45CaCl2 autoradiography in brain from rabbits with encephalopathy from acute liver failure or acute hyperammonemia

In experimental hepatic encephalopathy and hyperammonemia, extracellular levels of glutamate are increased in hippocampus and cerebral cortex. It has been suggested that overstimulation of glutamate receptors causes a pathological entry of calcium into neurons via receptor-operated (NMDA- and AMPA-type) or voltage-dependent calcium channels leading to calcium overload and cell death. Neurodegeneration as a result of exposure to excitotoxins, including glutamate, can be localized and quantified using45CaCl2 autoradiography. This approach was used to study cerebral calcium accumulation in rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced in 6 rabbits, acute hyperammonemia in 4 rabbits; 4 control rabbits received sodium-potassium-acetate. At the start of the experiment 500 µCi45CaCl2 was given intravenously. After development of severe encephalopathy, the animals were killed by decapitation. All rabbits with acute liver failure or acute hyperammonemia developed severe encephalopathy, after 13.2±1.7 and 19.3±0.5 hours respectively (mean±SEM). Plasma ammonia levels were 425±46 and 883±21 µmol/l, respectively (p<0.05). Control rabbits maintained normal plasma ammonia levels (13±5 µmol/l), demonstrated normal behaviour throughout the study and were sacrificed after 16 hours.45Ca2+-autoradiograms of 40 µm brain sections were analyzed semiquantitatively using relative optical density and computerized image analysis. As compared to background levels45Ca was not increased in hippocampus or any other brain area of rabbits with severe encephalopathy from acute liver failure or acute hyperammonemia. This suggests that, despite increased extracellular brain glutamate levels in these conditions, glutamate neurotoxicity was not important for the development of encephalopathy in these rabbits

Manganese-induced hydroxyl radical formation in rat striatum is not attenuated by dopamine depletion or iron chelation in vivo

The present studies were aimed at investigating the possible roles of dopamine (DA) and iron in production of hydroxyl radicals (.OH) in rat striatum after Mn2+ intoxication. For this purpose, DA depletions were assessed concomitant with in vivo 2,3- and 2,5-dihydroxybenzoic acid (DHBA) formation from the reaction of salicylate with .OH, of which 2,3-DHBA is a nonenzymatic adduct. Following intrastriatal Mn2+ injection, marked 2,3-DHBA increases were observed in a time- and dose-dependent fashion reaching maximum levels at 6-18 h and a plateau beyond 0.4 μmol (fourfold increase). The delayed increase of 2,3-DHBA levels suggests that Mn2+ induces OH formation in the living brain by an indirect process. The early DA depletion (2 h) and relatively late .OH formation (6 h) indicate independent processes by Mn2+. In addition, depletion of DA (about 90%) by reserpine pretreatment did not significantly alter Mn2+-induced 2,3-DHBA formation or the extent of DA depletion, suggesting that DA or DA autoxidation are not participating in Mn2+-induced .OH formation in vivo. Furthermore, Mn2+ injection did not significantly alter the low molecular weight iron pool in striatum, and co-injections of the iron-chelator deferoxamine with Mn2+ into striatum did not significantly attenuate Mn2+-induced 2,3-DHBA formation. These findings suggest no role of chelatable iron in generation of Mn2+-induced .OH, but do not exclude a role for mitochondrial heme-iron or peroxynitrite (Fe-independent) in Mn2+-induced .OH formation

Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model

Migraine is a complex brain disorder, and understanding the complexity of this prevalent disease could improve quality of life for millions of people. Familial Hemiplegic Migraine type 2 (FHM2) is a subtype of migraine with aura and co-morbidities like epilepsy/seizures, cognitive impairments and psychiatric manifestations, such as obsessive-compulsive disorder (OCD). FHM2 disease-mutations locate to the ATP1A2 gene encoding the astrocyte-located α(2)-isoform of the sodium-potassium pump (α(2)Na(+)/K(+)-ATPase). We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (α(2)(+/G301R)) phenocopy several FHM2-relevant disease traits e.g., by mimicking mood depression and OCD. In vitro studies showed impaired glutamate uptake in hippocampal mixed astrocyte-neuron cultures from α(2)(G301R/G301R) E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in reduced recovery in α(2)(+/G301R) male mice. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific α(2)(+/G301R) behavioral phenotypes. Our findings demonstrate that studies of an in vivo relevant FHM2 disease knock-in mouse model provide a link between the female sex hormone cycle and the glutamate system and a link to co-morbid psychiatric manifestations of FHM2

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex

•TNF deficiency alters the spatial organization of neurogenic zones.•TNF deficiency decreases WNT signaling-related proteins.•TNF deficiency alters neuronal and microglial numbers.•Long-term use of non-selective TNF inhibitors impairs learning and memory.•Long-term use of the soluble TNF selective inhibitor XPro1595 does not affect neurogenesis, learning and memory. Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF−/−) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF−/− mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF−/− mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment

Non-Isothermal Model for Nematic Spherulite Growth

A computational study of the growth of two-dimensional nematic spherulites in an isotropic phase was performed using a Landau-de Gennes type quadrupolar ensor order parameter model for the first-order isotropic/nematic transition of 5CB (pentyl-cyanobiphenyl). An energy balance, taking anisotropy into account, was derived and incorporated into the time-dependent model. Growth laws were determined for two different spherulite morphologies of the form tn, with and without the inclusion of thermal effects. Results show that incorporation of the thermal energy balance correctly predicts the transition of the growth law exponent from the volume driven regime (n=1) to the thermally limited regime (approaching n=0.5), agreeing well with experimental observations. An interfacial nemato-dynamic model is used to gain insight into the interactions that result in the progression of different spherulite growth regimes

Competing orders in a magnetic field: spin and charge order in the cuprate superconductors

We describe two-dimensional quantum spin fluctuations in a superconducting Abrikosov flux lattice induced by a magnetic field applied to a doped Mott insulator. Complete numerical solutions of a self-consistent large N theory provide detailed information on the phase diagram and on the spatial structure of the dynamic spin spectrum. Our results apply to phases with and without long-range spin density wave order and to the magnetic quantum critical point separating these phases. We discuss the relationship of our results to a number of recent neutron scattering measurements on the cuprate superconductors in the presence of an applied field. We compute the pinning of static charge order by the vortex cores in the `spin gap' phase where the spin order remains dynamically fluctuating, and argue that these results apply to recent scanning tunnelling microscopy (STM) measurements. We show that with a single typical set of values for the coupling constants, our model describes the field dependence of the elastic neutron scattering intensities, the absence of satellite Bragg peaks associated with the vortex lattice in existing neutron scattering observations, and the spatial extent of charge order in STM observations. We mention implications of our theory for NMR experiments. We also present a theoretical discussion of more exotic states that can be built out of the spin and charge order parameters, including spin nematics and phases with `exciton fractionalization'.Comment: 36 pages, 33 figures; for a popular introduction, see http://onsager.physics.yale.edu/superflow.html; (v2) Added reference to new work of Chen and Ting; (v3) reorganized presentation for improved clarity, and added new appendix on microscopic origin; (v4) final published version with minor change

Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes

Background: In the central nervous system, glial cells provide metabolic and trophic support to neurons and respond to protracted stress and insults by up-regulating inflammatory processes. Reactive astrocytes and microglia are associated with the pathophysiology of neuronal injury, neurodegenerative diseases and major depression, in both animal models and human brains. Several studies have reported clear anti-inflammatory effects of anti-depressant treatment on astrocytes, especially in models of neurological disorders. Trazodone (TDZ) is a triazolopyridine derivative that is structurally unrelated to other major classes of antidepressants. Although the molecular mechanisms of TDZ in neurons have been investigated, it is unclear whether astrocytes are also a TDZ target. Methods: The effects of TDZ on human astrocytes were investigated in physiological conditions and following inflammatory insult with lipopolysaccharide (LPS) and tumour necrosis factor-aα (TNF-aα). Astrocytes were assessed for their responses to pro-inflammatory mediators and cytokines, and the receptors and signalling pathways involved in TDZ-mediated effects were evaluated. Results: TDZ had no effect on cell proliferation, but it decreased pro-inflammatory mediator release and modulated trophic and transcription factor mRNA expression. Following TDZ treatment, the AKT pathway was activated, whereas extracellular signal-regulated kinase and c-Jun NH2-terminal kinase were inhibited. Most importantly, a 72-h TDZ pre-treatment before inflammatory insult completely reversed the anti-proliferative effects induced by LPS-TNF-aα. The expression or the activity of inflammatory mediators, including interleukin-6, c-Jun NH2-terminal kinase and nuclear factor ΚB, were also reduced. Furthermore, TDZ affected astrocyte metabolic support to neurons by counteracting the inflammation-mediated lactate decrease. Finally, TDZ protected neuronal-like cells against neurotoxicity mediated by activated astrocytes. These effects mainly involved an activation of 5-HT1A and an antagonism at 5-HT2A/C serotonin receptors. Fluoxetine, used in parallel, showed similar final effects nevertheless it activates different receptors/intracellular pathways. Conclusions: Altogether, our results demonstrated that TDZ directly acts on astrocytes by regulating intracellular signalling pathways and increasing specific astrocyte-derived neurotrophic factor expression and lactate release. TDZ may contribute to neuronal support by normalizing trophic and metabolic support during neuroinflammation, which is associated with neurological diseases, including major depression

Liquid crystals and their defects

These lecture notes discuss classical models of liquid crystals, and the different ways in which defects are described according to the different models.Comment: CIME lecture course, Cetraro, 201