    Leventer, Richard J; Guerrini, Renzo; Dobyns, William B

    2008-01-01

    Malformations of cortical development (MCDs) are macroscopic or microscopic abnormalities of the cerebral cortex that arise as a consequence of an interruption to the normal steps of formation of the cortical plate. The human cortex develops its basic structure during the first two trimesters of pregnancy as a series of overlapping steps, beginning with proliferation and differentiation of neurons, which then migrate before finally organizing themselves in the developing cortex. Abnormalities at any of these stages, be they environmental or genetic in origin, may cause disruption of neuronal circuitry and predispose to a variety of clinical consequences, the most common of which is epileptic seizures. A large number of MCDs have now been described, each with characteristic pathological, clinical, and imaging features. The causes of many of these MCDs have been determined through the study of affected individuals, with many MCDs now established as being secondary to mutations in cortical development genes. This review will highlight the best-known of the human cortical malformations associated with epilepsy. The pathological, clinical, imaging, and etiologic features of each MCD will be summarized, with representative magnetic resonance imaging (MRI) images shown for each MCD. The malformations tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly, classical lissencephaly, subcortical band heterotopia, periventricular nodular heterotopia, polymicrogyria, and schizencephaly will be presented. PMID:18472484

  3. Cerebral palsy.

    PubMed

    Wimalasundera, Neil; Stevenson, Valerie L

    2016-06-01

    Cerebral palsy has always been known as a disorder of movement and posture resulting from a non-progressive injury to the developing brain; however, more recent definitions allow clinicians to appreciate more than just the movement disorder. Accurate classification of cerebral palsy into distribution, motor type and functional level has advanced research. It also facilitates appropriate targeting of interventions to functional level and more accurate prognosis prediction. The prevalence of cerebral palsy remains fairly static at 2-3 per 1000 live births but there have been some changes in trends for specific causal groups. Interventions for cerebral palsy have historically been medical and physically focused, often with limited evidence to support their efficacy. The use of more appropriate outcome measures encompassing quality of life and participation is helping to deliver treatments which are more meaningful for people with cerebral palsy and their carers.

  4. Cortical Reorganization of Language Functioning Following Perinatal Left MCA Stroke

    ERIC Educational Resources Information Center

    Tillema, Jan-Mendelt; Byars, Anna W.; Jacola, Lisa M.; Schapiro, Mark B.; Schmithorst, Vince J.; Szaflarski, Jerzy P.; Holland, Scott K.

    2008-01-01

    Objective: Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task. Methods: Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched…

  5. Aging and Cortical Mechanisms of Speech Perception in Noise

    ERIC Educational Resources Information Center

    Wong, Patrick C. M.; Jin, James Xumin; Gunasekera, Geshri M.; Abel, Rebekah; Lee, Edward R.; Dhar, Sumitrajit

    2009-01-01

    Spoken language processing in noisy environments, a hallmark of the human brain, is subject to age-related decline, even when peripheral hearing might be intact. The present study examines the cortical cerebral hemodynamics (measured by fMRI) associated with such processing in the aging brain. Younger and older subjects identified single words in…

  6. Both Myosin-10 isoforms are required for radial neuronal migration in the developing cerebral cortex.

    PubMed

    Ju, Xing-Da; Guo, Ye; Wang, Nan-Nan; Huang, Ying; Lai, Ming-Ming; Zhai, Yan-Hua; Guo, Yu-Guang; Zhang, Jian-Hua; Cao, Rang-Juan; Yu, Hua-Li; Cui, Lei; Li, Yu-Ting; Wang, Xing-Zhi; Ding, Yu-Qiang; Zhu, Xiao-Juan

    2014-05-01

    During embryonic development of the mammalian cerebral cortex, postmitotic cortical neurons migrate radially from the ventricular zone to the cortical plate. Proper migration involves the correct orientation of migrating neurons and the transition from a multipolar to a mature bipolar morphology. Herein, we report that the 2 isoforms of Myosin-10 (Myo10) play distinct roles in the regulation of radial migration in the mouse cortex. We show that the full-length Myo10 (fMyo10) isoform is located in deeper layers of the cortex and is involved in establishing proper migration orientation. We also demonstrate that fMyo10-dependent orientation of radial migration is mediated at least in part by the netrin-1 receptor deleted in colorectal cancer. Moreover, we show that the headless Myo10 (hMyo10) isoform is required for the transition from multipolar to bipolar morphologies in the intermediate zone. Our study reveals divergent functions for the 2 Myo10 isoforms in controlling both the direction of migration and neuronal morphogenesis during radial cortical neuronal migration. PMID:23300110

  7. CoREST/LSD1 control the development of pyramidal cortical neurons.

    PubMed

    Fuentes, Patricio; Cánovas, José; Berndt, F Andrés; Noctor, Stephen C; Kukuljan, Manuel

    2012-06-01

    The development of a neuron from a precursor cell comprises a complex set of steps ranging from regulation of the proliferative cycle through the acquisition of distinct morphology and functionality. How these processes are orchestrated is largely unknown. Using in utero manipulation of gene expression in the mouse embryonic cerebral cortex, we found that the transition between multipolar and bipolar stages of newborn cortical pyramidal neurons is markedly delayed by depletion of CoREST, a corepressor component of chromatin remodeling complexes. This profoundly affects the onset of their radial migration. The loss of CoREST function also perturbs the dynamics of neuronal precursor cell populations, transiently increasing the fraction of cells remaining in progenitor states, but not the acquisition of the neuronal glutamatergic fate of pyramidal cells. The function of CoREST in these processes appears to be independent of its best-known interactor, the RE-1 silencer of transcription/neural restrictive silencing factor, and requires the histone demethylase LSD1. This reveals the importance of epigenetic control in the execution of neural development programs, specifically in the cerebral cortex.

  8. RTTN Mutations Link Primary Cilia Function to Organization of the Human Cerebral Cortex

    PubMed Central

    Kheradmand Kia, Sima; Verbeek, Elly; Engelen, Erik; Schot, Rachel; Poot, Raymond A.; de Coo, Irenaeus F.M.; Lequin, Maarten H.; Poulton, Cathryn J.; Pourfarzad, Farzin; Grosveld, Frank G.; Brehm, António; de Wit, Marie Claire Y.; Oegema, Renske; Dobyns, William B.; Verheijen, Frans W.; Mancini, Grazia M.S.

    2012-01-01

    Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals. PMID:22939636

  9. Krypton laser-induced photothrombotic distal middle cerebral artery occlusion without craniectomy in mice.

    PubMed

    Sugimori, Hiroshi; Yao, Hiroshi; Ooboshi, Hiroaki; Ibayashi, Setsuro; Iida, Mitsuo

    2004-08-01

    Recent advances in genetical engineering of the mouse have highlighted the importance of reproducible and less invasive models of cerebral ischemia in mice. In this paper, we developed minimally invasive and reproducible model of distal middle cerebral artery (MCA) occlusion in mice using krypton (Kr) laser-induced photothrombosis. C57BL/6 or BALB mice (n=8 each) were anesthetized with halothane. The skin was cut, the temporal muscle was retracted, and the right distal MCA was observed through the skull. A Kr laser beam of wavelength 568 nm was focused onto the MCA over the intact skull. Upon laser irradiation, intravenous administration of a rose bengal solution was begun. After 4 min of irradiation, the laser beam was refocused on the MCA just proximal to the first spot, and another 4-min irradiation was performed. Then, the right common carotid artery (CCA) was ligated. Three days later, the brain was removed, and infarct volume was determined. Infarction confined almost solely to the cortical area was produced in each mouse. Mean infarct volume in C57BL/6 mice was 25.2+/-13.7 mm3. The BALB mice group showed significantly larger and more reproducible infarction (44.1+/-5.2 mm3; the coefficient of variation was 12%) than did C57BL/6 mice (P<0.005). Our photothrombosis model of stroke in mice can be performed without craniectomy, and its reproducibility is satisfactory when using BALB mice.

  10. Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice.

    PubMed

    Dono, R; Texido, G; Dussel, R; Ehmke, H; Zeller, R

    1998-08-01

    Fibroblast growth factor-2 (FGF-2) has been implicated in various signaling processes which control embryonic growth and differentiation, adult physiology and pathology. To analyze the in vivo functions of this signaling molecule, the FGF-2 gene was inactivated by homologous recombination in mouse embryonic stem cells. FGF-2-deficient mice are viable, but display cerebral cortex defects at birth. Bromodeoxyuridine pulse labeling of embryos showed that proliferation of neuronal progenitors is normal, whereas a fraction of them fail to colonize their target layers in the cerebral cortex. A corresponding reduction in parvalbumin-positive neurons is observed in adult cortical layers. Neuronal defects are not limited to the cerebral cortex, as ectopic parvalbumin-positive neurons are present in the hippocampal commissure and neuronal deficiencies are observed in the cervical spinal cord. Physiological studies showed that FGF-2-deficient adult mice are hypotensive. They respond normally to angiotensin II-induced hypertension, whereas neural regulation of blood pressure by the baroreceptor reflex is impaired. The present genetic study establishes that FGF-2 participates in controlling fates, migration and differentiation of neuronal cells, whereas it is not essential for their proliferation. The observed autonomic dysfunction in FGF-2-deficient adult mice uncovers more general roles in neural development and function. PMID:9687490

  11. Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice.

    PubMed

    Dono, R; Texido, G; Dussel, R; Ehmke, H; Zeller, R

    1998-08-01

    Fibroblast growth factor-2 (FGF-2) has been implicated in various signaling processes which control embryonic growth and differentiation, adult physiology and pathology. To analyze the in vivo functions of this signaling molecule, the FGF-2 gene was inactivated by homologous recombination in mouse embryonic stem cells. FGF-2-deficient mice are viable, but display cerebral cortex defects at birth. Bromodeoxyuridine pulse labeling of embryos showed that proliferation of neuronal progenitors is normal, whereas a fraction of them fail to colonize their target layers in the cerebral cortex. A corresponding reduction in parvalbumin-positive neurons is observed in adult cortical layers. Neuronal defects are not limited to the cerebral cortex, as ectopic parvalbumin-positive neurons are present in the hippocampal commissure and neuronal deficiencies are observed in the cervical spinal cord. Physiological studies showed that FGF-2-deficient adult mice are hypotensive. They respond normally to angiotensin II-induced hypertension, whereas neural regulation of blood pressure by the baroreceptor reflex is impaired. The present genetic study establishes that FGF-2 participates in controlling fates, migration and differentiation of neuronal cells, whereas it is not essential for their proliferation. The observed autonomic dysfunction in FGF-2-deficient adult mice uncovers more general roles in neural development and function.

  12. Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice.

    PubMed Central

    Dono, R; Texido, G; Dussel, R; Ehmke, H; Zeller, R

    1998-01-01

    Fibroblast growth factor-2 (FGF-2) has been implicated in various signaling processes which control embryonic growth and differentiation, adult physiology and pathology. To analyze the in vivo functions of this signaling molecule, the FGF-2 gene was inactivated by homologous recombination in mouse embryonic stem cells. FGF-2-deficient mice are viable, but display cerebral cortex defects at birth. Bromodeoxyuridine pulse labeling of embryos showed that proliferation of neuronal progenitors is normal, whereas a fraction of them fail to colonize their target layers in the cerebral cortex. A corresponding reduction in parvalbumin-positive neurons is observed in adult cortical layers. Neuronal defects are not limited to the cerebral cortex, as ectopic parvalbumin-positive neurons are present in the hippocampal commissure and neuronal deficiencies are observed in the cervical spinal cord. Physiological studies showed that FGF-2-deficient adult mice are hypotensive. They respond normally to angiotensin II-induced hypertension, whereas neural regulation of blood pressure by the baroreceptor reflex is impaired. The present genetic study establishes that FGF-2 participates in controlling fates, migration and differentiation of neuronal cells, whereas it is not essential for their proliferation. The observed autonomic dysfunction in FGF-2-deficient adult mice uncovers more general roles in neural development and function. PMID:9687490

  13. Gyrification from constrained cortical expansion

    PubMed Central

    Tallinen, Tuomas; Chung, Jun Young; Biggins, John S.; Mahadevan, L.

    2014-01-01

    The exterior of the mammalian brain—the cerebral cortex—has a conserved layered structure whose thickness varies little across species. However, selection pressures over evolutionary time scales have led to cortices that have a large surface area to volume ratio in some organisms, with the result that the brain is strongly convoluted into sulci and gyri. Here we show that the gyrification can arise as a nonlinear consequence of a simple mechanical instability driven by tangential expansion of the gray matter constrained by the white matter. A physical mimic of the process using a layered swelling gel captures the essence of the mechanism, and numerical simulations of the brain treated as a soft solid lead to the formation of cusped sulci and smooth gyri similar to those in the brain. The resulting gyrification patterns are a function of relative cortical expansion and relative thickness (compared with brain size), and are consistent with observations of a wide range of brains, ranging from smooth to highly convoluted. Furthermore, this dependence on two simple geometric parameters that characterize the brain also allows us to qualitatively explain how variations in these parameters lead to anatomical anomalies in such situations as polymicrogyria, pachygyria, and lissencephalia. PMID:25136099

  14. Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties

    PubMed Central

    Casale, Amanda E.; Foust, Amanda J.; Bal, Thierry

    2015-01-01

    The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca2+-activated K+ channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. SIGNIFICANCE STATEMENT Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons

  15. Regional vulnerability of longitudinal cortical association connectivity

    PubMed Central

    Ceschin, Rafael; Lee, Vince K.; Schmithorst, Vince; Panigrahy, Ashok

    2015-01-01

    Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior–anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior–anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal–thalamic–striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated

  16. Cerebral palsy.

    PubMed

    Graham, H Kerr; Rosenbaum, Peter; Paneth, Nigel; Dan, Bernard; Lin, Jean-Pierre; Damiano, Diane L; Becher, Jules G; Gaebler-Spira, Deborah; Colver, Allan; Reddihough, Dinah S; Crompton, Kylie E; Lieber, Richard L

    2016-01-07

    Cerebral palsy is the most common cause of childhood-onset, lifelong physical disability in most countries, affecting about 1 in 500 neonates with an estimated prevalence of 17 million people worldwide. Cerebral palsy is not a disease entity in the traditional sense but a clinical description of children who share features of a non-progressive brain injury or lesion acquired during the antenatal, perinatal or early postnatal period. The clinical manifestations of cerebral palsy vary greatly in the type of movement disorder, the degree of functional ability and limitation and the affected parts of the body. There is currently no cure, but progress is being made in both the prevention and the amelioration of the brain injury. For example, administration of magnesium sulfate during premature labour and cooling of high-risk infants can reduce the rate and severity of cerebral palsy. Although the disorder affects individuals throughout their lifetime, most cerebral palsy research efforts and management strategies currently focus on the needs of children. Clinical management of children with cerebral palsy is directed towards maximizing function and participation in activities and minimizing the effects of the factors that can make the condition worse, such as epilepsy, feeding challenges, hip dislocation and scoliosis. These management strategies include enhancing neurological function during early development; managing medical co-morbidities, weakness and hypertonia; using rehabilitation technologies to enhance motor function; and preventing secondary musculoskeletal problems. Meeting the needs of people with cerebral palsy in resource-poor settings is particularly challenging.

  17. Cerebral palsy.

    PubMed

    Graham, H Kerr; Rosenbaum, Peter; Paneth, Nigel; Dan, Bernard; Lin, Jean-Pierre; Damiano, Diane L; Becher, Jules G; Gaebler-Spira, Deborah; Colver, Allan; Reddihough, Dinah S; Crompton, Kylie E; Lieber, Richard L

    2016-01-01

    Cerebral palsy is the most common cause of childhood-onset, lifelong physical disability in most countries, affecting about 1 in 500 neonates with an estimated prevalence of 17 million people worldwide. Cerebral palsy is not a disease entity in the traditional sense but a clinical description of children who share features of a non-progressive brain injury or lesion acquired during the antenatal, perinatal or early postnatal period. The clinical manifestations of cerebral palsy vary greatly in the type of movement disorder, the degree of functional ability and limitation and the affected parts of the body. There is currently no cure, but progress is being made in both the prevention and the amelioration of the brain injury. For example, administration of magnesium sulfate during premature labour and cooling of high-risk infants can reduce the rate and severity of cerebral palsy. Although the disorder affects individuals throughout their lifetime, most cerebral palsy research efforts and management strategies currently focus on the needs of children. Clinical management of children with cerebral palsy is directed towards maximizing function and participation in activities and minimizing the effects of the factors that can make the condition worse, such as epilepsy, feeding challenges, hip dislocation and scoliosis. These management strategies include enhancing neurological function during early development; managing medical co-morbidities, weakness and hypertonia; using rehabilitation technologies to enhance motor function; and preventing secondary musculoskeletal problems. Meeting the needs of people with cerebral palsy in resource-poor settings is particularly challenging. PMID:27188686

  18. [Macro- and microscopic systematization of cerebral cortex malformations in children].

    PubMed

    Milovanov, A P; Milovanova, O A

    2011-01-01

    For the first time in pediatric pathologicoanatomic practice the complete systematization of cerebral cortex malformations is represented. Organ, macroscopic forms: microencephaly, macroencephaly, micropolygyria, pachygyria, schizencephaly, porencephaly, lissencephaly. Histic microdysgenesis of cortex: type I includes isolated abnormalities such as radial (IA) and tangential (I B) subtypes of cortical dislamination; type II includes sublocal cortical dislamination with immature dysmorphic neurons (II A) and balloon cells (II B); type III are the combination focal cortical dysplasia with tuberous sclerosis of the hippocampus (III A), tumors (III B) and malformations of vessels, traumatic and hypoxic disorders (III C). Band heterotopias. Subependimal nodular heterotopias. Tuberous sclerosis. Cellular typification of cortical dysplasia: immature neurons and balloon cells.

  19. Loss of γ-tubulin, GCP-WD/NEDD1 and CDK5RAP2 from the Centrosome of Neurons in Developing Mouse Cerebral and Cerebellar Cortex

    PubMed Central

    Yonezawa, Satoshi; Shigematsu, Momoko; Hirata, Kazuto; Hayashi, Kensuke

    2015-01-01

    It has been recently reported that the centrosome of neurons does not have microtubule nucleating activity. Microtubule nucleation requires γ-tubulin as well as its recruiting proteins, GCP-WD/NEDD1 and CDK5RAP2 that anchor γ-tubulin to the centrosome. Change in the localization of these proteins during in vivo development of brain, however, has not been well examined. In this study we investigate the localization of γ-tubulin, GCP-WD and CDK5RAP2 in developing cerebral and cerebellar cortex with immunofluorescence. We found that γ-tubulin and its recruiting proteins were localized at centrosomes of immature neurons, while they were lost at centrosomes in mature neurons. This indicated that the loss of microtubule nucleating activity at the centrosome of neurons is due to the loss of γ-tubulin-recruiting proteins from the centrosome. RT-PCR analysis revealed that these proteins are still expressed after birth, suggesting that they have a role in microtubule generation in cell body and dendrites of mature neurons. Microtubule regrowth experiments on cultured mature neurons showed that microtubules are nucleated not at the centrosome but within dendrites. These data indicated the translocation of microtubule-organizing activity from the centrosome to dendrites during maturation of neurons, which would explain the mixed polarity of microtubules in dendrites. PMID:26633906

  20. Loss of γ-tubulin, GCP-WD/NEDD1 and CDK5RAP2 from the Centrosome of Neurons in Developing Mouse Cerebral and Cerebellar Cortex.

    PubMed

    Yonezawa, Satoshi; Shigematsu, Momoko; Hirata, Kazuto; Hayashi, Kensuke

    2015-10-29

    It has been recently reported that the centrosome of neurons does not have microtubule nucleating activity. Microtubule nucleation requires γ-tubulin as well as its recruiting proteins, GCP-WD/NEDD1 and CDK5RAP2 that anchor γ-tubulin to the centrosome. Change in the localization of these proteins during in vivo development of brain, however, has not been well examined. In this study we investigate the localization of γ-tubulin, GCP-WD and CDK5RAP2 in developing cerebral and cerebellar cortex with immunofluorescence. We found that γ-tubulin and its recruiting proteins were localized at centrosomes of immature neurons, while they were lost at centrosomes in mature neurons. This indicated that the loss of microtubule nucleating activity at the centrosome of neurons is due to the loss of γ-tubulin-recruiting proteins from the centrosome. RT-PCR analysis revealed that these proteins are still expressed after birth, suggesting that they have a role in microtubule generation in cell body and dendrites of mature neurons. Microtubule regrowth experiments on cultured mature neurons showed that microtubules are nucleated not at the centrosome but within dendrites. These data indicated the translocation of microtubule-organizing activity from the centrosome to dendrites during maturation of neurons, which would explain the mixed polarity of microtubules in dendrites. PMID:26633906

  1. Reduced response of splenocytes after mitogen-stimulation in the prion protein (PrP) gene-deficient mouse: PrPLP/Doppel production and cerebral degeneration

    SciTech Connect

    Kim, Chi-Kyeong; Hirose, Yuko; Sakudo, Akikazu; Takeyama, Natsumi; Kang, Chung-Boo; Taniuchi, Yojiro; Matsumoto, Yoshitsugu; Itohara, Shigeyoshi; Sakaguchi, Suehiro; Onodera, Takashi . E-mail: aonoder@mail.ecc.u-tokyo.ac.jp

    2007-06-29

    Splenocytes of wild-type (Prnp {sup +/+}) and prion protein gene-deficient (Prnp {sup -/-}) mice were treated with various activation stimuli such as T cell mitogen concanavalin A (ConA), phorbol 12-myristate 13-acetate (PMA) + ionomycin (Io), or B cell mitogen lipopolysaccharide (LPS). Cellular prion protein (PrP{sup C}) expression was enhanced following ConA stimulation, but not PMA + Io or LPS in Prnp {sup +/+} splenocytes. Rikn Prnp {sup -/-} splenocytes elicited lower cell proliferations than Prnp {sup +/+} or Zrch I Prnp {sup -/-} splenocytes after LPS stimulation and showed sporadic nerve cells in the cerebral cortex and deeper structure. Around the degenerated nerve cells, mild vacuolation in the neuropil was observed. This neural alteration correlated well to the suppressed response of B cells in the spleen. The finding that discrete lesions within the central nervous systems induced marked modulation of immune function probably indicates the existence of a delicately balanced neural-endocrine network by PrP{sup C} and PrPLP/Doppel.

  2. Cerebral palsy

    MedlinePlus

    ... with pain and spasticity Place feeding tubes Release joint contractures ... the hip joint Injuries from falls Pressure sores Joint ... of the people who are affected by cerebral palsy) Social stigma

  3. Cerebral Palsy

    MedlinePlus

    ... Español (Spanish) Recommend on Facebook Tweet Share Compartir Cerebral palsy (CP) is a group of disorders that affect a ... ability to move and maintain balance and posture. CP is the most common motor disability in childhood. ...

  4. Cerebral Arteriosclerosis

    MedlinePlus

    ... Cerebral arteriosclerosis is the result of thickening and hardening of the walls of the arteries in the ... cause an ischemic stroke. When the thickening and hardening is uneven, arterial walls can develop bulges (called ...

  5. Cerebral hypoxia

    MedlinePlus

    ... death. Treatment depends on the cause of the hypoxia. Basic life support is most important. Treatment involves: Breathing ... Complications of cerebral hypoxia include a prolonged vegetative ... sleep-wake cycle, and eye opening, but the person is not alert ...

  6. Coordinated scaling of cortical and cerebellar numbers of neurons.

    PubMed

    Herculano-Houzel, Suzana

    2010-01-01

    While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species - an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of four different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora), Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble.

  7. Coordinated Scaling of Cortical and Cerebellar Numbers of Neurons

    PubMed Central

    Herculano-Houzel, Suzana

    2010-01-01

    While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species – an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of four different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora), Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble. PMID:20300467

  8. Subplate Neurons: Crucial Regulators of Cortical Development and Plasticity

    PubMed Central

    Kanold, Patrick O.

    2009-01-01

    The developing cerebral cortex contains a distinct class of cells, subplate neurons, which form one of the first functional cortical circuits. Subplate neurons reside in the cortical white matter, receive thalamic inputs and project into the developing cortical plate, mostly to layer 4. Subplate neurons are present at key time points during development. Removal of subplate neurons profoundly affects cortical development. Subplate removal in visual cortex prevents the maturation of thalamocortical synapse, the maturation of inhibition in layer 4, the development of orientation selective responses in individual cortical neurons, and the formation of ocular dominance columns. In addition, monocular deprivation during development reveals that ocular dominance plasticity is paradoxical in the absence of subplate neurons. Because subplate neurons projecting to layer 4 are glutamatergic, these diverse deficits following subplate removal were hypothesized to be due to lack of feed-forward thalamic driven cortical excitation. A computational model of the developing thalamocortical pathway incorporating feed-forward excitatory subplate projections replicates both normal development and plasticity of ocular dominance as well as the effects of subplate removal. Therefore, we postulate that feed-forward excitatory projections from subplate neurons into the developing cortical plate enhance correlated activity between thalamus and layer 4 and, in concert with Hebbian learning rules in layer 4, allow maturational and plastic processes in layer 4 to commence. Thus subplate neurons are a crucial regulator of cortical development and plasticity, and damage to these neurons might play a role in the pathology of many neurodevelopmental disorders. PMID:19738926

  9. Cerebral Paragonimiasis.

    PubMed

    Miyazaki, I

    1975-01-01

    The first case of cerebral paragonimiasis was reported by Otani in Japan in 1887. This was nine years after Kerbert's discovery of the fluke in the lungs of Bengal tigers and seven years after a human pulmonary infection by the fluke was demonstrated by Baelz and Manson. The first case was a 26-year-old man who had been suffering from cough and hemosputum for one year. The patient developed convulsive seizures with subsequent coma and died. The postmortem examination showed cystic lesions in the right frontal and occipital lobes. An adult fluke was found in the occipital lesion and another was seen in a gross specimen of normal brain tissue around the affected occipital lobe. Two years after Otani's discovery, at autopsy a 29-year-old man with a history of Jacksonian seizure was reported as having cerebral paragonimiasis. Some time later, however, it was confirmed that the case was actually cerebral schistosomiasis japonica. Subsequently, cases of cerebral paragonimiasis were reported. However, the majority of these cases were not confirmed histologically. It was pointed out that some of these early cases were probably not Paragonimus infection. After World War II, reviews as well as case reports were published. Recently, investigations have been reported from Korea, with a clinicla study on 62 cases of cerebral paragonimiasis seen at the Neurology Department of the National Medical Center, Seoul, between 1958 and 1964. In 1971 Higashi described a statistical study on 105 cases of cerebral paragonimiasis that had been treated surgically in Japan.

  10. Cerebral Paragonimiasis.

    PubMed

    Miyazaki, I

    1975-01-01

    The first case of cerebral paragonimiasis was reported by Otani in Japan in 1887. This was nine years after Kerbert's discovery of the fluke in the lungs of Bengal tigers and seven years after a human pulmonary infection by the fluke was demonstrated by Baelz and Manson. The first case was a 26-year-old man who had been suffering from cough and hemosputum for one year. The patient developed convulsive seizures with subsequent coma and died. The postmortem examination showed cystic lesions in the right frontal and occipital lobes. An adult fluke was found in the occipital lesion and another was seen in a gross specimen of normal brain tissue around the affected occipital lobe. Two years after Otani's discovery, at autopsy a 29-year-old man with a history of Jacksonian seizure was reported as having cerebral paragonimiasis. Some time later, however, it was confirmed that the case was actually cerebral schistosomiasis japonica. Subsequently, cases of cerebral paragonimiasis were reported. However, the majority of these cases were not confirmed histologically. It was pointed out that some of these early cases were probably not Paragonimus infection. After World War II, reviews as well as case reports were published. Recently, investigations have been reported from Korea, with a clinicla study on 62 cases of cerebral paragonimiasis seen at the Neurology Department of the National Medical Center, Seoul, between 1958 and 1964. In 1971 Higashi described a statistical study on 105 cases of cerebral paragonimiasis that had been treated surgically in Japan. PMID:1095292

  11. Cortical thickness reduction in individuals at ultra-high-risk for psychosis.

    PubMed

    Jung, Wi Hoon; Kim, June Sic; Jang, Joon Hwan; Choi, Jung-Seok; Jung, Myung Hun; Park, Ji-Young; Han, Ji Yeon; Choi, Chi-Hoon; Kang, Do-Hyung; Chung, Chun Kee; Kwon, Jun Soo

    2011-07-01

    Although schizophrenia is characterized by gray matter (GM) abnormalities, particularly in the prefrontal and temporal cortices, it is unclear whether cerebral cortical GM is abnormal in individuals at ultra-high-risk (UHR) for psychosis. We addressed this issue by studying cortical thickness in this group with magnetic resonance imaging (MRI). We measured cortical thickness of 29 individuals with no family history of psychosis at UHR, 31 patients with schizophrenia, and 29 healthy matched control subjects using automated surface-based analysis of structural MRI data. Hemispheric mean and regional cortical thickness were significantly different according to the stage of the disease. Significant cortical differences across these 3 groups were found in the distributed area of cerebral cortices. UHR group showed significant cortical thinning in the prefrontal cortex, anterior cingulate cortex, inferior parietal cortex, parahippocampal cortex, and superior temporal gyrus compared with healthy control subjects. Significant cortical thinning in schizophrenia group relative to UHR group was found in all the regions described above in addition with posterior cingulate cortex, insular cortex, and precentral cortex. These changes were more pronounced in the schizophrenia group compared with the control subjects. These findings suggest that UHR is associated with cortical thinning in regions that correspond to the structural abnormalities found in schizophrenia. These structural abnormalities might reflect functional decline at the prodromal stage of schizophrenia, and there may be progressive thinning of GM cortex over time. PMID:20026559

  12. Cerebral Palsy (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Cerebral Palsy KidsHealth > For Parents > Cerebral Palsy Print A A ... kids who are living with the condition. About Cerebral Palsy Cerebral palsy is one of the most common ...

  13. Cerebral palsy - resources

    MedlinePlus

    Resources - cerebral palsy ... The following organizations are good resources for information on cerebral palsy : National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov/disorders/cerebral_palsy/cerebral_palsy. ...

  14. Spindle Bursts in Neonatal Rat Cerebral Cortex

    PubMed Central

    Yang, Jenq-Wei; Reyes-Puerta, Vicente; Kilb, Werner; Luhmann, Heiko J.

    2016-01-01

    Spontaneous and sensory evoked spindle bursts represent a functional hallmark of the developing cerebral cortex in vitro and in vivo. They have been observed in various neocortical areas of numerous species, including newborn rodents and preterm human infants. Spindle bursts are generated in complex neocortical-subcortical circuits involving in many cases the participation of motor brain regions. Together with early gamma oscillations, spindle bursts synchronize the activity of a local neuronal network organized in a cortical column. Disturbances in spindle burst activity during corticogenesis may contribute to disorders in cortical architecture and in the activity-dependent control of programmed cell death. In this review we discuss (i) the functional properties of spindle bursts, (ii) the mechanisms underlying their generation, (iii) the synchronous patterns and cortical networks associated with spindle bursts, and (iv) the physiological and pathophysiological role of spindle bursts during early cortical development. PMID:27034844

  15. Spindle Bursts in Neonatal Rat Cerebral Cortex.

    PubMed

    Yang, Jenq-Wei; Reyes-Puerta, Vicente; Kilb, Werner; Luhmann, Heiko J

    2016-01-01

    Spontaneous and sensory evoked spindle bursts represent a functional hallmark of the developing cerebral cortex in vitro and in vivo. They have been observed in various neocortical areas of numerous species, including newborn rodents and preterm human infants. Spindle bursts are generated in complex neocortical-subcortical circuits involving in many cases the participation of motor brain regions. Together with early gamma oscillations, spindle bursts synchronize the activity of a local neuronal network organized in a cortical column. Disturbances in spindle burst activity during corticogenesis may contribute to disorders in cortical architecture and in the activity-dependent control of programmed cell death. In this review we discuss (i) the functional properties of spindle bursts, (ii) the mechanisms underlying their generation, (iii) the synchronous patterns and cortical networks associated with spindle bursts, and (iv) the physiological and pathophysiological role of spindle bursts during early cortical development.

  16. Nicotinic modulation of cortical circuits

    PubMed Central

    Arroyo, Sergio; Bennett, Corbett; Hestrin, Shaul

    2014-01-01

    The ascending cholinergic neuromodulatory system sends projections throughout cortex and has been shown to play an important role in a number of cognitive functions including arousal, working memory, and attention. However, despite a wealth of behavioral and anatomical data, understanding how cholinergic synapses modulate cortical function has been limited by the inability to selectively activate cholinergic axons. Now, with the development of optogenetic tools and cell-type specific Cre-driver mouse lines, it has become possible to stimulate cholinergic axons from the basal forebrain (BF) and probe cholinergic synapses in the cortex for the first time. Here we review recent work studying the cell-type specificity of nicotinic signaling in the cortex, synaptic mechanisms mediating cholinergic transmission, and the potential functional role of nicotinic modulation. PMID:24734005

  17. Bilaterally symmetric focal cortical dysplasia in a golden retriever dog.

    PubMed

    Casey, K M; Bollen, A W; Winger, K M; Vernau, K M; Dickinson, P J; Higgins, R J; Sisó, S

    2014-11-01

    A 10-year-old golden retriever dog was referred with a 24-h history of generalized seizures. Magnetic resonance imaging of the brain found no abnormalities on 3 mm transverse sections and the dog was subsequently humanely destroyed. Microscopically there was bilaterally symmetrical focal disorganization of cortical grey matter within the tips of the right and left suprasylvian gyri of the temporal cortex. The focal abnormal cortical lamination was characterized by loss of pyramidal neurons with abnormal, irregular, angular, remaining neurons occasionally forming clusters, surrounded by fibrillary astrogliosis and microgliosis and vascular proliferation. These histological findings are consistent with focal cortical dysplasia, a cerebral cortical malformation that causes seizures in people, but not reported previously in the dog. PMID:25246180

  18. [Noradrenaline and cerebral aging].

    PubMed

    Jouvet, M; Albarede, J L; Lubin, S; Meyrignac, C

    1991-01-01

    The central functions of norepinephrine (NE) are a recent discovery: regulation of alertness and of the wakefulness-sleep cycle, maintenance of attention, memory and learning, cerebral plasticity and neuro-protection. The anatomical, histological, biochemical and physiological properties of the central noradrenergic system: extreme capacity for ramification and arborization; slow conduction, non-myelinized axons with extrasynaptic varicosities producing and releasing NE; frequency of co-transmission phenomena, and; neuromodulation with fiber effect responsible for improvement in the signal over background noise ratio and selection of significant stimuli form a true interface between the outside world and the central nervous system, notably for the neocortex in the context of the cognitive treatment of information. This central noradrenergic system is involved in the neurophysiology and the clinical features of cerebral aging (ideation-motor and cognitive function slowing down, loss of behavioral adjustment), neuro-degenerative disorders (SDAT, Parkinson's disease), certain aspects of depression and less obvious conditions (head injuries, sequelae of cerebrovascular accidents, sub-cortical dementia). The recent development of medications improving alertness (adrafinil, modafinil) with a pure central action and specifically noradrenergic, may contribute to an improvement in these multifactorial disorders. PMID:1864252

  19. Cerebral palsy.

    PubMed

    Colver, Allan; Fairhurst, Charles; Pharoah, Peter O D

    2014-04-01

    The syndrome of cerebral palsy encompasses a large group of childhood movement and posture disorders. Severity, patterns of motor involvement, and associated impairments such as those of communication, intellectual ability, and epilepsy vary widely. Overall prevalence has remained stable in the past 40 years at 2-3·5 cases per 1000 livebirths, despite changes in antenatal and perinatal care. The few studies available from developing countries suggest prevalence of comparable magnitude. Cerebral palsy is a lifelong disorder; approaches to intervention, whether at an individual or environmental level, should recognise that quality of life and social participation throughout life are what individuals with cerebral palsy seek, not improved physical function for its own sake. In the past few years, the cerebral palsy community has learned that the evidence of benefit for the numerous drugs, surgery, and therapies used over previous decades is weak. Improved understanding of the role of multiple gestation in pathogenesis, of gene environment interaction, and how to influence brain plasticity could yield significant advances in treatment of the disorder. Reduction in the prevalence of post-neonatal cerebral palsy, especially in developing countries, should be possible through improved nutrition, infection control, and accident prevention.

  20. Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography.

    PubMed

    Jordan, Graeme R; McCulloch, James; Shahid, Mohammed; Hill, David R; Henry, Brian; Horsburgh, Karen

    2005-08-01

    AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.

  1. Apraxia in deep cerebral lesions.

    PubMed Central

    Agostoni, E; Coletti, A; Orlando, G; Tredici, G

    1983-01-01

    In a series of 50 patients with cerebrovascular lesions (demonstrated with CT scan), seven patients had lesions located in the basal ganglia and/or thalamus. All these seven patients were apractic. Ideomotor apraxia was present in all patients; five also had constructional apraxia, and one had bucco-facial apraxia. None of the patients had utilisation apraxia. These observations indicated that apraxia is not only a "high cerebral (cortical) function", but may depend also on the integrity of subcortical circuits and structures. PMID:6619888

  2. Effects of cerebral ischemia on neuronal hemoglobin

    PubMed Central

    He, Yangdong; Hua, Ya; Liu, Wenquan; Hu, Haitao; Keep, Richard F.; Xi, Guohua

    2009-01-01

    Summary The present study examined whether or not neuronal hemoglobin (Hb) is present in rats. It then examined whether cerebral ischemia or ischemic preconditioning (IPC) affects neuronal Hb levels in vivo and in vitro. In vivo, male Sprague-Dawley rats were subjected to either 15 minutes of transient middle cerebral artery occlusion with 24 hours of reperfusion, an IPC stimulus, or 24 hours of permanent middle cerebral artery occlusion (pMCAO), or IPC followed three days later by 24 hours of pMCAO. In vitro, primary cultured neurons were exposed to 2 hours of oxygen-glucose deprivation with 22 hours of reoxygenation. Results showed that Hb is widely expressed in rat cerebral neurons but not astrocytes. Hb expression was significantly upregulated in the ipsilateral caudate and the cortical core of the middle cerebral artery territory after IPC. Hb levels also increased in more penumbral cortex and the contralateral hemisphere 24 hours after pMCAO, but expression in the ipsilateral caudate and cortical core area were decreased. Ischemic preconditioning modified pMCAO-induced brain Hb changes. Neuronal Hb levels in vitro were increased by 2 hours of oxygen-glucose deprivation and 22 hours of reoxygenation. These results indicate that Hb is synthesized in neurons and can be upregulated by ischemia. PMID:19066615

  3. Radionuclide cerebral perfusion imaging: Normal pattern

    SciTech Connect

    Goldsmith, S.J.; Stritzke, P.; Losonczy, M.; Vallabhajosula, S.; Holan, V.; DaCosta, M.; Muzinic, M.

    1991-12-31

    Regional cerebral perfusion imaging using a new class of {sup 99m}Tc and {sup 123}I labeled compounds which traverse the blood brain barrier and SPECT imaging technology provides an opportunity to assess this physiologic phenomenon during normal cerebral function and as a manifestation of disease in the central nervous system disease. These applications pose a challenge to the nuclear medicine physician for several reasons: (a) the complex and somewhat unfamiliar functional anatomy, (b) the marked regional differences in regional cerebral perfusion at rest, (c) the lack of understanding of the effect of variations in ambient conditions on regional cerebral perfusion. The difficulties in interpretation are augmented by the display itself. There is frequently no difficulty in differentiating between gray and white matter. However, the frequently used {open_quotes}hot body{close_quotes} color maps, introduce a good deal of contrast, producing displays with apparent interruption in regional cortical perfusion whereas black and white displays provide minimal contrast in the regional cortical activity. The authors sought to define how much variation in regional cerebral perfusion is {open_quotes}allowed{close_quotes} under controlled conditions, to establish a basis to interpret if changes in the environment, psychological interventions, or disease states are accompanied by a measurable change. 2 figs., 1 tab.

  4. Cortical control of anticipatory postural adjustments prior to stepping.

    PubMed

    Varghese, J P; Merino, D M; Beyer, K B; McIlroy, W E

    2016-01-28

    Human bipedal balance control is achieved either reactively or predictively by a distributed network of neural areas within the central nervous system with a potential role for cerebral cortex. While the role of the cortex in reactive balance has been widely explored, only few studies have addressed the cortical activations related to predictive balance control. The present study investigated the cortical activations related to the preparation and execution of anticipatory postural adjustment (APA) that precede a step. This study also examined whether the preparatory cortical activations related to a specific movement is dependent on the context of control (postural component vs. focal component). Ground reaction forces and electroencephalographic (EEG) data were recorded from 14 healthy adults while they performed lateral weight shift and lateral stepping with and without initially preloading their weight to the stance leg. EEG analysis revealed that there were distinct movement-related potentials (MRPs) with concurrent event-related desynchronization (ERD) of mu and beta rhythms prior to the onset of APA and also to the onset of foot-off during lateral stepping in the fronto-central cortical areas. Also, the MRPs and ERD prior to the onset of APA and onset of lateral weight shift were not significantly different suggesting the comparable cortical activations for the generation of postural and focal movements. The present study reveals the occurrence of cortical activation prior to the execution of an APA that precedes a step. Importantly, this cortical activity appears independent of the context of the movement. PMID:26608123

  5. Cortical spreading depression: An enigma

    NASA Astrophysics Data System (ADS)

    Miura, R. M.; Huang, H.; Wylie, J. J.

    2007-08-01

    The brain is a complex organ with active components composed largely of neurons, glial cells, and blood vessels. There exists an enormous experimental and theoretical literature on the mechanisms involved in the functioning of the brain, but we still do not have a good understanding of how it works on a gross mechanistic level. In general, the brain maintains a homeostatic state with relatively small ion concentration changes, the major ions being sodium, potassium, and chloride. Calcium ions are present in smaller quantities but still play an important role in many phenomena. Cortical spreading depression (CSD for short) was discovered over 60 years ago by A.A.P. Leão, a Brazilian physiologist doing his doctoral research on epilepsy at Harvard University, “Spreading depression of activity in the cerebral cortex," J. Neurophysiol., 7 (1944), pp. 359-390. Cortical spreading depression is characterized by massive changes in ionic concentrations and slow nonlinear chemical waves, with speeds on the order of mm/min, in the cortex of different brain structures in various experimental animals. In humans, CSD is associated with migraine with aura, where a light scintillation in the visual field propagates, then disappears, and is followed by a sustained headache. To date, CSD remains an enigma, and further detailed experimental and theoretical investigations are needed to develop a comprehensive picture of the diverse mechanisms involved in producing CSD. A number of mechanisms have been hypothesized to be important for CSD wave propagation. In this paper, we briefly describe several characteristics of CSD wave propagation, and examine some of the mechanisms that are believed to be important, including ion diffusion, membrane ionic currents, osmotic effects, spatial buffering, neurotransmitter substances, gap junctions, metabolic pumps, and synaptic connections. Continuum models of CSD, consisting of coupled nonlinear diffusion equations for the ion concentrations, and

  6. Pathophysiological analyses of cortical malformation using gyrencephalic mammals

    PubMed Central

    Masuda, Kosuke; Toda, Tomohisa; Shinmyo, Yohei; Ebisu, Haruka; Hoshiba, Yoshio; Wakimoto, Mayu; Ichikawa, Yoshie; Kawasaki, Hiroshi

    2015-01-01

    One of the most prominent features of the cerebral cortex of higher mammals is the presence of gyri. Because malformations of the cortical gyri are associated with severe disability in brain function, the mechanisms underlying malformations of the cortical gyri have been of great interest. Combining gyrencephalic carnivore ferrets and genetic manipulations using in utero electroporation, here we successfully recapitulated the cortical phenotypes of thanatophoric dysplasia (TD) by expressing fibroblast growth factor 8 in the ferret cerebral cortex. Strikingly, in contrast to TD mice, our TD ferret model showed not only megalencephaly but also polymicrogyria. We further uncovered that outer radial glial cells (oRGs) and intermediate progenitor cells (IPs) were markedly increased. Because it has been proposed that increased oRGs and/or IPs resulted in the appearance of cortical gyri during evolution, it seemed possible that increased oRGs and IPs underlie the pathogenesis of polymicrogyria. Our findings should help shed light on the molecular mechanisms underlying the formation and malformation of cortical gyri in higher mammals. PMID:26482531

  7. Pathophysiological analyses of cortical malformation using gyrencephalic mammals.

    PubMed

    Masuda, Kosuke; Toda, Tomohisa; Shinmyo, Yohei; Ebisu, Haruka; Hoshiba, Yoshio; Wakimoto, Mayu; Ichikawa, Yoshie; Kawasaki, Hiroshi

    2015-01-01

    One of the most prominent features of the cerebral cortex of higher mammals is the presence of gyri. Because malformations of the cortical gyri are associated with severe disability in brain function, the mechanisms underlying malformations of the cortical gyri have been of great interest. Combining gyrencephalic carnivore ferrets and genetic manipulations using in utero electroporation, here we successfully recapitulated the cortical phenotypes of thanatophoric dysplasia (TD) by expressing fibroblast growth factor 8 in the ferret cerebral cortex. Strikingly, in contrast to TD mice, our TD ferret model showed not only megalencephaly but also polymicrogyria. We further uncovered that outer radial glial cells (oRGs) and intermediate progenitor cells (IPs) were markedly increased. Because it has been proposed that increased oRGs and/or IPs resulted in the appearance of cortical gyri during evolution, it seemed possible that increased oRGs and IPs underlie the pathogenesis of polymicrogyria. Our findings should help shed light on the molecular mechanisms underlying the formation and malformation of cortical gyri in higher mammals. PMID:26482531

  8. Research on relation between cortical functional section and acupuncture point

    NASA Astrophysics Data System (ADS)

    Chen, Shuwang; Li, Chunhua; Liang, Guozhuang; Wang, Shuhai

    2008-02-01

    The application of the infrared imaging using in the brain cognition and the acupuncture is introduced. Acupuncturing a certain point of the healthy experimental cats, observing the responds of the cerebral cortical temperature by using of infrared imaging, and researching the corresponding relation between the acupuncture points with the active sections of the cerebral cortex, so the effect of the acupuncture is obtained. The theory of the refreshment and induce resuscitation pinprick is approved. The method of the "refreshment and induce resuscitation pinprick" can promote the metabolize renovation, improve the living function and increase the healing rate. However, the relations between the points and the cortical functional sections have not the last word still. After removing the skulls on the head, full of the cerebral cortex of a cat are exposed. Observing the infrared imaging and measuring the temperatures of the visual cerebral cortex during the process of acupuncturing the points to judge the activation position. During the process of acupuncture, the trend of the rising temperature on cerebral cortex is primary in terms of the phenomena in the infrared pictures. The cortical hemogram variety is measured in terms of the infrared pictures and the temperature values, so the characteristic curve of the temperature for a corresponding position on the cerebral cortex and the acupuncture point can be obtained. When the acupuncture point is changed, the position where temperature varied on cerebral cortex is different correspondingly. The variety in the cortical functional sections is corresponding to the result of the acupuncture point in terms of the imaging and the temperatures. The experimental results accord with the theoretic model, so they validate the correctness of the "refreshment and induce resuscitation pinprick". According to the experimental results, we know that the variety of a cortical functional section is corresponding to a special acupuncture

  9. Progenitor genealogy in the developing cerebral cortex.

    PubMed

    Laguesse, Sophie; Peyre, Elise; Nguyen, Laurent

    2015-01-01

    The mammalian cerebral cortex is characterized by a complex histological organization that reflects the spatio-temporal stratifications of related stem and neural progenitor cells, which are responsible for the generation of distinct glial and neuronal subtypes during development. Some work has been done to shed light on the existing filiations between these progenitors as well as their respective contribution to cortical neurogenesis. The aim of the present review is to summarize the current views of progenitor hierarchy and relationship in the developing cortex and to further discuss future research directions that would help us to understand the molecular and cellular regulating mechanisms involved in cerebral corticogenesis. PMID:25141969

  10. CORTICAL SURFACE PARAMETERIZATION BY P-HARMONIC ENERGY MINIMIZATION

    PubMed Central

    JOSHI, ANAND A.; SHATTUCK, DAVID W.; THOMPSON, PAUL M.; LEAHY, RICHARD M.

    2010-01-01

    Cortical surface parameterization has several applications in visualization and analysis of the brain surface. Here we propose a scheme for parameterizing the surface of the cerebral cortex. The parameterization is formulated as the minimization of an energy functional in the pth norm. A numerical method for obtaining the solution is also presented. Brain surfaces from multiple subjects are brought into common parameter space using the scheme. 3D spatial averages of the cortical surfaces are generated by using the correspondences induced by common parameter space. PMID:20721316

  11. Impairment of Oligodendroglia Maturation Leads to Aberrantly Increased Cortical Glutamate and Anxiety-Like Behaviors in Juvenile Mice

    PubMed Central

    Chen, Xianjun; Zhang, Weiguo; Li, Tao; Guo, Yu; Tian, Yanping; Wang, Fei; Liu, Shubao; Shen, Hai-Ying; Feng, Yue; Xiao, Lan

    2015-01-01

    Adolescence is the critical time for developing proper oligodendrocyte (OL)-neuron interaction and the peak of onset for many cognitive diseases, among which anxiety disorders display the highest prevalence. However, whether impairment of de novo OL development causes neuronal abnormalities and contributes to the early onset of anxiety phenotype in childhood still remains unexplored. In this study, we tested the hypothesis that defects in OL maturation manifests cortical neuron function and leads to anxiety-like behaviors in juvenile mice. We report here that conditional knockout of the Olig2 gene (Olig2 cKO) specifically in differentiating OLs in the mouse brain preferentially impaired OL maturation in the gray matter of cerebral cortex. Interestingly, localized proton magnetic resonance spectroscopy revealed that Olig2 cKO mice displayed abnormally elevated cortical glutamate levels. In addition, transmission electron microscopy demonstrated increased vesicle density in excitatory glutamatergic synapses in the cortex of the Olig2 cKO mice. Moreover, juvenile Olig2 cKO mice exhibited anxiety-like behaviors and impairment in behavioral inhibition. Taken together, our results suggest that impaired OL development affects glutamatergic neuron function in the cortex and causes anxiety-related behaviors in juvenile mice. These discoveries raise an intriguing possibility that OL defects may be a contributing mechanism for the onset of anxiety in childhood. PMID:26696827

  12. Prediction for human intelligence using morphometric characteristics of cortical surface: partial least square analysis.

    PubMed

    Yang, J-J; Yoon, U; Yun, H J; Im, K; Choi, Y Y; Lee, K H; Park, H; Hough, M G; Lee, J-M

    2013-08-29

    A number of imaging studies have reported neuroanatomical correlates of human intelligence with various morphological characteristics of the cerebral cortex. However, it is not yet clear whether these morphological properties of the cerebral cortex account for human intelligence. We assumed that the complex structure of the cerebral cortex could be explained effectively considering cortical thickness, surface area, sulcal depth and absolute mean curvature together. In 78 young healthy adults (age range: 17-27, male/female: 39/39), we used the full-scale intelligence quotient (FSIQ) and the cortical measurements calculated in native space from each subject to determine how much combining various cortical measures explained human intelligence. Since each cortical measure is thought to be not independent but highly inter-related, we applied partial least square (PLS) regression, which is one of the most promising multivariate analysis approaches, to overcome multicollinearity among cortical measures. Our results showed that 30% of FSIQ was explained by the first latent variable extracted from PLS regression analysis. Although it is difficult to relate the first derived latent variable with specific anatomy, we found that cortical thickness measures had a substantial impact on the PLS model supporting the most significant factor accounting for FSIQ. Our results presented here strongly suggest that the new predictor combining different morphometric properties of complex cortical structure is well suited for predicting human intelligence. PMID:23643979

  13. Focal thinning of the cerebral cortex in multiple sclerosis.

    PubMed

    Sailer, Michael; Fischl, Bruce; Salat, David; Tempelmann, Claus; Schönfeld, Mircea Ariel; Busa, Evelina; Bodammer, Nils; Heinze, Hans-Jochen; Dale, Anders

    2003-08-01

    Brain atrophy as determined by quantitative MRI can be used to characterize disease progression in multiple sclerosis. Many studies have addressed white matter (WM) alterations leading to atrophy, while changes of the cerebral cortex have been studied to a lesser extent. In vivo, the cerebral cortex has been difficult to study due to its complex structure and regional variability. Measurement of cerebral cortex thickness at different disease stages may provide new insights into grey matter (GM) pathology. In the present investigation, we evaluated in vivo cortical thickness and its relationship to disability, disease duration, WM T2 hyper-intense and T1 hypo-intense lesion volumes. High-resolution MRI brain scans were obtained in 20 patients with clinically definite multiple sclerosis and 15 age-matched normal subjects. A novel method of automated surface reconstruction yielded measurements of the cortical thickness for each subject's entire brain and computed cross-subject statistics based on the cortical anatomy. Statistical thickness difference maps were generated by performing t-tests between patient and control groups and individual thickness measures were submitted to analyses of variance to investigate the relationship between cortical thickness and clinical variables. The mean overall thickness of the cortical ribbon was reduced in multiple sclerosis patients compared with controls [2.30 mm (SD 0.14) versus 2.48 mm (SD 0.11)], showing a significant main effect of group (controls versus patients). In patients, we found significant main effects for disability, disease duration, T2 and T1 lesion volumes. The visualization of statistical difference maps of the cortical GM thickness on inflated brains across the cortical surface revealed a distinct distribution of significant focal thinning of the cerebral cortex in addition to the diffuse cortical atrophy. Focal cortical thinning in frontal [2.37 mm (SD 0.17) versus 2.73 mm (SD 0.25)] and in temporal [2.65 mm

  14. Development and specification of GABAergic cortical interneurons

    PubMed Central

    2013-01-01

    GABAergic interneurons are inhibitory neurons of the nervous system that play a vital role in neural circuitry and activity. They are so named due to their release of the neurotransmitter gamma-aminobutyric acid (GABA), and occupy different areas of the brain. This review will focus primarily on GABAergic interneurons of the mammalian cerebral cortex from a developmental standpoint. There is a diverse amount of cortical interneuronal subtypes that may be categorized by a number of characteristics; this review will classify them largely by the protein markers they express. The developmental origins of GABAergic interneurons will be discussed, as well as factors that influence the complex migration routes that these interneurons must take in order to ultimately localize in the cerebral cortex where they will integrate with the neural circuitry set in place. This review will also place an emphasis on the transcriptional network of genes that play a role in the specification and maintenance of GABAergic interneuron fate. Gaining an understanding of the different aspects of cortical interneuron development and specification, especially in humans, has many useful clinical applications that may serve to treat various neurological disorders linked to alterations in interneuron populations. PMID:23618463

  15. Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder.

    PubMed

    Smiley, John F; Saito, Mariko; Bleiwas, Cynthia; Masiello, Kurt; Ardekani, Babak; Guilfoyle, David N; Gerum, Scott; Wilson, Donald A; Vadasz, Csaba

    2015-09-01

    Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10-13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD.

  16. Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder

    PubMed Central

    Smiley, John F.; Saito, Mariko; Bleiwas, Cynthia; Masiello, Kurt; Ardekani, Babak; Guilfoyle, David N.; Gerum, Scott; Wilson, Donald A.; Vadasz, Csaba

    2015-01-01

    Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10–13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD. PMID:26252988

  17. Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder.

    PubMed

    Smiley, John F; Saito, Mariko; Bleiwas, Cynthia; Masiello, Kurt; Ardekani, Babak; Guilfoyle, David N; Gerum, Scott; Wilson, Donald A; Vadasz, Csaba

    2015-09-01

    Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10-13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD. PMID:26252988

  18. Labeling of cerebral amyloid in vivo with a monoclonal antibody.

    PubMed

    Walker, L C; Price, D L; Voytko, M L; Schenk, D B

    1994-07-01

    We assessed the ability of a murine monoclonal antibody to bind selectively to beta-amyloid in the brains of living nonhuman primates. To circumvent the blood-brain barrier, we injected unlabeled antibody 10D5 (murine whole IgG1 and/or Fab fragments) into the cerebrospinal fluid of the cisterna magna in three aged monkeys. A control animal was given an intracisternal injection of nonimmune mouse whole IgG plus Fab. Twenty-four hours later, the animals were perfused and prepared for immunohistochemical detection of bound murine immunoglobulin in brain. All three experimental animals showed selective binding of 10D5 to approximately 5-15% of amyloid deposits in cerebral cortex, primarily near the cortical surface. There was no labeling in the control animal. In vivo-labeled deposits were confirmed to be beta-amyloid by electron microscopy and by in vitro immunohistochemistry in adjacent sections. The animals tolerated the injection well, although some polymorphonuclear leukocytes infiltrated portions of the subarachnoid space and superficial neocortex. These results provide the first demonstration that it may be feasible to selectively direct a tagged monoclonal antibody to beta-amyloid in the brain for therapeutic or diagnostic purposes. With enhancement of labeling efficiency, the method also may be useful for studying the progression of beta-amyloidosis in experimental animals using emission tomography. PMID:8021711

  19. Neural Networks of the Mouse Neocortex

    PubMed Central

    Zingg, Brian; Hintiryan, Houri; Gou, Lin; Song, Monica Y.; Bay, Maxwell; Bienkowski, Michael S.; Foster, Nicholas N.; Yamashita, Seita; Bowman, Ian; Toga, Arthur W.; Dong, Hong-Wei

    2014-01-01

    SUMMARY Numerous studies have examined the neuronal inputs and/or outputs of many areas of the brain cortex, but how these areas organize into broader communication networks across the cortex is unclear. Over 600 labeled neuronal pathways acquired from tracer injections placed across the entire mouse neocortex enabled us to generate a cortical connectivity atlas. 240 intracortical connections were manually reconstructed within a common neuroanatomic framework, forming a cortico-cortical connectivity map that facilitates comparison of connections from different cortical targets. Connectivity matrices were generated to provide an overview of all intracortical connections and subnetwork clusterings. The connectivity matrices and cortical map revealed that the entire cortex is organized into four somatic sensorimotor, two medial, and two lateral subnetworks that display unique topologies and can interact through select cortical areas. Together, these data provide a resource that can be used to further investigate cortical networks and their corresponding functions. PMID:24581503

  20. Cortical control of thermoregulatory sympathetic activation.

    PubMed

    Fechir, M; Klega, A; Buchholz, H G; Pfeifer, N; Balon, S; Schlereth, T; Geber, C; Breimhorst, M; Maihöfner, C; Birklein, F; Schreckenberger, M

    2010-06-01

    Thermoregulation enables adaptation to different ambient temperatures. A complex network of central autonomic centres may be involved. In contrast to the brainstem, the role of the cortex has not been clearly evaluated. This study was therefore designed to address cerebral function during a whole thermoregulatory cycle (cold, neutral and warm stimulation) using 18-fluordeoxyglucose-PET (FDG-PET). Sympathetic activation parameters were co-registered. Ten healthy male volunteers were examined three times on three different days in a water-perfused whole-body suit. After a baseline period (32 degrees C), temperature was either decreased to 7 degrees C (cold), increased to 50 degrees C (warm) or kept constant (32 degrees C, neutral), thereafter the PET examination was performed. Cerebral glucose metabolism was increased in infrapontine brainstem and cerebellar hemispheres during cooling and warming, each compared with neutral temperature. Simultaneously, FDG uptake decreased in the bilateral anterior/mid-cingulate cortex during warming, and in the right insula during cooling and warming. Conjunction analyses revealed that right insular deactivation and brainstem activation appeared both during cold and warm stimulation. Metabolic connectivity analyses revealed positive correlations between the cortical activations, and negative correlations between these cortical areas and brainstem/cerebellar regions. Heart rate changes negatively correlated with glucose metabolism in the anterior cingulate cortex and in the middle frontal gyrus/dorsolateral prefrontal cortex, and changes of sweating with glucose metabolism in the posterior cingulate cortex. In summary, these results suggest that the cerebral cortex exerts an inhibitory control on autonomic centres located in the brainstem or cerebellum. These findings may represent reasonable explanations for sympathetic hyperactivity, which occurs, for example, after hemispheric stroke.

  1. Multinutrient diets improve cerebral perfusion and neuroprotection in a murine model of Alzheimer's disease.

    PubMed

    Zerbi, Valerio; Jansen, Diane; Wiesmann, Maximilian; Fang, Xiaotian; Broersen, Laus M; Veltien, Andor; Heerschap, Arend; Kiliaan, Amanda J

    2014-03-01

    Nutritional intervention may retard the development of Alzheimer's disease (AD). In this study we tested the effects of 2 multi-nutrient diets in an AD mouse model (APPswe/PS1dE9). One diet contained membrane precursors such as omega-3 fatty acids and uridine monophosphate (DEU), whereas another diet contained cofactors for membrane synthesis as well (Fortasyn); the diets were developed to enhance synaptic membranes synthesis, and contain components that may improve vascular health. We measured cerebral blood flow (CBF) and water diffusivity with ultra-high-field magnetic resonance imaging, as alterations in these parameters correlate with clinical symptoms of the disease. APPswe/PS1dE9 mice on control diet showed decreased CBF and changes in brain water diffusion, in accordance with findings of hypoperfusion, axonal disconnection and neuronal loss in patients with AD. Both multinutrient diets were able to increase cortical CBF in APPswe/PS1dE9 mice and Fortasyn reduced water diffusivity, particularly in the dentate gyrus and in cortical regions. We suggest that a specific diet intervention has the potential to slow AD progression, by simultaneously improving cerebrovascular health and enhancing neuroprotective mechanisms. PMID:24210253

  2. Stage-specific requirement for cyclin D1 in glial progenitor cells of the cerebral cortex.

    PubMed

    Nobs, Lionel; Baranek, Constanze; Nestel, Sigrun; Kulik, Akos; Kapfhammer, Josef; Nitsch, Cordula; Atanasoski, Suzana

    2014-05-01

    Despite the vast abundance of glial progenitor cells in the mouse brain parenchyma, little is known about the molecular mechanisms driving their proliferation in the adult. Here we unravel a critical role of the G1 cell cycle regulator cyclin D1 in controlling cell division of glial cells in the cortical grey matter. We detect cyclin D1 expression in Olig2-immunopositive (Olig2+) oligodendrocyte progenitor cells, as well as in Iba1+ microglia and S100β+ astrocytes in cortices of 3-month-old mice. Analysis of cyclin D1-deficient mice reveals a cell and stage-specific molecular control of cell cycle progression in the various glial lineages. While proliferation of fast dividing Olig2+ cells at early postnatal stages becomes gradually dependent on cyclin D1, this particular G1 regulator is strictly required for the slow divisions of Olig2+/NG2+ oligodendrocyte progenitors in the adult cerebral cortex. Further, we find that the population of mature oligodendrocytes is markedly reduced in the absence of cyclin D1, leading to a significant decrease in the number of myelinated axons in both the prefrontal cortex and the corpus callosum of 8-month-old mutant mice. In contrast, the pool of Iba1+ cells is diminished already at postnatal day 3 in the absence of cyclin D1, while the number of S100β+ astrocytes remains unchanged in the mutant.

  3. Partial volume correction using cortical surfaces

    NASA Astrophysics Data System (ADS)

    Blaasvær, Kamille R.; Haubro, Camilla D.; Eskildsen, Simon F.; Borghammer, Per; Otzen, Daniel; Ostergaard, Lasse R.

    2010-03-01

    Partial volume effect (PVE) in positron emission tomography (PET) leads to inaccurate estimation of regional metabolic activities among neighbouring tissues with different tracer concentration. This may be one of the main limiting factors in the utilization of PET in clinical practice. Partial volume correction (PVC) methods have been widely studied to address this issue. MRI based PVC methods are well-established.1 Their performance depend on the quality of the co-registration of the MR and PET dataset, on the correctness of the estimated point-spread function (PSF) of the PET scanner and largely on the performance of the segmentation method that divide the brain into brain tissue compartments.1, 2 In the present study a method for PVC is suggested, that utilizes cortical surfaces, to obtain detailed anatomical information. The objectives are to improve the performance of PVC, facilitate a study of the relationship between metabolic activity in the cerebral cortex and cortical thicknesses, and to obtain an improved visualization of PET data. The gray matter metabolic activity after performing PVC was recovered by 99.7 - 99.8 % , in relation to the true activity when testing on simple simulated data with different PSFs and by 97.9 - 100 % when testing on simulated brain PET data at different cortical thicknesses. When studying the relationship between metabolic activities and anatomical structures it was shown on simulated brain PET data, that it is important to correct for PVE in order to get the true relationship.

  4. Familial Precocious Fetal Abnormal Cortical Sulcation.

    PubMed

    Frassoni, Carolina; Avagliano, Laura; Inverardi, Francesca; Spaccini, Luigina; Parazzini, Cecilia; Rustico, Maria Angela; Bulfamante, Gaetano; Righini, Andrea

    2016-08-01

    The development of the human cerebral cortex is a complex and precisely programmed process by which alterations may lead to morphological and functional neurological abnormalities. We report familial cases of prenatally diagnosed abnormal brain, characterized by aberrant symmetrical mesial oversulcation of the parietooccipital lobes, in fetuses affected by abnormal skeletal features. Fetal brain anomalies were characterized by prenatal magnetic resonance imaging at 21 weeks of gestation and histologically evaluated at 22 weeks. Histological examination added relevant information showing some focal cortical areas of micropoligyria and heterotopic extension of the cortical plate into the marginal zone beneath the cortical surface. Genetic analysis of the fetuses excluded FGFR3 mutations known to be related to skeletal dysplasia and aberrant symmetrical oversulcation in other brain areas (temporal lobes). Hence, the present report suggests the existence of a class of rare syndromes of skeleton and brain development abnormality unrelated to FGFR3 mutations or related to other not described FGFR3 gene defects. Using magnetic resonance imaging, histopathology and molecular characterization we provide an example of a translational study of a rare and unreported brain congenital malformation. PMID:27177044

  5. Cortical Reorganization following Injury Early in Life

    PubMed Central

    Artzi, Moran; Shiran, Shelly Irene; Weinstein, Maya; Myers, Vicki; Tarrasch, Ricardo; Schertz, Mitchell; Fattal-Valevski, Aviva; Miller, Elka; Gordon, Andrew M.; Green, Dido; Ben Bashat, Dafna

    2016-01-01

    The brain has a remarkable capacity for reorganization following injury, especially during the first years of life. Knowledge of structural reorganization and its consequences following perinatal injury is sparse. Here we studied changes in brain tissue volume, morphology, perfusion, and integrity in children with hemiplegia compared to typically developing children, using MRI. Children with hemiplegia demonstrated reduced total cerebral volume, with increased cerebrospinal fluid (CSF) and reduced total white matter volumes, with no differences in total gray matter volume, compared to typically developing children. An increase in cortical thickness at the hemisphere contralateral to the lesion (CLH) was detected in motor and language areas, which may reflect compensation for the gray matter loss in the lesion area or retention of ipsilateral pathways. In addition, reduced cortical thickness, perfusion, and surface area were detected in limbic areas. Increased CSF volume and precentral cortical thickness and reduced white matter volume were correlated with worse motor performance. Brain reorganization of the gray matter within the CLH, while not necessarily indicating better outcome, is suggested as a response to neuronal deficits following injury early in life. PMID:27298741

  6. Looking for the roots of cortical sensory computation in three-layered cortices

    PubMed Central

    Fournier, Julien; Müller, Christian M.; Laurent, Gilles

    2016-01-01

    Despite considerable effort over a century and the benefit of remarkable technical advances in the past few decades, we are still far from understanding mammalian cerebral cortex. With its six layers, modular architecture, canonical circuits, innumerable cell types, and computational complexity, isocortex remains a challenging mystery. In this review, we argue that identifying the structural and functional similarities between mammalian piriform cortex and reptilian dorsal cortex could help reveal common organizational and computational principles and by extension, some of the most primordial computations carried out in cortical networks. PMID:25291080

  7. The human cerebral cortex flattens during adolescence.

    PubMed

    Alemán-Gómez, Yasser; Janssen, Joost; Schnack, Hugo; Balaban, Evan; Pina-Camacho, Laura; Alfaro-Almagro, Fidel; Castro-Fornieles, Josefina; Otero, Soraya; Baeza, Immaculada; Moreno, Dolores; Bargalló, Nuria; Parellada, Mara; Arango, Celso; Desco, Manuel

    2013-09-18

    The human cerebral cortex appears to shrink during adolescence. To delineate the dynamic morphological changes involved in this process, 52 healthy male and female adolescents (11-17 years old) were neuroimaged twice using magnetic resonance imaging, approximately 2 years apart. Using a novel morphometric analysis procedure combining the FreeSurfer and BrainVisa image software suites, we quantified global and lobar change in cortical thickness, outer surface area, the gyrification index, the average Euclidean distance between opposing sides of the white matter surface (gyral white matter thickness), the convex ("exposed") part of the outer cortical surface (hull surface area), sulcal length, depth, and width. We found that the cortical surface flattens during adolescence. Flattening was strongest in the frontal and occipital cortices, in which significant sulcal widening and decreased sulcal depth co-occurred. Globally, sulcal widening was associated with cortical thinning and, for the frontal cortex, with loss of surface area. For the other cortical lobes, thinning was related to gyral white matter expansion. The overall flattening of the macrostructural three-dimensional architecture of the human cortex during adolescence thus involves changes in gray matter and effects of the maturation of white matter.

  8. The human cerebral cortex flattens during adolescence.

    PubMed

    Alemán-Gómez, Yasser; Janssen, Joost; Schnack, Hugo; Balaban, Evan; Pina-Camacho, Laura; Alfaro-Almagro, Fidel; Castro-Fornieles, Josefina; Otero, Soraya; Baeza, Immaculada; Moreno, Dolores; Bargalló, Nuria; Parellada, Mara; Arango, Celso; Desco, Manuel

    2013-09-18

    The human cerebral cortex appears to shrink during adolescence. To delineate the dynamic morphological changes involved in this process, 52 healthy male and female adolescents (11-17 years old) were neuroimaged twice using magnetic resonance imaging, approximately 2 years apart. Using a novel morphometric analysis procedure combining the FreeSurfer and BrainVisa image software suites, we quantified global and lobar change in cortical thickness, outer surface area, the gyrification index, the average Euclidean distance between opposing sides of the white matter surface (gyral white matter thickness), the convex ("exposed") part of the outer cortical surface (hull surface area), sulcal length, depth, and width. We found that the cortical surface flattens during adolescence. Flattening was strongest in the frontal and occipital cortices, in which significant sulcal widening and decreased sulcal depth co-occurred. Globally, sulcal widening was associated with cortical thinning and, for the frontal cortex, with loss of surface area. For the other cortical lobes, thinning was related to gyral white matter expansion. The overall flattening of the macrostructural three-dimensional architecture of the human cortex during adolescence thus involves changes in gray matter and effects of the maturation of white matter. PMID:24048830

  9. Employees with Cerebral Palsy

    MedlinePlus

    ... Resources Home | Accommodation and Compliance Series: Employees with Cerebral Palsy (CP) By Eddie Whidden, MA Preface Introduction Information About ... SOAR) at http://AskJAN.org/soar. Information about Cerebral Palsy (CP) What is CP? Cerebral palsy is a ...

  10. Cerebral Aneurysms Fact Sheet

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS Cerebral Aneurysms Fact Sheet See a list of all NINDS ... I get more information? What is a cerebral aneurysm? A cerebral aneurysm (also known as an intracranial ...

  11. Cortical metabolism, acetylcholinesterase staining and pathological changes in Alzheimer's disease.

    PubMed

    McGeer, E G; McGeer, P L; Kamo, H; Tago, H; Harrop, R

    1986-11-01

    The local cerebral metabolic rate for glucose (LCMRgl) was determined by positron emission tomography (PET) using the 18F-fluorodeoxyglucose method in a series of Alzheimer patients and normal controls. The LCMRgl declined in the cerebral cortex with age, but the decrement was significantly greater in the clinically diagnosed Alzheimer's cases. Comparison of PET and psychological data indicated that, as the disease progressed clinically, the reduction in cortical LCMRgl and the number of cortical regions involved also increased. Variable regions of cortex were involved in the early stages but the temporal, parietal and frontal regions were most typically affected. One case coming to autopsy showed that the severity of the LCMRgl decline paralleled loss of neurons in the cortex and their replacement with astroglia. A case of Pick's disease coming to autopsy had shown a different and highly characteristic pattern of cortical metabolic defect. In this case also a poor metabolic rate was associated with extensive gliosis. Acetylcholinesterase (AChE) staining of the cerebral cortex in elderly normals and Alzheimer's disease cases with a new, highly sensitive method showed that in Alzheimer's disease there was an extensive loss of AChE-positive fibers with senile plaques frequently incorporating AChE-positive fiber debris. AChE staining of the substantia innominata area, where the cells giving rise to these neocortical fibers are presumably located, also showed evidence of degenerating cells and fibers.

  12. Research on acupuncture points and cortical functional activation position in cats by infrared imaging detection

    NASA Astrophysics Data System (ADS)

    Chen, Shuwang; Sha, Zhanyou; Wang, Shuhai; Wen, Huanming

    2007-12-01

    The research of the brain cognition is mainly to find out the activation position in brain according to the stimulation at present in the world. The research regards the animals as the experimental objects and explores the stimulation response on the cerebral cortex of acupuncture. It provides a new method, which can detect the activation position on the creatural cerebral cortex directly by middle-far infrared imaging. According to the theory of local temperature situation, the difference of cortical temperature maybe associate with the excitement of cortical nerve cells, the metabolism of local tissue and the local hemal circulation. Direct naked detection of temperature variety on cerebral cortex is applied by middle and far infrared imaging technology. So the activation position is ascertained. The effect of stimulation response is superior to other indirect methods. After removing the skulls on the head, full of cerebral cortex of a cat are exposed. By observing the infrared images and measuring the temperatures of the visual cerebral cortex during the process of acupuncturing, the points are used to judge the activation position. The variety in the cortical functional sections is corresponding to the result of the acupuncture points in terms of infrared images and temperatures. According to experimental results, we know that the variety of a cortical functional section is corresponding to a special acupuncture point exactly.

  13. Secretory function in subplate neurons during cortical development

    PubMed Central

    Kondo, Shinichi; Al-Hasani, Hannah; Hoerder-Suabedissen, Anna; Wang, Wei Zhi; Molnár, Zoltán

    2015-01-01

    Subplate cells are among the first generated neurons in the mammalian cerebral cortex and have been implicated in the establishment of cortical wiring. In rodents some subplate neurons persist into adulthood. Here we would like to highlight several converging findings which suggest a novel secretory function of subplate neurons during cortical development. Throughout the postnatal period in rodents, subplate neurons have highly developed rough endoplasmic reticulum (ER) and are under an ER stress condition. By comparing gene expression between subplate and layer 6, we found that several genes encoding secreted proteins are highly expressed in subplate neurons. One of these secreted proteins, neuroserpin, encoded by the serpini1 gene, is localized to the ER in subplate cells. We propose that subplate might influence cortical circuit formation through a transient secretory function. PMID:25859180

  14. Impact of prenatal environmental stress on cortical development

    PubMed Central

    Ishii, Seiji; Hashimoto-Torii, Kazue

    2015-01-01

    Prenatal exposure of the developing brain to various types of environmental stress increases susceptibility to neuropsychiatric disorders such as autism, attention deficit hyperactivity disorder and schizophrenia. Given that even subtle perturbations by prenatal environmental stress in the cerebral cortex impair the cognitive and memory functions, this review focuses on underlying molecular mechanisms of pathological cortical development. We especially highlight recent works that utilized animal exposure models, human specimens or/and induced Pluripotent Stem (iPS) cells to demonstrate: (1) molecular mechanisms shared by various types of environmental stressors, (2) the mechanisms by which the affected extracortical tissues indirectly impact the cortical development and function, and (3) interaction between prenatal environmental stress and the genetic predisposition of neuropsychiatric disorders. Finally, we discuss current challenges for achieving a comprehensive understanding of the role of environmentally disturbed molecular expressions in cortical maldevelopment, knowledge of which may eventually facilitate discovery of interventions for prenatal environment-linked neuropsychiatric disorders. PMID:26074774

  15. Cortical thickness in adults with agenesis of the corpus callosum.

    PubMed

    Beaulé, Vincent; Tremblay, Sara; Lafleur, Louis-Philippe; Tremblay, Sébastien; Lassonde, Maryse; Lepage, Jean-François; Théoret, Hugo

    2015-10-01

    Agenesis of the corpus callosum (AgCC) is a congenital malformation that can occur in isolation or in association with other neurological conditions. Although the behavioral manifestations associated with AgCC have been widely studied, the effects of complete absence of the corpus callosum (CC) on cerebral cortex anatomy are still not completely understood. In this study, cortical thickness in adults with complete AgCC was compared to a group of healthy controls. Results showed highly variable patterns of cortical thickness in AgCC individuals, with few areas showing significant and consistent alterations including primary visual cortex, primary somatosensory cortex and primary motor cortex. These results suggest relatively limited effects of AgCC on cortical morphology, which are mostly restricted to primary sensory and motor areas.

  16. Comparison of gray matter volume and thickness for analysis of cortical changes in Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Liu, Jiachao; Li, Ziyi; Chen, Kewei; Yao, Li; Wang, Zhiqun; Li, Kunchen; Guo, Xiaojuan

    2011-03-01

    Gray matter volume and cortical thickness are two indices of concern in brain structure magnetic resonance imaging research. Gray matter volume reflects mixed-measurement information of cerebral cortex, while cortical thickness reflects only the information of distance between inner surface and outer surface of cerebral cortex. Using Scaled Subprofile Modeling based on Principal Component Analysis (SSM_PCA) and Pearson's Correlation Analysis, this study further provided quantitative comparisons and depicted both global relevance and local relevance to comprehensively investigate morphometrical abnormalities in cerebral cortex in Alzheimer's disease (AD). Thirteen patients with AD and thirteen age- and gender-matched healthy controls were included in this study. Results showed that factor scores from the first 8 principal components accounted for ~53.38% of the total variance for gray matter volume, and ~50.18% for cortical thickness. Factor scores from the fifth principal component showed significant correlation. In addition, gray matter voxel-based volume was closely related to cortical thickness alterations in most cortical cortex, especially, in some typical abnormal brain regions such as insula and the parahippocampal gyrus in AD. These findings suggest that these two measurements are effective indices for understanding the neuropathology in AD. Studies using both gray matter volume and cortical thickness can separate the causes of the discrepancy, provide complementary information and carry out a comprehensive description of the morphological changes of brain structure.

  17. Cortical State and Attention

    PubMed Central

    Harris, Kenneth D.; Thiele, Alexander

    2012-01-01

    Preface The brain continuously adapts its processing machinery to behavioural demands. To achieve this it rapidly modulates the operating mode of cortical circuits, controlling the way information is transformed and routed. This article will focus on two experimental approaches by which the control of cortical information processing has been investigated: the study of state-dependent cortical processing in rodents, and attention in the primate visual system. Both processes involve a modulation of low-frequency activity fluctuations and spiking correlation, and are mediated by common receptor systems. We suggest that selective attention involves processes similar to state change, operating at a local columnar level to enhance the representation of otherwise nonsalient features while suppressing internally generated activity patterns. PMID:21829219

  18. The primate connectome in context: Principles of connections of the cortical visual system.

    PubMed

    Hilgetag, Claus C; Medalla, Maria; Beul, Sarah F; Barbas, Helen

    2016-07-01

    Which principles determine the organization of the intricate network formed by nerve fibers that link the primate cerebral cortex? We addressed this issue for the connections of primate visual cortices by systematically analyzing how the existence or absence of connections, their density as well as laminar patterns of projection origins and terminations are correlated with distance, similarity in cortical type as well as neuronal density or the thickness of cortical areas. Analyses were based on four extensive compilations of qualitative as well as quantitative data for connections of the primate visual cortical system in macaque monkeys (Felleman and Van Essen 1991; Barbas 1986; Barbas and Rempel-Clower 1997; Barone et al. 2000; Markov et al. 2014). Distance and thickness similarity were not consistently correlated with connection features, but similarity of cortical type, determined by qualitative features of laminar differentiation, or measured quantitatively as the areas' overall neuronal density, was a reliable predictor for the existence of connections between areas. Cortical type similarity was also consistently and closely correlated with characteristic laminar connection profiles: structurally dissimilar areas had origin and termination patterns that were biased to the upper or deep cortical layers, while similar areas showed more bilaminar origins and terminations. These results suggest that patterns of corticocortical connections of primate visual cortices are closely linked to the stratified architecture of the cerebral cortex. In particular, the regularity of laminar projection origins and terminations arises from the structural differences between cortical areas. The observed integration of projections with the intrinsic cortical architecture provides a structural basis for advanced theories of cortical organization and function. PMID:27083526

  19. Cerebral Laterality and Verbal-Performance Discrepancies in Intelligence.

    ERIC Educational Resources Information Center

    Dean, Raymond S.

    1979-01-01

    The cerebral laterality of children with various configurations of verbal-performance discrepancies was inferred with an objective measure of lateral preference using Verbal and Performance IQ scores of the WISC-R. Results were interpreted as lending support to the notion of competition antagonism between cortical hemispheres and a possible…

  20. Cerebral organoids in a dish: progress and prospects.

    PubMed

    Bershteyn, Marina; Kriegstein, Arnold R

    2013-09-26

    A three-dimensional culture of cortical tissues derived from pluripotent stem cells offers an opportunity to model human brain development and disorders. In a recent issue of Nature, Lancaster et al. describe a new method for generating cerebral organoids in a dish and use it to model microcephaly. PMID:24074857

  1. FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry.

    PubMed

    La Fata, Giorgio; Gärtner, Annette; Domínguez-Iturza, Nuria; Dresselaers, Tom; Dawitz, Julia; Poorthuis, Rogier B; Averna, Michele; Himmelreich, Uwe; Meredith, Rhiannon M; Achsel, Tilmann; Dotti, Carlos G; Bagni, Claudia

    2014-12-01

    Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity. PMID:25402856

  2. Cerebral Microdialysis.

    PubMed

    Young, Bethany; Kalanuria, Atul; Kumar, Monisha; Burke, Kathryn; Balu, Ramani; Amendolia, Olivia; McNulty, Kyle; Marion, BethAnn; Beckmann, Brittany; Ciocco, Lauren; Miller, Kimberly; Schuele, Donnamarie; Maloney-Wilensky, Eileen; Frangos, Suzanne; Wright, Danielle

    2016-03-01

    A variety of neuromonitoring techniques are available to aid in the care of neurocritically ill patients. However, traditional monitors lack the ability to measure brain biochemistry and may provide inadequate warning of potentially reversible deleterious conditions. Cerebral microdialysis (CMD) is a safe, novel method of monitoring regional brain biochemistry. Analysis of CMD analytes as part of a multimodal approach may help inform clinical decision making, guide medical treatments, and aid in prognostication of patient outcome. Its use is most frequently documented in traumatic brain injury and subarachnoid hemorrhage. Incorporating CMD into clinical practice is a multidisciplinary effort.

  3. Cerebral malaria.

    PubMed

    Postels, Douglas G; Birbeck, Gretchen L

    2013-01-01

    Malaria, the most significant parasitic disease of man, kills approximately one million people per year. Half of these deaths occur in those with cerebral malaria (CM). The World Health Organization (WHO) defines CM as an otherwise unexplained coma in a patient with malarial parasitemia. Worldwide, CM occurs primarily in African children and Asian adults, with the vast majority (greater than 90%) of cases occurring in children 5 years old or younger in sub-Saharan Africa. The pathophysiology of the disease is complex and involves infected erythrocyte sequestration, cerebral inflammation, and breakdown of the blood-brain barrier. A recently characterized malarial retinopathy is visual evidence of Plasmodium falciparum's pathophysiological processes occurring in the affected patient. Treatment consists of supportive care and antimalarial administration. Thus far, adjuvant therapies have not been shown to improve mortality rates or neurological outcomes in children with CM. For those who survive CM, residual neurological abnormalities are common. Epilepsy, cognitive impairment, behavioral disorders, and gross neurological deficits which include motor, sensory, and language impairments are frequent sequelae. Primary prevention strategies, including bed nets, vaccine development, and chemoprophylaxis, are in varied states of development and implementation. Continuing efforts to find successful primary prevention options and strategies to decrease neurological sequelae are needed. PMID:23829902

  4. Visualization of Cortical Dynamics

    NASA Astrophysics Data System (ADS)

    Grinvald, Amiram

    2003-03-01

    Recent progress in studies of cortical dynamics will be reviewed including the combination of real time optical imaging based on voltage sensitive dyes, single and multi- unit recordings, LFP, intracellular recordings and microstimulation. To image the flow of neuronal activity from one cortical site to the next, in real time, we have used optical imaging based on newly designed voltage sensitive dyes and a Fuji 128x 128 fast camera which we modified. A factor of 20-40 fold improvement in the signal to noise ratio was obtained with the new dye during in vivo imaging experiments. This improvements has facilitates the exploration of cortical dynamics without signal averaging in the millisecond time domain. We confirmed that the voltage sensitive dye signal indeed reflects membrane potential changes in populations of neurons by showing that the time course of the intracellular activity recorded intracellularly from a single neuron was highly correlated in many cases with the optical signal from a small patch of cortex recorded nearby. We showed that the firing of single cortical neurons is not a random process but occurs when the on-going pattern of million of neurons is similar to the functional architecture map which correspond to the tuning properties of that neuron. Chronic optical imaging, combined with electrical recordings and microstimulation, over a long period of times of more than a year, was successfully applied also to the study of higher brain functions in the behaving macaque monkey.

  5. Cortical thinning in psychopathy

    PubMed Central

    Ly, Martina; Motzkin, Julian C.; Philippi, Carissa L.; Kirk, Gregory R.; Newman, Joseph P.; Kiehl, Kent A.; Koenigs, Michael

    2013-01-01

    Objective Psychopathy is a personality disorder associated with severely antisocial behavior and a host of cognitive and affective deficits. The neuropathological basis of the disorder has not been clearly established. Cortical thickness is a sensitive measure of brain structure that has been used to identify neurobiological abnormalities in a number of psychiatric disorders. The purpose of this study is to evaluate cortical thickness and corresponding functional connectivity in criminal psychopaths. Method Using T1 MRI data, we computed cortical thickness maps in a sample of adult male prison inmates selected based on psychopathy diagnosis (n=21 psychopathic inmates, n=31 non-psychopathic inmates). Using rest-fMRI data from a subset of these inmates (n=20 psychopathic inmates, n=20 non-psychopathic inmates), we then computed functional connectivity within networks exhibiting significant thinning among psychopaths. Results Relative to non-psychopaths, psychopaths exhibited significantly thinner cortex in a number of regions, including left insula and dorsal anterior cingulate cortex, bilateral precentral gyrus, bilateral anterior temporal cortex, and right inferior frontal gyrus. These neurostructural differences were not due to differences in age, IQ, or substance abuse. Psychopaths also exhibited a corresponding reduction in functional connectivity between left insula and left dorsal anterior cingulate cortex. Conclusions Psychopathy is associated with a distinct pattern of cortical thinning and reduced functional connectivity. PMID:22581200

  6. Optical monitoring of oxygen tension in cortical microvessels with confocal microscopy

    PubMed Central

    Yaseen, Mohammad A.; Srinivasan, Vivek J.; Sakadžić, Sava; Wu, Weicheng; Ruvinskaya, Svetlana; Vinogradov, Sergei A.; Boas, DavidA

    2010-01-01

    Evaluating cerebral oxygenation is of critical importance for the understanding of brain function and several neuropathologies. Although several techniques exist for measuring cerebral oxygenation in vivo, the most widely accepted techniques offer limited spatial resolution. We have developed a confocal imaging system for minimally invasive measurement of oxygen tension (pO2) in cerebral microvessels with high spatial and temporal resolution. The system relies on the phosphorescence quenching method using exogenous porphyrin-based dendritic oxygen probes. Here we present high-resolution phosphorescence images of cortical microvasculature and temporal pO2 profiles from multiple locations in response to varied fraction of inspired oxygen and functional activation. PMID:20052157

  7. Cerebral organoids model human brain development and microcephaly.

    PubMed

    Lancaster, Madeline A; Renner, Magdalena; Martin, Carol-Anne; Wenzel, Daniel; Bicknell, Louise S; Hurles, Matthew E; Homfray, Tessa; Penninger, Josef M; Jackson, Andrew P; Knoblich, Juergen A

    2013-09-19

    The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.

  8. Cerebral organoids model human brain development and microcephaly

    PubMed Central

    Lancaster, Madeline A.; Renner, Magdalena; Martin, Carol-Anne; Wenzel, Daniel; Bicknell, Louise S.; Hurles, Matthew E.; Homfray, Tessa; Penninger, Josef M.; Jackson, Andrew P.; Knoblich, Juergen A.

    2013-01-01

    The complexity of the human brain has made it difficult to study many brain disorders in model organisms, and highlights the need for an in vitro model of human brain development. We have developed a human pluripotent stem cell-derived 3D organoid culture system, termed cerebral organoid, which develops various discrete though interdependent brain regions. These include cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNAi and patient-specific iPS cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could explain the disease phenotype. Our data demonstrate that 3D organoids can recapitulate development and disease of even this most complex human tissue. PMID:23995685

  9. An essential role of SVZ progenitors in cortical folding in gyrencephalic mammals

    PubMed Central

    Toda, Tomohisa; Shinmyo, Yohei; Dinh Duong, Tung Anh; Masuda, Kosuke; Kawasaki, Hiroshi

    2016-01-01

    Because folding of the cerebral cortex in the mammalian brain is believed to be crucial for higher brain functions, the mechanisms underlying its formation during development and evolution are of great interest. Although it has been proposed that increased neural progenitors in the subventricular zone (SVZ) are responsible for making cortical folds, their roles in cortical folding are still largely unclear, mainly because genetic methods for gyrencephalic mammals had been poorly available. Here, by taking an advantage of our newly developed in utero electroporation technique for the gyrencephalic brain of ferrets, we investigated the role of SVZ progenitors in cortical folding. We found regional differences in the abundance of SVZ progenitors in the developing ferret brain even before cortical folds began to be formed. When Tbr2 transcription factor was inhibited, intermediate progenitor cells were markedly reduced in the ferret cerebral cortex. Interestingly, outer radial glial cells were also reduced by inhibiting Tbr2. We uncovered that reduced numbers of SVZ progenitors resulted in impaired cortical folding. When Tbr2 was inhibited, upper cortical layers were preferentially reduced in gyri compared to those in sulci. Our findings indicate the biological importance of SVZ progenitors in cortical folding in the gyrencephalic brain. PMID:27403992

  10. Astrocyte-Dependent Vulnerability to Excitotoxicity in Spermine Oxidase-Overexpressing Mouse.

    PubMed

    Cervetto, Chiara; Vergani, Laura; Passalacqua, Mario; Ragazzoni, Milena; Venturini, Arianna; Cecconi, Francesco; Berretta, Nicola; Mercuri, Nicola; D'Amelio, Marcello; Maura, Guido; Mariottini, Paolo; Voci, Adriana; Marcoli, Manuela; Cervelli, Manuela

    2016-03-01

    Transgenic mice overexpressing spermine oxidase (SMO) in the cerebral cortex (Dach-SMO mice) showed increased vulnerability to excitotoxic brain injury and kainate-induced epileptic seizures. To investigate the mechanisms by which SMO overexpression leads to increased susceptibility to kainate excitotoxicity and seizure, in the cerebral cortex of Dach-SMO and control mice we assessed markers for astrocyte proliferation and neuron loss, and the ability of kainate to evoke glutamate release from nerve terminals and astrocyte processes. Moreover, we assessed a possible role of astrocytes in an in vitro model of epileptic-like activity in combined cortico-hippocampal slices recorded with a multi-electrode array device. In parallel, as the brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms, we analyzed the oxidative status of the cerebral cortex of both SMO-overexpressing and control mice by evaluating enzymatic and non-enzymatic scavengers such as metallothioneins. The main findings in the cerebral cortex of Dach-SMO mice as compared to controls are the following: astrocyte activation and neuron loss; increased oxidative stress and activation of defense mechanisms involving both neurons and astrocytes; increased susceptibility to kainate-evoked cortical epileptogenic activity, dependent on astrocyte function; appearance of a glutamate-releasing response to kainate from astrocyte processes due to activation of Ca(2+)-permeable AMPA receptors in Dach-SMO mice. We conclude that reactive astrocytosis and activation of glutamate release from astrocyte processes might contribute, together with increased reactive oxygen species production, to the vulnerability to kainate excitotoxicity in Dach-SMO mice. This mouse model with a deregulated polyamine metabolism would shed light on roles for astrocytes in increasing vulnerability to excitotoxic neuron injury.

  11. Astrocytes refine cortical connectivity at dendritic spines

    PubMed Central

    Risher, W Christopher; Patel, Sagar; Kim, Il Hwan; Uezu, Akiyoshi; Bhagat, Srishti; Wilton, Daniel K; Pilaz, Louis-Jan; Singh Alvarado, Jonnathan; Calhan, Osman Y; Silver, Debra L; Stevens, Beth; Calakos, Nicole; Soderling, Scott H; Eroglu, Cagla

    2014-01-01

    During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines. DOI: http://dx.doi.org/10.7554/eLife.04047.001 PMID:25517933

  12. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas.

    PubMed

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-08-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas.

  13. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas.

    PubMed

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas. PMID:25081193

  14. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas

    PubMed Central

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas. PMID:25081193

  15. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.

    PubMed

    Zeisel, Amit; Muñoz-Manchado, Ana B; Codeluppi, Simone; Lönnerberg, Peter; La Manno, Gioele; Juréus, Anna; Marques, Sueli; Munguba, Hermany; He, Liqun; Betsholtz, Christer; Rolny, Charlotte; Castelo-Branco, Gonçalo; Hjerling-Leffler, Jens; Linnarsson, Sten

    2015-03-01

    The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Here, we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in the mouse somatosensory cortex and hippocampal CA1 region. We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex. We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location. We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity.

  16. Cerebral hemiatrophy: a clinicopathological report of two cases with a contribution to pathogenesis and differential diagnosis.

    PubMed

    Vosskämper, M; Schachenmayr, W

    1990-01-01

    "Cerebral hemiatrophy" describes a condition of different etiologies that is characterized by a marked asymmetry of cerebral hemispheres. Case reports of two different forms of cerebral hemiatrophy are presented. In the first case perinatal asphyxia led to severe white matter lesions with predominance on the left side and marked asymmetry of the pyramidal tracts. Symptoms were present immediately after birth ("primary cerebral hemiatrophy"). The second case displayed postictal cerebral hemiatrophy with a widespread loss of cortical neurons of the entire left hemisphere. The disease process started at the age of two years after a widely normal early development ("secondary cerebral hemiatrophy"). A modified classification of cerebral hemiatrophy is presented, and concepts of pathogenesis and differential diagnosis are discussed. PMID:2125535

  17. [Cerebral palsy].

    PubMed

    Malagón Valdez, Jorge

    2007-01-01

    The term cerebral palsy (CP), is used for a great number of clinical neurological syndromes. The syndromes are characterized by having a common cause, motor defects. It is important, because they can cause a brain damage by presenting motor defects and some associated deficiencies, such as mental deficiency, epilepsy, language and visual defects and pseudobulbar paralysis, with the non-evolving fact. Some authors prefer using terms such as "non-evolving encephalopathies". In the treatment the utility of prevention programs of early stimulation and special rehabilitation methods, and treatment of associated deficiencies such as epilepsy, mental deficiency, language, audition and visual problems, and the attention deficit improve the prognosis in an important way. The prognosis depends on the severity of the disease and the associated manifestations. PMID:18422084

  18. A Developmental and Genetic Classification for Malformations of Cortical Development: Update 2012

    ERIC Educational Resources Information Center

    Barkovich, A. James; Guerrini, Renzo; Kuzniecky, Ruben I.; Jackson, Graeme D.; Dobyns, William B.

    2012-01-01

    Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics…

  19. Increase in Prefrontal Cortical Volume following Cognitive Behavioural Therapy in Patients with Chronic Fatigue Syndrome

    ERIC Educational Resources Information Center

    de Lange, Floris P.; Koers, Anda; Kalkman, Joke S.; Bleijenberg, Gijs; Hagoort, Peter; van der Meer, Jos W. M.; Toni, Ivan

    2008-01-01

    Chronic fatigue syndrome (CFS) is a disabling disorder, characterized by persistent or relapsing fatigue. Recent studies have detected a decrease in cortical grey matter volume in patients with CFS, but it is unclear whether this cerebral atrophy constitutes a cause or a consequence of the disease. Cognitive behavioural therapy (CBT) is an…

  20. Cortical injury in multiple sclerosis; the role of the immune system

    PubMed Central

    2011-01-01

    The easily identifiable, ubiquitous demyelination and neuronal damage that occurs within the cerebral white matter of patients with multiple sclerosis (MS) has been the subject of extensive study. Accordingly, MS has historically been described as a disease of the white matter. Recently, the cerebral cortex (gray matter) of patients with MS has been recognized as an additional and major site of disease pathogenesis. This acknowledgement of cortical tissue damage is due, in part, to more powerful MRI that allows detection of such injury and to focused neuropathology-based investigations. Cortical tissue damage has been associated with inflammation that is less pronounced to that which is associated with damage in the white matter. There is, however, emerging evidence that suggests cortical damage can be closely associated with robust inflammation not only in the parenchyma, but also in the neighboring meninges. This manuscript will highlight the current knowledge of inflammation associated with cortical tissue injury. Historical literature along with contemporary work that focuses on both the absence and presence of inflammation in the cerebral cortex and in the cerebral meninges will be reviewed. PMID:22145746

  1. Applications of brain blood flow imaging in behavioral neurophysiology: cortical field activation hypothesis

    SciTech Connect

    Roland, P.E.

    1985-01-01

    The /sup 133/xenon intracarotid method for rCBF measurements has been a very useful method for functional mapping and functional dissection of the cerebral cortex in humans. With this method it has been shown that different types of cortical information treatment activate different cortical areas and furthermore that sensory and motor functions of the cerebral cortex could be dissected into anatomical and informational subcomponents by behavioral manipulations. The brain organizes its own activity. One of the principles of organization was that the brain could recruit in advance cortical fields that were expected to participate in a certain type of information operation. During brain work in awake human beings the cerebral cortex was activated in fields that, projected on the cerebral surface, most often had a size greater than 3 CM/sup 2/. Such activated fields appeared no matter which type of information processing was going on in the brain: during planning and execution of voluntary movements, during preparation for sensory information processing, and during sensory information processing, as well as during cognitive brain work and retrieval of specific memories. Therefore, it was hypothesized that cortical field activation was the physiological manifestation of normal brain work in awake humans.

  2. Purely Cortical Anaplastic Ependymoma

    PubMed Central

    Romero, Flávio Ramalho; Zanini, Marco Antônio; Ducati, Luis Gustavo; Vital, Roberto Bezerra; de Lima Neto, Newton Moreira; Gabarra, Roberto Colichio

    2012-01-01

    Ependymomas are glial tumors derived from ependymal cells lining the ventricles and the central canal of the spinal cord. It may occur outside the ventricular structures, representing the extraventicular form, or without any relationship of ventricular system, called ectopic ependymona. Less than fifteen cases of ectopic ependymomas were reported and less than five were anaplastic. We report a rare case of pure cortical ectopic anaplastic ependymoma. PMID:23119204

  3. Purely cortical anaplastic ependymoma.

    PubMed

    Romero, Flávio Ramalho; Zanini, Marco Antônio; Ducati, Luis Gustavo; Vital, Roberto Bezerra; de Lima Neto, Newton Moreira; Gabarra, Roberto Colichio

    2012-01-01

    Ependymomas are glial tumors derived from ependymal cells lining the ventricles and the central canal of the spinal cord. It may occur outside the ventricular structures, representing the extraventicular form, or without any relationship of ventricular system, called ectopic ependymona. Less than fifteen cases of ectopic ependymomas were reported and less than five were anaplastic. We report a rare case of pure cortical ectopic anaplastic ependymoma.

  4. Brief anesthesia, but not voluntary locomotion, significantly alters cortical temperature

    PubMed Central

    Shirey, Michael J.; Kudlik, D'Anne E.; Huo, Bing-Xing; Greene, Stephanie E.; Drew, Patrick J.

    2015-01-01

    Changes in brain temperature can alter electrical properties of neurons and cause changes in behavior. However, it is not well understood how behaviors, like locomotion, or experimental manipulations, like anesthesia, alter brain temperature. We implanted thermocouples in sensorimotor cortex of mice to understand how cortical temperature was affected by locomotion, as well as by brief and prolonged anesthesia. Voluntary locomotion induced small (∼0.1°C) but reliable increases in cortical temperature that could be described using a linear convolution model. In contrast, brief (90-s) exposure to isoflurane anesthesia depressed cortical temperature by ∼2°C, which lasted for up to 30 min after the cessation of anesthesia. Cortical temperature decreases were not accompanied by a concomitant decrease in the γ-band local field potential power, multiunit firing rate, or locomotion behavior, which all returned to baseline within a few minutes after the cessation of anesthesia. In anesthetized animals where core body temperature was kept constant, cortical temperature was still >1°C lower than in the awake animal. Thermocouples implanted in the subcortex showed similar temperature changes under anesthesia, suggesting these responses occur throughout the brain. Two-photon microscopy of individual blood vessel dynamics following brief isoflurane exposure revealed a large increase in vessel diameter that ceased before the brain temperature significantly decreased, indicating cerebral heat loss was not due to increased cerebral blood vessel dilation. These data should be considered in experimental designs recording in anesthetized preparations, computational models relating temperature and neural activity, and awake-behaving methods that require brief anesthesia before experimental procedures. PMID:25972579

  5. A Computational Growth Model for Measuring Dynamic Cortical Development in the First Year of Life

    PubMed Central

    Nie, Jingxin; Li, Gang; Wang, Li; Gilmore, John H.; Lin, Weili

    2012-01-01

    Human cerebral cortex develops extremely fast in the first year of life. Quantitative measurement of cortical development during this early stage plays an important role in revealing the relationship between cortical structural and high-level functional development. This paper presents a computational growth model to simulate the dynamic development of the cerebral cortex from birth to 1 year old by modeling the cerebral cortex as a deformable elastoplasticity surface driven via a growth model. To achieve a high accuracy, a guidance model is also incorporated to estimate the growth parameters and cortical shapes at later developmental stages. The proposed growth model has been applied to 10 healthy subjects with longitudinal brain MR images acquired at every 3 months from birth to 1 year old. The experimental results show that our proposed method can capture the dyna